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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:
comparable to guideline study
Objective of study:
excretion
Qualifier:
no guideline followed
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 or test system 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
Dose / conc.:
0.3 mg/kg bw/day
Remarks:
renal clearance study, corresponds to 0.052 mg Boron/kg bw/day
Dose / conc.:
3 mg/kg bw/day
Remarks:
renal clearance study, corresponds to 0.52 mg Boron/kg bw/day
Dose / conc.:
30 mg/kg bw/day
Remarks:
renal clearance study, corresponds to 5.2 mg Boron/kg bw/day
Dose / conc.:
30 other: mg/kg bw
Remarks:
Plasma half-life study
No. of animals per sex per dose / concentration:
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 reference chemical:
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 mg B/kg bw).
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:
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.

Description of key information

- Vaziri and Ovesiri, 2000 (not metabolised; rats);
- Hui et al., 1996 and Hartway et al. 1997 (percutaneous absorption in humans: 0.226 ± 0.125 %)
- Pahl and Culver, 2000 (excretion data of boron in humans: mainly excreted in the urine);
- Dourson et al., 1998: justification of data-specific assessment factors for toxicokinetics and toxicodynamic of boron;
- Dunlop 1981, Krutzen et al. 1992, Sturgiss et al. 1996. (GFR in sensitive population, justification for intraspecies AFs);
- Maier et al., 2014 (Data derived assessment factors for human variability in toxicokinetics and toxicodynamics are reported).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
0.5
Absorption rate - inhalation (%):
100

Additional information

There is little difference between animals and humans in absorption, distribution, and metabolism. A difference in renal clearance is the major determinant in the differences between animals and humans, with the renal clearance in rats approximately 3 times faster 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.

Interspecies differences in toxicokinetics based on data for boron clearance rates in rats versus humans and intraspecies differences in human toxicokinetics based on data on human variability in glomerular filtration rates (GFR) are critical determinates in evaluating human toxicity of boric acid. GFR was identified as the primary determinant of boron clearance rates. A toxicokinetic adjustment factor for boron for human variability is based on the variability in GFR during pregnancy (Dunlop, 1981; Krutzén et al., 1992; Sturgiss et al., 1996) ensuring adequate coverage of the sensitive subpopulation of preeclamptic women (US. EPA 2004; Dourson et al. 1998; Maier et al. 2014).

 

Read Across

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. As noted previously, only boric acid and the borate anion are present at environmentally and physiologically relevant concentrations. Read-across between the different boron compounds can be done on the basis of boron (B) equivalents. 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

Na2B8O13·4H2O 

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

Please also refer to the read-across statement attached to section 13.