Toxicological Evaluation of Iron Chelators: The Intravenous and Oral Acute and Subacute Toxicity in Rodents and Subchronic Toxicity in Dogs of Ethylenediamine-N,N'-Bis(2-Hydroxyphenylacetic Acid)

摘要

The i.v. and oral toxicology of ethylenediamine-N,N'-bis(2-hydroxphenylacetic acid) (EDBHPA) in rodents and dogs was studied. The acute i.v. LD 50 was 57 mg/kg for mice and 48 mg/kg for rats. CNS-inhibition led to apnea and cardiac arrest. Both species survived oral doses up to 6000 mg/kg. Five i.v. injections 5, 10 or 20 mg/kg failed to produce any deaths or abnormal behavior in rats. Growth rate and food intake declined. Other physiologic parameters pathological findings were incidental or related to trapped particles in the alveoli. Oral doses of 150, 300 or 600 mg/kg in rats reduced growth rates but other physiological parameters were normal. Changes in organ weights were not related to dose and varied between sexes. No drug-related morphological aberrations were found. In mice, 5 oral treatments evoked CNS-inhibition and delayed deaths and growth rates decreased. Organ weights were altered due to body weight losses. Dogs given 14 i.v. dosages of 6, 12 or 18 mg/kg or oral dosages of 30, 100 or 240 mg/kg had emesis but otherwise were normal. Organ weight changes were not dose related but were sex related. Pathological findings were predominantly attributable to drug particles lodged in lung capillaries resulting in focal foreign body granulomas. One orally mid-dosed female had a delayed death associated with nephrotoxicity. Aberrant blood values had no consistent pattern to dose or sex. Pathological findings were minimal. Organ weight changes occurred for kidneys, liver, spleen, pancreas and thymus at the higher doses in both sexes. The delayed lethality and nephrotoxicity found in 1 dog mandates caution in the use of this drug. A greater sensitivity of mice (delayed deaths) to the drug revealed a difference in species reaction to EDBHPA.