Registration Dossier

Administrative data

Description of key information

In vivo irritation study on skin was performed on potassium tetraborate (Young & Doyle, 1973). An in vivo eye irritation study with potassium tetraborate has been conducted in rabbits (OECD 405) and according to the results obtained in this study, potassium tetraborate is classified as a nonirritant to the eyes. Further, eye and respiratory tract irritation of sodium tetraborate pentahydrate were performed. Disodium tetraborates are Category 2 eye irritants based on reversible effects in eye irritation studies in test animals.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin Irritation

Potassium tetraborate is not a skin irritant.

Eye Irritation

An eye irritation study in rabbits according to OECD 405 has been carried out on potassium tetraborate. No positive irritation scores were observed in any animal throughout the study for iris lesions. Conjunctival redness scores were 1.0 for all animals, and conjunctival chemosis scores ranged from 0.7 to 1.0. No signs of any ocular irritation were present at 14 days after dosing (initial testing) or 7 days after dosing (confirmatory testing).

Disodium Tetraborate Pentahydrate

A number of eye irritancy studies have been carried on disodium tetraborate pentahydrate which involved testing various batches of substance and under varying conditions, all indicating eye irritation. However the key study was carried out at the request of the US EPA to confirm that the eye irritation previously seen was caused by the glassy nature of the crystals of substance and not a chemical effect of irritation. To confirm this, the sample was ground to a fine powder before instillation to reduce the glassy, sharp crystals in the sample (0.08 ml dosed). As a result for this study the US EPA accepted that the effects were mechanical downgraded its classification according to US FIFRA to Toxicity II (40 CFR 156) by ocular administration (Corneal involvement or irritation clearing in 8-21 days).

Disodium Tetraborate Decahydrate

Two studies have been carried out both indicating eye irritancy. In the second study, regarded as the key study the sample was ground to a fine powder to reduce the glassy, sharp crystals in the sample.

Respiratory tract

Borates act as mild sensory irritants, indicated by the effects observed in humans (i. e. nose, eye and throat irritation; sneezing) and by the results of the Alarie-tests Kirkpatrick (2010). This reflex can be triggered by agents that stimulate receptors in the respiratory tract e. g. on the trigeminal nerve (Wegman et al. 1991, Nielsen et al., 2007, Krystofiak & Schaper, 1996, Kirkpatrick, 2010). The actual mechanism, however, has not yet been elucidated.

Wegman et al. (1991) and Woskie et al. (1998) proposed changes of osmolarity in the lining fluid of the mucous membrane as possible cause for receptor activation. Changes in osmolarity could also act indirectly by stimulating mast cells to secrete histamine or other immune modulators. Histamine is known to be able to mediate the sensory component of irritation. The importance of osmolarity in the case of borate dusts is further substantiated by Cain et al. (2008) where the changes of local osmolality from a desiccating dust may cause sensations of dryness. They also indicated that more acidic dusts, as compared to borate dusts, would lead to a change in nasal pH which might trigger the nasal receptors in a different way.

Acute irritant effects are extensively documented in human workers exposed to boric acid and sodium borates (EPA, 2004; Wegman et al. 1991; Garabrant 1984, 1985; Woskie et al., 1994, 1998; Cain et al., 2004, 2008). The described symptoms are typical for those which would be produced in the exposed population rather than being an isolated reaction or response triggered only in individuals with hypersensitive airways. Symptoms include nasal and eye irritation, throat irritations, cough, and breathlessness.

In the Transitional Annex XV Dossier, used Poisson regression analysis of the results from Wegman et al. (1991) to estimate a NOEC (See Appendix A). For NOEC derivation 15-minute interval exposure data were plotted against the sum of “any symptom” (nose, eye, and throat irritation, sneezing breathlessness, coughing; Table 37, Wegman et al., 1991). The lower limits of the exposure ranges presented in Table 37 were used for the non-linear regression analysis (Poisson-model). Applying the equation derived from the regression analysis, resulted in a predicted rate for effects at background of 0,002, with lower and upper 95% CI of 0,0002 and 0,016, respectively. Theupper 95% CI of this rate was considered equivalent to “no-observed-effect”. The boron concentration with a lower 95% CI of the predicted rate of symptoms equal to this value (0,016) was used as the point of departure for DNEL derivation. The corresponding boron concentration equals 0,4 mg B/m3. A correction factor of 2 was then applied for the methodological underestimation of exposure measurements resulting in a NOEC of 0.8 mg B/m3.

