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Diss Factsheets

Administrative data

Description of key information

In vivo irritation studies on skin were performed on sodium metaborate dihydrate (Gardner, 1998). No primary eye irritation studies of sodium metaborates have been conducted in rabbits. However, because of the alkalinity of sodium metaborate in solution, it may be irritating to eyes. Eye irritation studies were performed on the analogue substances sodium tetraborate pentahydrate and decahydrate, which support this assumption.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15-03-1998 to 24-03-1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study.
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Uk, Ltd.
- Age at study initiation: 14 - 19 weeks old
- Weight at study initiation: 2.8 - 3.84 kg
- Housing: In floor pens accommodating one animal throughout the acclimatisation and experimental phases.
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: A period of between 5 and 7 weeks.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 - 22 °C
- Humidity (%): Humidity was not actively controlled, but was expected to remain within the range of 40 to 80 % RH.
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 h dark/12 h light.
Type of coverage:
semiocclusive
Preparation of test site:
other: Clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 500 mg. Skin was moistened with water prior to application.
Duration of treatment / exposure:
The sentinal was dosed for 3 min, 1 h and 4 h.
Two further rabbits were subjected to single 4 h applications.
Observation period:
Three days
Number of animals:
Three
Details on study design:
TEST SITE
- Area of exposure: 30 x 20 mm
- Type of wrap if used: The test sites were covered iwth a dense gauze patch (30 x 20 mm) which was in turn covered by a larger gauze patch (40 x 40 mm) and an open-weave, elasticated adhesive bandage which was wrapped firmly around the torso to secure the applied dose and patch to the correct position.

REMOVAL OF TEST SUBSTANCE
- Washing: On removal of the patches the treated skin was lightly brushed clean of any solid residue and swabbed with moist cotton wool.
- Time after start of exposure: The sentinal was dosed for 3 min, 1 h and 4 h. Two further rabbits were subjected to single 4 h applications.
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 72 h
Score:
0
Max. score:
8
Reversibility:
other: Not applicable
Irritant / corrosive response data:
There were no irritation reactions or other dermal changes following single, semi-occluded topical applications of the test article to skin for 4 h.
Other effects:
There were no signs of toxicity or ill health in any rabbit during the observation period.
Interpretation of results:
other: EU GHS criteria not met
Conclusions:
A single semi-occluded application of sodium metaborate 4 mol to intact rabbit skin for 4 h did not elicit any irritation reacions or other dermal changes.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Harvey’s Lake, PA.
- Weight at study initiation: 2.4 – 2.8 kg
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.08 mL equivalent.
Duration of treatment / exposure:
14 days.
Observation period (in vivo):
14 days.
Number of animals or in vitro replicates:
Six.
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: No rinsing was done.


SCORING SYSTEM: Scoring in report according to Draize, but scoring reported here according to EU 67/548/EEC.

Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.22
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.22
Max. score:
2
Reversibility:
fully reversible within: 14 d
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
mean
Time point:
24/48/72 h
Score:
2.8
Max. score:
3
Reversibility:
fully reversible within: 14 d
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.89
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritant / corrosive response data:
No data
Other effects:
No data

Results:

 

Cornea

Iris

Conjunctiva

Redness

Chemosis

score (average of animals investigated)

0 to 4

0 to 2

0 to 3

0 to4

60 min

0.00

0.00

2.33

3.00

24 h

0.00

0.67

3.00

2.00

48 h

0.00

0.00

3.00

2.00

72 h

0.67

0.00

2.33

1.67

Average 24h, 48h, 72h

0.22

0.22

2.80

1.89

Maximum average score

(including area affected, max 110)

 

 

 

 

Reversibility

yes

yes

yes

yes

average time for reversion

By Day 14

By Day 14

By Day 14

By Day 14

This study was carried out at the request of the US EPA to confirm that the eye irritation previously seen with disodium tetraborate pentahydrate was caused by the glassy nature of the crystals of substance and not a chemical effect of irritation, the sample in this study was ground to a fine powder before instillation to reduce the glassy, sharp crystals in the sample.

In normal handling and use the large glassy crystals would not be able to enter the eye easily and in addition over 50 years of occupational exposure to disodium tetraborate pentahydrate as well as other borates have indicated no adverse effects on the human eye.

 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).

The substance is not classifiable in the EU under Regulation (EC) No 12727/2008.

Disodium tetraborate decahydrate is used as a buffer in eyewashes.

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
Based on the mean redness score >2, the substance is classified as irritant to the eyes.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

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

Additional information

Skin Irritation


An in vivo irritation study on skin was performed on sodium metaborate dihydrate (Gardner, 1998). Based on the results of this study sodium metaborate is not a skin irritant.


Eye Irritation


No primary eye irritation studies of sodium metaborates have been conducted. Since sodium metaborates quickly form an alkaline solution, sodium metaborates are likely to be eye irritants. The pH of an aqueous solution of the metaborate at 20°C ranges from 10.5 at 0.1% w/w to 12.0 at 18% w/w. However, since a low alkaline reserve for sodium metaborates has been estimated (according to Young et al., 1988), the sodium metaborates are not likely to be serious irritants/corrosives (Hubbard 1998).


This assumption is further supported by the studies caried out with disodium tetraborate.


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. Also, two studies were conducted on disodium tetraborate decahydrate both indicating eye irritancy. In the second 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. The upper 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 in Chapter 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-response 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 BMDL05 value of 0.94 mg B/m3 based 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 BMDL05 of 2.35 mg B/m3 for 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 irritancy 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 mice for 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 limit values (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 achievable 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.


 


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

Justification for classification or non-classification

Sodium metaborate does not meet criteria under Regulation (EC) No 1272/2008 for classification and labelling as a skin irritant.


According to Regulation (EC) No 1272/2008, sodium metaborate meet the criteria for classification as Eye irritant Category 2 (H 319) based on reversible effects in eye irritation studies in test animals for disodium tetraborate.


Moreover, Sodium metaborate does not meet the criteria defined under Regulation (EC) No 1272/2008 for classification and labelling as a respiratory irritant.