Registration Dossier

Administrative data

Description of key information

In vivo irritation study on skin was performed with potassium tetraborate (Young & Doyle, 1973) as well as with the UVCB test item (Zechel, 1983). An in vivo eye irritation study with potassium tetraborate as well as with the UVCB test item (Zechel, 1983) has been conducted in rabbits (OECD 405); according to the results obtained in these studies, potassium tetraborate and teh test item are 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

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Qualifier:
equivalent or similar to
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 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:
other: Not specified
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Irritation parameter:
edema score
Basis:
mean
Time point:
other: Not specified
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Irritant / corrosive response data:
No adverse effects were seen.
Other effects:
No data
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: not specified
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:
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: Meets generally accepted scientific standards with acceptable restrictions.
Qualifier:
according to
Guideline:
other: Section 173.240 under Title 49 of the code of Federal Regulations (Federal Register, 1973).
Deviations:
not specified
GLP compliance:
no
Remarks:
Study pre-dates GLP
Species:
rabbit
Strain:
not specified
Type of coverage:
occlusive
Preparation of test site:
abraded
Vehicle:
not specified
Controls:
no
Amount / concentration applied:
No data
Duration of treatment / exposure:
4 h
Observation period:
48 h
Number of animals:
Six
Details on study design:
TEST SITE
- Area of exposure: 1 inch by 1 inch on the saddle.
- % coverage:
- Type of wrap if used: 12-ply surgical gauze held in place with adhesive tape. After application of the patches, the trunk of each rabbit was wrapped with rubber dental damming secured with staples.

REMOVAL OF TEST SUBSTANCE
- Washing: Gently sponged with a moistened towel.
- Time after start of exposure: 4 h
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 48 h
Score:
0
Max. score:
8
Reversibility:
other: Not applicable
Remarks on result:
other: Result on intact skin.
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 48 h
Score:
0
Max. score:
8
Reversibility:
other: Not applicable
Remarks on result:
other: Result on abraded skin.
Irritant / corrosive response data:
Very slight erytehma was noted. No corrosive effects were noted at any time.

Primary irritation and corrosive scores in rabbits following a 4-h patch application of potassium tetraborate powder:

Rabbit

No.

Skin

Erythema-Eschar Observation

Edema Observation

4 h

24 h

48 h

4 h

24 h

48 h

55

Intact

0

0

0

0

0

0

Abraded

0

0

0

0

0

0

56

Intact

0

0

0

0

0

0

Abraded

0

0

0

0

0

0

57

Intact

0

0

0

0

0

0

Abraded

1

1

0

0

0

0

58

Intact

0

0

0

0

0

0

Abraded

0

0

0

0

0

0

59

Intact

0

0

0

0

0

0

Abraded

0

0

0

0

0

0

60

Intact

0

0

0

0

0

0

Abraded

1

0

0

0

0

0

Interpretation of results:
other: Not corrosive
Remarks:
Criteria used for interpretation of results: other: Section 173.40 under Title 49 of the Code of Federal Regulations (Federal Register, 1973).
Conclusions:
The corrosive potential of potassium tetraborate was assessed and found not corrosive according to Section 173.40 under Title 49 of the Code of Federal Regulations (Federal Register, 1973).
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983-02-21 to 1983-03-07
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Guideline study reliable with restrictions - the purity and the stability of the test substance was not stated in the study report. In this study the test substance was not only tested on intact skin, but also in abraded skin. The results of the intact skin were reported in this endpoint study record. The results of the abraded skin were reported in the following endpoint study record: Section 7.3.1 Skin irritation / corrosion: s_Zechel_1983
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
adopted 1981-05-12
Deviations:
no
GLP compliance:
no
Species:
rabbit
Strain:
other: White Russian (Albino)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Asta-Werke AG
- Age at study initiation: approx. 8-10 months
- Weight at study initiation: 2.1-2.2 kg
- Housing: caging: stainless steel cages type Asta; number of animals per cage: 1
- Diet: Standard test animal diet Altromin®
- Water (ad libitum): water
- Acclimation period: 1 day

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C±1°C
- Relative humidity: 50-60%
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
other: shorn skin
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g/patch
Duration of treatment / exposure:
4 hours
Observation period:
1, 24, 48 and 72 hours after removal of the bandage (maximum 14 days)
Number of animals:
3 male rabbits
Details on study design:
TEST SITE
- Area of exposure / Type of wrap if used: the test substance was given on a wad of cotton, in order to ensure application without loss on the shorn dorsal skin area between shoulder and sacrum. The site of application was covered with an approximate 6.25 cm^2 linen cloth which adhered to a synthetic adhesive film. A bandage wrapped around the trunk (Acrylastic, supplied by P. Beiersdorf adn Co. AG, Hamburg, No. 2408, width 8 cm) provided occlusion. The dorsal skin area of each rabbit was subdivided into two areas on each side of the vertebral column (a total of 4). The contralateral areas differed from one another in that they consisted on the left side of uninjured (intact) skin and on the right side of artificially injured (sacrified) skin. Scarification took place solely superficially avoiding deeper defects and bleeding. Each of the 4 areas was covered with a patch of appropriate size; 2 patches served for covering the applied test product (one each on intact and sacrified region), 2 covered untreated skin regions at corresponding places.

