title: A 13-week subchronic toxicity study of ferric citrate in F344 rats.
abstract: 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).
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan. Electronic address: t-toyoda@nihs.go.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Toyoda
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Young-Man
authors.initials: YM
authors.lastname: Cho
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Mizuta
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan; Division of Pharmacology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Akagi
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced; D004435:Eating / Q000187:drug effects; D004802:Eosinophilia / Q000139:chemically induced; D005260:Female; D005290:Ferric Compounds / Q000008:administration & dosage / Q000633:toxicity*; D005503:Food Additives / Q000008:administration & dosage / Q000633:toxicity*; D008198:Lymph Nodes / Q000187:drug effects; D008297:Male; D010758:Phosphorus / Q000097:blood; D051381:Rats; D011916:Rats, Inbred F344; D013154:Spleen / Q000187:drug effects; D059550:Toxicity Tests, Subchronic
chemical_list: D005290:Ferric Compounds; D005503:Food Additives; D010758:Phosphorus; C025314:ferric citrate
keywords: Eosinophilic enteritis; F344 rats; Ferric citrate; Food additive; Subchronic toxicity