In this CSR, the dose-response assessment was conducted using benchmark dose (BMD) analysis as recommended inChapter R.8 of the Guidance on IR and CSA. The Wegman data is based on subjective responses on a severity scale assigned to exposure ranges rather than a specific exposure level and contains no clear dose-response information. There is no way to identify where in this exposure spectrum symptoms occurred. Furthermore, symptoms were also reported in the group of workers not considered to be exposed (office workers), making any estimate of the NOEC unreliable. Therefore benchmark dose analysis is considered the preferred dose-reponse assessment method. 

Benchmark dose analysis was conducted of the data presented in Table 37 of Wegman et al. (1991) (See Appendix A). Table 37 presents the incidence of “Any Symptom” reported by a participant in the study that was confirmed by both the marker being pressed on the data logger worn by the worker and by a subsequent questionnaire administered by a study technician. The exposure doses used were the calculated mean concentration of each concentration range presented in the table. The identified dose-descriptor for acute irritant effects is the BMDL05value of 0.94 mg B/m3based on Wegman et al. (1991). The methods used for exposure measurements in this study were underestimates and a conversion factor of 2.5 was used to correct for the methodological underestimation of exposure measurements. This results in a final BMDL05of 2.35 mg B/m3for exposure to sodium borate dusts.

An airway sensory irritation respiratory depression (RD50) study of boric acid and sodium tetraborate pentahydrate was conducted in male Swiss-Webster mice based on the ASTM E981-04 (2004) standard test method of estimating sensory irritancy of airborne chemicals. The ASTM E981-04 sensory iritancy test (Alarie assay) has been demonstrated to be a reliable test for estimating sensory irritancy of airborne irritants and RD50s are a basis, at least partially, for OELs by ACGIH (Kuwabara et al. 2007). ECHA guidelines (Chapter R.8) acknowledges the use of the Alarie assay in assessing respiratory irritation. 

It was not possible to achieve an aerosol concentration high enough to result in 50% respiratory depression in micefor sodium tetraborate pentahydrate based on the results in the mouse sensory irritation model.  The highest concentration of sodium borate that was achievable with acceptable control of the aerosol concentration was 1704 mg/m3 with a %RD of 33%. Based on these results, the RD50 is > 1704 mg/m3 for sodium tetraborate pentahydrate. The ASTM standard uses the value of 0.03 x RD50 for estimation of threshold limitvalues (TLV). Alarie et al. (2001) has established that a value of 0.01 x RD50 as the concentration where no sensory irritation would be seen in humans. Therefore, although the highest chievable concentration was below the RD50 value for sodium tetraborate pentahydrate, based on the high aerosol concentrations achieved with %RD values below 50%, it is clear that sodium tetraborate pentahydrate has an extremely low potency as a sensory irritant. The practical side of these results is that occupational exposure limit of 10 mg/m3 total particulates will prevent any sensory irritation in workers.

Read Across

A number of these studies were 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 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 under CSR section 5.1.3, which corresponds to IUCLID section 7.1 (toxicokinetics, metabolism and distribution endpoint summary).

References:

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


Effects on respiratory irritation: irritating

Justification for classification or non-classification

Dipotassium tetraborate was not classified for skin irritation under criteria defined in directive 67/548/EEC as no irritating effects were observed on application to the skin of test animals.

An eye irritation study of potassium tetraborate has been conducted in rabbits. Potassium tetraborate is classified as a nonirritant to the eyes of New Zealand White rabbits, based on corneal opacity mean scores of less than 1.0, iris lesion mean scores of less than 1.0, conjunctival redness scores of less than 2.0 and chemosis mean scores of less than 2.0 in at least two of the three rabbits tested. Recovery from all signs of irritation had occurred by 14 days after dosing (initial testing) or 7 days after dosing (confirmatory testing) with potassium tetraborate.