The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 17 , Issue SupplementII
Showing 1-11 articles out of 11 articles from the selected issue
  • Kazumasa YAMASHITA, Shigeki NAKANO, Masahiko KUWATA, Hideaki YADA, Ken ...
    1992 Volume 17 Issue SupplementII Pages 1-9
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Single dose toxicity studies of suplatast tosilate (IPD-1151T) were carried out in mice, rats and dogs of both sexes. The results were as follows: 1. The LD50 values of IPD-1151T were as follows: Mice, 12500 (both sexes) mg/kg or more in oral route (maximum dose for technical manner); Mice, 81 (male) and 96 (female) mg/kg in intravenous route; Rats, 10000 (both sexes) mg/kg or more in oral route (maximum dose for technical manner); Rats, 96 (male) and 93 (female) mg/kg in intravenous route; Dogs, 2124 (male) and 2660 (female) mg/kg in oral route. On the LD50 values, no sexual difference was apparent in all species, but the species difference was noted between the rodent and dog. LD50 values of dog were lower level than those of rodent. 2. As toxic signs, mucous diarrhea with specific smell was noted in orally administered rodent. In addition, rats showed soiled fur in the perianal. In intravenous route, the rodent showed dyspnea, tonic convulsion and lateral position and deaths occured within l0 min in mice and within 30 min in rats after administration. Dog showed toxic signs similar to those in rodents and deaths occured within 3 hours. 3. In pathological examinations, dead mice and dogs administered orally showed lung congestion, liver fading or slight hemorrhage in the endo-and/or exocardium. Dead rodent administered intravenously showed only slight hemorrhage and congestion in the lung. Alived mice, rats and dogs showed no remarkable changes. 4. The main cause of deaths seemed to be respiratory disturbance in all species.
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  • Shigeki NAKANO, Taiji HAYASHI, Kenji IRIMURA, Akira MARUDEN, Kazutoshi ...
    1992 Volume 17 Issue SupplementII Pages 11-38
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 13-week oral repeated dose toxicity study of Suplatast tosilate (IPD-1151T), a new anti-allergic agent, as well as a 5-week recovery study were carried out at dose levels of 0 (control), 200, 600, 1800 and 5400 mg/kg/day using male and female rats. The results were as follows: 1. In general conditions, salivation were observed in some rats of both sexes given 1800 mg/kg/day. Both sexes given 5400 mg/kg/day disclosed salivation and soft stool and then died after showing ataxic gait, hyperesthesia and convulsion of legs. 2. Inhibition of body weight gain in both sexes given 5400 mg/kg/day were obsereved from the early stage of the treatment period. 3. The food consumption was decreased from about 3-week and the water consumption was increased from the initiation of study to about 3-week in both sexes given 5400 mg/kg/day. However, both of them were remarkably decreased prior to death. 4. Fecal examination for occult blood showed an increasing tendency in the incidence of positive findings in both sexes given 1800 mg/kg/day. 5. Hematological examination showed slight decreases in erythrocytic parameters in both sexes given 1800 mg/kg/day. In both sexes given 5400 mg/kg/day hemoconcentration was obsereved, some animals showing decreases in leucocyte and lymphocyte counts and lymphocyte percentage. 6. Biochemical examination showed increases in total and free cholesterol levels in males given 600 mg/kg/day or more, an increased cholinesterase and decreased levels of triglyceride and cholesterol ester ratio in males given 1800 mg/kg/day. An increase in LDH was observed in both sexes given 5400 mg/kg/day and half of these animals also showed increases in GOT and Urea N. 7. The absolute weights of the pituitary, brain, thymus, heart, lungs and kidneys were increased. However, no histopathological lesion was observed in these organs. As treatment-related histological changes, atrophy in the thymus and spleen, dilation in digestive tracts, neuronal necrosis and necrotic foci in the central nervous system, necrosis of lymphocytes in the lymphoid organs and a decrease in bone marrow cell were observed in both sexes given 5400 mg/kg/day. 8. After a 5-week recovery period, above-mentioned changes had disappeared. 9. From the above results, the non-effective dose level was estimated to be 200 mg/kg/day in males and 600 mg/kg/day in females, and toxic dose level 1800∼540 mg/kg/day in both sexes.
