Potassium metaborate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Remarks:

reported in a publication

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Documentation slightly limited, but given data indicates that testing was performed similarly to the procedure as set out in OECD TG 401.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
see target record

Cross-reference

Reason / purpose for cross-reference:

read-across source

Remarks:

target record

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

reported in a publication

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Documentation slightly limited, but given data indicates that testing was performed similarly to the procedure as set out in OECD TG 401 on a read-across substance.

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Borates in general dissociate immediately upon contact with water and are converted rapidly into i.a. boric acid. This includes salts of boric acid (borates), metaboric acid (metaborates), hydrated borates (hydroborates) or borax. Boron compounds are highly soluble in water, and upon dissolving form essentially two species, undissociated boric acid (H3BO3) and borate anion (B(OH)4- [Soucek, Environmental Toxicology and Chemistry, Vol. 30, No. 8, pp. 1906–1914, 2011]. Orthoboric acid (Short: Boric acid, H3BO3) is a weak monobasic acid, which does not act as a proton donator but OH- acceptor (Lewis base) according to the following equilibrium:
B(OH)3 + 2 H2O ↔ B(OH)4- + H3O+ pKs = 9.2
Metaboric acid ((HBO2)n is formed during heating >90°C via intermolecular condensation while releasing a water molecule. Upon solubilisation in water, orthoboric acid is formed again. In diluted solutions practically only the monomeric H3BO3 are present [Riedel, Anorganische Chemie, de Gruyter, 1999]. A study by Zhu et al. [Zhu FY, Journal of Molecular Structure, Volume 1070, 24 July 2014, Pages 80-85] shows that the main borate species in aqueous KB(OH)4 solutions is B(OH)4−. This ion is in an equilibrium with H3BO3.
So 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 [WHO, Environmental Health Criteria 204, boron, World Health Organization, Geneva, 1998]. Also borax readily dissolves in water to form undissociated boric acid (H3BO3) and borate anion (B(OH)4-) [Soucek, 2011]. Most of the simple inorganic borates exist predominantly as undissociated boric acid in dilute aqueous solution at physiological pH [Hubbard SA, Biological Trace Element Research Vol. 66, 1998]. In aqueous solution, the metaborate ion is rapidly converted to the borate anion and the weakly dissociated boric acid by the sequential reactions shown by the following equations [Antia NJ, 1975, J. Fish. Res. Board Can. 32: 2487-2494]:
BO2- + 2 H2O → B(OH)4-
B(OH)4- + H3O+ ↔ B(OH)3 + 2 H2O
So if metaboric acid (resp. borates) is dissolved in water, orthoboric acid is formed [Riedel, 1999].
So summarizing, upon contact with water, potassium metaborate dissociates immediately into potassium and metaborate ions, whereas the latter is converted rapidly into boric acid.
As stated above, in diluted solutions and biologically relevant pH values, only undissociated boric acid is present, irrespective of which borate was dissolved in water, which so also applies to potassium metaborate. This is applicable for both ecotoxicity tests (usual limit concentration: 100 mg/l) as well as toxicological studies. Borates are readily absorbed orally in humans and animals [Hubbard, 1998], so the expected plasma levels are maximally as high as the applied dose, which still indicates that the boron species dissolved in plasma is H3BO3.
In consequence, data from boric acid and also all types of borates mentioned above, may be used to cover data gaps for potassium metaborate via read-across.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Target: Potassium metaborate, CAS 13709-94-9, EC 237-262-2, BKO2, MW = 81.9081 g/mol, SMILES [K+].[O-]B=O
Source: Boric acid / Orthoboric acid, CAS 10043-35-3, EC 233-139-2, H3BO3, MW = 61.83 g/mol, SMILES OB(O)O
Source: Borax / di-Sodium tetraborate decahydrate / sodium borate, CAS 1303-96-4, EC 603-411-9, Na2B4O7 *10H2O, MW = 381.365, SMILES (anhydrous) [Na+].[Na+].[O-]B(OB=O)OB([O-])OB=O
Source: Sodium tetraborate pentahydrate / Boron sodium oxide, pentahydrate, CAS 12179-04-3, EC 601-808-1, B4-O7.2Na.5H2-O, MW = 291.291 g/mol, SMILES B(=O)OB([O-])OB([O-])OB=O.O.O.O.O.O.[Na+].[Na+]
Source: Disodium octaborate tetrahydrate / Boron sodium oxide, tetrahydrate, CAS ‎12280-03-4, EC 602-894-3, B8Na2O13
Source: Sodium metaborate tetrahydrate / Boric acid, sodium salt, tetrahydrate, CAS 10555-76-7, EC 600-663-1
Source: Dipotassium tetraborate / boron potassium oxide, CAS 1332-77-0, EC 215-575-5, B4K2O7, MW = 233.4358, SMILES [K+].[K+].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-]
Source: Diammonium tetraborate tetrahydrate / azane;2-hydroxy-4-[(4-hydroxy-1,3,2,4-dioxadiboretan-2-yl)oxy]-1,3,2,4-dioxadiboretane;tetrahydrate, CAS 10135-84-9; 12228-87-4, B4H16N2O11, MW = 263.371, SMILES B1(OB(O1)OB2OB(O2)O)O.N.N.O.O.O.O
Source: Zinc borate, hydrate / dodecaboron tetrazinc docosaoxide heptahydrate / Boron zinc hydroxide oxide / hexaboron dizinc undecaoxide, CAS 138265-88-0, EC 235-804-2, B12Zn4(OH)14O15, MW = 425.7 g/mol

