3.2.1.1. Death

No studies were located regarding death in humans after inhalation exposure to boron. The 4-hour LC₅₀ for boric acid, borax, and disodium borates is >2 mg boron/m³ (Hubbard 1998). No fatalities were observed in rats exposed for 6 hours/day, 5 days/week, to 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks, or dogs exposed to 57 mg boron oxide/m³ (9 mg boron/m³) for 23 weeks (Wilding et al. 1959).

3.2.1.2. Systemic Effects

No studies were located regarding cardiovascular, gastrointestinal, hematological, musculoskeletal, or renal effects in humans after inhalation exposure to boron. No studies were located regarding dermal effects after acute inhalation exposure in humans or animals for any duration category, but eye irritation has been reported in sodium-borate mining and processing workers. Information on respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, and renal effects in animals and respiratory effects and dermal/ocular effects in humans is discussed below. The highest NOAEL values and all reliable LOAEL values for these systemic effects for each species and duration category involving exposure to boric acid, borates, or boron oxide are recorded in Table 3-1 and plotted in Figure 3-1. Results from a few mouse inhalation studies of diborane gas indicate that it is a potent respiratory toxicant, much more potent than borates or boron oxide. Since it is not expected to be as important an environmental compound as borates or boron oxide, NOAEL and LOAEL values from these mouse studies of diborane gas are not included in Table 3-1 or Figure 3-1.

Respiratory Effects. Occupational studies of workers exposed to dusts of sodium borates, the most important commercial forms of boron, have identified irritation of the respiratory tract and eyes, without measurable changes in pulmonary function. In an early cross-sectional surveillance of 629 U.S. workers in a sodium borate open-pit mining and production plant, past occurrence of symptoms of respiratory irritation such as dryness of the mouth, nose, or throat, dry cough, nose bleeds, and sore throat were reported at elevated frequencies in workers in areas with mean dust concentrations of 8.4 and 14.6 mg particulates/m³ (1.8 and 3.1 mg boron/m³, respectively), compared with workers in areas with lower mean dust levels of 4.0 and 1.1 mg particulate/m³ (0.9 and 0.2 mg boron/m³) (Garabrant et al. 1984; 1985). These boron concentrations are upper bound estimates, assuming that all of the sampled dust is anhydrous borax. A reduction in forced expiratory volume in 1 second (FEV₁) was measured in a subgroup of smoking workers with estimated high cumulative exposure (≥80 mg particulate/m³, ≥9 mg boron/m³) to sodium borate dusts, but not in groups of less-exposed smoking workers or in nonsmoking workers. However, a subsequent surveillance of FEV₁ in 303 of the original 629 borax workers, 7 years after the original surveillance, , some of whom were exposed to ≥15 mg boron/m³, found no exposure-related changes in FEV₁ over this period, when adjustments were made for the effects of age, height, and smoking on FEV₁ (Wegman et al. 1991, 1994). Although the prevalence of workers reporting acute respiratory irritation symptoms increased with the mean dust concentrations for different job categories in the plant, the cross-sectional design of the Garabrant et al. (1985) study prevented the determination of whether the elevation of acute respiratory symptoms was a consequence of acute or repeated exposure to sodium borate dusts. Thus, the effect levels associated with the measured prevalence of acute respiratory symptoms in this study are not included in Table 3-1 or Figure 3-1.

Table 3-1

Levels of Significant Exposure to Boron - Inhalation.

Figure 3-1

Levels of Significant Exposure to Boron - Inhalation.

The occurrence of acute respiratory symptoms as a possible consequence of acute exposure to dusts of sodium borate (the decahydrate, pentahydrate, and anhydrous tetraborates) was studied in a later study by interviewing workers about acute irritation symptoms before the work shift began and at regular hourly intervals during the work shift, and by measuring personal air concentrations of particulates at concurrent intervals for 4 consecutive days (Hu et al. 1992; Wegman et al. 1991, 1994). Seventy-nine exposed production workers and 27 nonexposed workers were included in the study. In the latest analysis of the collected data, the incidence rates for irritation symptoms in exposed workers were statistically significantly higher than those in nonexposed workers, with exposed workers 9-, 5-, and 3-fold more likely to report incidents of nasal, eye, and throat irritation, respectively, than comparison workers (Hu et al. 1992; Wegman et al. 1991, 1994). For the unexposed groups, the arithmetic means of the 6-hour TWA daily dust concentration was 0.45 mg particulates/m³ (0.02 mg boron/m³), with 100% of samples ≤1.0 mg particulates/m³ and about 90% of samples ≤0.5 mg particulates/m³. The arithmetic mean of the 6-hour TWA daily dust concentrations for the exposed group was 5.72 mg particulates/m³ (0.44 mg boron/m³), with a majority of air concentrations between 1.0 and 10.0 mg particulates/m³ (Wegman et al. 1991, 1994). Several factors make it difficult to identify a NOAEL or LOAEL for this study, precluding its inclusion in Table and Figure 3-1. Study participants rated their perception of individual episodes of eye, throat, and nasal irritancy on a scale of 0 (not at all) to 10 (very, very much), with ratings of 1, 2, and 3 representing “very little”, “fairly little”, and “moderate” irritation, respectively. Unexposed responders to the pre-shift survey reported a mean rating of 1.9 for all symptoms, while the mean rating for nasal irritation (the most commonly reported effect) among exposed workers was just slightly higher at 2.2. Thus, the cutoff for boron dust-induced effects is likely to be for ratings of ≥3. In the exposed group, 91% of reported symptoms were rated with severity scores ≤3 and 96% of symptoms were rated with severity scores of ≤4 (“pretty much”). For incidences in which the workers depressed a counter button to record time of symptom onset, and the study surveyor recorded an occurrence of effect, the probability of reporting an effect did not change markedly until 0.25-hour TWA exposure levels reached 0.8–1.2 mg boron/m³ (Wegman et al. 1991). There was no significant difference in reporting of symptoms based on the type of borate dust, which differ in boron content by almost a factor of two (i.e., 4.7 mg anhydrous borax/m³ and 8.8 mg/m³ of the decahydrate provide 1 mg boron/m³). Finally, the data do not indicate a temporal increase in effect intensity, as would be expected for a local irritant. Further, since no chronic effects (i.e., reduced FEV₁) were observed in workers assessed by Wegman et al. (1994), 7 years after being assessed by Garabrant et al. (1985), the acute-duration inhalation MRL of 0.3 mg/m³ should also be health-protective for intermediate- and chronic-duration exposures.

Acute-duration laboratory exposures of volunteers to boric acid and sodium borate (sodium borate pentahydrate) dust provide more precise estimates of effect levels than the occupational studies. Male and female volunteers were trained to recognize the difference in chemesthetic feel (pungency or irritancy) of various levels of CO₂ offered to the eyes, nose, and throat (Cain et al. 2004, 2008). Exposures of ≥17.7% CO₂ resulted in a “feel” described by the volunteers as irritating. Male volunteers exposed to ≤3.0 mg boron/m³ (≤20 mg sodium borate/m³) for 20 minutes reported increasingly higher magnitude of feel of the dust in eyes, nose, and throat. However, the mean reported level of feel, compared to equivalent CO₂ levels, was not considered irritating by the study subjects. The mean reported perception of feel at ≥4.5 mg boron/m³ (≥30 sodium borate/m³) was reported to feel irritating to the nose (Cain et al. 2004). Significantly increased nasal secretions (by mass) occurred at 1.5 mg boron/m³ (10 mg sodium borate/m³), but not 0.8 mg boron/m³ (5 mg sodium borate/m³) (Cain et al. 2004). In a similar experiment, male and female volunteers exposed to 1.5 mg boron/m³ (10 mg sodium borate/m³) or 1.8 mg boron/m³ (10 mg boric acid/m³) for 47 minutes while exercising reported a mean sense of feel that initially increased and peaked at the equivalent of slightly less than 17.7% CO₂. These boron exposures, with a mean reported feel equivalent to <17.7% CO₂, were considered non-irritating by the study subjects, although increases in nasal secretions were observed at 1.8 mg boron/mg³ (10 mg boric acid/m³), but not at 0.9 mg boron/mg³ (5 mg boric acid/m³) (Cain et al. 2008). The volume of nasal secretions increased above controls for the first 20 minutes of exposure, but did not continue to increase thereafter, suggesting that increased secretions resulted from possible dust-induced changes in osmolarity rather than an irritation response. No dose-related changes in nasal airway resistance or breathing patterns were observed. Together, these studies were used to identify a minimal LOAEL of 1.5 mg boron/m³, with an associated NOAEL of 0.8 mg/m³, for significantly increased mass of nasal secretions, from which an acute-duration inhalation MRL of 0.3 mg boron/m³ was derived (see Appendix A).

