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Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Comparable to a guideline study. This study is conducted on an analogue substance. Read-across is justified on the following basis: In aqueous solutions at physiological and acidic pH, low concentrations of simple inorganic borates such as boric acid, disodium tetraborate decahydrate, disodium tetraborate pentahydrate, boric oxide and disodium octaborate tetrahydrate will predominantly exist as undissociated boric acid. At about pH 10 the metaborate anion (B(OH)4-) becomes the main species in solution (WHO, 1998). This leads to the conclusion that the main species in the plasma of mammals and in the environment is un-dissociated boric acid. Since other borates dissociate to form boric acid in aqueous solutions, they too can be considered to exist as un-dissociated boric acid under the same conditions. For comparative purposes, exposures to borates are often expressed in terms of boron (B) equivalents based on the fraction of boron in the source substance on a molecular weight basis. Some studies express dose in terms of B, whereas other studies express the dose in units of boric acid. Since the systemic effects and some of the local effects can be traced back to boric acid, results from one substance can be transferred to also evaluate the another substance on the basis of boron equivalents. Therefore data obtained from studies with these borates can be read across in the human health assessment for each individual substance. Conversion factors are given in the table below. Conversion factor for equivalent dose of B Boric acid H3BO3 0.175 Boric Oxide B2O3 0.311 Disodium tetraborate anhydrous Na2B4O7 0.215 Disodium tetraborate pentahydrate Na2B4O7•5H2O 0.148 Disodium tetraborate decahydrate Na2B4O7•10H2O 0.113 Disodium octaborate tetrahydrate Na2B8O13•4H2O 0.210 Sodium metaborate (anhydrous) NaBO2 0.1643 Sodium metaborate (dihydrate) NaBO2•2H2O 0.1062 Sodium metaborate (tetrahydrate) NaBO2•4H2O 0.0784 Sodium pentaborate (anhydrous) NaB5O8 0.2636 Sodium pentaborate (pentahydrate) NaB5O8∙5H2O 0.1832 References: WHO. Guidelines for drinking-water quality, Addendum to Volume 1, 1998.
Objective of study:
excretion
Qualifier:
according to
Guideline:
other: No data
Deviations:
not specified
Principles of method if other than guideline:
Groups of 10 Sprague-Dawley (Charles River) pregnant or non-pregnant rats, were maintained on a specially prepared low boron diet (approximately equivalent to 0.3 boric mg/kg/day) for 7 days prior and switched to a lower boron diet 24 h prior to treatment. Doses of 0.3 (0.052), 3.0 (0.52) or 30 (5.2) mg boric acid (mg B)/kg in water was administered by gavage. Plasma boron was determined at 3 h and 15 h after administration of boric acid and urine was collected for 12 h after the first blood sample was taken. A separate experiment was performed to estimate the plasma half-life. Six pregnant and six non-pregnant rats were treated in the same way as for the renal clearance study. They received a single dose of 30 (5.2) mg boric acid (mg B)/kg (on GD 16) for the pregnant rats. Blood samples (0.25 mL) were taken by periorbital puncture after light anaesthesia at 3, 5, 7, 9,12 and 15 hours post dosing.
GLP compliance:
not specified
Radiolabelling:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 12-weeks old
- Weight at study initiation: 200 - 250 g
In addition 37 timed-pregnant rats of simillar weight range were used.
- Diet: Ad libitum
- Water: Ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 50 - 60 %
- Photoperiod (hrs dark / hrs light): 12h dark/light
- Other: Animals were maintained in stainless steel cages and potential soures of boron were minimised.
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
All pregnant and non-pregnant rats were maintained on a casein-based rat diet. To ensure an adequate amount of dietary boron a "low boron" diet (1.4 mg BA/kg diet, or 0.25 mg B/kg diet) was used and supplemented with boric acid (3.5 mg BA/kg diet, or 0.64 mg B/kg diet) and the rats were given the supplemented diet on days 1 through 7 of the study (prior to gavage adminsitration of boric acid). Pregnant rats were placed on the supplemented diet beginning on day 9 of gestation for the first 7 days of the study. This diet aimed to acheive steady state conditions for rats given a diet comparable to that ingested by humans in terms of boron intake. The supplemented diet contained about 15 - 25 times less than boron in Purina rat chow and was designed to deliver a dose of approximately 0.3 mg/kg/day of boric acid (equivalent to 0.05 mg B/kg/day).
On the afternoon of the 7th day (GD 15 for pregnant rats) through the evening of the 8th day of the study all pregnant and non-pregnant rats were switched to low-boron caein diets without the boric acid supplementation to minimise any cross-contaminiation of the urine with boron in the diet.

