Species: Rat Strain/breeder: Wistar Wu (CR) Sex: Male, Female Age: 20 weeks Study type: Reprotox Segment I (fertility and early embryonal development) Treatment: Oral, high dose Animal status: Scheduled death, end of study Clinical findings: Lameness, Organ: Tibia Macroscopic finding(s): Swollen feet Staining: H&E (slide a, b) Literature: Längle UW, Brüggemann S, Prentice DE, Ettlin RA, Richardson B, Naef R, Cordier A (1994) Hypertrophic osteopathy in rats following chronic administration of SDZ MNS 949, an Isoquinolin. Exp Toxic Pathol 45: 473-479

Fig. 1 (91k) Fig. 2 (77k)

Abstract

Aim of the study
A phosphodiesterase inhibitor type IV was tested for its influence on male and female fertility in the rat (reproduction toxicity).

Materials & methods
Oral administration of the test compound at 3 dose levels to Wistar rats, to males for 70 - 109 days and to females for 30 - 47 days. Histology of the tibias and tails, which showed swelling in the high dose group.

Results
Swollen legs were seen in 12 of 28 males (43%) and 11 of 28 females (39%) in the high dose group. This was the reason why the dose was reduced first in males on test day 50. In the males, the distal part of the tibias showed hyperostosis and/or a bony shell formation as a peripheral circle with fat marrow in between in 7 of 9 animals examined histologically. In the females, 4 of 10 animals examined showed the same changes, but in a further 4 animals, a high grade of chondrogenesis with an inflammatory component was seen. In 3 animals the vertebrae of the tail root showed also a hyperostosis. It is assumed that the process begins with an inflammation provoking the chondrogenesis, which in turn leads to the hyperostosis with shell formation as a resting state.

Conclusions
The longer administration of the test substance in males resulted in a chronic state of the osteopathy, the shorter treatment in females, however, demonstrated also the acute changes.