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Ranitidine hydrochloride, a histamine H2-receptor antagonist, was orally given to pregnant rabbits of Japanese White strain from day 6 to 18 of gestation at doses of 25, 100 and 400 mg/kg/day, as ranitidine base, and teratogenicity of the drug was studied. The results were as follows: (1) At dose of 400 mg/kg/day, ranitidine hydrochloride showed no effects on dams, excepting slight suppression in body weight gain in early period of administration. (2) In fetuses, no effects of ranitidine hydrochloride on fetal growth, sex ratio, viability and degree of ossification were observed. (3) External and visceral abnormalities were observed 5, 3, 3 and 4 fetuses in control, 25, 100 and 400 mg/kg/day groups, respectively, but there was no significant difference of the incidence ratio in the treated groups from control, and was no increase in the same type of abnormality. Ranitidine hydrochloride induced no increase in incidence of visceral and skeletal variations. Therefore it was concluded that ranitidine hydrochloride had no teratogenic effect on rabbits at dose of 400 mg/kg/day or lower than that.

The toxicity of tetrahydrofuran (THF) was evaluated by repeated inhalation experiments on rats. The animals were separated into a control group and groups exposed to 100, 200, 1,000 or 5,000 ppm THF for 4 hours a day, 5 days a week over a 12-week period. No significant differences appeared between the groups exposed to 100 ppm as well as 200 ppm and the control group, except for slight local irritant symptoms of the mucosa. The group exposed to 1,000 ppm showed an effect on the liver function according to the results by serum chemistry test. In the group exposed to 5,000 ppm, marked local irritant symptoms and morphological damage of the respiratory mucous membrane were found upon histological examinations. Also significant differences were noted between this group and the control group in white blood cell counts, blood sugar values and liver functions by hematological and serum chemistry tests.

Acute and subacute toxicities of ranitidine hydrochloride, a new histamine H2-receptor antagonist, and acute toxicity of ranitidine N-oxide, a metabolite of ranitidine hydrochloride, were investigated. The results are summarized as follows: (1) Oral, intravenous, subcutaneous, intraperitoneal and intramuscular LD50 values of ranitidine hydrochloride in 5- and 12-weeks old mice and rats and 12-weeks old rabbits were ranged from ca. 60 mg/kg (12-weeks old male mice, i.v.) to 6610 mg/kg (12-weeks old male rats, p.o.). In comparison of the LD50 values, it was revealed that female rats were more sensitive to the drug than males in the case of oral administration. (2) A single intravenous injection with ranitidine N-oxide at a dose of 1000 mg/kg, induced no lethal cases in mice, indicating that the N-oxide has very low toxicity in a comparison with that of ranitidine hydrochloride. (3) In the subacute toxicity test, male and female rats were orally administered with ranitidine hydrochloride for 35 days. Dose dependent changes such as increase in liver weight and water consumption, decrease in spontaneous movement and others were induced at doses of more than 500 mg/kg/day in females and 1000 mg/kg/day in males. These results indicate that the no effects were observed at levels of 250 mg/kg/day in females and 500 mg/kg/day in males. In the recovery test, however, no marked changes were observed in the rats which had been administered at 1000 and 2000 mg/kg/day for 35 days.

Chronic toxicity of ranitidine hydrochloride, a new histamine H2-receptor antagonist, was studied using Sprague Dawley rats. Ranitidine was administered orally at dose levels of 30, 100, 300 and 1000 mg/kg/day for 26 or 53 weeks. In the 1000 mg/kg/day group, ten of 31 females died showing acute toxic signs. In the survived animals of this dose group, changes were observed, such as salivation, depression of body weight gain, increase in water consumption, increase in urinary Na and K excretion, increase in serum albumin content, increase in weights of the liver, kidneys and heart. Main histopathological findings were as follows: centrolobular or midzonal fat deposition in liver, increase in s-ER in hepatocytes, increase in foamy cells in lung and some slight degenerative changes occasionally seen in renal tubules. In the 300 mg/kg/day group, the changes similar to those in the 1000 mg/kg/day group were observed, however, the degree of these changes was more moderate. All of the above-mentioned findings were demonstrated to be reversible in recovery period for 8 weeks. In the 100 and 30 mg/kg/day groups, no remarkable changes were observed in both sexes. It was concluded that the maximum nontoxic dose of ranitidine hydrochloride was 100 mg/kg/day in male and female rats.

