Thirteen Week Oral Toxicity Study of WR238605 with a Thirteen Week Recovery Period in Dogs. Volume 1
Abstract
This study evaluated the toxicity of WR238605 in dogs following thirteen weeks of daily oral (gavage) administration. A thirteen week recovery period was included for all groups. Dose levels studied were 0 (vehicle control), 0.1, 2.0 and 6.0 mg base/kg/day. The primary toxic effects of WR238605 were seen in the lungs and RBCs. Drug treatment was associated with hemolytic anemia which was supported by reticulocytosis, bone marrow hypercellularity, decrease in bone marrow M/E ratio, splenomegaly, extramedullary hematopoiesis, and hemosiderosis in the liver and spleen. Mild hepatotoxicity as evidenced by hepatocyte necrosis (high dose males) was supported by altered clinical chemistry values. Possibly, secondary to the hematologic alterations, congestion of retinal vessels was seen in one high dose female, which was no longer evident by the end of the recovery period. Generalized or secondary toxic effects related to the stress produced by the anemic and/or methemoglobinemic state included decreases in weight gain; neutrophilic and monocytic leukocytosis; and depletion of thymic lymphocytes. Methemoglobinemia was manifested by clinical signs of cyanosis (blue gums, tongue, and sclera). Lung lesions induced by WR238605 included alveolar proteinosis and subacute inflammation. Also, chronic inflammation of the alveolar and bronchiolar epithelium developed in the recovery period. This was deemed to be part of the process of resolution of alveolar proteinosis and as such a secondary lesion to a direct treatment-related effect All of the above described toxic effects were generally seen at the high and mid dose levels. Hemosiderosis and subacute inflammation of the liver (minimal severity), secondary to hemolytic anemia, and bone marrow hypercellularity (minimal severity) were also seen in low dose animals.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 11, 1993
- Accession Number
- ADA640035
Entities
People
- Barry S. Levine
- Michael J. Tomlinson
Organizations
- University of Illinois at Chicago