The toxicity variations of puffer fishes toxin on species, sex, organs seasons and sea area collecting subjects were observed in 615. subjects of 15 species during 1978-1981. The remarkable differences of toxicity were found by species and/or by subjects. Takifugu pardalis, Takifugu poecilonotus and Takifugu niphobles, which are habitually eaten in Japan, had a strong toxicity and some of them were strongly toxic in the muscle. It was indicated that female puffer fishes have a higher toxicity than the male. In particular, the toxicity from genital organs was significantly higher in the female puffer fishes than in male. No difference no sex was observed in the skin. Compared with the toxicities on the collecting sea areas, Inland sea of Seto and Japan sea, the mean of toxicity and the incidence rate of toxic subjects collected in Japan sea, were higher than those of in Inland Sea of Seto i.e. The difference was observed by the living sea environment of puffer fishes. The wild Takifugu rubripes was obviously more toxic than the cultured. It was suggested that the variations between the wild and culutred puffer fishes should be due to the difference of the metabolism for the production and accumulation of tetrodotoxin which would be influenced by the foods and the closed enviroment.

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The effects of ranitidine hydrochloride, a histamine H₂-receptor antagonist, on the reproductivity of male and female rats of Crj : CD (SD) strain and the development of their fetuses were examined. Ranitidine hydrochloride was intravenously administered once daily at dose levels of 5, 15 and 40 mg/kg in base weight respectively, to males from 60 days before mating until the completion of mating, and to females from 14 days before mating up to day 7 of gestation. All pregnant females were killed on day 20 of gestation and their fetuses were examined morphologically. Tachypnea, prone position and transient tremor were observed for a short period of time directly after an intravenous administration of ranitidine in the dose of 40 mg/kg, which were probably induced by a rapid fall in blood pressure. There was a significant decrease in the weight of spleen in males of 15 and 40 mg/kg groups. Treatment with ranitidine hydrochloride did not have any influence on mating performances and pregnancy at all dose levels. In observation of the fetuses, there was no influence of ranitidine hydrochloride administration on fetal growth and development. A few external, skeletal and visceral malformations were seen sporadically in each group, and 19 cases of dwarf fetuses were observed in 2 dams of 40 mg/kg group, but these changes were not attributable to administration of the drug. These results indicated that ranitidine hydrochloride intravenously administered to males and females before mating and to pregnant females in early stages of gestation had no toxic effects on reproductivity in either sex at the dose of 40 mg/kg/day or less.

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The effects of ranitidine hydrochloride, a histamine H₂-receptor antagonist, on development and general behavior of F₁ generation of Crj : CD (SD) rats were examined. Ranitidine hydrochloride was intravenously administered once daily from day 7 to 17 of gestation at dose levels of 5, 15 and 40 mg/kg in base weight respectively. Two-thirds of females were killed on day 20 of gestation to examine the development of fetuses, the remaining females were allowed to litter naturally and the postnatal development of the offsprings was observed. Tachypnea, prone position and transient tremor were observed for approximately 15 from 30 seconds directly after an intravenous administration of ranitidine hydrochloride in the dose of 40 mg/kg, which were probably induced by a rapid fall in blood pressure. During the gestation period, there occurred a slight depression of the maternal body weight gain in the ranitidine-treated groups. At the stage of lactation, the body weights of dams showed slightly lower levels than control and their liver weights of dams were also inclined to decrease in 15 and 40 mg/kg groups. In the observation of the fetuses, there were no significant differences between the control and ranitidine-treated groups concerning fetal growth and development, external, skeletal and internal anomalies in fetuses. In delivery and postpartum observation, no influence of ranitidine administration was observed on the litter size, mortality rate of F₁ pups. There was a tendency towards decrease in body weight in males of the ranitidine-treated group. But no significant changes were observed in general behavior, postnatal development, various functions such as reflex response, learning and reproductive performances of F_l generation. Therefore, it was concluded that ranitidine hydrochloride had no effects on fetal and postnatal development, general behavior and various functions of F₁ generation at the dose of 40 mg/kg/day or less.

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The effects of ranitidine hydrochloride, a histamine H₂-receptor antagonist, on delivery, lactation, postnatal development of F₁ generation of Crj : CD (SD) rats were examined. Ranitidine hydrochloride was intravenously administered once daily from day 17 of gestation to day 21 after delivery at dose levels of 5, 15 and 40 mg/kg in base weight respectively. All females were allowed to litter naturally, and postnatal development of offsprings was observed. Tachypnea, prone position and transient tremor were observed for approximately one minute directly after an intravenous administration of ranitidine in the dose of 40 mg/kg, which were probably induced by a rapid fall in blood pressure. In delivery and postpartum observation, there occurred no influence of the ranitidine administration on maternal body weight, delivery and lactation. In studies on general behavior of F₁ rats, no abnormal changes were observed on postnatal development and various functions such as reflex response and learning. Ranitidine treatment did not affect reproductive performances of F₁ generation. A slight inhibition in body weight gain and a slight decrease in average weight of liver were observed in F₁ females of 40 mg/kg group, but no other influence attributable to the ranitidine administration was observed on the general state and development of offsprings. In necropsy of offsprings, hydronephrosis, transitional epithelial cartinoma; kinky tail; unilateral absence of testis and epididymis were observed in one case of ranitidine-treated groups. But they were not attributable to administration of ranitidine. In summary, it was concluded that ranitidine hydrochloride had no effects on delivery and lactation of dams, and also on viability, development and various functions of F₁ generation at the dose of 40 mg/kg/day or less.