Corroborating evidence in animals for the respiratory irritation potential of inhaled boron compounds is sparse. Mild respiratory irritation, indicated by a 20% reduction in breathing rate, occurred in mice inhaling 53 mg boron/m³ (300 mg boric acid/m³) for 3 hours (Krystofiak and Schaper 1996). Rats were exposed to aerosols of boron oxide (6 hours/day, 5 days/week) at concentrations of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks, and dogs were exposed to 57 mg boron oxide/m³ (9 mg boron/m³) for 23 weeks (Wilding et al. 1959). In rats, histological examination of a comprehensive set of tissues revealed no differences between the tissues of exposed and control animals. Signs of gross toxicity were restricted to the appearance of a reddish exudate from the nose of some of the rats exposed to 470 mg boron oxide/m³.

Mice (ICR) exposed to 0.7 ppm diborane gas (0.2 mg boron/m³) for 2 or 4 weeks exhibited slight infiltration of polymorphous neutrophil in peribronchiolar regions of the respiratory tract (Nomiyama et al. 1995). Mice exposed to 5 ppm diborane gas (1.7 mg boron/m³) for 2 weeks exhibited increased lung weight, nasal cavity changes, diffuse panbrochiolitis-like lesions, cellular infiltration of the bronchioles and perivascular area, appearance of alveolar macrophages, perivascular lymphoid hyperplasia, lung congestion, bleeding, and edema (Uemura et al. 1995).

Comparison of the results from the studies of mice exposed to diborane gas (Nomiyama et al. 1995; Uemura et al. 1995) and those from studies of rats and dogs exposed to boron oxide (Wilding et al. 1959) indicate that diborane gas is much more potent as a respiratory toxicant than boron oxide. Diborane gas is expected to have a very short half-life in the environment because of its reactivity. Thus, it is not expected to be a significant environmental toxicant, except in workplaces where it might be used and accidentally released.

Cardiovascular Effects. Rats exposed to aerosols of boron oxide at a concentration of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks showed no gross or microscopic effects in the cardiovascular system (Wilding et al. 1959).

Gastrointestinal Effects. No gross or microscopic changes were seen in the gastrointestinal tract of rats exposed to aerosols of boron oxide at a concentration of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks (Wilding et al. 1959).

Hematological Effects. Rats exposed to aerosols of boron oxide at concentrations of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks, and dogs exposed to aerosols of boron oxide at concentrations of 57 mg boron oxide/m³ (9 mg boron/m³) for 23 weeks showed no significant changes in total red and white blood cell count, hemoglobin, hematocrit, or differential count (Wilding et al. 1959).

Musculoskeletal Effects. No gross or microscopic effects of exposure were observed in the femur, rib, and muscle of rats exposed to concentrations of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks (Wilding et al. 1959).

Hepatic Effects. No gross or microscopic hepatic effects were observed in rats exposed to aerosols of boron oxide at concentrations of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks. No hepatic effects were indicated from serum chemistry of dogs exposed to aerosols of boron oxide at concentrations of 57 mg boron oxide/m³ (9 mg boron/m³) for 23 weeks (Wilding et al. 1959).

Renal Effects. No gross or microscopic renal effects were observed in rats exposed to aerosols of boron oxide at concentrations of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks. No renal effects were indicated from serum chemistry of dogs exposed to aerosols of boron oxide at concentrations of 57 mg boron oxide/m³ (9 mg boron/m³) for 23 weeks (Wilding et al. 1959).

Ocular Effects. Human occupational exposure to a mean concentration of 0.44 mg boron/m³ (5.72 mg particulates/m³) (Hu et al. 1992; Wegman et al. 1994) and 1.8–3.1 mg boron/m³ (8.4–14.6 mg particulates/m³) (Garabrant et al. 1984, 1985) as sodium borate dust produced eye irritation following acute-duration exposures. The cross-sectional study design of Garabrant et al. (1984, 1985) made it difficult to determine whether the observed effects were caused by acute or repeated exposures; however, the design employed by Wegman et al. (1994), which included 6-hour TWA air samples and worker reports of irritancy before the start of the work shift and during the shift, allowed the determination that this acute ocular irritation was due to acute exposure. No ocular effects were observed in rats exposed to aerosols of boron oxide at concentrations of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks (Wilding et al. 1959).

3.2.1.3. Immunological and Lymphoreticular Effects

No gross or microscopic effects on immunological or lymphoreticular tissues (lymph nodes and spleens) were observed in rats exposed to aerosols of boron oxide at concentrations of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks (Wilding et al. 1959).

3.2.1.4. Neurological Effects

No gross or microscopic effects on the brain were observed in rats exposed to aerosols of boron oxide at concentrations of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks (Wilding et al. 1959).

3.2.1.5. Reproductive Effects

A study of 28 male boric acid production workers occupationally exposed to 22–80 mg/m³ boron aerosols (boron form uncertain) for ≥10 years (Tarasenko et al. 1972) revealed low sperm counts, reduced sperm motility, and elevated fructose content of seminal fluids, compared to controls. These effects are consistent with high-dose animal exposures. However, this study is limited by the small number of subjects and limited data reporting. Furthermore, a cross-sectional survey of 753 employees working for at least 9 months at a borax production facility in California found worker fertility rates to be higher than the U.S. national average (Whorton et al. 1994). However, this study is limited by lack of exposure data.

In animals, no gross or microscopic effects were found on the ovary or testes of rats exposed to aerosols of boron oxide at concentrations of 470 mg boron oxide/m³ (73 mg boron/m³) for 10 weeks, 175 mg boron oxide/m³ (27 mg boron/m³) for 12 weeks, or 77 mg boron oxide/m³ (12 mg boron/m³) for 24 weeks (Wilding et al. 1959).

3.2.1.6. Developmental Effects

No studies were located regarding developmental effects in humans or animals after inhalation exposure to boron.

3.2.1.7. Cancer

No studies were located regarding cancer in humans or animals after inhalation exposure to boron.

3.2.2.1. Death

Case reports of lethal oral exposure of humans to boron primarily involve accidental or intentional exposures to high levels of boric acid. Similar clinical signs have been seen in adults and children. A review of 784 primarily acute boric acid exposures in adults and children found that 88% of cases were asymptomatic. The reports did not contain information on the dose response for boric acid, as symptomatic cases had doses ranging from 100 mg to 55 g boric acid (18 mg–10 g boron), while asymptomatic cases had doses ranging from 10 mg to 89 g boric acid (2 mg–16 g boron) (Litovitz et al. 1988). Nonetheless, death occurred in some children following oral doses in this wide dose range. Five infants who ingested formula accidentally prepared with 2.5% aqueous solution of boric acid became lethargic, developed vomiting and diarrhea, and died within 3 days after exposure (Wong et al. 1964). The estimated boric acid consumption ranged from 4.51 to 14 g (0.8–2.5g boron). In two infants who ingested 9.25 g boric acid (505 mg boron/kg/day) and 14 g boric acid (765 mg boron/kg/day), degenerative changes were seen in the liver, kidney, and brain (Wong et al. 1964). In a food poisoning incident in Malaysia, 13 children died after consuming Chinese noodles contaminated with boric acid (Chao et al. 1991a, 1991b). The deaths were determined by the study authors to be caused by unknown levels of aflatoxin and boric acid in the noodles. Clinical signs included vomiting, pyrexia, diarrhea, abdominal pain, anorexia, giddiness, seizures, and eventual coma. Postmortem examination revealed coagulative necrosis of the liver, proliferative metaplasia of the hepatocytes, giant cell formation, central vein sclerosis, bile stasis, and steatosis, acute renal tubule necrosis, upper gastrointestinal erosion, and encephalopathy. However, the relative contribution of boric acid to these effects could not be determined.