There are no impurities known in neither target nor source chemical(s) which may affect the feasibility of the read-across approach.

3. ANALOGUE APPROACH JUSTIFICATION
As obvious in detail from the available data matrix, all borates exhibit similar (eco-)toxicological properties.
With regard to ecotoxicity, all available studies on various borates on fish, invertebrates, and algae, both short and long term, consistently indicate that, recalculated from the molecular weight, Potassium metaborate does not need to be classified as aquatic toxic (acute and chronic) according to Regulation 1272/2008 and amendments.
Similarly, with regard to human-relevant endpoints, Potassium metaborate does not need to be classified as acutely toxic, as consistently indicated by various borates in also various species.
Both boric acid and borax do not trigger classification as skin sensitizing, no further study data is available, However, Sodium Borate and Boric Acid are used in cosmetics in various functions, and no sensitizing reactions induced by these cosmetic products have been reported.
Borax and Boric acid were similarly non-mutagenic in the Ames Test, and the non-genotoxic potential is further supported by a negative chromosome aberration test. Both Borax and Boric however gave in different species, although via partially species-specific mode of actions, indication that they interfere via a certain threshold with reproduction. Proof via human data is however not available.
Further, all borates chosen for read-across, incl. the registered substance itself, are highly soluble in water, and upon dissolving form essentially two species, undissociated boric acid (H3BO3) and borate anion (B(OH)4-. Hence, read-across is further based on common breakdown products.
So summarizing, read-across is justified via similar (eco-)toxicological effects and common breakdown products.

4. DATA MATRIX
See attachment

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not applicable

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

other: rats and dogs

Strain:

other: rats: Sprague-Dawly & Long Evans, dogs: mongrel

Remarks:

sex of dogs not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (Sprague-Dawley rats), Diablo Laboratories (Long-Evans rats)
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Fasting period before study: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Route of administration:

other: oral: stomach intubation (rats), capsule (dogs)

Vehicle:

other: 50 % w/v in 0.5 % aqueous methyl cellulose or distilled water suspension (rats) / not stated (capsule) (dogs)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50% (rats)

Doses:

n/a (rats)
various dose levels from 1.54 to 6.51 g/kg borax or from 1.0 to 3.98 g/kg boric acid (rats)

No. of animals per sex per dose:

6 groups of 5 rats / dogs not stated

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days (rats) / 7 days (dogs)
- Other examinations performed: clinical signs, body weights

Statistics:

Statistical method. Numerical deviation from the control observations were evaluated by conventional statistical tests using P < 0.05 as the fiducial limit (Snedecor, 1956).

