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Diss Factsheets

Toxicological information

Skin irritation / corrosion

Currently viewing:

Administrative data

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Remarks:
publication / peer-reviewed report
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
peer-reviewed
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:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
publication / peer-reviewed report
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
peer-reviewed, read-across
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:
no guideline required
Principles of method if other than guideline:
Review of literature data
GLP compliance:
no
Species:
other: mainly rabbits, also guinea pigs
Strain:
not specified
Remarks:
sometimes "albino" is mentioned
Details on test animals or test system and environmental conditions:
no details available
Type of coverage:
occlusive
Preparation of test site:
other: various, intact, abraded, shaved
Vehicle:
other: various: water, undiluted, urine, bath preparation
Controls:
not specified
Irritation parameter:
primary dermal irritation index (PDII)
Remarks:
Boric Acid, rabbits
Basis:
mean
Time point:
other: 24&72h
Score:
1.7
Max. score:
8
Reversibility:
not specified
Remarks on result:
other: indicative of mild irritation
Remarks:
Ten ml of 5% boric acid (aqueous) were applied under occlusion to the clipped intact and abraded skin of six rabbits.
Irritation parameter:
primary dermal irritation index (PDII)
Remarks:
Boric acid, guinea pigs
Basis:
mean
Time point:
other: 24&72h
Score:
2.1
Max. score:
8
Reversibility:
not specified
Remarks on result:
other: indicative of mild or moderate irritation
Remarks:
Ten ml of 5% boric acid (aqueous) were applied under occlusion to the clipped intact and abraded skin of six guinea pigs.
Irritation parameter:
primary dermal irritation index (PDII)
Remarks:
sodium borate, rabbits
Basis:
mean
Time point:
other: 24&72h
Score:
2
Max. score:
8
Reversibility:
not specified
Remarks on result:
other: indicative of mild or moderate irritation
Remarks:
Ten ml of 5% Sodium Borate (aqueous) were applied under occlusion to the clipped intact and abraded skin of six rabbits.
Irritation parameter:
primary dermal irritation index (PDII)
Remarks:
sodium borate, guinea pigs
Basis:
mean
Time point:
other: 24&72h
Score:
1.4
Max. score:
8
Reversibility:
not specified
Remarks on result:
other: indicative of mild irritation
Remarks:
Ten ml of 5% Sodium Borate (aqueous) were applied under occlusion to the clipped intact and abraded skin of six guinea pigs.
Remarks on result:
no indication of irritation
Remarks:
rabbits, 5% aqueous solutions of Boric Acid, pH of 3.81 (unadjusted),
Remarks on result:
other: moderate irritation
Remarks:
rabbits, 5% aqueous solutions of Boric Acid, pH 7.38, adjusted with ammonium carbonate
Remarks on result:
other: mild irritation
Remarks:
rabbits, 5% aqueous solutions of Boric Acid, pH 6.86, adjusted with ammonium carbonate
Remarks on result:
other: slight irritation
Remarks:
rabbits, 5% aqueous solutions of Boric Acid, pH 7.87, adjusted with sodium hydroxide
Remarks on result:
other: marked irritation
Remarks:
rabbits, 5% aqueous solutions of Boric Acid, pH 8.16, adjusted with ammonium carbonate and an ammonia solution
Remarks on result:
no indication of irritation
Remarks:
rabbits, 5% Boric Acid solution in freshly passed human urine
Irritation parameter:
erythema score
Time point:
24/48/72 h
Remarks on result:
other: not available
Irritation parameter:
edema score
Time point:
24/48/72 h
Remarks on result:
other: not available
Interpretation of results:
study cannot be used for classification
Remarks:
no erythema and edema scores given
Conclusions:
The present information was based on a literature review (peer-reviewed) of sodium borate and boric acid studies, which gave inconsistent results ranging from not irritating to irritating. Edema and erythema scores as indicated in Regulation 1272/2008, which are required for classification, are not given. Further, due to inconsistent results, no conclusion based on expert judgement can be drawn.
Executive summary:

A literature review of sodium borate and boric acid showed that these borates induced none to irritating responses, no conclusion on classification can be drawn.

Data source

Reference
Reference Type:
review article or handbook
Title:
Final Report on the Safety Assessment of Sodium Borate and Boric Acid
Author:
CIR
Year:
1983
Bibliographic source:
JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY, Volume 2, Number 7, 1983 Mary Ann Liebert, Inc., Publishers

Materials and methods

Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Review of literature data
GLP compliance:
no

