Flometoquin (Pesticides)

Food Safety Commission of Japan (FSCJ) conducted a risk assessment of flometoquin (CAS No. 875775-74-9), a quinoline insecticide, based on results from various studies. Major adverse effects of flometoquin observed were suppressed body weight and hepatocellular steatosis in rats, and ovarian atrophy with decreased numbers of small follicle in rats and mice. Neither teratogenicity nor genotoxicity relevant to human health was detected. Increased incidences of gonadal stromal tumor in female rats and of small intestine adenocarcinomas in male mice were identified in carcinogenicity studies. Genotoxic mechanisms were, however, unlikely involved in their tumor developments, and these enabled FSCJ to establish a threshold in the assessment. Mechanism and toxicity studies suggested that ovarian atrophy triggered the development of gonadal stromal tumor, through continuous stimulation of gonadotropin to the gonadal stroma, via negative feedback. A reproductive study showed the decreases in numbers of small follicle, implantation and also in litter size. Based on the results from various studies, flometoquin (parent compound only) was the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) obtained from all the studies was 0.8 mg/kg bw/day in a developmental toxicity study in rabbits. FSCJ specified an acceptable daily intake (ADI) of 0.008 mg/kg bw/day by applying a safety factor of 100 to the NOAEL. FSCJ recognized that in considering the ambiguity of the underlying mechanism, the adverse effect on small follicle possibly occurred after single oral administration of flometoquin. Thus FSCJ specified an acute reference dose (ARfD) to be 0.044 mg/kg bw by applying a safety factor of 100 to the NOAEL of 4.45 mg/kg bw per day in a two-generation reproductive toxicity study in rats, based on a comprehensive evaluation of NOAEL for ovarian toxicity.