The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 14 , Issue SupplementII
Showing 1-8 articles out of 8 articles from the selected issue
  • Kazumasa YAMASHITA, Shigeki NAKANO, Masahiko KUWATA, Hideaki YADA, Ken ...
    1989 Volume 14 Issue SupplementII Pages 1-11
    Published: October 31, 1989
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Acute toxicity studies of propiverine hydrochloride (P-4) were carried out in mice, rats and dogs of both sexes. 1. The LD50 values of P-4 were as follows : Mice ; 410(male) and 323(female) mg/kg in oral route, 223(male) and 283(female) mg/kg in subcutaneous route and 36(male and female) mg/kg in intravenous route, Rats ; 1000(male) and 1092(female) mg/kg in oral route, 1632(male) and 1411(female) mg/kg in subcutaneous route, and 22(male) and 25(female) mg/kg in intravenous route. On the LD50 values, no sexual difference was apparent but the species difference between mice and rats observed to be present in oral and subcutaneous routes. The approximate lethal doses of P-4 in dogs were 987-1137 mg/kg for male and 865-894 mg/kg for female in oral route, and the values were almost same as those in rats of oral route. 2. Major toxic signs such as clonic convulsion, bradypnoea, dyspnoea, decreased spontaneous activity and hematuria were observed in mice and rats. Furthermore mydriasis in rats, and transitory salivation and/or vocalization in mice and rats were observed. In some rats, sedation, salivation, soil at hypogastrium, rale and emaciation were detected from the next day of oral administration. In dogs, toxic signs such as vomiting, tremor, tonic and/or clonic convulsion, mydriasis and gasping were observed. 3. Pathological changes observed in dead animals were congestion of lungs, liver and kidneys in all routes, congestion and hemorrhage in digestive tracts in oral route, inflammatory changes at the injection site in subcutaneous route. In addition, retention of hematuria in urinary bladder in rats of oral and subcutaneous routes, the hemorrhagic changes of heart, atonia of urinary bladder and retention of urine in dogs were observed. 4. The main cause of death seemed to be respiratory disturbance in all species and the weakness in a few rats of oral route.
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  • Shigeki NAKANO, Masahiko KUWATA, Hiroyuki HASEGAWA, Kenzi IRIMURA, Aki ...
    1989 Volume 14 Issue SupplementII Pages 13-59
    Published: October 31, 1989
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A subacute toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out using male and female Wistar rats. P-4 was orally administered to rats at dose levels of 2, 10, 50 and 150 mg/kg/day for 13 weeks, followed by 5 weeks recovery period. The results obtained are as follows: 1. In the general conditions, transient salivation was observed immediately after administration and blotted fur at lower abdomen was noted in rats given 50 mg/kg/day or more. There were no deaths related to P-4. 2. Body weight gain was depressed in males given 50 mg/kg/day or more and females given 150 mg/kg/day. No significant changes in food consumption were observed. Water consumption increased in the groups of 50 mg/kg/day or more. 3. Urinalysis revealed an increase of urine volume, decreases of osmotic pressure, protein and urobilinogen, and a slight increase in excretion of electrolyte in rats given 50 mg/kg/day or more. 4. Hematological examinations revealed slight changes such as an increase in erythrocyte count and a shortening of APTT in rats given 150 mg/kg/day. 5. Serum biochemical examinations showed a decrease in triglyceride and increases in γ-GTP and AlP activities, and urea nitrogen in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Additionally, decreases in total and free cholesterol, and phospholipid for males and an increase of total cholesterol and a decrease of cholinesterase activity for females were detected. 6. At autopsy, atrophy of thymus and spleen was observed in rats given 50 mg/kg/day or more, but without histopathological correlation. Histopathological examinations revealed hypertrophy and fatty degeneration of hepatocytes, which were accompanied with increases of absolute and/or relative liver weight, in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Electron-microscopy showed proliferation of smooth endoplasmic reticulum in the same groups. In the kidney, eosinophilic and intranuclear inclusions in the tubular epithelium were detected, in which cytoplasm there were no toxic injuries, in males given 10 mg/kg/day or more and females given 50 mg/kg/day or more. 7. After 5 weeks recovery period, above-mentioned changes were generally disappeared, suggesting that these were reversible. 8. The non-effective dose levels and the toxic dose levels of P-4 were estimated to be 2 mg/kg/day for males and 10 mg/kg/day for females, and 50 mg/kg/day for males and 150 mg/kg/day for females, respectively.
