## 1 Introduction  
4-Hexylresorcinol (4 HR) has been widely used as an antiseptic [1] and food additive [2]. In the case of antiseptics, usage of 4 HR has been decreased because of substitute development. However,4 HR is still used as an antibrowning agent because it is a strong inhibitor of tyrosinase [3]. Recently, other effects of 4 HR have come into the limelight. 4 HR has anticancer properties via inducing cancer cell apoptosis [4; 5] and has been studied as an additive for graft materials because of its inhibitory effect on the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway [6] and foreign body giant cell formation [7]. When 4 HR is added to bone graft material, mineralization is increased [6; 7]. 4 HR helps macrophages to transform M2-type and angiogenesis [8]. Accordingly, 4 HR incorporation is a new strategy for immunomodulation. However, increased bone mass and angiogenesis by 4 HR may be similar to the actions of estrogen. Estrogen-like materials have been studied as endocrine disruptor and breast cancer inducer [9; 10]. Differentiation of 4 HR from other xenoestrogens is important for usage of 4 HR as immunomododulation agent. Xenoestrogen is the chemical that mimics the action of estrogen and results in endocrine system disruption [9; 10]. Xenoestrogen may pollute and destroy the natural endocrine system. Many types of mutation may be associated with abuse of, or contamination with, xenoestrogen [10]. Xenoestrogen is a member of a group of organic phenolic compounds with a benzene ring [11]. Bisphenol A (BPA) is a representative chemical [9; 10]. Global fear for xenoestrogen has sharply increased recently [12]. Even resveratrol in wine, which is a kind of phenolic compound, is also suspected to be a xenoestrogen [13]. However, there has been no clear evidence between wine drinking and endocrine system destruction. 4 HR is also a type of phenolic compound. The binding affinity of 4 HR to estrogen receptors (ER) has been reported as weak, but the application of 1-10 uM of 4 HR showed increased activity of estrogen responsive promoters in MCF-7 cells [14]. There has been no report of endocrine system disruption by 4 HR in human trials until now, despite its wide usage as a food additive. However, 1000 mg/kg body weight/day of 4 HR oral administration induced all rats' death during the first week of the administration, and the autopsy demonstrated a decreased spermatogenesis in 4 out of 10 animals [15]. The influence of the male genital system is a feature of xenoestrogen [16]. Thus, 4 HR cannot be excluded from the list of potential xenoestrogens. According to National Health Institute (NIH), United States of America database [15], there has been no available information about the half-life and serum concentration of 4 HR in humans because 4 HR has been approved in its primary indication as topical agent and its systemic exposure is rare due to poor absorption. Oral gargling is supposed to be used daily, and chronic exposure to 4 HR may have unknown risks. Accordingly, 4 HR has been listed as a banned component in oral gargling since 2014 by the US Food and Drug Administration (FDA) [17]. However, there has been no convincing evidence for 4 HR as a xenoestrogen. 4 HR can induce cellular apoptosis in a dose-dependent and cellular type-dependent manner [4; 18]. Thus, the inhibition of the spermatogenesis may be a complication of lethal dosage. Many types of anticancer drugs may influence rapidly regenerated normal cells, including sperm [19]. 4 HR also has anticancer effects [4; 5]. The increased expression of estrogen-responsive promoter in MCF-7 cells may be a nonspecific response of 4 HR or cross-activity mediated by an alternative signal pathway, excluding ER. Actually, there was no check of ER\(\alpha\) protein level or downstream signal changes in the previous report [14]. In this study, the effect of 4 HR on breast cancer cells and ovariectomized animals was evaluated with regard to its potential estrogen-like effects.