A 28-day subacute toxicity study of puberulic acid in Crl:CD(SD) rats

Abstract

In March 2024, a health hazard associated with the consumption of food products containing red yeast rice (beni-koji), which could lead to renal dysfunction, was reported in Japan. Puberulic acid (PA) was identified as an unintentional contaminant in these products; however, information on PA toxicity remains limited. The toxicological profile of PA was evaluated in a 28-day subacute toxicity study in rats. Synthesized PA was administrated by gavage to 6-week-old Crl:CD(SD) rats at 0, 1, 3, or 10 mg/kg/day (male) or 0, 0.3, 1, or 3 mg/kg/day (female) over 28 days, and satellite groups were used to evaluate the reversibility over a 14-day period. Male rats in the 10 mg/kg group exhibited increased urinary glucose and serum creatinine levels compared to controls. Histopathological examination revealed vacuolation, necrosis, and regeneration of proximal tubules in kidneys of all rats in the male 10 mg/kg and female 3 mg/kg groups. After the 14-day recovery period, focal interstitial fibrosis was observed in one male rats from the high-dose group, whereas no renal lesions were detected in the remaining rats of either sex. These results suggest that PA-induced nephrotoxicity is largely reversible under the conditions studied, although residual chronic lesions may occur in severe cases. Apoptosis/necrosis and diffuse hyperplasia of the glandular stomach mucosa were observed in male 3 and 10 mg/kg and female 3 mg/kg groups but were absent after the recovery period. These results indicate that, under the study conditions, the no-observed-adverse-effect level for PA was 1 mg/kg/day for both sexes.