Registration Dossier

Administrative data

Description of key information

In vivo irritation studies on skin and eye irritation were performed on disodium octaborate tetrahydrate (Doyle, 1989). Respiratory tract irritation of boric acid and sodium tetraborate pentahydrate were performed (Kirkpatrick, 2010). Disodium octaborate tetrahydrate is less irritating to the nose and throat than sodium tetraborate decahydrate or sodium tetraborate pentahydrate because of its more neutral pH. No threshold limit values (TLV) or occupational exposure limits have been established for disodium octaborate tetrahhydrate. Therefore, disodium octaborate tetrahydrate is not considered a respiratory irritant.

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:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study.
Qualifier:
according to
Guideline:
other: FIFRA ( 40 CFR 158, 162 ) and Toxic Substances Control Act (40 CFR 798).
Deviations:
not specified
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Clerco Research Farm
Type of coverage:
occlusive
Preparation of test site:
other: Hair was clipped from the dorsal area of each rabbit and one area on each rabbit treated with substance.
Vehicle:
physiological saline
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g
Duration of treatment / exposure:
4 h
Observation period:
72 h
Number of animals:
3 /sex/group
Details on study design:
TEST SITE
- Type of wrap if used: Occlusive


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Moistened towel
- Time after start of exposure: 4 h


SCORING SYSTEM: Draize, 1959
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 72 h
Score:
0.17
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 72 h
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Irritant / corrosive response data:
No irritancy was observed.
Other effects:
No data

Primary skin irritation in rabbits following a 4-h dermal application of disodium octaborate tetrahydrate:

Skin condition

Observation time (h)

Score for each rabbit

Total score

Average score

1

2

3

4

5

6

Erythema formation

Intact

½ - 1

1

1

1

2

1

1

7.00

1.17

24

0

0

1

1

0

1

3.00

0.5

48

0H*

1H

0H

0H

0H

0H

1.00

0.17

72

0H

0H

0H

0H

0H

0H

0.0

0.0

Edema formation

Intact

½ - 1

0

0

0

1

0

1

2.00

0.33

24

0

0

0

0

0

0

0.00

0.0

48

0

0

0

0

0

0

0.00

0.0

72

0

0

0

0

0

0

0.00

0.0

Primary irritation index (PII)

0.5

* Hair on site

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: not specified
Conclusions:
In the acute dermal irritation study no irritancy was observed. The protocol meets the requirements of OECD 404 although the report lacks detail. Since the data is in line with other data on sodium borates, further testing is not warranted in the interests of animal welfare and protecting laboratory animals.
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:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to a guidleine study.
Qualifier:
according to
Guideline:
other: No data
Deviations:
not specified
Principles of method if other than guideline:
The primary ocular irritancy of the test substance was evaluated in compliance with the conditions specified in the regulation for the enforcement of FIFRA (40 CFR).The test material was applied at a dose of 0.053 g to one eye of 6 rabbits. The eyes were rinsed after 24 h and fluorescein staining utilised for scoring.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Clerco Research Farm.
- Housing: Singly in suspension cages with wire mesh floors.
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: At least 1 day.


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 h dark/light
Vehicle:
not specified
Controls:
other: Test substance was administered to one eye only with the other eye acting as control.
Amount / concentration applied:
0.053 g
Duration of treatment / exposure:
24 h
Observation period (in vivo):
72 h
Number of animals or in vitro replicates:
Six
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: Not specified
- Time after start of exposure: 24 h


SCORING SYSTEM: Draize


TOOL USED TO ASSESS SCORE: Fluorescein
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24 h
Score:
3
Max. score:
110
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: Non Irritant. No animals met irritation criteria based on average scores for cornea and/or iris <1 and/or conjunctiva (redness and chemosis) < 2; calculated as the mean scores following grading at 24, 48 and 72 h after installation of the test substance.
Irritant / corrosive response data:
The test material produced iritis and conjunctival irritation persisting for less than 72 h when applied without rinsing. Irritation scores in individual animals ranged from 2 to 19. No evidence of corrosion was noted.
Other effects:
No data

Primary eye irritation in rabbits following an ocular application of disodium octoborate tetrahydrate:

Animal no.

