The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 21 , Issue SupplementII
Showing 1-13 articles out of 13 articles from the selected issue
  • Takashi IMAIZUMI, Masaaki TSURUTA, Tadaharu KITAGAKI, Masahiro ONO, Ki ...
    1996 Volume 21 Issue SupplementII Pages 277-285
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A single dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, administered subcutaneously (s.c.) and percutaneously (p.c.) was studied in Slc:SD rats (s.c. and p.c.) and beagle dogs (s.c.). The LD50 values of MC903 were as follows: rats, 2.19 mg/kg in males and 2.51 mg/kg in females by s.c., and more than 15 mg/kg in both sexes by p.c.; dogs, more than 1.5 mg/kg in males by p.c. No sexual difference was noted in LD50 values of rats. Death of rats was observed from 1 to 3 days after administration by both routes. Dead animals showed decreases in body weight and locomotor activity, reddish tear, abnormal gait and dirty hair by both routes. Furthermore, dead animals administered by s.c. showed salivation, nasal discharge, piloerection, ptosis, diarrhea, urorrhea, nasal and vaginal bleeding, subnormal temperature, loose stool, cyanosis, irregular and deep respirations, clonic and tonic convulsions. Survival of rats showed similar signs to those of dead animals except for nasal discharge, nasal and vaginal bleeding, cyanosis, agonal respiration and convulsion. Discoloration of the kidney, white patch of the heart and a dilatation of the stomach wall were observed on macroscoplc examinations. No mortalities were observed in dogs which showed vomiting, conjunctival congestion, circumoral and auricular reddenings, periblepharal purplish reddening, decreases in locomotor activity and defecation, emaciation, eye discharge, skin desquamation of treated area and an increase in respiration. On macroscopic examination, desquamation of the skin, reddening of the circumoral mucosa, pale gray yellow striations in renal tubules of the cortex and discoloration of the thyroid were observed. Histopathological findings revealed epidermal thickening with parakeratosis, fibrocytes, hypertrophy and hypersecretion of the sebaceous and sweat glands, formation of epitheloid glanulomas and infiltration of neutrophils in the subcutaneous tissues. Furthermore, moderate calcium deposits in the renal tubules, fatty cells and slight calcium deposits in interstitial tissues of the thyroid, and a cystic nest of an ectopic intestinal epithelium between muscle layers of the duodenum were observed at the highest dose. On the basis of results obtained in the present study, rats administered MC903 by s.c. or p.c. died probably due to the circulatory and renal disturbance resulted from effects of this drug on the heart and kidney.
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  • Tadaharu KITAGAKI, Toshiro SUZUKI, Yoshihide KOIKE, Masahiro ONO, Kiyo ...
    1996 Volume 21 Issue SupplementII Pages 287-307
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 4-week repeated percutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, followed by a recovery for 4 weeks was studied in Slc:SD rats at doses of 4, 20 and 100 μg/kg/day as low, mid and high dose levels. 1. One male and female at high dose died probably due to stress and circulatory failure. One female at mid dose died with clonic convulsion considered to be results in attached error of a neck collar. Survival of rats showed reddish tear, reddening and desquamation of the skin at application site, and vocalization at all groups including control. Furthermore, abnormal gait, dirty hair, emaciation and opacity of the eyeball surface in both sexes were observed at high dose. 2. A decreased body weight and a slight increased water consumption in both sexes; and a decreased food consumption in males were observed at high dose. 3. An increased incidence of corneal opacity was noted significantly in both sexes as compared with control at high dose. Urinalysis revealed an increased Ca excretion in both sexes at more than mid dose, and lower pH in females at mid dose and in both sexes at high dose, and a decreased urinary volume in males at high dose. The increases of neutrophil and serum β-globulin ratios in females, and serum Ca level in both sexes were observed at high dose. The increased mineralization of the cornea in males at mid dose and in both sexes at high dose, and of the kidney in males at high dose were observed. At the skin of application site, cellular infiltration in the epidermis and dermis in both sexes at more than mid dose was observed. Furthermore, hyperplasia of the squamous cell in females, and hyperkeratosis in the epidermis and hypertrophy of the sebaceous gland in both sexes were observed at high dose. 4. After a 4-week recovery period, the changes related with application disappeared except for opacity of the eyeball surface and cornea, and mineralization of organs. 5. On the basis of results obtained in the present study, it is considered that 4 μg/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of rats.