A common suite of symptoms was presented in case reports of adult oral exposures that resulted in death. A 77-year-old man ingested a single dose of 30 g of boric acid (85 mg boron/kg) to cure hiccups (Ishii et al. 1993). Effects included vomiting, diarrhea, erythema, cyanotic extremities, acute renal failure, cardiopulmonary hypotension, and death from cardiac insufficiency. Almost identical clinical signs and death occurred in a 45-year-old man ingesting approximately 49 g of boron (280 g boric acid, 700 mg boron/kg assuming a body weight of 70 kg) (Restuccio et al. 1992).

In animals, rats appear to be more sensitive than dogs or mice to the lethal effects of acute boron exposures. Oral LD₅₀ values for respective boron equivalents of boric acid or borax were 898 and 642 mg/kg in an unspecified rat strain (Smyth et al. 1969), 600 and 510 mg/kg in Sprague-Dawley rats (Weir and Fisher 1972), and 550 and 690 mg/kg in Long Evans rats (Weir and Fisher 1972). No deaths were reported in dogs exposed to a single dose of 696 mg boron/kg (3,977 mg boric acid/kg) and 738 mg boron/kg (5,549 mg borax/kg) (Weir and Fisher 1972). No single-dose LD₅₀ studies in mice were available; however, mortality rates of 20 and 60% were observed in males given 14 daily doses of 2,251 and 3,671 mg boron/kg/day (12.9 or 21.0 g boric acid/kg/day) in the diet, respectively (NTP 1987), but not at 926 mg boron/kg/day (5.3 g boric acid/kg/day). These animals were lethargic and exhibited discolored spleen, liver, and renal medullae and hyperplasia and dysplasia of the forestomach (NTP 1987).

With intermediate-duration oral exposure, rats appear to be slightly more sensitive than mice to the lethality of boric acid. There was 100% mortality in Sprague-Dawley rats fed 450 mg boron/kg/day within a 6-week period (Weir and Fisher 1972). Congestion of liver and kidneys, small gonads, and brain swelling were reported. Eighty percent of male and 60% of female B6C3F1 mice died in a study involving exposure to 577 mg boron/kg/day (3,298 mg boric acid/kg/day) in the diet for up to 90 days (NTP 1987). Hyperkeratosis and/or acanthosis in the stomach and extramedullary hematopoiesis of the spleen in both sexes of mice were observed at the same dose level.

With chronic exposure to boric acid in the diet, mortality at 103 weeks was ≥40 and ≥30% in male and female B6C3F1 mice, respectively, exposed to ≥79 mg boron/kg/day (≥450 mg boric acid/kg/day), compared to 18 and 34% in untreated male and female controls, respectively (NTP 1987). No clinical signs were reported for either sex; however, boron caused an increased incidence of testicular atrophy and interstitial hyperplasia in male mice exposed to doses ≥201 mg boron/kg/day (1,150 mg boric acid/kg/day).

LD₅₀ values and, in some cases, the lowest levels at which death was reported in humans and animals and the duration categories are recorded in Table 3-2 and plotted in Figure 3-2.

3.2.2.2. Systemic Effects

No studies were located regarding respiratory effects in animals or musculoskeletal effects in humans or animals after oral exposure to boron.

Information on respiratory, gastrointestinal, hematological, cardiovascular, hepatic, renal, and dermal/ocular effects is discussed below. The highest NOAEL values and all reliable LOAEL values for these systemic effects for each species and duration category are recorded in Table 3-2 and plotted in Figure 3-2.

Respiratory Effects. Widespread vascular congestion and hemorrhages in the lungs were reported in one infant who ingested an estimated dose of 505 mg boron/kg/day for 3–5 days (Wong et al. 1964).

Cardiovascular Effects. Ingestion of 85 mg boron/kg (as 30 g of boric acid) by a 77-year-old man (Ishii et al. 1993) resulted in cardiopulmonary hypotension and death from cardiac insufficiency.

Gastrointestinal Effects. Ingestion of boron in humans can cause gastrointestinal effects. Nausea, persistent vomiting, diarrhea, and colicky abdominal pain in infants were associated with acute ingestion of a total of ≥184 mg boron/kg/day (based on 1.9 kg body weight) as boric acid, which was accidentally incorporated in infant formula (Wong et al. 1964). Vomiting and diarrhea occurred following ingestion of 85 mg boron/kg (as 30g of boric acid) by a 77-year-old man (Ishii et al. 1993). Vomiting was the only sign of boron toxicity in two adult females who ingested 14 g boron (80 g boric acid) in a fungicide and 52 g boron (297 g boric acid) in a suicide attempt. In the absence of body weight data, doses for these cases could not be estimated. The subjects were hospitalized for 24–96 hours and did not develop further symptoms following release (Linden et al. 1986). Food poisoning of 13 children with unknown levels of aflatoxin and boric acid (Chao et al. 1991a, 1991b) resulted in vomiting, diarrhea, abdominal pain, anorexia, and upper gastrointestinal erosion.

Table 3-2

Levels of Significant Exposure to Boron - Oral.

Figure 3-2

Levels of Significant Exposure to Boron - Oral.

In B6C3F1 mice, dietary exposure to ≥2,251 mg boron/kg/day as boric acid for 14 days resulted in gastric hyperplasia and dysplasia (NTP 1987). Dogs given a single dose of 1,000 mg boron/kg as boric acid vomited (Weir and Fisher 1972).

Hematological Effects. In animals orally exposed for intermediate or chronic durations, effects on hematological end points have been observed sporadically in dogs and consistently in mice; they did not occur in rats exposed for 90 days. Mongrel dogs fed 60.5 mg boron/kg/day for 90 days in the diet as borax (but not as boric acid) had decreased packed cell volume and hemoglobin values, but no hematological effects were seen in dogs fed 81 mg boron/kg/day as borax or boric acid for 2 years (Weir and Fisher 1972). Erythrocyte count and total and differential leukocyte counts were comparable to control levels (Weir and Fisher 1972). Splenic extramedullary hematopoiesis occurred in mice fed 72 mg boron/kg/day as boric acid for 90 days and 79 mg boron/kg/day for 2 years (Dieter 1994; NTP 1987), while no hematological effects were observed in rats fed 450 mg boron/kg/day as borax or boric acid for 90 days (Weir and Fisher 1972). Decreased packed cell volume and hemoglobin values were seen in rats fed 81 mg boron/kg/day as borax for 2 years (Weir and Fisher 1972).

Hepatic Effects. Case reports in humans suggest that the liver is susceptible to boron toxicity at high dose levels (Wong et al. 1964). Jaundice has been reported, and there were mild alterations at histological examination in infants who ingested 505 or 765 mg boron/kg/day as boric acid (accidentally incorporated in infant formula) for 3–5 days (Wong et al. 1964). In the same incident, congestion and fatty changes were observed, and there was parenchymatous degeneration in newborn infants who ingested 505 or 765 mg boron/kg as boric acid for 3–5 days (Wong et al. 1964). Coagulative necrosis of the liver, proliferative metaplasia of the hepatocytes, giant cell formation, central vein sclerosis, bile stasis, and hepatic steatosis were observed in children ingesting unknown levels of aflatoxin and boric acid in Chinese noodles (Chao et al. 1991a, 1991b).

