Ethoxyquin

Summary

Abstract

The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of ethoxyquin (CAS No. 91-53-2), an antioxidant and a plant growth regulator. The data from all the in vitro reverse mutation tests were negative, while positive results were obtained in chromosomal aberration tests using Chinese hamster ovary cells and human peripheral blood lymphocytes and also in the mouse lymphoma TK test. As for in vivo studies, ethoxyquin gave a weak positive response in the liver micronucleus test in juvenile rats, but negative responses in the mouse bone marrow micronucleus test and the unscheduled DNA synthesis test using rat liver. Although ethoxyquin and/or its metabolite(s) induce chromosomal aberration, the influence on the chromosomal aberration is likely to be associated with ethoxyquin’s action on the functional protein component rather than the direct DNA damage in the body. Results from the 30-month combined chronic toxicity/carcinogenicity study suggest that ethoxyquin has a carcinogenic potential in the urinary bladder in female rats. Therefore, it is unlikely that ethoxyquin in normal uses exerts the carcinogenicity through a genotoxic mechanism. Based on various data, FSCJ designated ethoxyquin and its dimer to the residue definition in agricultural products. Residual ethoxyquin dimer has been found as an ethoxyquin metabolite at a substantial level in cultured fishes such as salmons. Toxicity of the dimer has been studied only in one 90-day subacute toxicity test where the toxicity was not observed at the dose of 12.5 mg/kg body weight/day. Ethoxiquin used for the most of toxicity studies seems to contain ethoxiquin dimer as an impurity. Taking the results from such toxicity studies into consideration, it is unlikely that toxicity of the dimer is stronger than that of the parent compound. Among the no-observed-adverse-effect levels (NOAELs) obtained in various studies, the lowest NOAEL was 2 mg/kg body weight/day obtained in the 90-day subacute toxicity study in dogs. FSCJ, however, judged that it was more appropriate to adopt the lowest-observed-adverse-effect level (LOAEL) of 2.5 mg/kg body weight/day obtained in the two-generation reproduction toxicity study in dogs which was performed more recently and administered for a longer period of time, as a basis for acceptable daily intake (ADI). Accordingly, FSCJ specified the ADI for ethoxyquin as 0.0083 mg/kg body weight/day, based on this LOAEL and applying a safety factor of 300.