SUBCHRONIC TOXICITY OF TRIETHYLENETETRAMINE DIHYDROCHLORIDE IN B6C3F1MICE AND F344 RATS

Triethylenetetramine dihydrochloride (trien-2HCl; CAS No. 38260-01-04) , a chelating agent used to treat Wilson's disease patients who are in tolerant of the drug of choice, was tested for subchronic toxicity in B6C3F1 mice and F344 rats. Mice and rats received trien-2HCl in the dr inking water at concentrations of 0, 120, 600, or 3000 ppm for up to 9 2 days. Twenty mice and 18 rats of each sex were assigned to each dose group fed either a cereal-based (NIH-31) or a purified (AIN-76A) diet , both containing nutritionally adequate levels of copper. An addition al control group of rats and mice received a Cu-deficient AIN-76A diet . This low copper diet resulted in Cu-deficiency symptoms, such as ane mia, liver periportal cytomegaly, pancreatic atrophy and multifocal ne crosis, spleen hematopoietic cell proliferation, and increased heart w eight, together with undetectable levels of plasma copper in rats but not in mice. Trien-2HCl lowered plasma copper levels somewhat (at 600 and 3000 ppm) in rats fed the AIN-76A diet, but did not induce the usu al signs of copper deficiency. Trien-2HCl caused an increased frequenc y of uterine dilatation at 3000 ppm in rats fed AIN-76A diet that was not noted in females fed the Cu-deficient diet. Trien-2HCl toxicity oc curred only in mice in the highest dose group fed an AIN-76A diet. Inc reased frequencies of inflammation of the lung interstitium and liver periportal fatty infiltration were seen in both sexes, and hematopoiet ic cell proliferation was seen in the spleen of males. Kidney and body weights were reduced in males as was the incidence of renal cytoplasm ic vacuolization. There were no signs of copper deficiency in mice exp osed to trien-2HCl. The only effect of trien-2HCl in animals fed the N IH-31 diet was a reduced liver copper level in both rat sexes, noted a t 3000 ppm. (C) 1996 Society of Toxicology