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Diss Factsheets

Administrative data

Description of key information

In vivo skin irritation/corrosion studies were performed on disodium tetraborate pentahydrate, disodium tetraborate decahydrate and boric acid. An in vivo eye irritation study with sodium pentaborate has been conducted in rabbits (OECD 405).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: 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:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
other: FIFRA (40 CFR 163)
Deviations:
no
GLP compliance:
no
Remarks:
Study pre-dates GLP
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan F Plummer
- Weight at study initiation: 1623 - 2922 g
Type of coverage:
occlusive
Preparation of test site:
abraded
Vehicle:
physiological saline
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g
- Concentration: Moistened with physiological saline.
Duration of treatment / exposure:
24 h
Observation period:
72 h
Number of animals:
10
Details on study design:
TEST SITE
- Area of exposure: Saddle area
- Type of wrap if used: Occlusive


REMOVAL OF TEST SUBSTANCE
- Washing: Moistened towel
- Time after start of exposure: 24 h


SCORING SYSTEM: Draize
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
72 h
Score:
0.1
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #1
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #3
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #4
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #5
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #6
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
animal 1 - 6
Time point:
48 h
Remarks on result:
not measured/tested
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
animal 1 - 6
Time point:
48 h
Remarks on result:
not measured/tested
Irritant / corrosive response data:
No irritancy was observed
Other effects:
No data

Results for skin irritation:

Site

Time

Erythema

Edema

Intact

24 h

0

0

72 h

0.25

0

Abraded

24 h

0

0

72 h

0.17

0

Average score

24 h, 72 h

0.105

0
Interpretation of results:
other: EU GHS criteria not met
Conclusions:
The study was performed according to FIFRA (40 CFR 163). No irritancy was observed and it is therefore not classifiable in the EU.
Classified in US in Toxicity Category IV (slight or no irritation).
Data from other studies confirm the results. Further testing not warranted in the interests of animal welfare.
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Qualifier:
equivalent or similar to guideline
Guideline:
other: This study was carried out to comply with US EPA-FIFRA guidelines at the time and carried out by the US Food and Drug Laboratories to GLP.
Deviations:
not specified
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: LaCrosse Industries Inc.
- Age at study initiation: Young adults
- Weight at study initiation: 2.13 – 2.45 kg
Type of coverage:
occlusive
Preparation of test site:
other: Clipped
Vehicle:
physiological saline
Controls:
no
Amount / concentration applied:
0.5 g of test substance was moistened with 0.5 mL physiological saline.
Duration of treatment / exposure:
4 h
Observation period:
72 h
Number of animals:
6 males
Details on study design:
TEST SITE
- Area of exposure: Two areas on the back of each rabbit were treated.
- % coverage: No data
- Type of wrap if used: No data


REMOVAL OF TEST SUBSTANCE
- Washing: the test substance was removed using a moistened towel.
- Time after start of exposure: 4 h


SCORING SYSTEM: Draize, 1959
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
No adverse effects were seen.
Other effects:
No data
Interpretation of results:
other: EU GHS criteria not met
Conclusions:
Skin irritation study carried out on disodium tetraborate pentahydrate to comply with US EPA-FIFRA guidelines at the time and carried out by the US Food and Drug Laboratories to GLP showed no irritancy was observed.
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:
2013-01-24 - 2013-03-27
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study.
Qualifier:
according 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: Kuiper Rabbit Ranch (Gary, IN).
- Age at study initiation: Approximately four months.
- Weight at study initiation: 3.24 – 3.4 kg
- Housing: The rabbits were housed individually in stainless steel cages suspended over excrement pans. Cage liners were placed in the pan below the stainless steel mesh floor of each animal cage to absorb liquids.
- Diet (e.g. ad libitum): Each rabbit was provided with approximately 150 g of Harlan Teklad (Harlan Laboratories, Madison, WI) Certified High Fiber Rabbit Diet #2031 daily.
- Water (e.g. ad libitum): Was Supplied ad libitum by means of an automatic watering system.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C to 22°C
- Humidity (%): 41% to 52%
- Photoperiod (hrs dark / hrs light): 12 hours of light followed by 12 hours of darkness.
Vehicle:
unchanged (no vehicle)
Controls:
other: Left eye served as a control and was not treated.
Amount / concentration applied:
0.1 g
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
Five per sex.
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Eyes were washed with room temperature water for 30 seconds using a volume and velocity that would not cause injury.
- Time after start of exposure: 24 hours after administration.