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  • Kazumasa YAMASHITA, Hideaki YADA, Taiji HAYASHI, Kenji IRIMURA, Tomio ...
    1992 Volume 17 Issue SupplementII Pages 39-67
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 13-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T), a new anti-allergic agent, as well as a 5-week recovery study were carried out at dose levels of 0 (control), 50, 150, 450 and 1350 mg/kg/day using male and female beagle dogs. The results were as follows: 1. In general conditions, soft feces and diarrhea with specific smell were dose-dependently observed in males and females given 450 mg/kg/day or more. Both sexes given 1350 mg/kg/day, revealed reeling with dropped head, abnormal gait, dysstasia, lying at lateral or prone position, sedation, and tremor, and one male and one female in this group died after showing respiratory depression, collapse and cyanosis. 2. There were no significant or remarkable changes in body weight, food consumption, water consumption, ophthalmology, electrocardiogram, urinalysis, hematology, biochemistry, fecal occult blood test, and absolute and relative organ weights. 3. Pathological examination in dead animals revealed hemorrhagic change in the heart and slight vacuolar changes in hepatocytes. In survived animals, there were no pathological changes attributable to the IPD-1151T. 4. In electron microscopic examination, there were no abnormalities in the liver and kidney attributable to the IPD-1151T. 5. After 5-week recovery period, above-mentioned changes disappeared. 6. From the above results, the non-effective dose level and the toxic dose level were estimated to be 150 mg/kg/day and 1350 mg/kg/day, respectively, and no sex differences were found.
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  • Masahiko KUWATA, Kenji IRIMURA, Kyoko KUROKAWA, Akihiro KASHIHARA, Kaz ...
    1992 Volume 17 Issue SupplementII Pages 69-99
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 52-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T), a new anti-allergic agent, as well as a 5-week recovery study were carried out at dose levels of 0 (control), 50, 300 and 1800 mg/kg/day using male and female fats. The results were as follows: 1. In general conditions, transient salivation after each administration and excretions with peculiar smells were noted in both sexes given 1800 mg/kg/day. Since one male and six female rats given 1800 mg/kg/day showed bradypnea, clonic/tonic convulsions, lying on the belly and/or side, subnormal temperature, abnormal gait, paralysis of extremities, they were sacrificed in moribund. 2. The body weight was lowered from the early stage of administration period in both sexes given 1800 mg/kg/day. 3. There were no remarkable changes in food consumption, urinalysis, fecal examination, hematology and ophthalmology. 4. Biochemical examination revealed a decrease in triglyceride in males given 300 mg/kg/day or more. 5. In pathological examination, the animals sacrificed in moribund showed necrosis and degeneration of neurons and/or sponge-like change of neuropile in nucleus caudatus of the cerebrum, necrosis and partial disappearance of granular cells and Purkinje's cells, and swelling of Bergmann's cells in the cerebellum. In survived animals, the relative organ weight in the liver increased in males given 300 mg/kg/day or more and females given 1800 mg/kg/day, and histopathological examination revealed slight vacuolization, hypertrophy of centrilobular hepatocytes in males given 1800 mg/kg/day. Furthermore, in some females, similar changes of the cerebrum and the cerebellum, as mentioned above, were slightly observed. In electron microscopic examination, slight proliferation of smooth endoplasmic reticulum in hepatocytic cytoplasm was observed in males given 1800 mg/kg/day. The necrobiotic changes, such as condensation of nuclear chromatin, increased electron density of cytoplasm and nuclei, mitochondrial accumulation and vacuolization, in the cells possibly derived from small granular cells in the cerebellum were observed in females given 1800 mg/kg/day. The mitochondrial swelling, decreased and dilated rough endoplasmic reticulum, and increased electron density of cytoplasm and nuclei with formation of cytoplasmic vacuole and membranous degenerated structure in neurons of cerebral temporal lobe cortex were observed in females given 1800 mg/kg/day. 6. In a recovery study, electron microscopic examination revealed a slight degeneration of myelinated nerve fibers in the cerebellum in males given 1800 mg/kg/day. On the contrary, there were no remarkable changes in general condition, body weight and various clinical parameters. It was noted that these changes induced by IPD-1151T seemed to be reversible changes. 7. From the above results, the non-effective dose levels were estimated to be 50 mg/kg/day in males and 300 mg/kg/day in females.