In mice, the liver appears to be a toxicity target of repeated oral exposure to boric acid, but it is not a target in rats and dogs repeatedly exposed to boric acid or borates. Two-year dietary exposures of ≥79 mg boron/kg/day as boric acid to B6C3F1 mice resulted in chronic inflammation and coagulative necrosis in the liver (NTP 1987; Dieter 1994), but no exposure-related hepatic lesions were found in Sprague-Dawley rats fed 81 mg boron/kg/day as boric acid or borax in the diet for 2 years or in mongrel dogs fed 6.8 mg boron/kg/day as boric acid or borax in the diet for 2 years (Weir and Fisher 1972). No exposure-related liver lesions were seen in mice fed 577 mg boron/kg/day as boric acid for 13 weeks (Dieter 1994; NTP 1987); in Sprague-Dawley rats fed 450 mg boron/kg/day as boric acid or borax for 90 days (Weir and Fisher 1972); or in mongrel dogs fed 60.5 mg boron/kg/day as boric acid or borax for 90 days (Weir and Fisher 1972).

Boron-related changes in liver weights have not been consistently observed in animal studies. Reduced liver weights were observed in rats fed 86 mg boron/kg/day as borax for 30 days (Dixon et al. 1979) and fed 150 mg boron/kg/day as borax or boric acid for 90 days (Weir and Fisher 1972), while increased relative liver weights were seen in mongrel dogs fed 60.5 mg boron/kg/day as boric acid for 90 days (Weir and Fisher 1972).

In liver microsomal fractions from rats given approximately 20.8 mg boron/kg/day as borax in drinking water, NADPH-cytochrome C reductase activity and cytochrome b5 content decreased in the liver microsomal fraction after 10 and 14 weeks of exposure (Settimi et al. 1982). There was also a reduction in the cytochrome P-450 concentration detected at 14 weeks (Settimi et al. 1982). The toxicological significance of these biochemical changes is not clear, especially since intermediate- and chronic-duration feeding studies with Sprague-Dawley rats fed boric acid or borax did not report exposure-related hepatic lesions (Weir and Fisher 1972).

Renal Effects. Human case reports involving high accidental ingestion levels show that boron can cause injury to the kidney. Acute renal failure was observed in a 77-year-old man ingesting 85 mg boron/kg (as 30 g of boric acid) (Ishii et al. 1993). Degenerative changes in parenchymal cells with oliguria and albuminuria have been demonstrated in two newborn infants after ingestion of 505 and 765 mg boron/kg/day as boric acid in an evaporated milk formula over a period of 3–5 days (Wong et al. 1964). Acute renal tubule necrosis was seen in children dying from ingestion of unknown levels of aflatoxin and boric acid in Chinese noodles (Chao et al. 1991a, 1991b).

No exposure-related renal lesions were observed in Sprague-Dawley rats fed up to 450 mg boron/kg/day as borax or boric acid for 90 days (Weir and Fisher 1972), in mice fed 577 mg boron/kg/day as boric acid for 13 weeks (NTP 1987; Dieter 1994), or in dogs fed up to 60.5 mg boron/kg/day as borax or boric acid for 90 days (Weir and Fisher 1972). With 2 years of dietary exposure, no exposure-related renal lesions were observed in Sprague-Dawley rats fed 81 mg boron/kg/day as borax or boric acid (Weir and Fisher 1972), in B6C3F1 mice fed up to 201 mg boron/kg/day as boric acid (Dieter 1994; NTP 1987), or in mongrel dogs fed 6.8 mg boron/kg/day as borax or boric acid (Weir and Fisher 1972). The available data indicate that the kidney is not a sensitive toxicity target of oral exposure to boric acid or borates.

Endocrine Effects. Human data for endocrine effects from orally ingested boron are limited to studies of low-dose boron nutritional supplementation. Postmenopausal women ingesting 0.4 mg boron/day (as 3.25 mg sodium borate/day) in the diet had a 3-fold increase in plasma testosterone levels compared to those ingesting 0.03 mg boron/day (as 0.25 mg sodium borate/day) (Nielsen et al. 1987). However, bodybuilders taking daily supplements of 2.5 mg boron (approximately 0.03 mg/kg; calculated using mean body weights from study data) for 7 weeks did not exhibit differences from controls in free or total plasma testosterone levels (Ferrando and Green 1993).

Rats fed diets with 61 mg boron/kg/day as boric acid (9000 ppm) for 28 days had decreases of approximately 60–78% in plasma testosterone levels beginning on day 4 of exposure (Treinen and Chapin 1991). Follicle stimulating hormone (FSH) and leutenizing hormone (LH) levels in the blood of rats fed 26–68 mg boron/kg/day as boric acid (3,000–9,000 ppm; doses estimated by study authors) in the diet were increased, possibly in response to testicular atrophy observed in the 52 and 68 mg boron/kg/day groups (Ku et al. 1993a). No histologic lesions were observed in thyroid, adrenals, or pituitary tissues of Sprague-Dawley rats fed 450 or 81 mg boron/kg/day as boric acid or borax in the diet for 90 days or 2 years, respectively, or in mongrel dogs fed 60.5 or 6.8 mg boron/kg/day as boric acid or borax in the diet for 90 days or 2 years, respectively (Weir and Fisher 1972) or in pituitary tissues of mice fed 577 or 201 mg boron/kg day as boric acid for 90 days or 2 years, respectively (Dieter 1994; NTP 1987).

Dermal Effects. Skin effects can occur following ingestion of boron (as boric acid) in humans. Extensive exfoliative dermatitis began in infants as an erythema involving palms, soles, and buttocks. It eventually became generalized with subsequent bulbous formation, massive desquamation, and sloughing (Wong et al. 1964). These changes were associated with ingestion of 505 mg boron/kg/day; however, skin lesions were lacking following ingestion of 765 mg boron/kg/day. Similarly, extensive erythema with desquamation was observed in an adult who ingested single doses of boric acid powder (Schillinger et al. 1982). The exact amount ingested was not stated. However, 14 g (equivalent to 22.5 mg boron/kg based on 109 kg body weight) was measured as missing from a container from which the patient admitted consuming half its contents.

In animals studies, skin lesions were observed in Sprague-Dawley rats fed 150 mg boron/kg/day as borax or boric acid in the diet for 90 days (skin desquamations on the paws and tails) or 81 mg boron/kg/day for 2 years (scaly tails and desquamation on footpads) (Weir and Fisher 1972), but dermal lesions were not observed in B6C3F1 mice exposed to boric acid in the diet for 13 weeks or 2 years (Dieter 1994; NTP 1987) or in mongrel dogs exposed to boric acid or borax in the diet for 90 days or 2 years (Weir and Fisher 1972).

Ocular Effects. There are no reports of ocular effects in humans following oral exposure to humans.

Sprague-Dawley rats fed 150 mg boron/kg/day as borax or boric acid for 90 days exhibited inflammation of the eyes, while 81 mg boron/kg/day as borax or boric acid in the diet for 2 years resulted in bloody ocular discharge (Weir and Fisher 1972). No ocular effects were seen in dogs fed 60.5 mg boron/kg/day as borax or boric acid for 90 days or 6.8 mg boron/kg/day borax or boric acid for 2 years (Weir and Fisher 1972). Likewise, mice fed 201 mg boron/kg/day as boric acid for 2 years exhibited no ocular effects.

Body Weight Effects. Fisher 344 rats fed 68 mg boron/kg/day as boric acid (9,000 ppm) for 9 weeks had 6% lower body weight gain than controls (Ku et al. 1993a). Male and female B6C3F1 mice fed 288 and 577 mg boron/kg/day as boric acid (0.5% of diet) for 13 weeks had 17 and 23% decreased weight gains, respectively, while 2-year exposures to 201 mg boron/kg/day as boric acid resulted in 19% lower weight gains in both sexes (NTP 1987, Dieter 1994).

3.2.2.3. Immunological and Lymphoreticular Effects

No studies were located regarding immunological effects in humans or animals after oral exposure to boron.

