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EC number: 233-139-2 | CAS number: 10043-35-3
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Description of key information
There is a large database of accidental or intentional poisoning incidents for humans. In the literature, the human oral lethal dose is regularly quoted as 2-3 g boric acid for infants, 5-6 g boric acid for children and 15-30 g boric acid for adults based on an old case review by Goldbloom and Goldbloom (1953). This data is largely unsubstantiated and considerable confusion surrounds differences between acute and chronic boric acid ingestions. In most cases it is difficult to make a good quantitative judgment particularly since medical intervention occurred in most cases and there were often other unrelated medical conditions (Culver and Hubbard, 1996). While boron has been shown to adversely affect male reproduction in laboratory animals, there is no clear evidence of male reproductive effects attributable to boron in studies of highly exposed workers (Whorton et al. 1994; Sayli 1998, 2001; Robbins et al. 2010; Scialli et al. 2010, Duydu 2011). There is also no evidence of developmental effects in humans attributable to boron in studies of populations with high exposures to boron (Tuccar et al 1998; Col et al. 2000; Chang et al. 2006). However, studies of human developmental effects are not as robust as the studies of male reproduction because of developmental ascertainment issues.
Additional information
ADME parameters and toxicokinetics behaviour:
There is little difference between animals and humans in absorption, distribution, and metabolism. A difference in renal clearance (based on body mass) is the major determinant in the differences between animals and humans, with the renal clearance in pregnant rats approximately 3 times greater than in pregnant women (Vaziri et al. 2001; Pahl et al. 2002).
Absorption of borates via the oral route is nearly 100 % (Job 1973; Schou et al. 1984; Jansen et al. 1984a). For the inhalation route 100 % absorption is assumed as worst case scenario. Dermal absorption through intact skin is very low with a percent dose absorbed of 0.226 ± 0.125 in humans (Friis-Hansen et al. 1982, Hui et al. 1996, Hartway et al. 1997). Using the % dose absorbed plus standard deviation (SD) for boric acid, a dermal absorption for borates of 0.5 % (rounded from 0.45 %) can be assumed as a worse case estimate).
In the blood boric acid is the main species present and is not further metabolised. Boric acid is distributed rapidly and evenly through the body, with concentrations in bone 2 - 3 higher than in other tissues. Boric acid is excreted rapidly, with elimination half-lives of 1 h in the mouse, 3 h in the rat and < 27.8 h in humans, and has low potential for accumulation. Boric acid is mainly excreted in the urine(Jansen et al., 1984a,b).
Interspecies differences in toxicokinetics based on data for boron clearance rates in rats versus humans and intraspecies differences in human toxicokinetics based on data on human variability in glomerular filtration rates (GFR) are critical determinates in evaluating human toxicity of boric acid. GFR was identified as the primary determinant of boron clearance rates. A toxicokinetic adjustment factor for boron for human variability is based on the variability in GFR during pregnancy (Dunlop, 1981; Krutzén et al., 1992; Sturgiss et al., 1996) ensuring adequate coverage of the sensitive subpopulation of preeclamptic women (US.EPA 2004; Dourson et al. 1998; Maier et al. 2014).
Acute oral:
There is a large database of accidental or intentional poisoning incidents for humans. In the literature, the human oral lethal dose is regularly quoted as 2-3 g boric acid for infants, 5-6 g boric acid for children and 15-30 g boric acid for adults based on an old case review by Goldbloom and Goldbloom (1953). This data is largely unsubstantiated andconsiderable confusion surrounds differences between acute and chronic boric acid ingestions.In most cases it is difficult to make a good quantitative judgment particularly since medical intervention occurred in most cases and there were often other unrelated medical conditions (Culver and Hubbard, 1996). Of more recent reports of accidental ingestion, none were reported as fatal and 88.3 % were asymptomatic. The estimated dose range was 10 mg to 88.8 g (Litovitz et al, 1988). Symptoms of acute effects may include nausea, vomiting, gastric discomfort, skin flushing, excitation, convulsions, depression and vascular collapse. Linden et al. (1988) reported the case of a 2-year-old who ingested an estimated 10 g of boric acid, experienced only vomiting, and had a boric acid level of 580 µg/mL seven hours after ingestion. These authors also described a 35-year-old woman who ingested 80 g of boric acid and only experienced vomiting and facial flushing despite a serum boric acid level of 2320 µg/mL one hour after the ingestion (Linden et al. 1988). Litovitz et al. (1988) conducted a meticulous review of prior reports of boric acid poisoning and found that prior reports of toxic effects following single acute ingestions of boric acid are few in number. Only two cases from the 1920s are the only fatalities following the acute ingestion of boric acid or sodium borate reported in the medical literature. The first case is a 66 year-old man following the accidental ingestion of 1 to 1.5 oz of borax (sodium borate) powder mistaken for a saline cathartic and a second case in 1928 of a fatality in a 53-year-old woman following the ingestion of four pancakes made from flour containing 51% sodium borate. The authors found that the majority of acute boric acid ingestions produce no toxicity and that boric acid ingestions produce minimal toxicity at serum boric acid levels of 340 ug/mL or less. A review of previously reported cases indicate that much higher blood levels are well tolerated (Litovitz et al. 1988).