Sex:

male

Dose descriptor:

LD50

Remarks:

for Sprague-Dawley rats

Effect level:

4 500 mg/kg bw

Based on:

test mat.

Remarks:

Borax

95% CL:

>= 4 140 - <= 5 010

Remarks on result:

other: corresponding to 510.3 mg/kg boron equivalents or 3866 mg/kg BHO2.K

Key result

Sex:

male

Dose descriptor:

LD50

Remarks:

for Sprague-Dawley rats

Effect level:

3 450 mg/kg bw

Based on:

test mat.

Remarks:

Boric acid

95% CL:

>= 2 950 - <= 4 040

Remarks on result:

other: corresponding to 603.2 mg/kg boron equivalents or 4570.3 mg/kg BHO2.K

Sex:

female

Dose descriptor:

LD50

Remarks:

for Sprague-Dawley rats

Effect level:

4 980 mg/kg bw

Based on:

test mat.

Remarks:

Borax

95% CL:

>= 4 310 - <= 5 760

Remarks on result:

other: corresponding to 564.7 mg/kg boron equivalents or 4278.3 mg/kg BHO2.K

Sex:

female

Dose descriptor:

LD50

Remarks:

for Sprague-Dawley rats

Effect level:

4 080 mg/kg bw

Based on:

test mat.

Remarks:

Boric acid

95% CL:

>= 3 640 - <= 4 560

Remarks on result:

other: corresponding to 713.4 mg/kg boron equivalents or 5404.9 mg/kg BHO2.K

Sex:

male

Dose descriptor:

LD50

Remarks:

for Long-Evans rats

Effect level:

6 080 mg/kg bw

Based on:

test mat.

Remarks:

Borax

95% CL:

>= 3 540 - <= 10 400

Remarks on result:

other: corresponding to 689.4 mg/kg boron equivalents or 5223.4 mg/kg BHO2.K

Sex:

male

Dose descriptor:

LD50

Remarks:

for Long-Evans rats

Effect level:

ca. 3 160 mg/kg bw

Based on:

test mat.

Remarks:

Boric acid

Remarks on result:

other: estimate, corresponding to 552.5 mg/kg boron equivalents or 4186.1 mg/kg BHO2.K

Dose descriptor:

LD50

Remarks:

for mongrel dogs

Effect level:

> 6 510 mg/kg bw

Based on:

test mat.

Remarks:

Borax

Remarks on result:

not determinable

Remarks:

corresponding to 738.2 mg/kg boron equivalents or 5592.8 mg/kg BHO2.K, no deaths occurred at the highest dose tested

Dose descriptor:

LD50

Remarks:

for mongrel dogs

Effect level:

> 3 980 mg/kg bw

Based on:

test mat.

Remarks:

Boric acid

Remarks on result:

not determinable

Remarks:

corresponding to 695.9 mg/kg boron equivalents or 5272.4 mg/kg BHO2.K, no deaths occurred at the highest dose tested

Mortality:

There were no deaths during the 14 day postdosage observation period in dogs.

Clinical signs:

In rats, the signs oftoxicity included depression, ataxia, convulsion and death and were similar for borax and boric acid.
When either borax or boric acid was administered po to dogs at various dose levels from 1.54 to 6.51 g/kg borax or from 1.0 to 3.98 g/kg boric acid, all animals, excluding a few at the low dose levels, vomited within the first hour. The severity of the emetic response varied with dosage. There were no deaths during the 14 day postdosage observation period.