3.2.2.4. Neurological Effects

Case reports in humans have indicated neurological effects after accidental ingestion of high levels of boron (as boric acid). Newborn infants who ingested 4.5–14 g boric acid showed central nervous system involvement manifested by headache, tremors, restlessness, and convulsions followed by weakness and coma (Wong et al. 1964). Histological examination of 2 of 11 infants revealed congestion and edema of brain and meninges with perivascular hemorrhage and intravascular thrombosis at a dose ≥505 mg boron/kg/day (Wong et al. 1964). Seizure disorders have been associated with boron exposures (as borax) in infants who ingested 12–120 g borax for 4–10 weeks (O’Sullivan and Taylor 1983) and 9–125 g borax over a period of 5–12 weeks (Gordon et al. 1973). Estimates of boron dose could not be determined since the authors did not provide body weight data. Blood boron levels in the infants exposed who ingested borax ranged from 2.6 to 8.5 µg/mL (O’Sullivan and Taylor 1983). In one infant with a seizure disorder who ingested (via pacifier dipped in honey and borax mixture) approximately 125 g borax over 3 months, the blood boron level was 1.64 mg/100 mL (Gordon et al. 1973).

Existing animal studies do not provide evidence that the nervous system is a toxicity target of repeated oral exposure to boric acid or borates, but no studies have examined batteries of neurological end points in animals following exposure to boron compounds. Relative brain weights were increased in mongrel dogs fed 60.5 mg boron/kg/day as borax, but not boric acid, for 90 days and in rats fed 170 or 81 mg boron/kg/day as borax or boric acid for 90 days or 2 years, respectively (Weir and Fisher 1972). No histological lesions were observed in these animals or in the brain or spinal cord of mice fed 577 or 201 mg boron/kg/day as boric acid for 13 weeks or 2 years, respectively (NTP 1987; Dieter 1994).

In Wistar rats, exposure to approximately 20.8 mg boron/kg/day as borax (based on weight of 0.35 kg and average water consumption of 20.7 mL) in drinking water for up to 14 weeks caused increased cerebral succinate dehydrogenase activity after 10 and 14 weeks of exposure (Settimi et al. 1982). Increased ribonucleic acid (RNA) concentration and increased acid proteinase activity in brain occurred after 14 weeks (Settimi et al. 1982). The neurological significance of these biochemical changes is unclear.

All LOAEL values for neurological effects in humans and animals are recorded in Table 3-2 and plotted in Figure 3-2.

3.2.2.5. Reproductive Effects

A survey of Turkish subpopulations compared fertility rates of 1,068 families living in two Turkish villages having drinking water boron levels of 2–29 mg/liter (from nearby geological deposits of calcium borate) with 610 families living in three other villages having drinking water boron levels of 0.03–0.4 mg/liter (Sayli 1998a, 1998b; Sayli et al. 1998). Assuming 70-kg body weights and 2-L/day drinking water consumption, these boron levels would results in an estimated range of daily doses of 0.06–0.8 mg/kg/day. Three generations of families were represented. No significant differences in frequencies of infertility were observed between high- (2.34% infertility) and low-exposure (2.62% infertility) village groups. A separate analysis of the same subpopulation found no association of higher drinking water borate concentrations with increased rates of spontaneous abortions, stillbirths, or infant death (Tuccar et al. 1998). A follow-up study of this population reported no significant differences in infertility frequencies between the two populations (Sayli 2003).

A questionnaire was administered to 542 male workers at a borax and boric acid production facility in California inquiring about the ability to conceive a child after at least 9 months of employment at the facility (Whorton et al. 1994). The worker population was categorized as having low, mid, or high exposures to borax or boric acid (exposure levels were not reported). A standardized birth ratio (SBR) was calculated as the number of children born to wives compared to the number of births expected in the same fraction of the U.S. population. The calculated SBR of 113 indicated higher birth rates among the borate workers relative to the U.S. population. Thus, this survey provided no evidence for association between occupational exposure to borax or boric acid and impaired fertility; however, the study is limited by non-rigorous survey design, lack of quantitative exposure data, and lack of a comparable comparison (control) group.

A cross-sectional survey of 1,187 Chinese boron mining and processing workers examined the association of boron exposure and various lifestyle factors to multiple reproductive indices (Chang et al. 2006). No exposure estimates were reported, but boron levels in drinking water and staple foodstuffs were significantly higher for surveyed workers compared to a comparison population. After correcting for age, race, diet, alcohol consumption, smoking, and education, there were no statistically significant differences between workers and the comparison population for ability to sire offspring, delayed pregnancy, multiple births, miscarriages, induced abortions, stillbirths, or tubal or ectopic pregnancies.

Liu et al. reported two studies of 176 (2006a) and 195 (2006b) Chinese men exposed to between 13 and 430 mg boron/day. The investigators found no significant difference in semen quality and sperm motility, speed, or departure from a straight-line path in groups of borate workers, non-occupationally exposed men from a nearby community with high environmental levels of borates, and men from a community with low environmental levels of borates. However, data for estimated boron exposures for each group were not available.

A study of 146 Chinese men comprising borate workers, a community group, and controls were assessed for chromosomal shifts in the ratio of Y:X chromosomes in sperm (Robbins et al. 2008). A significant correlation was found for Y:X ratios and internal boron doses in blood, semen, and urine. Estimated daily boron exposures of 41.2, 4.3, and 2.3 mg/day in the borate workers, community group, and controls were associated with mean Y:X sperm ratios of 0.93, 0.96, and 0.99, respectively. However, no dose-response relationship was observed in the reported percentage of men who had fathered “more boys than girls”, which was 57.7, 42.3, and 76.7% in the borate workers, community group, and controls, respectively. There were several possible confounding factors in this study, including (1) the exclusion of men who had fathered equal numbers of boys and girls, (2) the average number of children/subject was <2 (approximately 1.3), and (3) a high rate of elective abortions across groups (49.2, 28.2, and 50.0% for borate workers, community group, and controls, respectively), in which some men may have favored raising male offspring while complying with China’s one-child-only policy. Thus, it cannot be determined from these data if a boron-associated shift in the Y:X sperm ratio resulted in a change in sex of offspring.

While the human survey database is extensive in that large populations with chronic exposure durations were sampled from multiple locations (Chang et al. 2006; Liu et al. 2006a, 2006b; Robbins et al. 2008; Sayli 1998a, 1998b, 2003; Sayli et al. 1998; Whorton et al. 1994), they are limited for informing dose response relationships for reproductive effects. Specifically, the reliance on questionnaires and lack of clinical observations, absence of an appropriate comparison population (Robbins et al. 2008; Whorton et al. 1994), or low confidence in estimates of personal or group boron exposure (Liu et al. 2006a, 2006b) preclude these data from providing a basis for deriving an oral MRL.

Animal studies of acute-, intermediate-, and chronic- oral exposure to boric acid or borax consistently identified testicular atrophy and histological lesions and the associated impacts on spermatogenesis as the most sensitive reproductive effect. The majority of studies were performed in rats; however, the effects observed in rats were also observed in mice and dogs. The effects of boron on animal testes appear to be dose- and duration-related.

Acute-duration (2-week) oral gavage or dietary exposures of Wistar rats to 88 mg boron/kg/day as boric acid produced significant damage to male reproductive tissues, but doses of 53 or 44 mg boron/kg/day were without effect (Fukuda et al. 2000; Ku et al. 1993a; Kudo et al. 2000). Exposure to 88 mg boron/kg/day resulted in 12 and 13% reduction in absolute and relative testes weights, respectively, multinucleated giant cell formation, increased residual body-like structures in the testes, degeneration/necrosis of germ cells, increased cellular debris in the epididymal ducts, exfoliation of round spermatids, and mild inhibition of spermiation (retention of step 19 spermatids at stages IX–XI) (Fukuda et al. 2000; Kudo et al. 2000).