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  • Takashi IMAIZUMI, Masaaki TSURUTA, Yoshihide KOIKE, Masahiro ONO, Kiyo ...
    1996 Volume 21 Issue SupplementII Pages 309-323
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 4-week repeated percutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, followed by a 4-week recovery was studied in beagle dogs at doses of 0.04, 0.4 and 4 μg/kg/day. 1. In general conditions, reddening, desquamation, rash, and wet and hot skin were observed at the skin of application site at 4 μg/kg/day. 2. In urinalysis, a tendency to an increase in Ca level, was observed at 4 μg/kg/day. In hematology, an increase in the segmented neutrophils and tendency to a decrease in the lymphocyte counts were observed at 4 μg/kg/day. In biochemistry of serum, an increase in γ-globulin ratio, and decreases in A/G and albumin ratios were observed at 4 μg/kg/day. 3. In organ weights, tendency to decreases of the absolute and relative weights in the thymus was observed at 4 μg/kg/day. 4. Histopathological examination revealed squamous cell hyperplasia and hyperkeratosis at the skin of application site at 4 μg/kg/day. 5. The above changes disappeared after the 4-week recovery period and suggested that they were reversible. 6. On the basis of results obtained in the present study, it is considered that 0.4 μg/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of beagle dogs.
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  • Tadaharu KITAGAKI, Toshiro SUZUKI, Yoshihide KOIKE, Masahiro ONO, Kiyo ...
    1996 Volume 21 Issue SupplementII Pages 325-343
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 26-week repeated subcutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, followed by a recovery for 5 weeks was studied in Slc:SD rats at doses of 0.4, 2 and 10 μg/kg/day as low, mid and high dose levels. 1. No mortality during the experimental period was observed in both sexes of all groups including control. An increased incidence of opacity of the eyeball surface in males was noted at high dose. There were no difference in body weight and food consumption between control. An increased water consumption in both sexes was observed at high dose. 2. An increased incidence of the corneal opacity was noted significantly at high dose in both sexes compared with that observed in control. Urinalysis revealed the increased excretions of Ca at more than mid dose, and Na, Cl and IP in males at high dose, and an decreased urinary volume in females and lower pH in both sexes at high dose. An increaded serum Ca level in males at mid dose and in both sexes at high dose, and an elevated ALP activity in males at high dose were observed. The increased weights of the kidney in males at more than mid dose and adrenal gland in both sexes at high dose were observed. The increased incidence of mineralization of the cornea and kidney was noted significantly in males at more than mid dose as compared with control. Dilatation of endoplasmic reticulum of distal tubular cells of the kidney in both sexes was observed at high dose on electron microscopic examination. 3. After a 5-week recovery period, the changes related with the treatment of MC903 almost disappeared except for mineralizations of the cornea and kidney. 4. On the basis of results obtained in the present study, it is considered that 0.4 μg/kg/day is the no-toxic dose of MC903 administered subcutaneously in both sexes of rats.
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  • Tadaharu KITAGAKI, Toshiro SUZUKI, Yoshihide KOIKE, Masahiro ONO, Kiyo ...
    1996 Volume 21 Issue SupplementII Pages 345-363
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 26-week repeated percutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, was studied in Slc:SD rats at doses of 0.8, 4 and 20 μg/kg/day as low, mid and high dose levels. 1. No mortality were observed in both sexes of all groups including control. An increased water consumption was observed in females at mid dose and in both sexes at high dose. 2. An increased incidence of the corneal opacity in males at mid dose and in both sexes at high dose was noted significantly as compared with that observed in control. Urinalysis revealed a slight increased urinary volume, increased excretions of Ca and IP, and lower pH in both sexes at more than mid dose. Levels of the serum IP in females and Ca in both sexes were elevated at high dose. 3. The increased weights of the kidney in males and adrenal gland in females were observed at high dosd. The kidney in females at mid dose and in both sexes at high dose showed a higher incidence of minerarization than in control. Furthermore, osteosclerosis of the sternum and femur in both sexes, and hyperkeratosis of the skin at application site in females at high dose were observed. Electron microscopic examination revealed no abnormality in the liver and kidney. 4. On the basis of results obtained in the present study, it is considered that 0.8 μg/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of rats.
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  • Takashi IMAIZUMI, Masaaki TSURUTA, Yoshihide KOIKE, Masahiro ONO, Kiyo ...