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  • Kazumasa YAMASHITA, Hideaki YADA, Kenzi IRIMURA, Akira MARUDEN, Ken-ic ...
    1989 Volume 14 Issue SupplementII Pages 61-109
    Published: October 31, 1989
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A subacute oral toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out at dose-levels of 0, 1, 3, 9, and 27 mg/kg/day using male and female beagle dogs. They were treated for 13 weeks, followed by 5 weeks recovery period. The results obtained from the present study were as follows. 1. In the observation of general symptoms, mydriasis was observed in females receiving 3 mg/kg/day or more and in males receiving 9 mg/kg/day or more, every day, intermittently or sporadically. The incidence of mydriasis varied greatly in individuals. However, this sign disappeared within administration period. 2. Body weight gain was slightly suppressed in males and females receiving 27 mg/kg/day. 3. There were no significant changes in food consumption, water consumption, hematology, urinalysis and fecal occult blood, and no remarkable changes in ophthalmology, electrocardiogram. 4. Serum biochemical findings showed a decrease in Total cholesterol (T. cho), Free cholesterol (F. cho), Triglyceride (TG), Phospholipid (PL), Total protein (TP), Albumin (ALB), α1-Globulin (α1-GLO) and Calcium (Ca), and an increase in Alkaline phosphatase (Ae P), γ-Glutamyltranspeptidase (γ-GTP) activities and Choresterol ester ratio (EST/T) in males and females receiving 27 mg/kg/day. Further, a decrease in lipoprotein-T. cho, -TG and -PL were noted, on the other hand, lipoprotein-T. cho, -TG and -PL in the liver tissue increased. Similar slight changes were observed in males and females receiving 9 mg/kg/day. 5. Pathological examination revealed an enlargement of hepatocytes in a few animals receiving 3 mg/kg/day. In males and females receiving 9 mg/kg/day or more, yellowish liver, a increase in liver weights, an enlargement of hepatocytes with fatty degeneration and the appearance of eosinophilic inclusions in the hepatocytes were observed. Furthermore, some males and females receiving 27 mg/kg/day showed a slight cellular infiltration in glisson's sheaths, proliferation of the bile ducts and deposition of lipid droplets. Histochemical examination of liver tissue showed an increase in Ae P and γ-GTP activities in addition. Electronmicroscopically, the proliferation of smooth endoplasmic reticulum, increases in myelin-like inclusions and small lipid droplets in the hepatocytes were noted and these changes suggested the induction of drug-metabolizing enzyme in the liver. 6. After 5 weeks recovery period, above-mentioned changes were disappeared and it was suggested that these were reversible ones. 7. From the above results, the non-effective dose and the toxic one were estimated to be 1 mg/kg/day and 9 mg/kg/day for males and females, respectively.
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  • Shigeru KOHDA, Hiroshi NISHIKAWA, Masayuki SUMINO, Masaki SANO, Junji ...
