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Endpoint:
specific investigations: other studies
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01/10/2009 to 07/12/2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study.
Qualifier:
according to
Guideline:
other: The protocol was designed based on the ASTM E981-04 (2004) method, Standard Test Method for Estimating Sensory Irritancy of Airborne Chemicals (American Society for Testing and Materials, published May, 2004).
Deviations:
not specified
Principles of method if other than guideline:
The objective of this study was to evaluate the potential for boric acid and sodium tetraborate pentahydrate to produce depression of respiratory rate resulting from airway sensory irritation when administered to male Swiss-Webster mice by whole-head (head-only) inhalation exposure. Respiratory depression may result from upper airway sensory irritation and/or pulmonary irritation.
The protocol was designed based on the ASTM E981-04 (2004) method, Standard Test Method for Estimating Sensory Irritancy of Airborne Chemicals (American Society for Testing and Materials, published May, 2004).
The respiratory depression of boric acid and sodium tetraborate pentahydrate, was evaluated in 30-minute, single-exposure study in Swiss-Webster Crl:CFW® (SW)BR mice. Boric acid was administered to several exposure levels of 4 male mice via head-only inhalation exposure as a dust aerosol at geometrically spaced concentrations.
GLP compliance:
yes
Type of method:
in vivo
Endpoint addressed:
respiratory irritation
Species:
mouse
Strain:
Swiss Webster
Sex:
male
Route of administration:
inhalation: dust
Vehicle:
not specified
Details on exposure:
Decreases in respiratory rate of less than 12 % are graded as no irritatiion, 12 to 20 % as a slight response, 20 to 50 % as a moderate response, and 50 to 85 % as an extreme response (ASTM E981-04 (2004)).
No. of animals per sex per dose:
4 males.
Details on results:
It was not possible to achieve an RD50 for sodium tetraborate pentahydrate based on the results in the mouse sensory irritation model.

The highest concentration of sodium borate that was achievable with acceptable control of the aerosol concentration was 1704 mg/m3 with a %RD of 33%.
Respiratory depression expressed as group mean percent decrease from baseline respiratory rate was as follows for sodium tetraborate pentahydrate: 14%, 11%, 17%, 17%, 19%, 25%, 28%,and 33% for aerosol exposure concentrations of 231, 186, 394, 681, 886, 798, 1442, and 1704 mg/m3, respectively.

Based on these results, the RD50 is > 1704 mg/m3 for sodium tetraborate pentahydrate.
The maximum exposure of 1704 mg/m3 resulted in a reduced respiratory rate of 33%, graded as moderate irritation. The lowest exposure tested of 186 mg/m3 sodium tetraborate pentahydrate resulted in a reduced respiration rate of 11%, graded as no irritation.

Conclusions:
The objective of this study was to evaluate the potential for boric acid and sodium tetraborate pentahydrate to produce depression of respiratory rate resulting from airway sensory irritation when administered to male Swiss-Webster mice by whole-head (head-only) inhalation exposure. Respiratory depression may result from upper airway sensory irritation and/or pulmonary irritation.
The protocol was designed based on the ASTM E981-04 (2004) method, Standard Test Method for Estimating Sensory Irritancy of Airborne Chemicals (American Society for Testing and Materials, published May, 2004).
The respiratory depression of boric acid and sodium tetraborate pentahydrate, was evaluated in 30-minute, single-exposure study in Swiss-Webster Crl:CFW® (SW)BR mice. Boric acid was administered to several exposure levels of 4 male mice via head-only inhalation exposure as a dust aerosol at geometrically spaced concentrations.
It was not possible to achieve an RD50 for boric acid or sodium tetraborate pentahydrate based on the results in the mouse sensory irritation model.

The highest concentration of sodium borate that was achievable with acceptable control of the aerosol concentration was 1735 mg/m3 with a %RD of 41%.

The highest concentration of boric acid that was achievable with acceptable control of the aerosol concentration was 1097 mg/m3 with a %RD of 19%.

Based on these results, the RD50 is > 1097 mg/m3 for boric acid, and > 1735 mg/m3 for sodium tetraborate pentahydrate.

The RD10 values calculated for both substances was 189 mg/m3.
Read-across is justified on the basis detailed in the rationale for reliability above. This study is therefore considered to be of sufficient adequacy and reliability to be used as a supporting study and no further testing is justified.
Endpoint:
endocrine system modulation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Meets generally accepted scientific standards with acceptable restrictions. This study is 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, disodium tetraborate decahydrate, disodium tetraborate pentahydrate, boric oxide and disodium octaborate tetrahydrate will predominantly exist as undissociated boric acid. At about pH 10 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 un-dissociated boric acid. Since other borates dissociate to form boric acid in aqueous solutions, they too can be considered to exist as un-dissociated 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 below. Conversion factor for equivalent dose of B Boric acid H3BO3 0.175 Boric Oxide B2O3 0.311 Disodium tetraborate anhydrous Na2B4O7 0.215 Disodium tetraborate pentahydrate Na2B4O7•5H2O 0.148 Disodium tetraborate decahydrate Na2B4O7•10H2O 0.113 Disodium octaborate tetrahydrate Na2B8O13•4H2O 0.210 Sodium metaborate (anhydrous) NaBO2 0.1643 Sodium metaborate (dihydrate) NaBO2•2H2O 0.1062 Sodium metaborate (tetrahydrate) NaBO2•4H2O 0.0784 Sodium pentaborate (anhydrous) NaB5O8 0.2636 Sodium pentaborate (pentahydrate) NaB5O8∙5H2O 0.1832 References: WHO. Guidelines for drinking-water quality, Addendum to Volume 1, 1998.
Qualifier:
according to
Guideline:
other: No data
Deviations:
not specified
Principles of method if other than guideline:
A simple screening procedure using the yeast-two hybrid system based on the ligand-dependent interation of nuclear hormone receptors with coactivators was described. The estrogenic activity of more than 500 chemicals was evaluated.
GLP compliance:
not specified
Type of method:
in vitro
Species:
other: Yeast
Strain:
other: Y190
Sex:
not specified
Route of administration:
other: The test substance was added to the growth medium
Vehicle:
other: DMSO
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
4 h
Frequency of treatment:
Single exposure
Post exposure period:
None
Remarks:
Doses / Concentrations:
No data
Basis:
no data
No. of animals per sex per dose:
Not applicable
Control animals:
not specified
Details on results:
Estrogenic activity of boric acid by yeast two-hybrid system gave a REC10(M) > E-04, where REC10 was the concentration showing 10 % activity of 10-7 17β-estradiol (relative activity). Boric acid was not considered positive for estrogenic activity. Most of the chemicals that were positive in this study had a common structure, namely a phenol with a hydrophobic moiety at the para position without bulky groups at the ortho-position.
Conclusions:
Estrogenic activity of boric acid by yeast two-hybrid system gave a REC10(M) > E-04, where REC10 was the concentration showing 10 % activity of 10-7 17β-estradiol (relative activity). Boric acid was not considered positive for estrogenic activity. Most of the chemicals that were positive in this study had a common structure, namely a phenol wit ha hyrophobic moiety at the para position without bulky groups at the ortho-position.
Read-across is justified on the basis detailed in the rationale for reliability above. This study is therefore considered to be of sufficient adequacy and reliability to be used as a supporting study and no further testing is justified.

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.

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