A 13-week subchronic toxicity study of ferric citrate in F344 rats

•Ferric citrate was investigated for its subchronic toxicity.•In the 13-week study, eosinophilic colitis was noted in 4.0% ferric citrate-treated F344 rats.•Eosinophilic infiltration in mesenteric lymph nodes and increased hemosiderosis in spleen were observed in 4.0% groups.•Reduction of body weight gain and increased serum inorganic phosphorus levels were also detected in 4.0% groups.•The no-observed-adverse-effect level (NOAEL) of ferric citrate was 1.0% (596 for males and 601 mg/kg bw/day for females).

Ferric citrate has been used as a food additive for supplementation of iron. We performed a 13-week subchronic toxicity study of ferric citrate in F344 rats with oral administration in the diet at concentrations of 0%, 0.25%, 1.0%, and 4.0%. Reduction of body weight gain was noted in 4.0% males and females. On hematology assessment, decreases of red blood cells and lymphocytes and increases of platelets and eosinophils were noted in 4.0% males and females. Serum biochemistry demonstrated increased iron and decreased total protein and transferrin in both sexes treated with 4.0% ferric citrate. In addition, an increase of serum inorganic phosphorus levels was noted in 4.0% females. Regarding organ weights, an increase of relative spleen weights was detected in 4.0% males and females and a decrease of absolute and relative heart weights in 4.0% females. On histopathological assessment, colitis with infiltration of eosinophils and hyperplasia of mucosal epithelium, eosinophilic infiltration in mesenteric lymph nodes, and increased hemosiderosis in spleen were observed as treatment-related toxicological changes in 4.0% males and females. Based on the results, the no-observed-adverse-effect level (NOAEL) of ferric citrate was estimated to be 1.0% (596 mg/kg bw/day for males and 601 mg/kg bw/day for females).