Intermediate-duration gavage studies in rats resulted in similar effects as observed in the acute studies, but at lower exposure levels. Wistar rats given gavage doses of 26 mg boron/kg/day as boric acid for 3 weeks exhibited decreased sperm motility, morphologically-abnormal sperm heads and tails, and increased preimplantation fetal loss when treated males were mated with untreated females; no reproductive effects occurred in this study with exposure to 9 mg boron/kg/day (Yoshizaki et al. 1999). Four-week daily gavage doses of 44 mg boron/kg/day as boric acid resulted in exfoliation of testicular and epididymal germ cells in Wistar rats (Kudo et al. 2000). Fukuda et al. (2000) gave gavage doses of 53 mg boron/kg/day to Wistar rats for 4 weeks and observed 13 and 15% reductions in absolute and relative testes weights, respectively, cellular debris in the testes, caudal and caput epididymis, focal atrophy of the seminiferous tubules, and decreased number of sperm in the ducta lumina. Rats given 4-week daily gavage doses of 88 mg boron/kg/day group exhibited reduced sperm motility, reduced total sperm in caudal epididymis, atrophy of seminiferous tubules, atypical residual bodies, multinucleated giant cell formation, and the inability to impregnate females (Yoshizaki et al. 1999).

Intermediate-duration feeding studies in rats reported effects similar to those of the gavage studies. Rats fed 100 mg boron/kg/day as borax in the diet, but not 50 mg boron/kg/day, for 30 and 60 days showed testicular atrophy (Lee et al. 1978). Sprague-Dawley rats fed 86 mg boron/kg/day as borax in the diet for 30 or 60 days were infertile for 3 or 5 weeks after exposure, respectively (Dixon et al. 1979). Exposure to 43 mg boron/kg/day as borax for 60 days produced reduced testicular and epididymal weights and diameter of seminiferous tubules occurred, and reduced testicular levels of hyaluronidase, sorbitol dehydrogenase, and lactic acid dehydrogenase (isoenzyme-X) at 30 days (Dixon et al. 1979). Mildly inhibited spermiation was observed in Fischer 344 rats exposed to 26 mg boron/kg/day in the diet for 5–9 weeks (Ku et al. 1993a). Fischer 344 rats fed 61 mg boron/kg/day as boric acid for 4 weeks showed inhibited spermiation, appearance of peripheral spermatid nuclei, and spermatocyte sloughing/epithelial disorganization (Treinen and Chapin 1991), while severe inhibition of spermiation and testicular atrophy were observed in Fischer 344 rats exposed to 68 or 52 mg boron/kg/day as boric acid in the diet for 6 or 9 weeks (Ku et al. 1993a). Full recovery from inhibition of spermiation was observed in a 38 mg boron/kg/day group by 16 weeks after cessation of exposure for 9 weeks, but no recovery from testicular atrophy was observed in the 52 and 68 mg boron/kg/day groups up to 32 weeks after exposure ended (Ku et al. 1993a). Dose-related elevations of FSH and LH suggested that boron exposure did not affect the compensatory response to atrophy (Ku et al. 1993a). In a recent study, Sprague-Dawley rats fed 136 mg boron/kg/day as boric acid for 60 days exhibited decreased weights of testes, epididymes, seminal vesicles, prostate, and vas deferens; decreased sperm motility, spermatocyte, spermatid, and Leydig cell numbers; decreased testosterone levels, sexually aggressive behavior, sexual mounts, number of females impregnated, and viable pups/impregnated female; and increased cellular degeneration, ejaculation time, postejaculatory interval, and fetal resorptions in impregnated females (Nusier and Bataineh 2005).

In intermediate-duration drinking water studies in rats, no reproductive effects (reproductive organ weight or histolopathology) were evident in Sprague-Dawley rats following exposure to 0.6 mg boron/kg/day as borax for 90 days (Dixon et al. 1976). In another study, impaired spermatogenesis was observed in Long-Evans rats given 44.7 mg boron/kg/day as borax in drinking water for 70 days (Seal and Weeth 1980). Complete sterility was observed in Sprague-Dawley rats fed 1,170 ppm boron equivalents in the diet as boric acid or borax (at an estimated dose level of 101 and 116 mg boron /kg/day for males and females); sterility was associated with a lack of viable sperm in atrophied testes in males and decreased ovulation in females (Weir and Fisher 1972). Rats were exposed for 14 weeks before mating in this study. No pregnancies occurred when female rats exposed to this dose level were mated with non-exposed male rats. At lower exposure levels (10 or 30 mg boron/kg/day for males and 12 or 35 mg boron/kg/day for females), no exposure-related adverse effects were found on overall fertility indices in three successive generations (Weir and Fisher 1972).

Studies in mice and dogs support the observations of reproductive effects seen in rats. In a study in which male CD-1 mice were exposed to gavage doses of boric acid of 0, 21, 70, or 210 mg boron/kg/day for 21 days (5 days before mating, during 5 days of mating, and extending to 21 total days of exposure), average testes weights were decreased at doses ≥70 mg boron/kg/day, and exfoliation/disruption of seminiferous tubules and inhibited spermiation were observed at 210 mg boron/kg/day (Harris et al. 1992). Exposed male mice were mated to similarly exposed female mice (except that females were exposed for 8 days before mating), but no exposure-related effects were found on the percentage of females who became pregnant, the number of live pups per litter, or the weight of pups at birth (Harris et al. 1992). Degeneration of the seminiferous tubules was seen in mice exposed to 288 mg boron/kg/day as boric acid in the diet for 13 weeks, while 103-week dietary exposure to 201 mg boron/kg/day as boric acid resulted in testicular atrophy, degeneration of the seminiferous tubules, and interstitial hyperplasia (Dieter 1994; NTP 1987).

In a 2-generation (27-week) feeding study in CD-1 mice using a continuous breeding protocol, seminiferous tubule degeneration, impaired spermatogenesis, and reduced sperm motility resulted from ≥111 mg boron/kg/day as boric acid (Fail et al. 1991). These doses were also associated with reduced litter size and fetal body weight. No effects were observed in a 27 mg boron/kg/day dose group.

In mongrel dogs fed boric acid or borax for 90 days, severe testicular atrophy was seen at 60.5, but not at 6 mg boron/kg/day (Weir and Fisher 1972). With 2 years of exposure, testicular atrophy and spermatogenic arrest were observed in dogs exposed to 22.8, but not in dogs exposed to 6.8 mg boron/kg/day (Weir and Fisher 1972).

Effects of boric acid or borates on female reproductive organs and their functions are less clearly identified and studied in animals than effects on male reproductive organs. When pregnant CD-1 mice were exposed to gavage doses of 210 mg boron/kg/day on gestation days 8–14, all dams failed to deliver litters (Harris et al. 1992). Exposure to 21 or 70 mg boron/kg/day during the same period did not affect littering ability, average litter weight, or the number of live neonates at postnatal days 0, 1, and 4 (Harris et al. 1992). Mechanistic aspects of this effect of gestational exposure on littering capability of pregnant rats are unstudied. As discussed earlier, female Sprague Dawley rats exposed for 14 weeks to 1,170 ppm boron equivalents in the diet as boric acid or borax (estimated dose level of 116 mg boron/kg/day) did not become pregnant when mated with non-exposed males (Weir and Fisher 1972). The female sterility response at this dose level was associated with decreased ovulation.

The highest NOAEL values and all reliable LOAEL values for reproductive effects in animals and duration category are recorded in Table 3-2 and plotted in Figure 3-2.

3.2.2.6. Developmental Effects

No studies were available identifying developmental toxicity in humans from exposure to boron. However, several types of developmental effects (e.g., decreased fetal body weight, increased incidence of skeletal abnormalities) in animals were observed in standard developmental toxicity studies involving oral exposure of pregnant mice, rats, and rabbits to boric acid of borate salts. In addition, reduced pup weight at birth has been observed in animals receiving intermediate-duration exposures.

In mice, reduced fetal body weight and skeletal malformations were seen following acute- and intermediate-duration maternal oral exposures to boric acid.

Pregnant CD-1 mice fed 79 mg boron/kg/day as boric acid on gestation days 0–17 had fetuses with 33% lower body weight compared with controls, while fetal skeletal effects (e.g., short rib XIII, agenesis of lumbar vertabra, fused ribs) were reported at 175.3 mg boron/kg/day on gestation days 0–17 (Heindel et al. 1992, 1994). No effects on fetal development were observed in the 43.4 mg boron/kg/day dose group (Heindel et al. 1992, 1994).