Acute dermal:
Several poisoning cases have been reported in humans. In pharmaceutical preparations boric acid has been used in the past as skin and mucosa antiseptic. Such medical uses are now obsolete, but have led to poisoning in the past when skin integrity was compromised (Kliegel, 1980; Wong et al. 1964, Litovitz et al, 1988; Goldbloom and Goldbloom, 1953; Valdes-Dapena and Arey, 1962).
Irritant effects:
Acute irritant effects have been documented in human workers exposed to sodium borates (Garabrant 1984, 1985; Wegman 1991 and, Woskie, 1998).
A survey of 113 workers exposed (214 unexposed) to boron oxide and boric acid in a borax mining and refining plant was conducted by Garabrant et al. (1984). The mean total dust exposure was 4.1 mg/m³ (10.25 Institute of Occupational Medicine air sampler (IOM)) equivalent boron oxide or 4.1 mg/m³ (10.25 IOM) boric acid equivalent to 1.3 and 0.7 mg B/m³, (3.25 and 1.75 mg B/m³ IOM equivalent) respectively. All measured of exposure were made at various times (days to weeks) prior to the interview of the study participants and study participants were asked to remember what symptoms they experienced at the time when the exposures were measured. Significant associations were found for respiratory symptoms. Symptoms were eye irritation, dryness of mouth, nose or throat, sore throat, and productive cough. This study did not distiquish which of the two exposures was associated with reported symptoms.
Wegman et al (1991, 1994) conducted a study to examine for work-related acute irritative effects and chronic pulmonary function abnormalities in mining and processing plant workers exposed to boron-containing dust. This approach was reported more fully by Hu et al. 1992 and Woskie et al (1994, 1998). However, this study did not evaluate worker exposure to boric acid. Average daily exposure (6 h time weighted average) for the exposed group was 5.72 mg/m³of total dust (0.44 mg B/m³ B).The mean total boron value of 0.44 mg B/m³ from Wegman et al. 1991 as reported in the text of the report is incorrect since it appears that it includes the background or comparison group exposure level of 0.02 mg/m³, which when included in the calculation of the mean, gives a lower exposure value than the true exposure level of the exposed group. The background or comparison group included non-office hourly employees who had no routine exposure to borate particulate matter, other than background (Wegman et al. 1991). When the background value is excluded from the calculation, the mean total boron value of all exposed groups is 0.52 mg B/m³. When this value is corrected by 2.5 for under sampling bias (Vincent 2007) that occurs with total dust sampling the mean total boron exposure for the exposed group is 1.3 mg B/m³.
The exposure – response trends were statistically significant (p < 0.05), except for eye irritation. The most striking difference was for nasal irritation where 23 % of the exposed group reported at least two incident symptoms as compared to none of the unexposed. Despite some drawbacks of this study a concentration response curve can be derived. The number of workers investigated and the evaluated exposure intervals was high, the exposure was representative for the workplace situation and the protocol of the observations is adequate. The investigators considered these findings to be compatible with an OEL of 10 mg/m³ TWA (Total Dust) without a STEL (short-team exposure limit) for all the sodium borates (Wegman et al 1991). It is therefore used as a supporting study for deriving a DNEL(acute, inhalation, local) for sodium borates. A bench mark dose analysis BMDL05value of 0.95 mg B/m³ (Based on Total Dust sampler) was calculated using data from Wegman et al. 1991 (See appendix A).
