Safety assessment and single-dose toxicokinetics of the flavouring agent myricitrin in Sprague–Dawley rats

Abstract

Myricitrin, a flavonol rhamnoside of myricetin extracted from the Chinese bayberry (Myrica rubra Siebold) plant, has been used in Japan since 1992 as a flavour modifier in snack foods, dairy products, and beverages. It is affirmed as generally recognised as safe (GRAS) by the US Flavour and Extract Manufacturer Association (FEMA) and is considered safe by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at current estimated dietary exposures. In anticipation of expanded marketing, 97% pure myricitrin was fed to male and female Sprague–Dawley rats at dietary concentrations of 0.5%, 1.5% and 5.0% in a 90-day toxicity study. There was increased food consumption and decreased body weight gain in males exposed to 5% myricitrin. Blood values were within laboratory reference ranges except for mean increases in basophils in low- and high-dose males and serum phosphorus in high-dose males. In the absence of abnormal clinical or histopathological changes, these changes are not considered adverse. Based on the 90-day rat toxicity study, the no observed adverse effect level (NOAEL) is 2926 mg kg^–1 day^–1 in males and 3197 mg kg^–1 day^–1 in females. Gavage administration of myricitrin resulted in blood levels of myricitrin within 1 h after single oral doses of 250, 500 or 1000 mg kg^–1 body weight, indicating direct absorption of the glycosylated form of this flavonoid. Blood levels of myricetin, a metabolite of myricitrin, were not present in rats dosed orally with 1.6 mg kg^–1 myricetin, but were present only at 12 or 24 h in one of five, in three of five, and in four of five rats dosed with 250, 500 and 1000 mg myricitrin kg^–1 body weight, respectively, possibly a result of hepatic conversion of myricitrin to myricetin and enterohepatic recirculation of the resulting myricetin. The current studies further support prior safety assessments of myricitrin as a food flavouring.

Keywords:

• flavour modifier
• flavonol
• myricetin
• GRAS

Acknowledgements

The authors thank the investigative toxicology staff and the necropsy and histology teams of Integrated Laboratory Systems, Inc., for technical support, and Nuventra Pharma Sciences for toxicokinetic support.

Additional information

Funding

ILS, Inc., was responsible for the study design, collection, analysis and interpretation of data and for the preparation of the final study report. The manuscript was prepared by R. Maronpot. The decision to submit the paper for publication was made by San-Ei Gen, F.F.I., Inc.