Interpretation of results:

GHS criteria not met

Remarks:

EU implementation

Conclusions:

The study was performed similar to OECD TG 401 with minor deficiencies in documentation and performance on suitable read-across substances, so the given data can hence be considered sufficiently reliable. The lowest LD50 value found was 3016 mg/kg bw (estimation, Long-Evans rats). According to Regulation 1272/2008, the cut-off value for classification as acutely toxic (Cat. 4) is 2000 mg/kg in oral acute toxicity studies. Hence, the test item(s) do(es) not need to be classified as acutely toxic according to Regulation 1272/2008.

Executive summary:

The study was performed similar to OECD TG 401 on Sprague-Dawley and Long-Evans rats and mongrel dogs. In Sprague-Dawley rats the acute po LD50 values for borax were 4.5 g/kg and 4.98 g/kg in males and females, respectively; boric acid, 3.45 g/kg in males and 4.08 g/kg in females. In Long-Evans male rats the LD50 values for borax and boric acid were 6.08 g/kg and 3.16 g/kg, respectively. When either borax or boric acid was administered po to dogs at various dose levels from 1.54 to 6.51 g/kg borax or from 1.0 to 3.98 g/kg boric acid, all animals, excluding a few at the low dose levels, vomited within the first hour. The severity of the emetic response varied with dosage. There were no deaths during the 14 day postdosage observation period.

The test item(s) do(es) not need to be classified as acutely toxic according to Regulation 1272/2008.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1972

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not applicable

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Boric acid

EC Number:

233-139-2

EC Name:

Boric acid

Cas Number:

10043-35-3

Molecular formula:

H3BO3

IUPAC Name:

Boric acid

Constituent 2

Reference substance name:

1303-96-4

EC Number:

603-411-9

Cas Number:

1303-96-4

IUPAC Name:

1303-96-4

Specific details on test material used for the study:

Both borax (Na2B407. 10H2O) and boric acid (H3BO3) of ACS grade were supplied by the U.S. Borax Research Corporation, Anaheim, California. The boron equivalent is generally referred to throughout the text. Values for deriving these equivalents are as follows.
Weight boric acid (H3BO3) x 0.1750 = equivalent weight boron
Weight borax x 0.1134 = equivalent weight boron

Test animals

Species:

other: rats and dogs

Strain:

other: rats: Sprague-Dawly & Long Evans, dogs: mongrel

Remarks:

sex of dogs not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (Sprague-Dawley rats), Diablo Laboratories (Long-Evans rats)
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Fasting period before study: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:

other: oral: stomach intubation (rats), capsule (dogs)

Vehicle:

other: 50 % w/v in 0.5 % aqueous methyl cellulose or distilled water suspension (rats) / not stated (capsule) (dogs)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50% (rats)

Doses:

n/a (rats)
various dose levels from 1.54 to 6.51 g/kg borax or from 1.0 to 3.98 g/kg boric acid (rats)

No. of animals per sex per dose:

6 groups of 5 rats / dogs not stated

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days (rats) / 7 days (dogs)
- Other examinations performed: clinical signs, body weights

Statistics:

Statistical method. Numerical deviation from the control observations were evaluated by conventional statistical tests using P < 0.05 as the fiducial limit (Snedecor, 1956).

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Remarks:

for Sprague-Dawley rats

Effect level:

4 500 mg/kg bw

Based on:

test mat.

Remarks:

Borax

95% CL:

>= 4 140 - <= 5 010

Remarks on result:

other: corresponding to 510.3 mg/kg boron equivalents or 3866 mg/kg BHO2.K

Effect levels 2

Key result

Sex:

male

Dose descriptor:

LD50

Remarks:

for Sprague-Dawley rats

Effect level:

3 450 mg/kg bw

Based on:

test mat.

Remarks:

Boric acid

95% CL:

>= 2 950 - <= 4 040

Remarks on result:

other: corresponding to 603.2 mg/kg boron equivalents or 4570.3 mg/kg BHO2.K

Effect levels 3

Sex:

female

Dose descriptor:

LD50

Remarks:

for Sprague-Dawley rats

Effect level:

4 980 mg/kg bw

Based on:

test mat.