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  • Michiko AOKI, Tsuneo OHTAKI, Takayuki SEKI, Koichi KOJIMA, Shinsuke YO ...
    1992 Volume 17 Issue SupplementII Pages 101-139
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 52-Week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T), a newly developed anti-allergic agent, was carried out in beagles by oral administration of 30, 90, 270 and 810 mg/kg/day for 52 weeks. The recovery study was carried out by the withdrawal for 5 weeks using control and the 810 mg/kg groups. The results are as follows: 1. Observation of general conditions revealed soft feces, mucous feces, and diarrhea in both sexes of the 270 and 810 mg/kg groups during the administration period, and these findings disappeared during the withdrawal period. One female of the 810 mg/kg group exhibited tremors in the legs and neck, staggering, a decrease of spontaneous motor activity, and clonic convulsions in Week 17 of administration and died on Day 118. One male of the same group exhibited whole body tremors and staggering from Week 32 to Week 52. 2. Body weight gain tended to be inhibited in males of the 810 mg/kg group during the administration period. The body weight of the female that died decreased rapidly after the appearance of neurological symptoms. The body weight of the male that exhibited neurological symptoms decreased after their appearance but later increased. 3. There were no abnormal changes in food consumption in all of the sacrificed dogs. The female that died did not eat at all after the appearance of neurological symptoms. The male that exhibited neurological symptoms did not eat at all for 1 week after their appearance, but the food consumption returned to normal thereafter. 4. Prothrombin times were prolonged in males of the 270 and 810 mg/kg groups at Week 26, and activated partial thromboplastin times were prolonged in males of the 8l0 mg/kg group at Week 52. 5. Plasma levels of alkaline phosphatase, GPT and LDH were elevated in some males and females of the 810 mg/kg groups. 6. No abnormalities due to IPD-1151T administration were found in urinalysis, ophthalmological examination, electrocardiography, and fecal occult blood examination, or organ weights. 7. Autopsies including histopathological and electron microscopic examinations on the sacrificed dogs revealed no abnormalities. Subserosal hemorrhage in the base of the heart, congestion in the lungs, congestion and vacuolation in the liver and slight cell infiltration around vessels of the brain were found in the female that died. 8. Accordingly, the non-effective dose level for IPD-1151T was estimated to be 90 mg/kg for both sexes, and the recovery after the withdrawal was found to be fast.
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  • Sunao ASO, Shojiro SUETA, Yasuhiro KAJIWARA, Satoshi MORITA, Shin-ichi ...
    1992 Volume 17 Issue SupplementII Pages 141-154
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The effect of suplatast tosilate (IPD-1151T) on reproductive ability and fetal development of the rat was studied. IPD-1151T was administered orally at dose levels of 0 (control), 200, 600, and 1800 mg/kg/day for the premating, mating and early pregnant period. For parent animals, IPD-1151T caused no abnormalities in clinical signs, reproductive ability, or autopsy findings; the females at 180O mg/kg/day showed a reduction in body weight gain from one week after the start of administration and a decrease in food consumption from the day of the start of administration to day 6 of pregnancy. For fetuses, IPD-1151T produced no abnormalities in external, visceral or skeletal examinations; embryofetal mortality was increased at 1800 mg/kg/day. The results suggest that the non-effective dose level of IPD-1151T is 1800 mg/kg/day for males and 600 mg/kg/day for females in general toxicity, 1800 mg/kg/day for both sexes in reproductive ability, and 600 mg/kg/day for fetuses under the conditions of this study.
