The estrogenic potential of salicylate esters and their possible risks in foods and cosmetics

Salicylate esters (SEs), a class of chemicals extensively used as flavor and fragrance additives in foods, beverages and a wide variety of consumer products, are suspected to have estrogenic activity based on chemical analysis of in silica molecular docking. We evaluated the estrogenic potentials of phenyl salicylate (PhS), benzyl salicylate (BzS), phenethyl salicylate (PES), ethyl salicylate (ES) and methyl salicylate (MS) using an in vitro human estrogen receptor α (hERα)-coactivator recruiting assay and in vivo immature rodent uterotrophic bioassays. We found that PhS, BzS and PES showed obvious in vitro hERα agonistic activities; BzS in particular exhibited a higher estrogenic activity compared to bisphenol A (BPA). The uterine weights were significantly increased in mice treated with 11.1, 33.3, 100 and 300 mg/kg/day BzS and 33.3 mg/kg/day PES and rats treated with 3.7, 11.1, 33.3 and 100 mg/kg/day BzS for 3 days (P < 0.05). Finally, we transformed the daily intakes and the dermal exposures of SEs in the real world into estradiol equivalent concentrations (EEQs). We found that the EEQ of BzS daily intake in consumers in the U.S. and the EEQs of dermal BzS and PES exposure among high-volume users worldwide were higher than the maximum secure daily estradiol intake recommended by the U.S. Food and Drug Administration (FDA). In particular, the EEQ for dermal BzS exposure was up to 162 ng EEQ/kg, which is 3.3 times higher than the maximal acceptable daily E2 intake recommended by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).

► This study well forecasted estrogenic potentials of salicylate esters by in silico.
► PhS, BzS and PES showed obvious in vitro and in vivo estrogenic activities.
► As flavor, BzS may be risk for consumers in the USA with respect to estrogenicity.
► The dermal exposure of BzS and PES may be risk for high-volume users worldwide.