Reaction product of mixed inorganic base and acid resulting in potassium trihydroxy fluoroborate, dipotassium tetrahydroxy tetraboronpentaoxide dehydrate, potassium tetrafluroborate in powder form

Specific investigations: other studies

Description of key information

The data indicates that any endocrine effects are secondary to germ cell changes and that boric acid does not bind directly to the estrogen receptor. The structure of boric acid is fundamentally different from the multi-ringed chemical structures that are more often found to be estrogenic.

Additional information

Boric acid does not exhibit the properties or characteristics of hormones, including estrogens and androgens. Several studies have evaluated possible endocrine effects of boron compounds (Wang et al., 2008; Sauls et al., 1992; Anderson et al., 1992; Fail et al., 1992, Fail et al., 1991; Treinen & Chapin, 1991; Linder et al., 1990; Grizzle et al., 1989; Lee et al., 1978). The data indicates that any endocrine effects are secondary to germ cell changes since histologic changes occurred by Day 7 while peripheral hormone changes were not detected before Day 14 of treatment (Fail et al. 1998). Boric acid-induced testicular toxicity in rodents appears to be due to a direct effect on Sertoli cells (not an effect on the endocrine system). Boric acid was not carcinogenic in either mice (NTP, 1987) or rats (Weir and Fisher, 1972); endocrine-disrupting substances typically produce hormonally-related tumors in chronic toxicity studies in animals. Boric acid was negative in a yeast two-hybrid estrogenicity assay, indicating that boric acid does not bind directly to the estrogen receptor and mimic endogenous estrogen (Nishihara et al 2000). The structure of boric acid is fundamentally different from the multi-ringed chemical structures that are more often found to be estrogenic. Boric acid may be too small molecularly to interact with the estrogen receptor or other steroid hormone receptors. Conflicting evidence of estrogenic activity was observed in a battery of short-term in vitro and in vivo studies (Wang et al., 2008). For example, an increase in “organ coefficient of uterus” (wet uterine weight/body weight) was observed at the high dose in ovariectomized rats administered boric acid (Wang et al., 2008); however, uterine and body weights were not reported, and a dose-response relationship was not demonstrated. In comparison, boric acid did not stimulate the proliferation of MCF-7 human breast cancer cells (Wang et al., 2008).

No evidence of hormonally-related clinical symptoms have been reported in workers exposed to boric acid (Whorton et al., 1994; Sayli et al., 1998; Scialli et al., 2010; Robbins et al., 2010). An increase in the serum concentrations of both 17b-estradiol and testosterone were reported in postmenopausal women given a daily boron supplement (3 mg B/day) following 119 days on a boron-deficient diet; the elevation appeared more marked when dietary magnesium was low (Nielsen et al., 1987; Nielsen, 1994). In contrast,decreasesin serum 17b-estradiol and progesterone were reported in another study of postmenopausal women given 3.25 mg/B in the diet when dietary magnesium was low compared to postmenopausal women receiving a boron-deficient diet (Nielsen, 2004). In a NASA study of young male bodybuilders, boron supplementation had no effect on blood testosterone levels or lean body mass (Green and Ferrando, 1994). 

Epidemiological, animal, and cell culture studies have identified boric acid as a chemopreventative agent in prostate cancer (Cui et al., 2004; Barranco and Eckhert, 2004; Barranco and Eckhert, 2006; Barranco et al., 2007; Barranco et al., 2009; Henderson et al., 2009).   Although estrogens are frequently used to treat prostate cancer, the chemopreventative effects of boric acid on prostate cancer appear to have a non-endocrine mode of action. It was recently demonstrated in human prostate cancer cells that boron causes a dose dependent decrease of Ca(2+) release from ryanodine receptor sensitive stores, suggesting that higher boric acid blood levels lower the risk of prostate cancer by reducing intracellular Ca(2+) signals and storage (Henderson et al., 2009). Similarly, Barranco et al. (2009) hypothesized that the toxicity of boric acid in human prostate cancer cells stems from the ability of high concentrations to impair Ca2+ signaling.

Read Across

A number of these studies were conducted on an analogue substance. Read-across is justified on the following basis:

In aqueous solutions at physiological and acidic pH, low concentrations of simple inorganic borates such as boric acid B(OH)3, potassium pentaborate (K2B10O16.8H2O), potassium tetraborate (K2B4O7.4H2O), disodium tetraborate decahydrate (Na2B4O7.10H2O; borax), disodium tetraborate pentahydrate (Na2B4O7.5H2O; borax pentahydrate), boric oxide (B2O3) and disodium octaborate tetrahydrate (Na2B8O13.4H2O) will predominantly exist as undissociated boric acid. Above pH 9 the metaborate anion (B(OH)4-) becomes the main species in solution (WHO, 1998). This leads to the conclusion that the main species in the plasma of mammals and in the environment is undissociated boric acid. Since other borates dissociate to form boric acid in aqueous solutions, they too can be considered to exist as undissociated boric acid under the same conditions.

For comparative purposes, exposures to borates are often expressed in terms of boron (B) equivalents based on the fraction of boron in the source substance on a molecular weight basis. Some studies express dose in terms of B, whereas other studies express the dose in units of boric acid. Since the systemic effects and some of the local effects can be traced back to boric acid, results from one substance can be transferred to also evaluate the another substance on the basis of boron equivalents. Therefore data obtained from studies with these borates can be read across in the human health assessment for each individual substance. Conversion factors are given in the table under CSR section 5.1.3, which corresponds to IUCLID section 7.1 (toxicokinetics, metabolism and distribution endpoint summary).

References:

WHO. Guidelines for drinking-water quality, Addendum to Volume 1, 1998