No effects on implantation sites, littering, number of live pups per litter, or postnatal pup weight were observed following gavage exposure of pregnant CD-1 mice to 70 mg boron/kg/day as boric acid on gestation days 8–14 (Harris et al. 1992).

In an acute-duration study, pregnant CD-1 mice were given gavage doses of boric acid on various gestation days to examine the influence of stage of fetal development on skeletal malformations caused by boric acid (Cherrington and Chernoff 2002). When two gavage doses of 70 mg boron/kg as boric acid were given on gestation day 6, 7, 8, 9, or 10, increased incidence of fetuses with cervical rib and rib agenesis were observed in the groups treated on gestation day 8, but not with exposure on gestation days 6, 7, 9, or 10 (Cherrington and Chernoff 2002). Similarly, increased incidences of fetuses with cervical rib, rib agenesis, reduced rib length, and fused ribs were seen after twice daily doses of 70 mg boron/kg on gestation days 6–8. Reduction in length of fetal rib XIII was seen in groups dosed once daily with 88 mg boron/kg/day on gestation days 6–10. A single dose of 131 mg boron/kg on gestation day 8 resulted in increased incidence of fetuses with cervical ossification, while two doses of 131 mg boron/kg on gestation day 8 caused multiple thoracic skeletal malformations. Reduced fetal weight was observed in all treated groups (Cherrington and Chernoff 2002). This study did not identify acute NOAELs for fetal skeletal effects in mice. The study authors suggested that boric acid may alter gastrulation and presomitic mesoderm formation in CD-1 mice, which are key gestational milestones for axial skeletal development.

In rats, acute-duration developmental toxicity data were not available. However, intermediate-duration oral exposure of pregnant rats exhibited effects on fetal skeletal development and fetal weight, similar to those observed in mice. Pregnant Sprague-Dawley rats fed 13.6 boron/kg/day as boric acid in the diet on gestation days 0–20 had reduced fetal body weight, and increased incidence of fetuses with skeletal abnormalities at gestation day 20 occurred in groups of dams fed 28.4 mg boron/kg/day (Heindel et al. 1992). Skeletal abnormalities observed in groups fed 28.4 mg boron/kg/day included agenesis or shortening of rib XIII, increased incidence of fetuses with enlargement of the lateral ventricles of the fetal brain, and increased resorptions (Heindel et al. 1992). Pregnant Sprague-Dawley rats fed 10 mg boron/kg/day as boric acid on gestation days 0–20 exhibited no developmental effects, but exposures of 13 mg boron/kg/day as boric acid resulted in decreased fetal body weight and skeletal abnormalities seen on gestation day 0. However, in a second phase of this study, identically treated dams were allowed to litter and pups were observed through postnatal day 21. Upon necropsy, these pups did not exhibit significantly different body weights or incidences of skeletal abnormalities seen and fetuses examined on gestation day 0 (Price et al. 1996a, 1998).

Developmental toxicity data in rabbits are available only for acute-duration oral exposures (Price et al. 1996b). Pregnant New Zealand white rabbits given gavage doses of 44 mg boron/kg/day as boric acid on gestation days 6–19 exhibited increased maternal body weight (corrected for gestation) and reduced maternal kidney weight, gravid uterine weight, fetal body weight, number of ovarian corpora lutea, number of implantation sites, and live fetuses, compared with controls. Resorptions and fetal external (cleft palate), visceral (enlarged lateral ventricle of the brain), skeletal (cleft sternum, fused sternebrae), and cardiovascular (enlarged aorta, interventricular septal defect) malformations were increased, compared with controls. No significant maternal or fetal effects were observed following gavage doses of 22 mg boron/kg/day as boric acid. The observed effects are consistent with those seen in acute-, intermediate-, and chronic-duration oral exposures in other animals. These data represent the most sensitive adverse effects observed in any species following acute-duration oral exposures. Thus, an acute-duration MRL of 0.2 mg boron/kg/day was derived based on a NOAEL of 22 mg boron/kg/day and a LOAEL of 44 mg boron/kg/day for developmental effects in New Zealand white rabbits (Price et al. 1996b).

With intermediate-duration oral exposure to boric acid, reduced fetal body weight and skeletal abnormalities were consistently observed in developmental toxicity assays of mice, rats, and rabbits. Skeletal malformations increased in variety and severity with dose. However, reductions in fetal body weight appear to occur at lower exposure levels than those associated with skeletal abnormalities. With intermediate-duration exposure during gestation, the most sensitive developmental effect identified across all three species was reduced fetal weight in pregnant Sprague-Dawley rats fed 13.6 mg boron/kg/day in the diet on gestation days 0–20. This effect was seen at lower intermediate-duration exposure levels than the lowest intermediate-duration oral dose associated with reproductive effects in rats (i.e., a LOAEL of 26 mg boron/kg/day was identified for inhibition of spermiation in rats) (Ku et al. 1993a). An intermediate oral MRL of 0.2 mg boron/kg/day was calculated as described in the footnote on Table 3-2, based on a benchmark dose analysis (Allen et al. 1996) of combined data sets (Heindel et al. 1992; Price et al. 1996a) for reduced fetal body weight in rats.

The highest NOAEL values and all reliable LOAEL values for developmental effects in animals and duration category are recorded in Table 3-2 and plotted in Figure 3-2.

3.2.2.7. Cancer

Three epidemiological studies have associated increased boron intake in drinking water with decreased incidences of prostate and vaginal cancer. Cui et al. (2004) used the cross-sectional data from the NHANES III study, conducted from 1988 to 1994, which contained health and diet information for the non-institutionalized U.S. population. These investigators reported that men with mean intakes of ≥1.54 mg boron/day had significantly less risk of developing prostate cancer than men ingesting ≤0.52 mg/day. This study was limited by its cross-sectional design and reliance on 1-day recall of diet information to estimate boron exposure. A second study (Barranco et al. 2007) on a Texas population correlated increased boron in groundwater with reduced prostate cancer incidence rates. However, the observed correlation appeared to be driven primarily by 2–3 specific cases. Korkmaz et al. (2007) studied 1,059 rural Turkish women and associated higher boron intake (as evidenced by approximately 8-fold higher urinary boron concentration) with lower incidences of cervical cytopathology (0 findings in the high-boron group, 15 cases in the low-boron group). While this study did attempt to correct for lifestyle factors and other genotoxic confounders, it was cross-sectional in design. The hypotheses drawn from these studies are interesting; however, no clinical studies in humans or animals are available to substantiate effects of anti-tumor protection offered by boron.

No evidence of exposure-related cancer was observed in rats exposed to 81 mg boron/kg/day as boric acid or borax for 2 years (Weir and Fisher 1972), dogs exposed to 6.8 mg boron/kg/day as boric acid or borax for 2 years (Weir and Fisher 1972), or mice exposed to 201 mg boron/kg/day as boric acid for 2 years (Dieter 1994; NTP 1987). In nude mice subcutaneously injected with human LNCaP cells (prostate tumor clones), oral gavage doses of boric acid were given for 8 weeks (Gallardo-Williams et al. 2004) to determine if boron offered protection against prostate tumor growth. Although there was no significant difference between control and boron-treated mice in tumor incidences, the tumor sizes in mice given 1.7 mg boron/kg/day were significantly smaller and the serum level of tumor specific antigen (PSA) was significantly less than controls.

3.2.3.1. Death

No studies were located regarding death in humans or animals after dermal exposure to boron.

3.2.3.2. Systemic Effects

No studies were located regarding hematological and dermal/ocular effects in humans or regarding respiratory, cardiovascular, gastrointestinal, musculoskeletal, hepatic, or renal effects in humans or animals after dermal exposure to boron.

Hematological Effects. Draize and Kelley (1959) reported the application of 25–200 mg/kg/day boric acid in aqueous solution did not produce hematological changes when rubbed onto intact skin during a 90-day rabbit study. No quantitative data were provided; therefore, these results could not be evaluated.