The total dust samples used for the studies by Garabrant (1984, 1985) and Wegman et al. (1991) were collected by personal samplers consisting of a 37 mm, 5-µm PVC filter in a closed-face cassette attached to a personal sampling pump set at a flow rate of 2 L/min as described by NIOSH Method 0500. This method is defined as collecting total aerosol mass or total dust. Wegman et al. (1991) used a closed-face 37 mm cassette attached in-line to a MINIRAM operated at 2 L/min. Since dust particles of different sizes deposit selectively in different parts of the respiratory tree, size selective dust sampling has replaced the total dust method. Because the most sensitive effect of borate exposure in the workplace is irritation of the nose and throat and to a lesser extent, eyes, current air sampling for borates is most frequently done with samplers designed to collect the inhalable particulate fraction (IOM sampler), the particle fraction that deposits in the upper respiratory tract. The relationship between total dust and inhalable dust air sampling results for borates becomes important when comparing measures of past exposures with current exposures. The samplers designed for the inhalable fraction collect larger dust particles more efficiently than do the total dust samplers so that in dust environments containing large particles the inhalable dust sampler will collect larger proportions of the airborne mass than the total dust sampler. Several studies have demonstrated that the 37-mm total dust sampler equipment under-samples suspended particles by factors ranging from 1.2 to 4.0 compared to the IOM sampler (Shen et al. 1991; Culver et al. 1994; Tsai et al. 1995; Werner et al. 1996; Katchen et al. 1998; Teikari et al. 2003; Vincent 2007). The dust particles associated with borate mining and processing typically have mass median aerodynamic diameters of 10-15 µm and in this environment the IOM sampler collects between 2 and 3 times more mass per unit volume of air than the total dust sampler (Culver et al. 1994; Katchen et al. 1998). A conversion factor of 2.5 has been suggested for converting “total” personal exposure measures from industries similar to the borate mining and processing facility to equivalent inhalable aerosol exposures (Werner et al. 1996; Vincent 2007) further supported by paired 37 mm closed face cassette and 25 mm IOM sampling at a borate processing facility in France (Shen et al. 1991).
Woskie et al. (1998) further analyzed the Wegman et al. 1991 data and concluded that those who may appear most susceptible to borate exposure, because of greater reactivity, were the healthy non-smoking workers not using nasal sprays/drops, not reporting allergies or colds on the test day or any history of bronchitis. To examine possible biologic mechanisms for the irritant response, a toxicokinetic dose model was used to calculate nasal osmolarity during symptom intervals. The estimated levels suggested that osmolar activation of mast cells to release histamine and other mediators is a plausible mechanism by which these workers may experience nasal irritation. The study cannot be used for DNEL derivation, but helps to interpret the data generated by Wegman et al. (1991).
Cain et al. (2008) investigated the sensory irritation and perception of dusts of boric acid, sodium tetraborate pentahydrate, calcium sulphate, and calcium oxide in human volunteers. Cain et al. (2008) reported a NOAEL for irritation among human volunteers inhaling boric acid of 1.75 mg B/m³ (10 mg/m³ of boric acid), the highest exposure evaluated for boric acid. The exposures of 2, 5 and 10 mg/m³ evaluated in Cain et al. did not reach a level defined by the investigators as being irritating. Furthermore, for any given point in exposure time the dose-response curve had a very low slope, not characteristic of an irritant.
The studies used to judge respiratory tract irritation do not support the designation of boric acid as a respiratory irritant. The Wegman et al. 1991 study for which a BMD calculation provides a BMDL.05 of 0.94 mgB/m³ (total dust) is flawed on several counts. First, the substance studied was not boric acid but an alkaline dust containing unspecified sodium borates. Secondly, in that study the study subjects were highly biased because while being studied they were able to see the dust conditions in which they were working and about which they were being asked to respond to questions of irritancy. Thirdly, the response scale of 0-10 had no external reference point and thus could not be compared from person to person. The Cain et al, 2008 study of boric acid was flawed because the exposures of 2, 5 and 10 mg/m³ did not reach a level defined by the investigators as being irritating and because for any given point in exposure time the dose-response curve had a very low slope, not characteristic of an irritant. The Kirkpatrick 2010 study using the Alarie ASTM mouse RD50 test was unable to reach an exposure concentration of boric that would cause a 50% depression of respiration and thus did not meet the criteria specified by the test protocol for a respiratory irritant.
Therefore, there are no reliable human or animal studies that identify boric acid as a respiratory irritant. This lack of boric acid irritancy to mucosal surfaces is not surprising in view of the use of saturated boric acid solutions for eye wash.
Chronic irritation - inhalation:
Garabrant et al. 1984 indicated that boron oxide and boric acid dusts caused upper respiratory tract and eye irritation at concentrations less than 10 mg/m³ (total dust). The mean exposures of 4.1 mg/m³ total dust (10.25 mg/m³ IOM equivalent) with a range of 1.2 mg/m³ to 8.5 mg/m³.