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This study was performed to compare the acute-renal toxicity of azosemide (SK-110) or furosemide (FM) treatment in combination with cephaloridine (CER). 1) Initially, the acute-renal toxicity of CER was studied after a subcutaneous administration at dose levels of 500, 1000, 1500 and 2000 mg/kg. The values of BUN, creatinine and relative kidney weights were increased in rats given CER at dose levels above 1500 mg/kg. Consequently, it was considered that the threshold of CER with regard to acute-renal toxicity was 1000 mg/kg. 2) Secondarily, the acute-renal toxicity of SK-110 or FM were studied after oral administration of 40, 80, 160 or 320 mg/kg doses alone or in combination with CER. Acute-renal toxicity was evident in the 320mg/kg-treated rats after both SK-110 and FM alone, as revealed by analysis of a number of parameters, i.e., BUN, serum creatinine, urine sediment and composition and pathological data composing both kidney weights and studies at the microscope level. However, the increase of BUN and relative kidney weights values, elevated numbers of epithelial cells in the urine and necrosis observed in the uriniferous-tubular epithelium on histopathological examination of kidneys were noted in rats given at dose levels of only 80 mg/kg with SK-110+CER, whereas they were seen in animals treated with FM even at the lowest applied dose of 40 mg/kg in combination with CER. In conclusion this study showed that the minimum dose of SK-110 or FM in combination with CER which causes acute-renal toxicity were, respectively, 80 mg/kg or less than 40 mg/kg.

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The effect of azosemide (SK-110), and its metabolites, 5-(2'-amino-4'-chloro-5'-sulfamoylphenyl)-tetrazole (M-1), 2-thiophenecarboxylic acid (TC), on mouse liver was investigated using biochemical and pathological parameters as indices of hepatotoxicity. The effects were compared with that of furosemide (FM) administration. A single dose of each compound was administered orally, or intraperitoneally, while multiple oral dosing was carried out once daily for a week. The results are summarized as follows: 1) SK-110 did not produce hepatotoxicity even after a single p.o. dose as high as 5000 mg/kg, a single i.p. dose of 400 mg/kg, or multiple p.o. doses of 700mg/kg/day. 2) M-1 also did not produce hepatotoxicity even after a single p.o. dose of 4000 mg/kg or multiple p.o. doses of 550 mg/kg/day. TC did not exert hepatotoxicity after a single i.p. dose of 150 mg/kg or multiple p.o. doses of 250mg/kg/day, but did produce hepatotoxicity after a single p.o. dose of more than 1000 mg/kg. However, it was presumed that, in vivo, TC formed as a metabolite of administered SK-110 would hardly produce hepatotoxicity. 3) FM produced hepatotoxicity after a single p.o. dose of more than 800mg/kg, or a single i.p. dose of more than 200 mg/kg, but not after multiple p.o. doses of 700 mg/kg/day. Based on these findings, it was concluded that, in contrast to FM, SK-110 had no hepatotoxic effect on the mouse liver.

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A teratogenicity study on bromperidol, a neuroleptic, was carried out in Wistar-Imamichi rats. Bromperidol was administered orally at the dose levels of 0.2, 1.5 and 10.0 mg/kg/day for 11 days from day 7 to day 17 of gestation. About two-thirds of pregnant females in each group were sacrificed on day 21 of gestation, and their fetuses were examined. The remaining dams were allowed to litter naturally, and the post-natal development of the offspring was observed. Treatment of bromperidol caused sedation of pregnant females in 1.5 and 10.0 mg/kg groups with concomitant decrease in body weight and in food and water intake in dose-dependent manner. Effect of bromperidol treatment on F₁ generation was observed mainly in animals of 10.0 mg/kg group, suggesting overall growth retardation such as decrease in live fetal weight, retarded ossification of metacarpals and metatarsals, a slight decrease in day 1 viability index, a marginal delay in eyelid opening, reduction in growth rate and decrease in organ weight. No treatment-related external and internal abnormalities were observed in fetuses (F₁), and no apparent effect on behavior, learning ability and reproductive function of offspring (F₁) was found.

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