Time

Corneaa

Iris

Conjunctivaa

Total scorebc

A

B

C

D

E

I-NP

1 h

0

0

1

2

2

0

13

24 h

0/0

0/0

0

1

0

0

2/2

48 h

0/0

0/0

0

0

0

0

0/0

72 h

0/0

0/0

0

0

0

0

0/0

2-P

1 h

0

0

1

2

2

1

15

24 h

0/0

0/0

0

0

0

0

0/0

48 h

0/0

0/0

0

0

0

0

0/0

72 h

0/0

0/0

0

0

0

0

0/0

3-P

1 h

0

0

1

3

2

1

17

24 h

0/0

0/0

0

0

0

0

0/0

48 h

0/0

0/0

0

0

0

0

0/0

72 h

0/0

0/0

0

0

0

0

0/0

4-P

1 h

0

0

0

2

1

0

6

24 h

0/0

0/0

0

1

0

0

2/2

48 h

0/0

0/0

0

0

0

0

0/0

72 h

0/0

0/0

0

0

0

0

0/0

5-P

1 h

0

0

1

3

2

1

17

24 h

0/0

0/0

0

2

0

0

4/4

48 h

0/0

0/0

0

0

0

0

0/0

72 h

0/0

0/0

0

0

0

0

0/0

6-P

1 h

0

0

1

3

2

2

19

24 h

0/0

0/0

1

2

1

0

11/11

48 h

0/0

0/0

1

1

0

0

7/7

72 h

0/0

0/0

0

0

0

0

0/0

a A = degree of opacity; B = area affected; C = erythema; D = swelling; E = discharge

b Scored accoring to Draize

c Total score is the sum of the following three sub-totals, with maximum score of 110; ( / ) = score without/with sodium fluorescein:

1. Degree of opacity x area involved x 5

2. Iris score x 5

3. (Sum of scores for erythema, swelling and discharge) x 2.

P - Photographs of all test eyes were taken at the 1 h; 24 h and 48 h readings. Animal No. 6 also have the control eye taken at the 48 h reading.

Interpretation of results:
other: Toxicity Category III - corneal involvement or irritation clearing in 7 days or less.
Remarks:
Criteria used for interpretation of results: other: 40 CFR (proposed)
Conclusions:
The primary ocular irritancy of disodium octaborate tetrahydrate was evaluated in compliance with the conditions specified in the regulation for the enforcememnt of FIFRA. The test material produced iritis and conjunctival irritation persisting for less than 72 h when applied without rinsing to the eyes of six New Zealand white rabbits. Irritation scores for individual animals ranged from 2 to 19. No evidence of corrosion was noted. The material was classified in Toxicity Category III by ocular administration.
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

Disodium octaborate tetrahydrate is not a skin irritant.

Eye Irritation

Disodium octaborate tetrahydrate produced slight iritis and conjunctival irritation persisting for less than 72 h without rinsing. When applied with rinsing at 24 h disodium octaborate tetrahydrate produced slight iritis and conjunctival irritation, which was fully reversible within 7 days in 5 of 6 animals, and within 10 days in one animal. None of animals met the criteria of irritating based on average scores for cornea and/or iris <1, and/or conjunctiva (redness and chemosis) < 2; calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the test material.

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 by Krystofiak & Schaper (1996) and Kirkpatrick (2010), which demonstrated a depression of the respiratory frequency in mice after exposure to sodium borate.. 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 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 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 guidance (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/m3with a %RD of 33%. Based on these results, the RD50is > 1704 mg/m3for sodium tetraborate pentahydrate. The ASTM standard uses the value of 0.03 x RD50for estimation of threshold limitvalues (TLV). Alarie et al. (2001) has established that a value of 0.01 x RD50as the concentration where no sensory irritation would be seen in humans. Therefore, although the highest achievable concentration was below the RD50value 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/m3total particulates will prevent any sensory irritation in workers.

Disodium octaborate tetrahydrate was not evaluated by Wegman, Garabrant, or Kirkpatrick and no threshold limit values (TLV) or occupational exposure limits have been established for disodium octaborate tetrahhydrate. Disodium octaborate tetrahydrate is less irritating to the nose and throat than sodium tetraborate decahydrate or sodium tetraborate pentahydrate because of its more neutral pH.  Therefore, disodium octaborate tetrahydrate is not considered a respiratory irritant.


Justification for selection of skin irritation / corrosion endpoint:
GLP guideline study conducted with disodium octaborate.

Justification for selection of eye irritation endpoint:
GLP comparable to guideline study conducted with disodium octaborate.

Justification for classification or non-classification

Disodium octaborate tetrahydrate 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.

Disodium octaborate tetrahydrate is not considered an eye irritant based on eye irritation studies in test animals. None of animals met the criteria of irritant based on average scores for cornea and/or iris <1, and/or conjunctiva (redness and chemosis) < 2; calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the test material. Disodium octaborate tetrahydrate does not meet also criteria under EU CLP Regulation (EC) No. 1272/2008) for classification and labelling as a skin or eye irritant. Disodium octaborate tetrahydrate is not considered a respiratory irritant.