Comparative Subacute Toxicity of Retinyl Acetate and Three Synthetic Retinamides in Swiss Mice2

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Abstract
Young adult male and female Swiss mice were treated once daily for 21 days with graded dosages of retinyl acetate (RAC) or one of three synthetic retinoids: N-ethylretinamide (EA), N-(2-hydroxyethyl)retinamIde (HEA), and N-(4-hydroxyphenyl)retinamlde (HPA), all derived from all-trans-retinoic acid. When the mice were killed, blood was obtained for hematology and clinical chemistry studies, and tissues were collected and fixed for histopathologic evaluation. Decreases in erythrocyte counts, hemoglobin concentration, and hematocrit and increases in reticulocyte counts were frequent in mice treated ip but not orally. Increases in granulocyte counts were seen in some retinold-treated groups. Changes in clinical chemistry tests included decreases in plasma glucose, total protein, albumin, and globulin concentration and increases in plasma glutamic-pyruvic transaminase and glutamic-oxaloacetic transaminase activity and in bllirubin and lnorganic phosphorus concentrations. Diagnostic X-rays indicated a dose-related incidence of fractures in mice that received RAC ip or orally but not in other treated groups. Degeneration and necrosis of hepatocytes were observed in mice receiving ip EA or ip or oral HEA except at the lowest dosages but not in mice receiving RAC or HPA. On the basis of the dosages used and the clinical and histopathologic evaluation, RAC was the most toxic after ip administration (RAC>HEA>EA>HPA) and after oral administration (RAC≈HEA>EA>HPA). Depending on the structure of the substituent, toxicity of synthetic-substituted retinamides may be less than that of a retinyl ester.

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