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. 60mg/kg (12-weeks old male mice, i.v.) to 6610mg/kg (12-webks 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.
Ranitidine, a histamine H2-receptor antagonist was orally administered to beagles, and acute, five-week subacute, 26-week chronic toxicity and recovery studies were carried out. I. Acute toxicity Ranitidine. in the single doses of 1, 000, 1, 500, 2, 500, 3, 000 or 3, 500mg/kg was administered to one male and one female beagles at each dose. Vomiting, tremor and motor ataxia were found shortly after the administration. However, no deaths occurred even at the highest level of 3, 500mg/kg, with the exception of the male at level of 3, 000 mg/kg. Levels higher than 3, 500 mg/kg were not studied because of extremely severe vomiting. II. Five-week subacute toxicity 1) Ranitidine was administered to three male and three female beagles at the dose level of 40, 80, 160 or 320 mg/kg/day for 5 weeks, but no death occured at any level. No sign of abnormality was seen at 40 mg/kg/day. 2) In the 80 mg/kg/day group, no sign was seen except for salivation. In the groups which received 160 mg/kg/day or more, salivation, vomiting and soft feces appeared, and in males, significant decreased in erythrocyte counts and hematocrit and hemoglobin values were noted in association with minute bleeding in the lower digestive tract accompanied by soft feces. In the 320 mg/kg/day group, food intake decreased. growth of body weight was suppressed and minor tarry feces were noted sporadically. In the males in this group, decreases in leukocyte count, hematoctit and hemoglobin values and serum protein and increases in platelet and reticulocyte counts were noted, in association with minute bleeding in the lower digestive tract. 4) In the histopathology, no notoworthy chatige was noted except for partial atrophy and erosion of the colonic mucosa in one female at 80 mg/kg and erosion of the colonic mucosa in one male at 320 mg/kg. 5) The 'maximum non-toxic' level of ranitidine was estimated to be approximately 40 mg/kg/day which corresponds to 7-8 times higher dose than the clinical daily dose for humans. III. Twenty-six week chronic toxicity 1) Ranitidine was orally administered to three male and three female beagles at 40, 80 and 160 mg/kg once a day for 26 weeks. Subdequently, in both the 80 and 160 mg/kg groups, a 30-day recovery study was carried out. No deaths occurred. In the 40 mg/kg group, no abnormality was noted. 2) At 80 mg/kg or more, salivation, vomiting and soft feces were seen just as in the subacute toxicity study. 3) In the 160 mg/kg group, decrease in food intake, suppression of body weight gain and occult blood in the feces were observed. In association with this bleeding, decreases in erythrocyte count and in hematocrit and hemoglobin values were noted in the males, but no other noteworthy change was observed. 4) In the histopatholgy either, no noteworthy change was found. 5) In electron microscopic observation, no noteworthy change was noted with the exception of a slight change in the tapetum in the 160 mg/kg group. 6) All the above-mentioned changes disappeared after withdrawal of the test drug: 7) The 'no observable effect' level of ranitidine was estimated to be approximately 40mg/kg/day which corresponds to 7-8 times higher dose than the clinical daily dose for humans.
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.
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 anagonist, 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 group and differentiation, behavior and reproductive ability of male and female offsprings.
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.