Skeletal muscle lesions in rats following 4-week repeated orally administration of zinc pyrithione

<p>【Background and Objective】 </p><p>Zinc pyrithione (ZnPT) is an organozinc complex in which pyrithione coordinates to zinc. ZnPT has been used in commercial shampoos because it has antibacterial and antiseptic effects and is effective against dandruff and seborrhea. However, some companies have excluded it from shampoo ingredients, since ZnPT was suspected of having endocrine disrupting effects. On the other hand, the toxicity information is old and the latest knowledge is not found. Therefore, we conducted a 4-week repeated oral toxicity study of ZnPT in rats to assess the toxicity of ZnPT. In addition, the toxicity of sodium pyrithione (NaPT) group was evaluated as a ligand control group to examine the effects of ligand pyrithione.</p><p></p><p>【Materials and Methods】 </p><p>Five male Crl:CD (SD) rats aged 6 to 7 weeks in each group were repeatedly orally administered ZnPT (2 or 5 mg/kg) or NaPT (4.7 mg/kg) once daily for 4 weeks. The control group received olive oil as vehicle of ZnPT. During the administration period, clinical sign observation was performed, and body weight, food consumption, urinalysis, and plasma zinc concentration (Day 1 and Day 28: 1, 4 and 24 hours after administration) were measured. About 24 hours after the final administration, necropsy was conducted. Furthermore, hematological examination, blood biochemical examination, organ weight measurement, macroscopic examination, histopathological examination, and electron microscopic examination were performed.</p><p></p><p>【Results and Discussion】 </p><p>One of the animals in the ZnPT 5 mg/kg group showed hind limb ataxia and gait disturbance from Day 24. In the ZnPT 5 mg/kg group and the NaPT group, weight gain was suppressed without a decrease in food intake, and a decrease creatinine in plasma and urine was observed in blood biochemistry and urinalysis. In the measurement of plasma zinc concentration, the animals of ZnPT 5 mg/kg group showed about a 1.5-fold increase in zinc concentration in AUC1-24h in compared to the control group. At necropsy, wasting of hindlimb skeletal muscle was observed in the ZnPT 5 mg/kg group. In the histopathological examination, atrophy with slightly degeneration and necrosis of the skeletal muscle fibers was observed in the femoral skeletal muscle in the ZnPT 5 mg/kg group as well as NaPT group. In addition, loss of nerve fiber and demyelination of the peripheral nerve were observed in the femoral skeletal muscle in the ZnPT 5 mg/kg group. These results suggest that ZnPT causes peripheral nerve and skeletal muscle changes in the hindlimb, and that these toxicological changes are derived from ligands. No zinc-related toxicity was observed although plasma zinc concentration was increased.</p>