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Description of key information

Elemental boron is biologically not available: the uptake of soluble boron has been shown to be minimal, and correlates with the analytically and structurally verified very thin surface layer of boric acid on the otherwise inert elemental boron particles.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
0.05

Additional information

The toxicity data in this registration dossier refer explicitly to elemental boron and document its negligible bioavailability and the complete lack of any human health hazard. It is noted here that a clear distinction should be made to what elsewhere in the public domain is referred to as “boron”: any such data can ultimately be traced back to various soluble forms of “borates”, as for example reviewed by ATSDR (2010), WHO/EHC (1998, 2006) and EPA/IRIS (2004). Contrastingly, experiments on the bioavailability of elemental boron are summarised and discussed in this section.

 

Summary of water solubility study (Klawonn, 2013)

Based on a water solubility study conducted acc. to guideline OECD 105 and under GLP, the following conclusion was derived: the concept of “equilibrium solubility” is not applicable to metals or metalloids like boron. Instead, it is reasonable to assume that an extremely thin, hardly measurable oxide layer exists on the surface of boron powder particles, and that it is this oxide layer which initially dissolves in water, leading to very low measurable concentrations of dissolved boron in this test (loading of 100 mg boron powder per litre; slow stirring for 72h at 20°C). Based on the measured concentrations of dissolved boron after filtration, approx. 0.155 % (mass) of the boron powder loading were detected as dissolved borate..

Summary of in-vitro bioaccessibility experiments (Knopf, 2013)

Water solubility is a poor surrogate for the assessment of bioavailability, which is why supplementary dissolution experiments in artificial physiological media (“bioaccessibility”) were conducted in vitro. These investigations are considered to represent conservative estimates of potential bioavailability for the most relevant exposure routes (oral, dermal and inhalation). In these experiments, the following five media were used:

- Gamble’s solution (GMB, pH 7.4) which mimics the interstitial fluid within the deep lung under normal health conditions,

- phosphate-buffered saline (PBS, pH 7.2), which is a standard physiological solution that mimics the ionic strength of human blood serum,

- artificial sweat (ASW, pH 6.5) which simulates the hypoosmolar fluid, linked to hyponatraemia (loss of Na+ from blood), which is excreted from the body upon sweating,

- artificial lysosomal fluid (ALF, pH 4.5), which simulates intracellular conditions in lung cells occurring in conjunction with phagocytosis and represents relatively harsh conditions and

- artificial gastric fluid (GST, pH 1.5), which mimics the very harsh digestion milieu of high acidity in the stomach.

Elemental boron powder was exposed to these media at a loading of 100 mg/L, for 2 or 24 h and at 37 °C. Dissolved boron concentrations were measured following separation of the media from undissolved particles.

The highest dissolution was observed in artificial gastric juice (HCl at pH = 1.5), in which 0.35% (mass) of the elemental boron powder dissolved after 24 h. However, this result is not taken into account further, as such a long exposure time of 24 h significantly overestimates actual gastric passage times. After 2 h in artificial gastric juice, 0.134% of the added boron dissolved. Note that the very low pH of 1.5 of this artificial gastric juice already represents a worst case scenario, since in reality - in a non-fasted state - the pH in the stomach is not so low.

Apart from the disregarded figure of 0.35% (24h in GST), dissolved borate concentrations under physiologically relevant conditions were generally between ca. 100 and 150 µg/L (0.1-0.15% of material dissolved) in all media.

 

Toxicokinetic screening data from a 28 day repeated dose oral toxicity study (Leuschner, 2013)

In a 28 day repeated dose toxicity study, male and female rats were given a daily dose of elemental boron of 1,000 mg/kg bw/day via gavage. Individual urine samples were collected from all animals prior to sacrifice in one cumulated 24-h fraction/animal after the last oral application, and blood samples were collected from each animal upon sacrifice. The plasma and urine samples were analysed for total boron content. No increase whatsoever in boron plasma concentrations of the treated animal in comparison to controls was observed, the (boron in plasma from the control group and dosed group being below detection limit in all samples.

Only a very slight increase in urine boron levels form treated animals was observed. The boron concentration of the 24h-urine samples, collected during the day before final sacrifice, ranged from 1.8 to 6.0 mg boron/L urine (mean: 4.24 ±1.72) and 2.5 to 4.5 mg boron/L urine (mean: 3.24 ±0.83) for the male and female animals of the control group, respectively. For the dosed group, the concentrations were 7.6 to 14.8 mg boron/L urine (mean: 12.16 ±2.81) and 5.5 to 11.2 mg boron/L urine (mean: 8.04 ±2.24) for the male and female animals of the dose group respectively.

Following a subtraction of the background urinary boron excretion (control group), and taking into account the excreted urine volume (mean 17.2 mL (m) and 16.8 mL (f)) and the body weight of the animals at the end of the study (mean 348 g (m) and 199 g (f)), the following conclusion can be made:

From a final dose of 1,000 mg/kg of boron that the animals received on the last day of the study, only cumulated relative amounts of 0.039 % (m) or 0.040% (f) were found in the terminal 24-h urine collection period.