Duration and frequency of treatment / exposure:
Single administration
Remarks:
Doses / Concentrations:
Renal clearance study: 0.3, 3.0 or 30 mg boric acid/kg bw; 0.052, 0.52 and 5.2 mg boron /kg respectively by gavage.
Plasma half-life study: 30 mg boric acid/kg.
No. of animals per sex per dose:
Renal clearance study: 10 rats per group, sex not specified
Plasma half-life study: 6 pregnant and 6 non-pregnant females.
Control animals:
yes, concurrent vehicle
Positive control:
No data
Details on study design:
Renal clearance study:
The lowest dose was comparable to the high end of the normal range of human dietary intake of boron. The highest dose was approximately half of the NOAEL.

Plasma half-life study:
The dose was equivalent to the highest dose in the clearance study and was selected because if any dose level exhibits a non-linear plasma curve it is most likely to be the high dose. It is assumed that if the high dose is linear then the lower doses would also be linear.
Details on dosing and sampling:
Renal clearance study:
Two blood samples were drawn from each rat, the first after approximately 3 h after administration; the second approximately 12 h after the first.
A 12 h urine sample was collected from each rat the clearance study during the period between the first and second blood samples being taken.

Plasma half-life study:
Six blood samples were drawn from each animal during a 12 h period starting 3 h after dosing on Day 8 of the study.
Statistics:
Reanal clearance was expressed as mean ± standard deviation. Two way analysis of variance, multiple range test (Student-Newman-Keuts Method) was used as appropriate. For all statistical analyses p values < 0.05 were considered statistically significant.
Type:
excretion
Results:
Renal clearance: 3.1 mL/min/kg for non-pregnant rats, 3.2 mL/min/kg for pregnant rats. Clearance independent of dose up to 30 mg boric acid/kg bw. (5.24 mgB/k).
Details on absorption:
Plasma half-life evaluation:
Gavage administration resulted in plasma levels of 1.82 ± 0.32 and 1.78 ± 0.32 μg B/mL among non-pregnant and pregnant rats in the first blood sample which was taken 3 h after dosing. This was followed by a monophasic decline in plasma boron concentrations in both pregnant and non-pregnant rats; the plasm levels were consistent with a compartmental model. There was no evidence of saturation kinetics. The estimated half-lives of boric acid in non-pregnant and pregnant rats were 2.93 ± 0.24 and 3.23 ± 0.28 h respectively. This difference was not statistically significant.
Details on distribution in tissues:
No data
Details on excretion:
The urinary concentration of boron was significantly higher in pregnant compared to non-pregnant rats at the high dose, but not at the mid or low dose. The concentration of boron in the urine during the 12 h collection period in the urine of non-pregnant rats was 1.67 ± 0.62, 10.12 ± 8.16 and 66.82 ± 47.00 μg B/mL at the low, mid and high doses respectively. In pregnant rats the corresponding urine boron concentrations were 1.62 ± 0.49, 12.30 ± 5.12 and 121.45 ± 47.09 μg B/mL, respectively. The amount of boron excreted in the urine increased proportionately with increasing dose. The percentage of the administered dose recovered in the urine was significantly higher in the low dose group compared to the mid and high dose groups. No significant dose-related differences in boric acid clearance were observed in either non-pregnant or pregnant rats.
Toxicokinetic parameters:
half-life 1st: The plasma half-life of boric acid in non-pregnant and pregnant rats given boric acid by gavage was 2.93 ± 0.24 and 3.23 ± 0.28 hours, respectively.
Metabolites identified:
no
Details on metabolites:
Boric acid is not metabolised.
Conclusions:
Interpretation of results (migrated information): no data
Gavage administration resulted in plasma levels of 1.82 ± 0.32 and 1.78 ± 0.32 μg B/mL among non-pregnant and pregnant rats in the first blood sample which was taken 3 h after dosing. This was followed by a monophasic decline in plasma boron concentrations in both pregnant and non-pregnant rats; the plasma levels were consistent with a compartmental model. There wsa no evidence of saturation kinetics. The estimated half-lives of boric acid in non-pregnant and pregnant rats were 2.93 ± 0.24 and 3.23 ± 0.28 h respectively. This difference was not statistically significant.
The urinary concentration of boron was significantly higher in pregnant compared to non-pregnant rats at the high dose, but not at the mid or low dose. The concentration of boron in the urine during the 12 h collection period in the urine of non-pregnant rats was 1.67 ± 0.62, 10.12 ± 8.16 and 66.82 ± 47.00 μg B/mL at the low, mid and high doses respectively. In pregnant rats the corresponding urine boron concentrations were 1.62 ± 0.49, 12.30 ± 5.12 and 121.45 ± 47.09 μg B/mL, respectively. The amount of boron excreted in the urine increased proportionately with increasing dose. The percentage of the administered dose recovered in the urine was significantly higher in the low dose group compared to the mid and high dose groups. No significant dose-related differences in boric acid clearance were observed in either non-pregnant or pregnant rats.
Read-across is justified on the basis detailed in the rationale for reliability above. This study is therefore considered to be of sufficient adequacy and reliability to be used as a supporting study and no further testing is justified.