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  • Osamu YAMAKITA, Mitsuhiro SHINOMIYA, Masahiro KOIDA, Shigenori KATAYAM ...
    1992 Volume 17 Issue SupplementII Pages 155-174
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A teratological study of suplatast tosilate (IPD-1151T), a new anti-allergic agent which has a suppressive action on IgE antibody formation, was conducted with pregnant Wistar rats. Dosage levels of IPD-1151T 0, 300, 900 and 2700 mg/kg/day were administered to dams orally by gavage on days 7 through 17 of gestation. Two-thirds of dams per group was caesarean-sectioned on day 20 of gestation and their fetuses were removed for examination of external, visceral and skeletal anomalies. The remaining one-third was allowed to deliver naturally. F1 neonates were examined developmental, functional and behavioral parameters and reproductive abilities. The results were as follows: 1. Toxicities on F0 dams in the 2700 mg/kg/day group were salivation, piloerection, and decreases in body weight and food consumption. Seven animals (19.4%) showed severe toxicity and were dead. Toxicity in the 900 mg/kg/day group was a slight decrease in food consumption. The dosage level of 300 mg/kg/day was non-toxic. 2. Toxicities on F1 fetuses in the 2700 mg/kg/day group were a decrease in body weight and an increase in visceral anomalies (main one was ventricular septal defect that might be related to developmental retardation). No toxicities were seen in the 300 and 900 mg/kg/day. 3. In F1 neonates, suppressions of body weight were observed clearly in the male and female 2700 mg/kg/day and slightly in the male 900 mg/kg/day groups. But no changes in parameters of development, function, behavior or reproductive ability were seen in any dosed groups. It was suggested that no effective dose levels of IPD-1151T were 300 mg/kg/day for F0 dams and F1 neonates, and 900 mg/kg/day for F1 fetuses.
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  • Osamu YAMAKITA, Mitsuhiro SHINOMIYA, Mitsuo KUROKAWA, Masahiro KOIDA, ...
    1992 Volume 17 Issue SupplementII Pages 175-185
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A teratological study of suplatast tosilate (IPD-1151T), a newly developed anti-allergic agent, was carried out in pregnant NZW rabbits to assess the effects on dams and fetuses. IPD-1151T was administered to dams orally at dose levels of 0, 100, 300, 450 and 700 mg/kg/day from day 6 through day 18 of gestation, and their fetuses were removed for teratological evaluation. The results were as follows: 1. In dams, marked increase in the incidence of abortion, and decrease in body weight gain, food consumption and feces mass were shown in the 700 mg/kg/day group. Slight decrease in body weight gain and food consumption were seen in the 450 mg/kg/day group, but no toxicities were observed in the 300 mg/kg/day or less groups. 2. In fetuses, marked increase in embryo-fetal deaths and decrease in alive fetal body weights and placental weights, but no teratogenicity were shown in the 700 mg/kg/day group. There were no fetal toxicity or teratogenicity in the 450 mg/kg/day or less groups. 3. No effective dose levels were 300 mg/kg/day for maternal general toxicity and 450 mg/kg/day for maternal reproductive toxicity and for fetuses.
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  • Sunao ASO, Yasuhiro KAJIWARA, Makiko ANAI, Shojiro SUETA, Shin-ichi HO ...
    1992 Volume 17 Issue SupplementII Pages 187-205
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    In order to assess the effect of suplatast tosilate (IPD-1151T) on pregnancy of the rat, and the post natal development to maturity of the F1 generation, daily doses of 0 (control), 200, 600 and l800 mg/kg/day were administered orally to female Wistar rats from day 17 of pregnancy to day 21 after delivery. All females were allowed to give birth and rear their young to weaning. F0 dams showed no treatment-related changes in general conditions including the state of delivery or nursing, gestation period, birth rate, or autopsy findings. The dams at 1800 mg/kg/day showed a tendency to reduction in body weight gain and a decrease in food consumption. F1 offspring showed no treatment-related changes in clinical signs on the birth day or during the nursing period, external examination on the birth day, general condition, physical or reflex development, open-field test, water multiple T-maze test, autopsy findings, organ weights, skeletal examination, reproductive ability, or histopathological examination on the reproductive organs of the animals of both sexes that failed to produce pregnancy. The offspring at 1800 mg/kg/day showed a reduction or its tendency in body weight gain. There were no treatment-related changes in any of reproductive parameters of F1 dams including external examination of F2 fetuses. The results suggest that the non-effective dose level of IPD-1151T is 600 and 1800 mg/kg/day for F0 dams in general toxicity and reproductive ability, respectively, and 600 mg/kg/day for F1 offspring in post natal development under the conditions of this study.