Dermal Effects. Human data are limited to case reports of accidental exposure of the head. Three male workers (59-year-old waste handler and 34- and 36-year-old automotive mechanics) presented with general or focal alopecia of the scalp, presumably from spillage or wiping of boric acid or borax, respectively, onto the head (Beckett et al. 2001). In the case of the waste handler, the concentration of boric acid in the milieu of other known solvents in the waste tank was unknown. In the cases of the automotive workers, exposure was determined to arise from under-the-chassis flushing of automobile radiators which contained coolant solutions of ethylene glycol and 1–5% borax. Actual exposures could not be determined. Blood sample analysis revealed no elevated blood boron levels in any of the subjects. Gradual and full hair re-growth occurred.

In animals, application of 1 g boron oxide dust to a 25 cm² area of the skin of four rabbits produced erythema that lasted for 2–3 days (Wilding et al. 1959).

Ocular Effects. Instillation of boron oxide dust (50 mg) into the eyes of four rabbits produced conjunctivitis (Wilding et al. 1959).

No studies were located regarding the following effects in humans or animals after dermal exposure to boron:

3.2.3.3. Immunological and Lymphoreticular Effects

3.2.3.4. Neurological Effects

3.2.3.5. Reproductive Effects

3.2.3.6. Developmental Effects

3.2.3.7. Cancer

3.4.1.1. Inhalation Exposure

Reports of upper respiratory tract symptoms of irritation following exposure to boron oxide and boric acid dusts suggest that boron can deposit in the upper airway (Garabrant et al. 1984, 1985). Borax production workers were found to have approximately an order of magnitude higher blood and urine concentrations of boron at the end of a work shift compared to the beginning, suggesting that inhaled boron is absorbed and systemically distributed (Culver et al. 1994a).

3.4.1.2. Oral Exposure

Near-complete gastrointestinal absorption was indicated in humans as evidenced by the urinary recovery of 93.9% of the ingested dose of boric acid over a 96-hour collection period (Jansen et al. 1984a). Dourson et al. (1998) reviewed data from the literature to estimate oral absorption fractions of 81–92% for humans and 95% for animals (rats).

3.4.1.3. Dermal Exposure

Volunteers exhibited 0.23 and 0.21% percutaneous absorption of 1.8 mL of 5% solutions of boric acid and borax (Wester et al. 1998). Urinary excretion studies in humans (Section 3.4.4.3) suggest there is very little absorption of boron through intact skin. Excretion studies (Section 3.4.4.3) in rabbits suggest that boron is readily absorbed following contact with damaged skin (Draize and Kelley 1959).

3.4.2.1. Inhalation Exposure

No studies were located regarding distribution of boron in animals after inhalation exposure.

3.4.2.2. Oral Exposure

Boron evenly distributed to liver, kidney, brain, muscle, adrenals, epididymis, testes, seminal vesicles, and blood, but not fat, of male rats fed 61 mg boron/kg/day as boric acid (9,000 ppm) for 1–28 days (Ku et al. 1991; Moseman 1994; Treinen and Chapin 1991), reaching steady-state by 4 days. Blood and testes boron levels were similar in rats fed 26–68 mg boron/kg/day as boric acid (3,000–9,000) for 9 weeks (Ku et al. 1991). However, boron accumulated in bone in male rats fed 61 mg boron/kg/day (as boric acid) for 9 weeks, with achievement of steady-state at 4 weeks. Bone levels were approximately 3-fold higher than soft tissue levels (Moseman 1994).

3.4.2.3. Dermal Exposure

No studies were located regarding distribution of boron in animals after dermal exposure.

3.4.4.1. Inhalation Exposure

Over 94% of estimated total boric acid (mean 11.84 mg boron/day) inhaled and ingested by Chinese borate workers was eliminated 24 hours later in the urine (Xing et al. 2005) as determined by the percent estimated daily dose recovered in the urine. In rats that inhaled average concentrations of 77 mg/m³ boron oxide aerosols over a 22-week period, an average of 11.90 mg boron/kg/day was detected in the urine compared to 0.24 mg/kg/day in untreated control groups (Wilding et al. 1959).

3.4.4.2. Oral Exposure

Over 93% of the administered dose was excreted in the urine of six male volunteers 96 hours after administration of a single oral dose of 1.9 mg boron/kg (as boric acid) (Jansen et al. 1984a). An analysis of nine cases involving boric acid poisoning revealed a mean half-life of 13.4 hours (range 4–27.8 hours).

There was no correlation between half-life and calculated serum boric acid level at t_o (r=0.08, p=0.84) (Litovitz et al. 1988). Boric acid was detected in urine of patients 23 days after a single ingestion (Wong et al. 1964). Renal clearance of dietary boron from fifteen pregnant women was calculated to be 1.02 mL/minute/kg, or 66.1 mL/minute (Pahl et al. 2001).

In rabbits, 50–66% of the administered dose was recovered in urine after ingestion of 17.1–119.9 mg boron/kg/day as boric acid (Draize and Kelley 1959). In rats fed 26–68 mg boron/kg/day as boric acid (3,000–6,000 ppm) for 9 weeks, boron concentrations in bone began decreasing after cessation of exposure; however, bone levels remained approximately 3-fold higher than controls for up to 32 weeks (Chapin et al. 1997; Moseman 1994). Blood levels in these same animals returned to control levels within 7 days of exposure cessation (Ku et al. 1991). Using literature data, Dourson et al. (1998) estimated the fraction eliminated of absorbed boron to be 67–98% in humans and 99% in rats. These investigators also calculated clearance values of 40 mg/kg/hour in humans, 163 mg/kg/hour in rats, and 397 mg/kg/hour in pregnant rats. Pregnancy did not affect renal clearance (0.2 L/hour/kg or 1.0 mL/minute) or elimination half-life (3.2 hours) in rats given gavage doses of 0.05–5 mg boron/kg/day (as boric acid) on gestation day 16 (Vaziri et al. 2001).

3.4.4.3. Dermal Exposure

Limited data in humans suggest that very little absorption of boron occurs through intact skin. There was no increase in the urinary excretion of boron in one human subject following the application of 15 g boric acid (37.5 mg boron/kg body weight) on the forearm for 4 hours (Draize and Kelley 1959). In volunteers having 1.8 mL of 5% boric acid or borax solutions applied to the back and left for 24 hours, urinary boron levels increased to peak values of <0.1% above background levels at 14 days following exposure (Wester et al. 1998).

Animal studies support human findings. Draize and Kelley (1959) applied 200 mg/kg as boric acid to intact, abraded or burnt, and partially denuded skin of rabbits. Net urinary excretion of boric acid per 24 hours during 4 consecutive days of compound treatment was 1.4, 7.6, and 21.4 mg/kg, respectively (0.25, 1.3, and 3.7 mg boron/kg, respectively).

3.4.4.4. Other Routes of Exposure

In eight adult volunteers administered a single dose of boric acid (562–611 mg) by intravenous infusion, 98.7% of the administered dose was recovered in urine 120 hours after injection (Jansen et al. 1984b).

Renal blood clearance averaged 39.1 mL/minute per 1.73 m² surface area in eight adult human subjects administered intravenous injections of 35 mg boron/kg (as sodium pentaborate). Urine boron concentrations on the day of administration averaged 1.19 mg/mL (Farr and Konikowski 1963). In rats administered an intravenous infusion of 86 mg boron/kg (as borax) (Tagawa et al. 2000), boron distributed rapidly to the extravascular tissues, giving a steady state volume of distribution of 1.19 L/kg. Excretion of boron was rapid, with 87.6% eliminated in the urine by 2 hours after infusion. Pharmacokinetic analysis of the blood time course data resulted in an estimated elimination rate constant (K_el) of 0.15 hour^-1 and a clearance rate of 0.11 L/hour/kg. The elimination half-life was 8.43 hours. Guinea pigs given intra-tympanic doses of 0.2 mL/day of 4% boric acid in saline did not exhibit changes in hearing level (Oztukcan et al. 2008).