Description of key information

Key value for chemical safety assessment

Additional information

Assessment entity approach

"Brazing fluxes" are mixtures of boron-containing constituents (potassium(fluoro)borates), which undergo chemical exchanges (anion exchange) and condensation reactions (e.g. formation of oligoborates, polyborates) upon mixing and further manufacturing. This results in a complex mixture of potassium borates, which cannot be fully chemically characterised for substance identity. Thus, according to the definition under REACH, such brazing fluxes must be described as a UVCB substance.

 

Toxicokinetic data specifically on the UVCB substance to be registered are not available. An assessment entity approach is followed based on the transformation products of this UVCB uppon dissolution in aqueous media. The substance is highly soluble and forms complex boron, potassium and fluoride constituents. The quantitatively predominant transformation product of this UVCB is represented by boric acid, which is assumed to be the determinant of human health effects because of its classification and its toxicity. For this reason, the assessment is based on information for “borates” (including potassium borate, boric acid and other borate substances).

 

Based on the information provided below, it may safely be assumed that under physiological conditions the chemical speciation of most of the unknown potassium boron compounds corresponds to boric acid. Thus, from a chemical point of view, there is no reason to assume that brazing fluxes would behave differently than boric acid and/or borates under physiological conditions.

 

The basis of this assessment entity approach is further justified by the following reasoning:

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

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

 

Substance

Formula

Conversion factor for equivalent dose of B (multiply by)

Boric acid

H3BO3

0.1748

Boric Oxide

B2O3

0.311

Disodium tetraborate anhydrous

Na2B4O7

0.2149

Disodium tetraborate pentahydrate

Na2B4O7•5H2O

0.1484

Disodium tetraborate decahydrate

Na2B4O7•10H2O

0.1134

Disodium octaborate tetrahydrate

Na2B8O13·4H2

0.2096

Sodium metaborate (anhydrous)

NaBO2

0.1643

Sodium metaborate (dihydrate)

NaBO2·2H2O

0.1062

Sodium metaborate (tetrahydrate)

NaBO2·4H2O

0.0784

Sodium pentaborate (anhydrous)

NaB5O8

0.2636

Sodium pentaborate (pentahydrate)

NaB5O8∙5H2O

0.1832

 Dipotassium tetraborate (anhydrous)

 

 K2B4O7

 

 0.185

 

 Dipotassium tetraborate (tetrahydrate)

 

 K2B4O7.4H2O

 

 0.1415

 

 Potassium pentaborate (anhydrous)

 

 B5KO8

 

 0.244

 

 Potassium pentaborate (tetrahydrate)

 

 B5KO8.4H2O

 

 0.1843

 

 

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

Toxicokinetic data (for borates):

There is little difference between animals and humans in absorption, distribution, and metabolism of borates, with the exception of renal clearance, which is approximately 3 times faster in rats than in humans.

Boric acid is not metabolised in either animals or humans, owing to the high energy level required (523 kJ/mol) to break the B - O bond (Emsley, 1989). Other inorganic borates convert to boric acid at physiological pH in the aqueous layer overlying the mucosal surfaces prior to absorption. Most of the simple inorganic borates exist predominantly as undissociated boric acid in dilute aqueous solution at physiological and environmental pH, leading to the conclusion that the main species in the plasma of mammals is un-dissociated boric acid. Since other borates dissociate to form boric acid in aqueous solutions, they too can be considered to exist as un-dissociated boric acid under the same conditions. Additional support for this derives from studies in which more than 90 % of administered doses of inorganic borates are excreted in the urine as boric acid. Absorption of borates via the oral route is nearly 100 %. For the inhalation route also 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. 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.