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  • Akinobu OHUCHIDA, Akemi FURUKAWA, Sachiko SATO, Yasuhiro MAEDA, Akihir ...
    1992 Volume 17 Issue SupplementII Pages 207-220
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    1. The reverse mutation test was carried out on suplatast tosilate (IPD-1151T) at dose range of 50∼5000μg/plate using Salmonella typhimurium strains TA100, TA1535, TA98 Ta1538 and TA1537, and Escherichia coli strains WP2, WP2uvrA. In all tester strains no significant difference were observed in the number of revertant colonies as compared with solvent control in the absence or presence of mammalian metabolic activation system. 2. The chromosomal aberration test on IPD-1151T was carried out using cultured Chinese hamster lung cells (CHL). The cells were treated with IPD-1151T at the doses of 125, 250 and 500μg/ml without S9 Mix and at the doses of 1250, 2500 and 5000 μg/ml with S9 Mix. The incidence of structural- and numeral-aberration was 0∼4 % in the absence or presence of mammalian metabolic activation system, no significant increases were observed in the incidence of chromosomal aberrations. 3. The micronucleus test using BDF1 male mice was conducted in order to evaluate the in vivo mutagenicity of IPD-1151T. IPD-1151T was orally administered at doses of 625, 1250, 2500 and 5000 mg/kg, with a sampling time of 24 hr. The frequency of polychromatic erythrocytes with micronuclei (MNPCE) was 0.23% in the lowest dose (625mg/kg) of IPD-1151T, but the frequency of MNPCE was 0.03∼0.13% in the groups treated with 1250∼5000 mg/kg of IPD-1151T and no significant increases were observed with dose dependence. The results indicated that IPD-1151T was negative, even in the assessment standard using our background data. 4. The present study indicates that IPD-1151T has no in vitro and in vivo mutagenic potential.
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  • Yasuhide KOUCHI, Akinobu OHUCHIDA, Yasuhiro MAEDA, Shigenori KATAYAMA, ...
    1992 Volume 17 Issue SupplementII Pages 221-233
    Published: May 11, 1992
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Antigenicity of suplatast tosilate (IPD-1151T) was investigated in guinea pigs and mice. The results were as follows: 1. Homologous passive cutaneous anaphylaxis (PCA), active systemic anaphylaxis (ASA), active cutaneous anaphylaxis (ACA) and Schultz-Dale reaction tests were carried out using guinea pigs which were immunized orally with IPD-1151T alone or subcutaneously with IPD-1151T and Freund's complete adjuvants (CFA). Positive reactions in these tests were not produced by eliciting injection of IPD-1151T or its metabolite, M-1. On the other hand, the sensitization of ovalbumin (OVA) with CFA produced positive reactions in all of PCA, ASA, ACA and Schultz-Dale tests. 2. Heterologous passive cutaneous anaphylaxis (PCA) test using rats was carried out using two strains of mice (C3H / He and BALB / c) which were immunized orally with IPD-1151T alone or intraperitoneally with IPD-1151T and aluminum hydroxide gel (Alum) as an adjuvant. No animals showed positive reaction to both eliciting antigens, IPD-1151T and M-1. On the other hand, a positive reaction in PCA test to eliciting antigen, OVA, was obtained in rats treated with sera of mice sensitized with OVA plus Alum. 3. These findings showed that IPD-1151T had no antigenicity in guinea pigs and mice.
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