Remarks:

Borax

95% CL:

>= 4 310 - <= 5 760

Remarks on result:

other: corresponding to 564.7 mg/kg boron equivalents or 4278.3 mg/kg BHO2.K

Effect levels 4

Sex:

female

Dose descriptor:

LD50

Remarks:

for Sprague-Dawley rats

Effect level:

4 080 mg/kg bw

Based on:

test mat.

Remarks:

Boric acid

95% CL:

>= 3 640 - <= 4 560

Remarks on result:

other: corresponding to 713.4 mg/kg boron equivalents or 5404.9 mg/kg BHO2.K

Effect levels 5

Sex:

male

Dose descriptor:

LD50

Remarks:

for Long-Evans rats

Effect level:

6 080 mg/kg bw

Based on:

test mat.

Remarks:

Borax

95% CL:

>= 3 540 - <= 10 400

Remarks on result:

other: corresponding to 689.4 mg/kg boron equivalents or 5223.4 mg/kg BHO2.K

Effect levels 6

Sex:

male

Dose descriptor:

LD50

Remarks:

for Long-Evans rats

Effect level:

ca. 3 160 mg/kg bw

Based on:

test mat.

Remarks:

Boric acid

Remarks on result:

other: estimate, corresponding to 552.5 mg/kg boron equivalents or 4186.1 mg/kg BHO2.K

Effect levels 7

Dose descriptor:

LD50

Remarks:

for mongrel dogs

Effect level:

> 6 510 mg/kg bw

Based on:

test mat.

Remarks:

Borax

Remarks on result:

not determinable

Remarks:

corresponding to 738.2 mg/kg boron equivalents or 5592.8 mg/kg BHO2.K, no deaths occurred at the highest dose tested

Effect levels 8

Dose descriptor:

LD50

Remarks:

for mongrel dogs

Effect level:

> 3 980 mg/kg bw

Based on:

test mat.

Remarks:

Boric acid

Remarks on result:

not determinable

Remarks:

corresponding to 695.9 mg/kg boron equivalents or 5272.4 mg/kg BHO2.K, no deaths occurred at the highest dose tested

Mortality:

There were no deaths during the 14 day postdosage observation period in dogs.

Clinical signs:

In rats, the signs oftoxicity included depression, ataxia, convulsion and death and were similar for borax and boric acid.
When either borax or boric acid was administered po to dogs at various dose levels from 1.54 to 6.51 g/kg borax or from 1.0 to 3.98 g/kg boric acid, all animals, excluding a few at the low dose levels, vomited within the first hour. The severity of the emetic response varied with dosage. There were no deaths during the 14 day postdosage observation period.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Remarks:

EU implementation

Conclusions:

The study was performed similar to OECD TG 401 with minor deficiencies in documentation and performance on suitable read-across substances, so the given data can hence be considered sufficiently reliable. The lowest LD50 value found was 3016 mg/kg bw (estimation, Long-Evans rats). According to Regulation 1272/2008, the cut-off value for classification as acutely toxic (Cat. 4) is 2000 mg/kg in oral acute toxicity studies. Hence, the test item(s) do(es) not need to be classified as acutely toxic according to Regulation 1272/2008.

Executive summary:

The study was performed similar to OECD TG 401 on Sprague-Dawley and Long-Evans rats and mongrel dogs. In Sprague-Dawley rats the acute po LD50 values for borax were 4.5 g/kg and 4.98 g/kg in males and females, respectively; boric acid, 3.45 g/kg in males and 4.08 g/kg in females. In Long-Evans male rats the LD50 values for borax and boric acid were 6.08 g/kg and 3.16 g/kg, respectively. When either borax or boric acid was administered po to dogs at various dose levels from 1.54 to 6.51 g/kg borax or from 1.0 to 3.98 g/kg boric acid, all animals, excluding a few at the low dose levels, vomited within the first hour. The severity of the emetic response varied with dosage. There were no deaths during the 14 day postdosage observation period.

The test item(s) do(es) not need to be classified as acutely toxic according to Regulation 1272/2008.