    1989 Volume 14 Issue SupplementII Pages 111-160
    Published: October 31, 1989
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The chronic oral toxicity of propiverine hydrochloride(P-4), a new anti-pollakiuria agent, was studied in beagle dogs. Groups of 6 males and 6 females were treated with P-4 at doses of 0, 0.3, 1, 3, 9 mg/kg/day for one year and thereafter 2 animals of both sexes in each group were placed on withdrawal for one month. During administration and recovery period, no death occured in any dosed animals. As a toxic sign, only the frequency of vomitting was increased in animals of 1, 3 and 9 mg/kg/day groups. Body weight, food and water consumption were not affected by the P-4 administration. In serum chemical examinations, γ-GTP activity was increased in both sexes of 9 mg/kg/day group at 6 month of administration. Further decrease in total and free cholesterol, triglyceride and phospholipid, increase in GPT activity were detected in some animals of 9 mg/kg/day group at 12 month of administration. In addition decreasing tendency in levels of albumin was noted in males of 9 mg/kg/day group at 9 and 12 month of administration. And also, a gradual increase in total protein level and a gradual decrease in alkaline phosphatase activity were seen in control group, but in females or males of 9 mg/kg/day group, those changes were mild. Urine pH rised slightly in females of 3 mg/kg/day group and in both sexes of 9 mg/kg/day group. No specific findings attributable to P-4 treatment were detected in ECG, heart rate, funduscopy, hematology, fecal occult blood test and necropsy. The absolute and/or relative liver weight in males of 3 and 9 mg/kg/day groups were significantly increased. Light-microscopically, the hypertrophy of hepatocytes characterized by homogenization and enlargement of cytoplasmic space, and concentric inclusions in hepatocytic cytoplasm were detected in both sexes of 3 and 9 mg/kg/day groups. Corresponding to these microscopical findings, the following changes were observed electron-microscopically, the proliferation of smooth surfaced endoplasmic reticulum in hepatocytes in both sexes of 1, 3 and 9 mg/kg/day groups, lamellar bodies in hepatocytes in females of 3 mg/kg/day group, and in both sexes of 9 mg/kg/day group, and annulate lamellae in hepatocytes were detected in one female of 9 mg/kg/day group. After the recovery period, the above mentioned abnormalities were markedly attenuated or disappeared except the changes in hepatocytes. From these results, it seemed that 9 mg/kg/day of P-4 might be safety dose. However, the hyperplasia of smooth surfaced endoplasmic reticulum in hepatocytes regarded as adaptation phenomenon was seen in 1 mg/kg/day group or more, therefore the non-effect dose level of P-4 in both sexes was estimated to be 0.3 mg/kg/day, when it is given orally to beagle dogs for one year.
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  • Minoru SAITO, Hiroshi OGAWA, Isao NARAMA, Ryouichi YOSHIDA
    1989 Volume 14 Issue SupplementII Pages 161-177
    Published: October 31, 1989
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A fertility study was performed in Sprague-Dawley rats by oral administration of propiverine hydrochloride (P-4) at dose levels of 0 (control), 2, 10 and 50 mg/kg/day. Male rats were treated for 9 weeks before mating and following 4 weeks including mating period. Female rats were administered the test substance from 2 weeks before mating to day 7 of pregnancy. The females were sacrificed on day 21 of pregnancy for examination of their fetuses. Toxic signs consisted of mydriasis, salivation and rale were observed in both male and female animals at the dose of 50 mg/kg group and in male animals at the dose of 10 mg/kg group. Body weight gain was supressed and food intake was decreased in the 50 mg/kg group throughout the administration period. Water intake of the 50 mg/kg group was decreased temporarily at the early stage of administration period, although increased thereafter. Autopsy revealed the enlargement of the liver with yellow-brownish coloration in one male rat at the 50 mg/kg group. Fertility and reproductive ability in both sexes were not affected by administration of P-4. There was no lethal effect and no growth-inhibiting or teratogenic effects on the embryos and the fetuses. The results suggest that the non-effective dose level of P-4 was 2 and 10 mg/kg/day for general toxicity in male and female parent animals respectively, 50 mg/kg/day for reproductive ability in parent animals and in embryos and fetuses.