An investigation into work-related chronic abnormality in pulmonary function associated with exposure to boron dust in mining and processing operations evaluated by Garabrant et al. (1984, 1985) was assessed by Wegman et al. (1991). This study relied on the availability of a 1981 survey by Garabrant et al (1984, 1985) which provided standardized measurements of pulmonary function and respiratory tract symptoms. Pulmonary function at the beginning and end of a 7-year study period was examined. Reduction of forced expiratory volume 1 sec (FEV1) was observed among smokers who had heavy cumulative sodium borate exposure (≥80 mg/m³-year), but not among less-exposed smokers and non-smokers. Change in pulmonary function over the 7 years was found unrelated to the estimate of cumulative exposure during that interval. The analysis of the relationship of sodium borate exposures in the workplace to chronic effects on pulmonary function was examined by evaluating annual, functional decline in relation to exposure between 1981 and 1988. In this analysis, no association was found between FEV1and exposure accumulated between surveys. The expected smoking-related abnormalities were observed. Thus, it appears that the 7-year exposure to dust in the work environment examined is not associated with long-term health effects. Approximately 50 % of subjects were lost to follow-up therefore conclusions that can be made regarding chronic respiratory effects of borate exposure are limited.
Sensitisation:
The data indicate that these borates are not sensitisers. No evidence of skin sensitisation in humans exposed occupationally to borates has been reported (Bruze et al., 1995).
Repeat dose toxicity:
Generally, it can be stated that chronic boric acid intoxication may have a mode of presentation quite different from that of the acute form (Gordon et al, 1973) and single large doses (~250-300 mg B/adult) are often less dangerous than repeated smaller doses (Jordon & Crissey, 1956). Since boric acid is principally eliminated by the kidney, impaired renal function may account for the high blood levels observed in some patients (Jordon & Crissey, 1956) and this might also be an explanation for differences in human responses.
Oral:
In humans multiple exposures to boric acid and borax result in various symptoms which may appear singly or together and include dermatitis, desquamation of the skin, alopecia, loss of appetite, nausea, vomiting, diarrhoea, menstruation disorders, anaemia and focal or generalized central nervous system irritation or convulsions. Much data comes from the mid 1800s to around 1940, when borates were used systematically for a variety of medical conditions including amenorrhea, malaria, epilepsy, urinary tract infection and exudative pleuritis (Kliegel, 1980).
The most frequently reported symptoms in poisoning cases between 113 mg – 500 mg B/day (equivalent to 646 – 1857 mg boric acid or 1000 – 4425 mg borax) are nausea, emesis, diarrhoea, skin rash, erythema, desquamation and alopecia, but it is important to note that in about half of these cases no vomiting was induced (Kliegel, 1980).
Dermal:
Several poisoning cases after treatment of burned or abraded skin have been described. Exact doses are difficult to derive for dermal application, but the described effects are the same as for oral exposure (Kliegel, 1980).
Inhalation:
One poisoning case via the inhalation route was described in a 50 year old man who was exposed to borax dust occupationally. The induced effects were alopecia, insomnia, headache, erythema and desquamation with verification of boron in the urine (Tan, 1970). The sole long-term (7-year) follow-up study failed to identify any long-term health effects, although a healthy worker effect cannot be entirely ruled out, given the rate of attrition (47 %) (Wegman et al. 1991; Wegman et al., 1994).
Fertility:
The potential reproductive effects of inorganic borate exposure to a population of workers at a large mining and production facility was assessed using the Standardised Birth Ratio (SBR), a measure of the ratio of observed to expected births. The average exposure for the highest exposure group was 28.4 mg B/day (approximately 0.4 mg B/kg bw/day) for two or more years. The average duration of exposure was 16 years. The number of offspring indicated no adverse effects on reproduction in these workers (Whorton et al., 1994). Exposure data used in this study was the same as reported by Wegman et al. 1991, and was collected using the total dust sampler. The IOM equivalent exposure would be 71 mg B/day.
In a study of a highly exposed population in Turkey, where exposure comes mainly from naturally high levels of B in drinking water (up to 29 mg B/L) as well as from mining and production, no adverse effect has been reported on fertility over three generations (Sayli, 1998; 2001).
Boron treatment of rats, mice and dogs has been associated with testicular toxicity, characterised by inhibited spermiation at lower dose levels and a reduction in epididymal sperm count at higher dose levels. Studies in human workers and populations have not identified adverse effects of boron exposure on fertility (Robbins et al. 2010, Scialli et al. 2010, Duydu et al., 2011, Duydu et al., 2012).
