[A 4-week repeated percutaneous dose toxicity study of calcipotriol (MC903) followed by a 4-week recovery test in rats].
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 micrograms/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 beta-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 micrograms/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of rats.
Kitagaki
T
T
Japan Seigiken Research Center Co., Ltd., Shizuoka, Japan.
Suzuki
T
T
Koike
Y
Y
Ono
M
M
Shirakawa
K
K
Nagata
M
M
Konishi
R
R
D000279:Administration, Cutaneous; D000818:Animals; D001609:Beta-Globulins / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D002118:Calcium / Q000097:blood / Q000652:urine; D003318:Corneal Opacity / Q000139:chemically induced; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D005260:Female; D006965:Hyperplasia; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009504:Neutrophils; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects / Q000473:pathology
D001609:Beta-Globulins; D003879:Dermatologic Agents; C055085:calcipotriene; D002117:Calcitriol; D002118:Calcium