[Single dose toxicity studies of calcipotriol (MC903) in rats and dogs].
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 macroscopic 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.
Imaizumi
T
T
Japan Seigiken Research Center Co., Ltd., Shizuoka, Japan.
Tsuruta
M
M
Kitagaki
T
T
Ono
M
M
Shirakawa
K
K
Nagata
M
M
Konishi
R
R
D000279:Administration, Cutaneous; D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007928:Lethal Dose 50; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D003879:Dermatologic Agents; C055085:calcipotriene; D002117:Calcitriol; D002118:Calcium