    1996 Volume 21 Issue SupplementII Pages 365-387
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A 26-week repeated percutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, was studied in beagle dogs at doses of 0.04, 0.4 and 4 μg/kg/day. 1. In general conditions, reddening, rash, desquamation, pruritus, wet and hot skin at 4 μg/kg/day, reddening, rash and desquamation at 0.4 μg/kg/day, pruritus and desquamation at 0.04 μg/kg/day, were observed at the skin of application site. 2. In urinalysis, an increase or a tendency to an increase in Ca level, were observed at 4 μg/kg/day. 3. Histopathological examinations revealed squamous cell hyperplasia and para-keratosis at the skin of application site in both sexes at 4 μg/kg/day. However, these findings were not shown at the skin of application site at 0.4 and 0.04 μg/kg/day. 4. On the basis of results obtained in the present study, it is considered that 0.4μg/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of beagle dogs.
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  • Toshiro SUZUKI, Hisashi UCHIYAMA, Yoshihide KOIKE, Masahiro ONO, Kiyom ...
    1996 Volume 21 Issue SupplementII Pages 389-401
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Calcipotriol (MC903), an anti-psoriasic agent, was given subcutaneously at dose levels of 1, 5 and 25 μg/kg/day during the prepairing period (9 weeks prior to pairing in males and 2 weeks prior to pairing in females) and the pairing period to male and female rats and in the early stage of pregnancy (day 0 through 7 of gestation) to female rats, and the effects of the test compound on male and female reproductive performance and fetal development were evaluated. 1. In the male 25 μg/kg group, opacity of the eyeball surface was observed, and depression of body weight gain, and decreases of body weight and food consumption, and increases in the weight of the kidney were statistically significant in comparison with vehicle controls. 2. In the female 25 μg/kg group, depression of body weight gain and food consumption were statistically significant in comparison with vehicle controls. 3. No changes in parameters of reproductive performance were seen in any dosed groups. 4. No changes in parameters of implantation performance were seen. There were no treated-related abnormalities in fetal mortality, weights of fetuses, and external, visceral and skeletal examinations. Based on these results, it is considered that in the present study the no-toxic dose levels of MC903 were 5 μg/kg/day for parents, 25 μg/kg/day for reproductive performance and fetal development.
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  • Hisashi UCHIYAMA, Toshiro SUZUKI, Yoshihide KOIKE, Masahiro ONO, Kiyom ...
    1996 Volume 21 Issue SupplementII Pages 403-424
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Teratogenicity of Calcipotriol (MC903), an anti-psoriasic agent, was studied. MC903 at doses of 6.25, 12.5 and 25 μg/kg/day were subcutaneously administered to pregnant Slc:SD rats from day 7 to 17 of gestation. 1. In animals administered 25 μg/kg/day MC903, food consumption decreased significantly and body weight gains lowered marginally. MC903 administered at any doses did not adversely affect female animals in regard to pregnancy, delivery and maternal behavior. 2. In fetuses, suppression of growth were noted at 25 μg/kg group. However, fetotoxicity and teratogenicity were not noted at all groups administered MC903. 3. In F1 pups, the postnatal growth, development, responses, behaviors, learning ability and reproductive ability were not influenced. Additionally, no embryonic or fetal abnormalities of their fetuses (F2) were detected. 4. On the basis of results obtained in the present study, it is considered that the no-toxic doses level of MC903 are 12.5 μg/kg/day for pregnant animals and fetuses, 25μg/kg/day for pups.
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  • Hisashi UCHIYAMA, Toshiro SUZUKI, Yoshihide KOIKE, Masahiro ONO, Kiyom ...
    1996 Volume 21 Issue SupplementII Pages 425-438
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Teratogenicity of calcipotriol (MC903), an anti-psoriasic agent, was studied. MC903 at doses of 0.1, 0.5, 1, 2.5 and 5 μg/kg/day was subcutaneously administered to pregnant Std:NZW rabbits from day 6 to 18 of gestation. 1. A decrease in locomotor activity was observed in the group administered MC903 5 μg/kg/day. Food consumption and body weight gain decreased dose-dependently in groups administered MC903 1 μg/kg/day or more. Granular whitish kidneys were observed in groups administered MC903 2.5 and 5 μg/kg/day. Rough and whitish aorta were noted in groups administered MC903 1 μg/kg/day or more. 2. Significant fetotoxicity was not induced by administration of MC903 up to 0.5 μg/kg/day. 3. On the basis of results obtained in the present study, it is considered that no-toxic dose level of MC903 is 0.5 μg/kg/day for pregnant animals and fetuses.