Chinese workers were studied by a research team from the Beijing University of Science and Technology and the China National Environmental Monitoring Centre in collaboration with University of California at Los Angeles (Robbins et al. 2010). Boron exposure/dose measures in workplace inhalable dust, dietary food/fluids, blood semen and urine were collected from boron workers and two comparison worker groups (n = 192) over three months and correlations between boron and semen parameters. Parameters for total sperm count, sperm concentration, motility and morphology were not significantly different across the three boron exposure comparison groups. Continuous measures of boron in workers' post-work shift urine and blood were correlated with percent normal morphology but this did not remain statistically significant after controlling for age, abstinence interval, smoking, alcohol intake, pesticide exposure and mg blood levels. No other significant correlations between boron levels and conventional semen parameters were found. DNA strand breakage and percent apoptotic cells were similar cross the exposure groups and not correlated with boron levels in post-work shift urine or blood (p > 0.05). Sperm aneuploidy and diploidy did not differ by exposure group or boron levels (Robbins, 2010).
Scialli et al. (2010) reviewed and summarized the papers of the study of Chinese workers that described the reproductive effects of boron exposure, particularly in North Eastern China. This study was reported in a series of publications, some of which were in Chinese and some in English. Boron workers (n = 75) had a mean daily boron intake of 31.3 mg B/day, and a subset of 16 of these men, employed at a plant where there was heavy boron contamination of the water supply, had an estimated mean daily boron intake of 125 mg B/day. Estimates of mean daily boron intake in local community and remote background controls were 4.25 mg B/day and 1.40 mg/day, respectively. Three categories of endpoints were identified: Semen analysis, reproductive outcome and sperm X: Y ratio. There were no statistically significant differences in semen characteristics between exposure groups including in the highly exposed subset, except that sperm X: Y ratio was reduced in boron workers. Within exposure groups the X: Y ratio did not correlate with the boron concentration in blood, semen and urine. While boron has been shown to adversely affect male reproduction in laboratory animals, there was no clear evidence of male reproductive effects attributable to boron in studies of highly exposed workers (Scialli et al. 2010).
The Chinese semen studies in highly exposed workers are a major source of information as to human reproductive toxicity. Not only are these the most exposed workers, but the Chinese worker study is themost sensitive study that has been carried out as semen analysis was performed, a very sensitive detection system for testicular damage.
A similar study was performed in Turkish workers employed in “Bandırma Boric Acid Production Plant”. The study was performed by a research team from the Ankara University, Faculty of Pharmacy and the Hacettepe University Faculty of Pharmacy in collaboration with Leibniz Research Center for Working Environment and Human Factors (IfADo). Two hundred and four workers were enrolled in this study. The daily boron exposure was estimated for each participated individual by determining the boron concentrations in inhaled dust, food and drinking water. The boron concentrations in semen, urine and blood were determined as the biomarkers of exposure. The workers were categorized according to their blood boron concentrations as control (n=49), low exposure (n=72), medium exposure n=44) and high exposure (n=39) groups. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone levels and sperm morphology, concentration and motility parameters were determined as the reproductive toxicity parameters of workers. The mean daily boron exposure and the mean blood boron concentration of the high exposure group were 14.45 mg/day and 223.89 ng/g blood respectively. There were no statistically significant differences in reproductive toxicity parameters between control and exposure groups (Duydu et al. 2011). DNA integrity of sperm cells was also determined within the study as the biomarker of male fertility. The DNA damage of sperm cells was determined by using the comet assay and expressed as the “tail % intensity”. Statistically significant differences in tail % intensity between control and exposure groups were not identified (Duydu et al. 2012). The results of the study performed in Turkish male workers emphasized once again that human boron exposures, even in the highest exposed cohorts, are too low to reach the blood boron concentrations that would be required to exert adverse effects on reproductive functions (Bolt et al. 2012).
Statistical Power
Study size and statistical power are often issues raised with epidemiological studies. The statistical power of the worker studies in China and Turkey are actually better than the animal studies. Robbins et al. (2010) reported a 90% power to detect a 20% difference between the exposure groups for the majority of motility parameters. Scialli et al. (2010) calculated the detection of a 25% difference in sperm concentration between groups at the 5% significance level with about 80% statistical power. Additionally, the study power to detect a doubling of risk of failure to meet WHO criteria for normal semen analysis at the 5% significance level is also about 80%. The German Federal Institute for Occupational Safety and Health calculated the statistical power to detect fertility effects in rodent bioassays. The authors reported a 90% power to detect approximately 32% difference in sperm count in rats, approximately 20% difference in sperm motility (%), and 86% detectable difference in abnormal sperm (%). In B6C3F1 mice, detectable differences for sperm count, sperm motility and abnormal sperm were 50%, 31% and 47% respectively. In CD-1 mice, detectable differences of 30%, 21-30%, and 66-106% for sperm concentration, motility and abnormal sperm. (Mangelsdorf and Buschmann, 2002).