SCORING SYSTEM: For each animal, mean scores for corneal opacity, iris lesions, conjunctival redness and conjunctival chemosis were calculated by adding the 24-, 48- and 72-hour post-dose scores for the respective parameter and dividing by three. The irritation potential of the test substance was assessed according to the following criteria, based upon the European Parliament and the Council of the European Union guidelines (Regulation (EC) No. 1272/2008, Dec. 2008):
- The test substance will be considered a nonirritant if, in at least two animals, the corneal opacity mean score is less than 1.0, the iris lesion mean score is less
than 1.0, the conjunctival redness mean score is less than 2.0, and the chemosis mean score is less than 2.0.
- The test substance will be considered a Category 2 (reversible eye effects) irritant if at least two of the three rabbits have a corneal opacity mean score greater than or equal to 1.0 but less than 3.0 and/or an iris lesion mean score greater than or equal to 1.0 but less than 1.5 and/or a conjunctival redness mean score greater than or equal to 2.0 and/or a chemosis mean score greater than or equal to 2.0.
- The test substance will be considered a Category 1 (irreversible eye effects) irritant if the corneal opacity mean score is greater than or equal to 3.0 and/or the iris lesion mean score is greater than 1.5 in at least two of the three rabbits tested.

TOOL USED TO ASSESS SCORE: The eye examinations were performed using a slit penlight and the treated eyes were scored for ocular reaction of the cornea, iris, conjunctivae, lids and nictitating membranes. Fluorescein stain was used to aid in the examination for corneal lesions at the 24-hour scoring interval.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
mean
Time point:
24/48/72 h
Score:
0 - 0.3
Max. score:
0.3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0

Mortality

No rabbits died during the study prior to scheduled euthanisation, nor were any adverse clinical observations noted at any time during the study.

Ocular Observations

No positive irritation scores were observed in any animal throughout the study for corneal opacity, iris lesions or conjuncitval chemosis. Conjunctival redness scores ranged from 0.0 to 0.3. No signs of any ocular irritation were present at 72 hours after dosing.

Individual and Mean Eye Irritation Scores

1. Cornea (A = Density of Opacity; B = Area of Opacity)

 Animal Number (Sex)   1 Hour     24 Hours     48 Hours     72 Hours     Meanb
 A  B  A  B  A  B  A  B  
 807 (F)  0  -a  0  -  0  -  0  -  0.0
 808 (F)  0  -  0  -  0  -  0  -  0.0
 809 (F)  0  -  0  -  0  -  0  -  0.0

a - = not applicable (no opacity)

b Mean = sum of individual animal "A" scores at the 24 -, 48- and 72 -hour scoring intervals divided by 3.

2. Iris

Animal Number (Sex)   1 Hour  24 Hours 48 Hours   72 Hours Meana 
 807 (F)  0  0  0  0  0.0
 808 (F)  0  0  0  0  0.0
 809 (F)  0  0  0  0  0.0

a Mean = sum of individual animal "A" scores at the 24 -, 48- and 72 -hour scoring intervals divided by 3.

3. Conjunctiva (A = Redness; B = Chemosis)

 Animal Number (Sex)   1 Hour     24 Hours     48 Hours     72 Hours     Meana   
 A  B  A  B  A  B  A  B  A  B
 807 (F)  0  0  0  0  0  0  0  0  0.0 0.0 
 808 (F)  0  0  0  0  0  0  0  0  0.0 0.0 
 809 (F)  1  0  1  0  0  0  0  0  0.3  0.0

a Mean ("A" and "B" scores, respectively) = sum of individual animal scores at the 24 -, 48- and 72 -hour scoring intervals divided by 3.

Interpretation of results:
other: EU GHS criteria not met
Conclusions:
Sodium pentaborate 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 mean scores of less than 2.0, and chemosis mean scores of less than 2.0 in at least two of the three rabbits tested [European Parliament and the Council of the European Union guidelines (Regulation (EC) No. 1272/2008, Dec. 2008)]. Recovery from all signs of irritation had occurred by 72 hours post-administration of sodium pentaborate.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

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

Additional information

Skin Irritation


No primary skin irritation studies of sodium pentaborate have been conducted. A number of studies were conducted on analogue substances. Boric acid, disodium tetraborate pentahydrate and disodium tetraborate decahydrate showed no skin irritation potential. Hence, it is concluded that sodium pentaborate is not irritant to skin.


 


Eye Irritation


An eye irritation study in rabbits according to OECD 405 has been carried out on sodium pentaborate. No positive irritation scores were observed in any animal throughout the study for corneal opacity, iris lesions or conjunctival chemosis. Conjunctival redness scores ranged from 0.0 to 0.3. No signs of any ocular irritation were present at 72 hours after dosing. Hence, sodium pentaborate is not classified as irritant to the eyes.


There are further in vivo skin and eye irritation studies on the analogue substances available supporting these results.


 


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 pentaborate does not meet the criteria defined in Regulation (EC) No 1272/2008 for classification as skin or eye irritant. Moreover, sodium pentaborate does not meet the criteria defined under Regulation (EC) No 1272/2008 for classification and labelling as a respiratory irritant.