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  • Hisashi UCHIYAMA, Toshiro SUZUKI, Yoshihide KOIKE, Masahiro ONO, Kiyom ...
    1996 Volume 21 Issue SupplementII Pages 439-455
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Perinatal and postnatal toxicity of calcipotriol (MC903), an anti-psoriasic agent, was studied. MC903 at doses of 6:25, 12.5 and 25 μg/kg/day were subcutaneously administered to pregnant Slc:SD rats from day 17 of gestation to day 21 after delivery. 1. Administration of MC903 at any doses did not adversely affect pregnant animals in regard to gestations delivery and maternal behavior. In dams administered MC903 25 μg/kg/day, food consumption and body weight gain were marginally lower than those of control animals during lactation period. 2. In group administered MC903 25 μg/kg/day, body weight gain in F1 offsprings was significantly lower as compared with those of control group. The drug did not have any adverse effects on the postnatal development of the offspring such as differentiation, functional development, emotionality, motor ability, learning ability or reproductive performance. 3. On the basis of results obtained in the present study, it is considered that the no-toxic dose level for general toxicity and reproduction in the dams was estimated to be 12.5 and 25 μg/kg/day, respectively, the no-toxic dose levels in the offspring was also estimated to be 12.5 μg/kg/day.
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  • Toshiro SUZUKI, Toshihiro KATO, Tadaharu KITAGAKI, Masahiro ONO, Kiyom ...
    1996 Volume 21 Issue SupplementII Pages 457-463
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Antigenicity of calcipotriol (MC903), an anti-psoriasic agent, was investigated in mice and guinea-pigs. 1. In mice, MC903 administered alone or with an adjuvant (Alum) did not result in the production of MC903-specific IgE antibody. 2. In guinea-pigs sensitized with MC903 alone or plus an adjuvant (FCA), systemic anaphylaxis was not induced by challenging with MC903. IgG1 antibody in MC903-sensitized guinea-pigs was not detected by the 4-hr PCA test. 3. Ovalbumin induced the production of ovalbumin-specific IgE antibody in mice, and ovalbumin-specific IgG1 antibody in guinea-pigs. Intense systemic anaphylaxis in the ovalbumin-sensitized guinea-pigs was induced by challenging with ovalbumin. 4. Results obtained in the present study suggest that MC903 does not induce the production of IgE antibody in mouse, and IgG1 antibody in guinea-pig, and in MC903-sensitized guinea-pig systemic anaphylaxis is not induced by challenging with MC903.
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  • Tadahatu KITAGAKI, Yoshihiro OGUMA, Fumio YOKOTA, Masahiro ONO, Kiyomi ...
    1996 Volume 21 Issue SupplementII Pages 465-474
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Calcipotriol (MC903), an anti-psoriasic agent, was examined for mutagenicity in the reverse mutation test and the chromosomal aberration test in vitro, and the micronucleus test in Slc:ddY mice. 1. In the reverse mutation test using Salmonella typhimurium (TA100, TA1535, TA98, TA1537) and Escherichia coli (WP2uvrA), MC903 did not significantly increase revertant colonies in any of the test strains with or without metabolic system. 2. In the chromosomal aberration test with a Chinese hamster fibroblast cell line (CHL); MC903 did not significantly increase aberrant cells in the direct method or in the activation method. 3. In the micronucleus test with male mice, MC903 did not significantly increase in the number of polychromatic erythrocytes with micronucrei in the bone marrow. These results suggest that MC903 has no mutagenic as well as clastogenic effects under the present experimental condition.
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  • Toshiro SUZUKI, Toshihiro KATO, Tadahatu KITAGAKI, Masahiro ONO, Kiyom ...
    1996 Volume 21 Issue SupplementII Pages 475-484
    Published: July 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    MC903 ointment was studied on primary skin irritation in rabbits and skin sensitization, skin photosensitization and phototoxicity in guinea-pigs. 1. MC903 ointment, ointment base and deteriorated MC903 ointment induced erythematous changes in rabbit skin. These erythematous changes were not so serious, and they were classified as a mild irritant. 2. MC903 ointment was almost negative in skin sensitization study. 3. MC903 ointment has no skin phototoxicity in guinea-pigs. 4. MC903 ointment has no skin photosensitizing activity in guinea-pigs.
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