Protective Effects of Zinc against Boric Acid Related Effects on Fertility
To investigate the effect of zinc on boric acid related toxicity on fertility effects an in vitro spermatogenesis study with boric acid in the presence of varying amounts of zinc was conducted (Durand, 2013). Seminiferous tubules were cultured in the presence of 32 µg/ml boric acid and varying concentrations of zinc chloride equivalent to 0.48, 1.2, 2.4 and 4.8 µg Zn/ml to determine the effects on the number of somatic cells (sertoli and myoid cells) and germ cells (pre-meiotic cells (spermatogonia), meiotic cells (young spermatocytes, middle to late pachytene spermatocytes and secondary spermatocytes), and post-meiotic cells (round spermatids)) after 1 and 2 weeks of culture. An absence of boric acid related effects on spermatogenesis was observed in the presence of zinc (Figure 3, see also Appendix G, Figure 15). All germ cells populations were decreased by boric acid at 32μg/ml. At Day 14, in the presence of boric acid increasing concentrations of zinc chloride lead to a dose dependent increase in the number of germ cells, an increased number of spermatogonia, a dose dependent increase in the number of young spermatocytes, a dose dependent increase of the number of middle to late pachytene spermatocytes, a dose dependent increase of secondary spermatocytes, and a dose dependent increase of round spermatids. Details of this study are presented in Appendix G.
In addition to the in vitro study, 28-day and 90-day oral (gavage) toxicity studies of zinc borate in Sprague-Dawley Rats were completed (See Kirkpatrick, 2013, 2014 in Zinc Borate Chemical Safety Report). Dosage levels tested in the 28-day study were 125, 250, 500, 1000 mg ZB/kg bw equivalent to 18.65, 37.3, 74.6 and 149.2 mg Boron/kg bw. The 500 mg/kg/day dose equivalent to74.6 mg B/kg bw was determined to be the no-observed-adverse-effect level (NOAEL) for male fertility effects based on the small magnitude or minimal to mild changes in the 125, 250, and 500 mg/kg/day groups. No microscopic changes were noted in the 125 mg/kg/day group. No microscopic findings were noted in the ovaries. The male fertility NOAEL for boric acid is 17.5 mg B/kg bw (Weir, 1966a).
Dosage levels tested in the 90-day study were 50, 100, 200, and 375 mg ZB/kg bw equivalent to 7.46, 14.92, 29.84 and 55.95 mg Boron/kg bw. The objectives of this study were to evaluate the potential toxicity of zinc borate when administered daily by oral gavage to Sprague Dawley rats for a minimum of 90 consecutive days and to assess recovery from such effects.
Adverse test substance-related microscopic findings were noted in the 375 mg/kg/day group males and consisted of germ cell degeneration in the testes, decreased size of the epididymides, inflammation of the prostate, and debris in the prostate. Test substance-related effects on spermatogenic parameters were noted in the 200 and 375 mg/kg/day group males at the study week 13 necropsies, as indicated by lower percentages of motility, progressive motility, and normal sperm at 200 and 375 mg/kg/day and a lower sperm production rate at 375 mg/kg/day. No microscopic findings were found in the testes or epididymis in the 200 mg/kg/day dose group. These effects for the 375 mg/kg/day group were considered adverse due to correlating microscopic findings.
Based on the results of this study, oral administration of zinc borate to Sprague Dawley rats for a minimum of 90 consecutive days resulted in no adverse effects for females at dosage levels of 50, 100, 200, and 375 mg/kg/day. For males, a dosage level of 375 mg/kg/day resulted in adverse effects on male reproductive organs, including effects on spermatogenic parameters with corresponding lower organ weights and gross and microscopic findings. Adverse effects on spermatogenic parameters were also noted at 200 mg/kg/day although there were no correlating microscopic findings.Therefore, no-observed-adverse-effect level (NOAEL) was 100 mg/kg/day for males and 375 mg/kg/day for females. Absence of microscopic findings in the testes and epididymides of the 200 mg/kg/day dose group suggests that zinc interacts with boric acid reducing boric acid induced toxicity on male reproductive organs.
Of note, even with high exposures to zinc, tissue concentrations in the testes, epididymis, and ovaries of rats remain well below normal zinc levels found in comparative human tissues. In a 90-day inhalation study of ZnO, exposure to 200 mg/m3 of ZnO resulted in a significantly increased total body burden of zinc with an increase in zinc levels in most tissues with exception of testes, epididymis, ovaries, and RBC during exposure. Tissues with no increase in zinc levels were testes, epididymis, ovaries, and RBC (Placke, 1990). A greater degree of protection from boric acid related fertility effects would be expected in human tissues with substantially greater concentrations of zinc.