Test material

Constituent 1
Chemical structure
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
Details on test material:
Boric Acid (CAS No. 10043-35-3) is an inorganic acid that conforms to the formula, H3B03. It is also called boracic acid and orthoboric acid. Sodium Borate (CAS No. 1303-96-4) is an inorganic salt that conforms to the formula, Na2B4O7*10H2O. It is also called borax and sodium tetraborate. Sodium Borate occurs in pentahydrate and anhydrous forms as well as the decahydrate form. The decahydrate is the Sodium Borate that appears in the FDA product formulation computer printout and the use of the name, Sodium Borate, in the chemistry section of this report refers to the decahydrate. In references appearing in other sections of this report the specific Sodium Borate has not usually been identified.
Boric Acid occurs as colorless, odorless, transparent, triclinic crystals or white granules or powder that is slightly oily to the touch. It has a molecular weight of 61.84 and a specific gravity of 1.435. A 0.1 M solution of Boric Acid has a pH of 5.1. Boric Acid is stable in air but volatile in steam without decomposition. Its melting point is approximately 171°C when heated in a closed space. With continued heating and higher temperatures, Boric Acid loses water in stages. It becomes metaboric acid, HBO2, and then pyroboric acid, H2B4O7, followed by the oxide, B2O3. Boric Acid is soluble in hot and cold water, alcohol, and glycerin. Its solubility in water is increased by citric, hydrochloric, and tartaric acids. It is slightly soluble in acetone and not very soluble in ether.
Sodium Borate occurs colorless to white, hard, odorless, monoclinic crystals or powder. It is efflorescent in dry air and crystals are often coated with white powder. It has a molecular weight of 381.37 and a specific gravity of 1.73. An aqueous solution of Sodium Borate has a pH of approximately 9.5. When heated rapidly, Sodium Borate has a melting point of 75°C. It becomes anhydrous at 320°C. Sodium Borate is soluble in hot and cold water, and glycerin. It is very slightly soluble in alcohol and is insoluble in acid.

Test animals

Species:
other: mainly rabbits, also guinea pigs
Strain:
not specified
Remarks:
sometimes "albino" is mentioned
Details on test animals or test system and environmental conditions:
no details available

Test system

Type of coverage:
occlusive
Preparation of test site:
other: various, intact, abraded, shaved
Vehicle:
other: various: water, undiluted, urine, bath preparation
Controls:
not specified

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
primary dermal irritation index (PDII)
Remarks:
Boric Acid, rabbits
Basis:
mean
Time point:
other: 24&72h
Score:
1.7
Max. score:
8
Reversibility:
not specified
Remarks on result:
other: indicative of mild irritation
Remarks:
Ten ml of 5% boric acid (aqueous) were applied under occlusion to the clipped intact and abraded skin of six rabbits.
Irritation parameter:
primary dermal irritation index (PDII)
Remarks:
Boric acid, guinea pigs
Basis:
mean
Time point:
other: 24&72h
Score:
2.1
Max. score:
8
Reversibility:
not specified
Remarks on result:
other: indicative of mild or moderate irritation
Remarks:
Ten ml of 5% boric acid (aqueous) were applied under occlusion to the clipped intact and abraded skin of six guinea pigs.
Irritation parameter:
primary dermal irritation index (PDII)
Remarks:
sodium borate, rabbits
Basis:
mean
Time point:
other: 24&72h
Score:
2
Max. score:
8
Reversibility:
not specified
Remarks on result:
other: indicative of mild or moderate irritation
Remarks:
Ten ml of 5% Sodium Borate (aqueous) were applied under occlusion to the clipped intact and abraded skin of six rabbits.
Irritation parameter:
primary dermal irritation index (PDII)
Remarks:
sodium borate, guinea pigs
Basis:
mean
Time point:
other: 24&72h
Score:
1.4
Max. score:
8
Reversibility:
not specified
Remarks on result:
other: indicative of mild irritation
Remarks:
Ten ml of 5% Sodium Borate (aqueous) were applied under occlusion to the clipped intact and abraded skin of six guinea pigs.
Remarks on result:
no indication of irritation
Remarks:
rabbits, 5% aqueous solutions of Boric Acid, pH of 3.81 (unadjusted),
Remarks on result:
other: moderate irritation
Remarks:
rabbits, 5% aqueous solutions of Boric Acid, pH 7.38, adjusted with ammonium carbonate
Remarks on result:
other: mild irritation
Remarks:
rabbits, 5% aqueous solutions of Boric Acid, pH 6.86, adjusted with ammonium carbonate
Remarks on result:
other: slight irritation
Remarks:
rabbits, 5% aqueous solutions of Boric Acid, pH 7.87, adjusted with sodium hydroxide
Remarks on result:
other: marked irritation
Remarks:
rabbits, 5% aqueous solutions of Boric Acid, pH 8.16, adjusted with ammonium carbonate and an ammonia solution
Remarks on result:
no indication of irritation
Remarks:
rabbits, 5% Boric Acid solution in freshly passed human urine
Irritation parameter:
erythema score
Time point:
24/48/72 h
Remarks on result:
other: not available
Irritation parameter:
edema score
Time point:
24/48/72 h
Remarks on result:
other: not available

Applicant's summary and conclusion

Interpretation of results:
study cannot be used for classification
Remarks:
no erythema and edema scores given
Conclusions:
The present information was based on a literature review (peer-reviewed) of sodium borate and boric acid studies, which gave inconsistent results ranging from not irritating to irritating. Edema and erythema scores as indicated in Regulation 1272/2008, which are required for classification, are not given. Further, due to inconsistent results, no conclusion based on expert judgement can be drawn.
Executive summary:

A literature review of sodium borate and boric acid showed that these borates induced none to irritating responses, no conclusion on classification can be drawn.