The toxicity of tetrahydrofuran (THF), an important solvent in chemical industries, was studied by experiments on mice and rats. Acute toxicity was studied by intraperitoneally injecting 20% THF solution in various doses and by causing THF of various concentrations to be inhaled. Toxic symptoms appearing during the experimental period were observed. The results are as follows: 1. Acute toxic dose of THF. LD50 was estimated to be 2,500 mg/kg in mice with intraperitoneal administration of 20% THF-olive oil solution and 1,900 mg/kg in mice and 2,900 mg/kg in rats with intraperitoneal administration of 20% THF-0.9% NaCl solution. LC50 was estimated to be 21,000 ppm in rats when THF was inhaled for three hours. 2. Acute toxicity by inhalation of THF for three ours. Rats exposed to 100 to 200 ppm of THF showed no significant effects, except for slight local irritant symptoms such as redness of the nose and eyelids. Almost all rats exposed to over 5,000 ppm of THF displayed marked local irritant symptoms such as edema or opacity of the cornea, salivation and discharge or bleeding in nasal mucosa. A cataleptoid posture, coma and clonic muscle spasms indicating irritant symptoms of the central nervous system were also observed.

A teratogenicity study was carried out in Crj: CD (SD) rats orally administered ranitidine hydrochloride, a histamine H2-receptor antagonist, at dose levels of 50, 200 and 800 mg/kg/day as base weight for a period of 11 days from day 7 to day 17 of gestation. Two-thirds of the pregnant females in each group were sacrificed on day 20 of gestation and their fetuses were examined. The remaining dams were allowed to litter naturally, and the postnatal development of the offspring was observed. The incidences of external, internal, and skeletal anomalies were not significantly increased in the fetuses of any treated group. Ranitidine treatment caused no effects on parturition, lactation, postnatal growth and reproductive ability of the male and female offspring.

A perinatal and postnatal study was carried out in the Crj:CD (SD) rats orally administered ranitidine hydrochloride, a histamine H2-receptor antagonist, at dose levels of 50, 200, and 800 mg/kg/day as base for a period of time from day 17 of gestation to day 21 after delivery. All pregnant rats were allowed to litter naturally, and the postnatal development of the offsprings was observed. In the 800 mg/kg group, the delivery rate was significantly decreased and offspring mortality during the lactation period showed a tendency to increase as compared with control, but the difference was not significant. No significant differences between the control group and the treated groups were found in postnatal growth and differentiation, behavior and reproductive ability of male and female offsprings.

A fertility study was carried out in Crj: CD (SD) rats orally administered ranitidine hydrochloride, a histamine H2-receptor antagonist, at dose levels of 50, 200 and 800 mg/kg/day in base weight. Male rats were treated from 60 days before mating until the completion of mating. Female rats were administered ranitidine hydrochloride from 14 days prior to mating up to day 7 of gestation. All pregnant females were sacrificed on day 20 of gestation and all fetuses were examined for abnormalities. Temporary salivation was noted in rats of both sexes given 800 mg/kg/day of ranitidine and in the male rat group given 200 mg/kg/day. No abnormal signs were seen in mating or fertility in the rats treated with ranitidine. No external, internal and skeletal anomalies attributable to ranitidine hydrochloride were observed in the fetuses. It was concluded that ranitidine hydrochloride has no harmful effect on mating, fertilization, implantation, or embryonic development.