Developmental:
While developmental effects of boron have been observed in rodent bioassays that include fetal body weight reduction and minor skeletal variations, there is no evidence of developmental effects in humans attributable to boron in studies of populations with high exposures to boron(Tuccar et al 1998; Col et al. 2000; Chang et al 2006). Three epidemiological studies evaluating high environmental exposures to boron and developmental effects in humans have been conducted. Epidemiological studies of human developmental effects have shown an absence of effects in exposed borate workers and populations living in areas with high environmental levels of boron. A more detail discussion of these studies is presented in Appendix B.
Protective Effects of Zinc against Boric Acid Related Developmental Effects
Comparative zinc concentrations in humans and rat indicate that the protective effects of zinc are present early in the developing human fetus. Significantly higher concentrations (3x) of zinc in the human fetus compared to laboratory animals have been reported (Figure 2, see also Appendix G, Figure 14).
To investigate the effect of zinc on boric acid related toxicity on developmental effects, a GLP-compliant embryonic stem cell test (EST) conducted according to INVITTOX Protocol No. 113 was conducted to investigate the embryotoxic potential of boric acid in the presence of varying concentrations of zinc in vitro. No greater sensitivity of embryonic stem cells compared to fully differentiated cells was observed and no concern for in vivo embryotoxicity is triggered for boric acid at various concentrations of zinc. A reduction in the boric acid inhibition of differentiation of D3 embryonic stem cells was observed with increasing concentrations of zinc (Figure 4, see also Appendix G, Figure 16) (Hofman-Huther, 2013).
The potential of zinc borate for developmental toxicity was evaluated based on the results of the Developmental Toxicity Test (Edwards 2014). Three treatment groups of 25 Sprague Dawley rats were administered the test article via oral gavage at dose levels of 100, 125 or 150 mg/kg/day. No test substance-related visceral developmental variations were noted in the 100, 125, and 150 mg/kg/day groups. There were no test substance-related skeletal malformations noted for foetuses in the test substance-treated groups. When the total malformations and developmental variations were evaluated on a proportional basis, no statistically significant differences from the control group were noted. Higher mean litter proportions of reduced ossification of the 13th rib(s) and sternebra(e) nos. 5 and/or 6 unossified were noted in the 100, 125, and 150 mg/kg/day groups compared to the control group. These findings were considered secondary to the reduced foetal weights noted in these groups. In addition, higher mean litter proportions of 7th cervical ribs and lower mean litter proportions of 14th rudimentary rib(s) were noted in the 100, 125, and 150 mg/kg/day groups and higher mean litter proportions of 25 presacral vertebrae were noted in the 125 and 150 mg/kg/day groups compared to the control group. No test substance-related foetal malformations were observed in the test substance-treated groups. Based on these results, a dosage level of 150 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity and a dosage level of <100 mg/kg/day was considered to be the NOAEL for embryo/foetal development when zinc borate was administered orally by gavage to bred Crl: CD(SD) rats.
These data show that humans are likely less sensitive to the reproductive and developmental effects of boric acid than laboratory animals due to the comparative high zinc stores in target tissues in humans compared to laboratory animals.