 

Summary of comparative Mass-Balance Study (Leuschner 2015a):

In a comparative mass balance study involving oral dosing of (i) amorphous (elemental) boron and (ii) a soluble borate substance (boric acid), the gastrointestinal absorption as well as urinary and faecal excretion were compared, plus consideration of dietary „background“ intake/excretion via a vehicle-dosed control. For details, please refer to the corresponding robust study summary. In brief, 10 (5m/5f) per group received a single oral dose of 1000 mg/kg of elemental boron or 572 mg/kg of boric acid (corresponding to 100 mg/kg of “boron”). A third group served as vehicle treated control. Animals were individually housed in metabolic cages and daily samples of urine and faeces were collected for three days. All samples were analysed for boron. The averaged “background” excretion via urine and faeces of the control animals was subtracted from the amounts excreted by the dosed animals, and a mass balance was calculated.

Animals that received 100 mg B/kg bw (as boric acid) orally excreted 86.1 % of the administered dose via urine and faeces during the first three days after exposure (mean for 10 animals).

The largest fraction (80.7 %) was excreted via urine already within the first 24h. These findings indicate a rapid absorption of boric acid in the gastrointestinal tracts, as well as a rapid renal clearance.

Animals that received 1000 mg B /kg bw (as elemental boron) orally excreted 0.05 % of the administered dose via urine and 99.45% via faeces during the first three days after exposure (mean for 10 animals); the cumulative excretion reached 99.5%.

The largest fraction (93.9 %) was excreted via faeces already within the first 24h with a further 5.1% being excreted via faeces on the second day. Urinary excretion was negligible (only 0.05% of administered dose excreted over three days combined).

At 99.5%, the mass balance is essentially complete and these findings indicate that elemental boron is not absorbed in the gastrointestinal tract of rats to any significant extent, but passes through the animal effectively unchanged.

 

Summary of relative bioavailability study (Leuschner 2015b):

A relative bioavailability study involving serum kinetics over a period of 72 hours p. a. involving an i. v. dosing of a soluble borate reference substance (boric acid) compared to single oral doses of boric acid and amorphous (elemental) boron. For details, please refer to the corresponding robust study summary. In brief, 20 animals (10m/10f) per group received single doses of (1) 572 mg/kg boric acid intravenously, (2) 572 mg/kg boric acid via oral gavage, and (3) 1000 mg/kg elemental boron via oral gavage.

Blood samples were taken at 0, 0.5, 1, 2, 3, 4, 8, 12, 24, 48 and 72 hours post exposure and blood plasma samples were prepared and analysed for boron. To reduce the stress for the animals, not every animal was sampled at every time-point. Instead, 10 animals (5m/f5) from each group were sampled at every second time-point.

Cmax-levels in plasma of 101.18 µg boron/mL and 95.41 µg boron/mL were noted 0.5 hours after intravenous administration of 572 mg boric acid/kg for the male and female rats on test day 1, respectively. Furthermore, Cmax-levels of 37.92 µg boron/mL and 34.03 µg boron/mL were noted 2 or 1 hours after oral administration of 572 mg boric acid/kg for the male and female rats on test day 1, respectively. Lastly, Cmax-levels of 1.15 µg boron/mL and 0.94 µg boron/mL were noted 2 hours after oral administration of 1000 mg boron, amorphous/kg for the male and female rats on test day 1, respectively. For comparison, the average (n=30) concentration of boron in plasma taken before exposure at t=0 h was (0.097 ± 0.059) µg/mL (min=0.04; max=0.34).

The plasma concentrations declined post dosing with an elimination half-life ranging from 2.73 to 4.91 hours.

A relative bioavailability of 91% was calculated for boric acid following oral administration compared to intravenous administration, and of approximately 0.1% for boron, amorphous (0.09 % in males, 0.10% in females).

 

Overall conclusion:

The in-vitro and in-vivo experiments described above are in very good agreement with regards to the negligible level of bioavailability of elemental boron.

(1) In pure water, approx. 0.16% of the loading of 100 mg/L of elemental boron were detected as dissolved boron following slow stirring for 72h at 20°C and subsequent filtration, which can be interpreted as the result of complete dissolution of a minute layer of oxidised boron (“boric acid”).

(2) In in-vitro dissolution experiments in five different artificial physiological media, a maximum of ca. 0.1-0.15% of elemental boron dissolved..

(3) In a 28-day oral toxicity study with 1,000 mg/kg elemental boron no increase in boron plasma concentrations and only a slight increase in boron urine levels was observed when sampled at the end of the 28-day exposure period. Out of the 1000 mg/kg of boron administered on the day, only 0.04% of the dose were found in 24h urine.

(4) In a mass balance study with a single oral dose of 1,000 mg/kg of elemental boron, 99.45% of the dose was excreted via faeces within 3 days, with only 0.05% of the dose being excreted via urine at the same time.

(5) In a relative bioavailability study, the bioavailability of orally administered elemental boron was calculated at 0.1 % in relation to boric acid injected i. v.

When comparing the findings of in-vitro dissolution testing (1 and 2) with in-vivo results (3-5), the in-vivo data consistently demonstrate slightly lower bioavailability. This is in agreement with the general understanding that in-vitro experiments in simulated gastric juice provide a conservative estimate of actual (in-vivo) bioavailability.

In conclusion, the oral bioavailability of elemental boron (powder) can be assumed to be negligible, as demonstrated in three independent in-vivo studies in rats yielding very comparable results and supported by in-vitro dissolution experiments in pure water and five different artificial physiological fluids. The apparent in-vivo absorption at levels < 0.1 % can be attributed to an extremely thin “oxidised” layer of boric acid on the surface of amorphous boron particles.

A rounded value of 0.05% for oral absorption can be taken forward from (i) terminal urine/plasma sampling in a study involving 28 repeated oral doses of 1,000 mg B/kg bw/d and (ii) a mass balance study involving a single dose of 1,000 mg B/kg bw.