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  • Minoru SAITO, Isao NARAMA, Ryouichi YOSHIDA
    1989 Volume 14 Issue SupplementII Pages 179-205
    Published: October 31, 1989
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A teratogenicity study was performed in Sprague-Dawley rats by oral administration of propiverine hydrochloride (P-4) at dose levels of 0(control), 2, 10 and 50 mg/kg/day to dams from day 7 to day 17 of pregnancy. Twenty two or twenty three female rats in each group were sacrificed on day 21 of pregnancy for examination of their fetuses, and thirteen female rats were allowed to deliver for the postnatal examination of their offspring. In dams, the dose of 50 mg/kg caused toxic signs consisting of mydriasis, salivation and rale, body weight loss in the early stage of administration, and reduced food intake and increased water intake. The dose of 10 mg/kg caused rale, very slight supression of body weight gain and slight reduction of food intake. Body weight of the fetuses was decreased very slightly in the 50 mg/kg group. However, embryonal or fetal mortality and incidences of external, visceral or skeletal anomalies were not increased. In offspring, P-4 had no adverse effect on the postnatal development such as viability, growth, differentiation, emotionality, learning ability or reproductive performance. The results suggest that the non-effective dose level of P-4 is 2 mg/kg/day in maternal animals, 10 mg/kg/day in fetuses and 50 mg/kg/day in offspring.
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  • Minoru SAITO, Toshiro SUZUKI, Isao NARAMA, Ryouichi YOSHIDA
    1989 Volume 14 Issue SupplementII Pages 207-219
    Published: October 31, 1989
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A teratogenicity study was performed in Newzealand white rabbits by oral administration of propiverine hydrochloride (P-4) at dose levels of 0(control), 2.4, 12 and 60 mg/kg/day to dams from day 6 to day 18 of pregnancy. Thirteen or fifteen pregnant rabbits in each group were sacrificed on day 29 of pregnancy for examination of their fetuses. In dams, the dose of 60 mg/kg caused mydriasis, body weight loss or decreased body weight gain and reduced food and water intakes. Autopsy and weighing of organ weight revealed no evidence due to drug administration in any group. There were no significant differences in embryo-fetal mortality, fetal body weight, or incidences of external, visceral or skeletal anomalies and skeletal variation between treated and control animals. The compound had no lethal effects on the embryos and no growth-inhibiting or teratogenic effects on the fetuses. The results suggest that the non-effective dose level of P-4 is 12 mg/kg/day in maternal animals and 60 mg/kg/day in fetuses.
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  • Minoru SAITO, Hiroshi OGAWA, Isao NARAMA, Ryouichi YOSHIDA
    1989 Volume 14 Issue SupplementII Pages 221-247
    Published: October 31, 1989
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A perinatal and postnatal study was performed in Sprague-Dawley rats by oral administration of propiverine hydrochloride (P-4) at dose levels of 0(control), 2, 10 and 50 mg/kg/day to dams from day 17 of pregnancy to day 21 after delivery. Twenty two or twenty four dams in each group were allowed to deliver for the postnatal examination of their offspring. In dams, the dose of 50mg/kg caused toxic signs consisting of mydriasis, salivation and rale. One dam of this group showed piloerection, low body temperature, blanching of extremity and auricle, and emaciation associated with marked prolongation of delivery. Body weight gain of the dams was retarded in the 50 mg/kg group throughout the administration period. Food and water intakes were reduced in the 50mg/kg group. In gross pathology of the dam that showed prolonged delivery, the spleen and thymus were moderately or severely atrophied and the adrenal was moderately enlarged. The viability index of the offspring on day 4 was reduced in the 50mg/kg group. Body weight of pups slightly decreased in the 50mg/kg group during sucking and rearing periods. Absolute weights of some organs of the three-week aged offspring were reduced due to attributable depression of body weight gain. However, P-4 had no adverse effect on the postnatal development such as emotionality, motor activity, learning ability or reproductive performance. The results suggest that the non-effective dose level of P-4 is 10 mg/kg/day in maternal animals and offspring.
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