Comparison of Blood, Semen and Testes Boron Levels in Human and Rat
A comparison of blood, semen and target organ boron levels in studies of laboratory animals and human studies shows that boron industry worker exposures are lower than untreated control rats (Figure 1). Background boron levels in standard rat chow are high (10-20 ppm), as a result control rats in toxicity studies receive 45 times more boron than background exposure in humans. Blood boron levels in female control rats is about 0.23 µg B/g (Price et al. 1997), approximately equal to the blood levels in boron industry workers in China, Turkey and U.S. of 0.25, 0.22 and 0.26 µg B/g, respectively (Scialli et al. 2010; Culver et al. 1994; Duydu et al. 2011). Plasma and seminal vesicle fluid (the major component of semen) boron levels in untreated male control rats were 1.94 and 2.05 µg B/g, respectively, while boron levels in testes in rats dosed at the rat fertility LOAEL (26 mg B/kg) was 5.6 µg B/g (Ku et al. 1991,1993). Values in male control rats were higher than corresponding boron levels in the highest exposed Chinese boron industry workers with blood boron levels of 1.56 µg B/g and 1.84 µg B/g in semen (Scialli et al. 2010). Blood and semen boron levels in highly exposed Turkish boron workers were also lower than control rats with levels of 0.22 and 1.88 µg B/g, respectively (Duydu et al. 2011). Boron levels in testes of rats dosed at the rat fertility LOAEL was over 3x the blood boron levels in highest exposure group of Chinese boron industry workers. The blood level at the lowest animal LOAEL (13 mg B/kg) was 1.53 µg B/g, about 6 times greater than typical boron industry workers (Price et al. 1997). No adverse effects on sperm were seen in Turkish boron industry workers or in the most highly exposed subgroup of Chinese boron industry workers drinking boron contaminated water (mean blood level 1.52 µg B/g, the human NOAEL). Only under extreme conditions do human levels reach those of the animal LOAEL: the subgroup of Chinese boron workers who also drank contaminated water. Since no boron accumulation occurs in soft tissues (testes) over plasma levels biological monitoring in humans provide direct comparison to test animal target organ boron levels. Workers in boron mining and processing industries represent the maximum possible human exposure however their blood and semen boron levels are less than levels in untreated control rats. This provides an explanation why studies of highly exposed boron industry workers have shown no adverse effects and demonstrates that maximal possible exposures in humans are insufficient to cause reproductive toxicity effects. Graphs comparing the rodent and human exposure, blood, semen and tissue boron levels are also presented in Appendix C.
Essentiality
A recent review of evidence for the essentiality of dietary boron shows that boron meets the criteria for essentiality in humans (Hunt 2007). A nutritional role for boron has been demonstrated in humans and animals (Nielsen 1994, 1996, 1998; Hunt 1994, 1996, 1998; Penland 1994, 1998; Hunt et al 1997; Nielsen and Penland 1999; Hunt and Idso 1999). The essentiality of dietary boron in humans is suspected but has not been directly proven (NRC 1989; Mertz 1993; Devirian and Volpe 2003). A World Health Organization (WHO) expert committee concluded that boron is “probably essential” (WHO1996). Although the data is not sufficient to confirm essentiality in humans, the U.S. Food and Nutrition Board in 2001 (FNB 2001) published a Tolerable Upper Intake Level (UL) for boron of 20 mg/day. Also, the UK Expert Group on Vitamins and Minerals (EGVM 2003) and the European Food Safety Authority (EFSA 2004) also regarded boron as nutritionally important and determined an acceptable daily intake for boron (0.16 mg /kg/day). More detail discussion of the essentiality and beneficial effects of boron presented in Appendix D.
Short description of key information
There is a large database of accidental or intentional poisoning incidents for humans. In the literature, the human oral lethal dose is regularly quoted as 2-3 g boric acid for infants, 5-6 g boric acid for children and 15-30 g boric acid for adults based on an old case review by Goldbloom and Goldbloom (1953). This data is largely unsubstantiated andconsiderable confusion surrounds differences between acute and chronic boric acid ingestions. In most cases it is difficult to make a good quantitative judgment particularly since medical intervention occurred in most cases and there were often other unrelated medical conditions (Culver and Hubbard, 1996).
While boron has been shown to adversely affect male reproduction in laboratory animals, there is no clear evidence of male reproductive effects attributable to boron in studies of highly exposed workers (Whorton et al. 1994; Sayli 1998, 2001; Robbins et al. 2010; Scialli et al. 2010, Duydu 2011). There is also no evidence of developmental effects in humans attributable to boron in studies of populations with high exposures to boron (Tuccar et al 1998; Col et al. 2000; Chang et al. 2006). However, studies of human developmental effects are not as robust as the studies of male reproduction because of developmental ascertainment issues.
An important difference between laboratory animals and humans is the intrinsically higher zinc concentration in humans compared to laboratory animals. Normal levels of zinc in soft tissues in humans are over two times greater than in comparative tissues in laboratory animals (Figure 2, see also Appendix G, Figure 14) (King et al. 2000; Ranjan et al. 2011; Yamaguchi et al. 1996; Florianczyk 2000). The high zinc concentrations in humans compared to laboratory animals is also found in the target organs of boric acid, including fetal tissue, epididymis, and testes (Ahokas et al. 1980; Dorea et al. 1987; Suescun et al. 1981).
Several in vitro studies recently completed investigated the protective effect of zinc against boric acid related developmental and fertility toxicity of boric acid. These studies provide important mechanistic data on the effects of zinc on boric acid related reproductive toxicity that raises doubt about the relevance of the effects for humans (Durand 2013; Hofman-Huther 2013).
The protective effect of the intrinsically large zinc stores in the human body against boric acid associated toxicity explains in part the absence of effects in humans exposed to high levels of boron.
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