SCORING SYSTEM: according to the Draize scale
Systemic toxic effects occurring were recorded.
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Very slight oedema was observed at the 1 hour observation.
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Very slight oedema was observed at the 1 hour observation.
Irritant / corrosive response data:
NOTE: The results of the intact skin were only stated in this result section. The results of the abraded skin were stated in the endpoint study record Section 7.3.1 Skin irritation / corrosion: s_Zechel_1983 (abraded skin).

The single application of 0.5 g Flußmittel Degussa h-Paste to the intact dorsal skin of the rabbit provoked erythemas and oedemas in 2 animals. In 1 animal neither erythema nor oedema was observed.
Erythemas occurred only 24 hours after the end of exposure and were assessed with gradings of 1 and 2 (very slight to well defined erythemas).
Oedemas, however, were immediately observed. They were seen at a maximum until day 2 of observation and obtained a grading of 1 (very slight oedemas).
Skin regions treated with solvent/suspension medium without test substance (control): without finding.
Other effects:
Systemic toxic effects did not occur after dermal application of the test product. The general condition of the test animals was undisturbed.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item is not irritating to the skin.
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is not a skin irritant.
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as skin irritant.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

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:
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:
other: Average 24, 48 & 72 h
Score:
0 - 0.7
Max. score:
0.7
Reversibility:
fully reversible within: 14 days (initial testing) / 7 days (confirmatory testing)
Irritation parameter:
iris score
Basis:
mean
Time point:
other: Average 24, 48 & 72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
mean
Time point:
other: Average 24, 48 & 72 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 14 days (initial testing) / 7 days (confirmatory testing)
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: Average 24, 48 & 72 h
Score:
0.7 - 1
Max. score:
1
Reversibility:
fully reversible within: 14 days (initial testing) / 7 days (confirmatory testing)

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 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).

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     7 Days     14 daysc     Meand
 A  B  A  B  A  B  A  B  A  B A B  
 804 (M)  0  -a  1  -b  1  -b  0  -  0  -  -  0.7
 805 (M)  0  -  1  -b  0  -  0  -  0  - NA  NA   0.7
 806 (F)  0  -  0  -  0  -  0  -  0  - NA  NA   0.0

a - = not applicable (no opacity)

b scattered/diffuse

c initial testing (animal 804) only

d 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 7 Days  14 Daysa  Meanb
 804 (M)  0  0  0  0  0  0  0.0
 805 (M)  0  0  0  0  0  NA  0.0
 806 (F)  0  0  0  0  0  NA  0.0

a initial testing (animal 804) only

b 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     7 Days  14 Days    Meanb   
 A  B  A  B  A  B  A  B  A  B  B  A  B
 804 (M)  1  1  1  1  1  1  1  1  1 0 0 1.0 1.0
 805 (M)  1  1  1  1  1  1  1  1  0 NA  NA  1.0 1.0
 806 (F)  1  1  1  0  1  1  1  1  0 0 NA NA 1.0 0.7

a initial testing (animal 804) only

b 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:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: EU GHS
Conclusions:
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 ofless 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 14 days after dosing (initial testing) or 7 days after dosing (confirmatory testing) with potassium tetraborate.
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983-03-01 to 1983-03-22
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions - the purity and stability of the test item were missing in the study report Deficiency from the guideline: - Draize scale: cornea and iris were not included in the scoring of conjunctival redness
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
adopted 1981-05-12
Deviations:
yes
Remarks:
please refer to "Rationale for reliability incl. deficiencies" above
GLP compliance:
no
Species:
rabbit
Strain:
other: White Russian (Albino)
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Asta-Werke AG, D-4800 Bielefeld 14
- Age at study initiation: 4-7 months
- Weight at study initiation: 2.0-2.6 kg
- Fasting period before study: diet withdrawal on the day of treatment
- Housing: caging: stainless steel cages type Asta; number of animals per cage: 1
- Diet: Standard test animal diet Altromin
- Water (ad libitum): water
- Acclimation period: 1 day

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C±1°C
- Relative humidity: 50-60%
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g of the test product was applied Into the conjunctival sac of one eye of the correspondingly fixed rabbit, after previously carefully pulling the lower lid away from the eyeball. Thereafter the lids were gently held together for about 1 second in order to prevent loss of Instilled test substance. The other eye of each animal remained untreated and acted as control.
Duration of treatment / exposure:
not applicable
Observation period (in vivo):
1, 24, 48, and 72 hours after the instillation of the test substance (maximum 21 days)
Number of animals or in vitro replicates:
3 female rabbits
Details on study design:
Only test animals without any signs of eye diseases were used in the study.

REMOVAL OF TEST SUBSTANCE
- Washing: the treated eyes were not rinsed with aqua font, after application of the test substance.

SCORING SYSTEM: according to the Draize scale
Apart from the assessment of the primary irritation of the test product, additional findings, which did not affect the eye, were recorded (systemic toxic effects).

TOOL USED TO ASSESS SCORE: the eyes were examined with a hand-slit-lamp (model Ophthalmoskop, supplied by Heine, type med. 261).
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 21 days
Remarks on result:
other: Scattered/diffuse area of opacity (grade 1) was observed at the 1 h observation. The area of cornea involved was > one quarter, but less than half during the 1, 24, and 48 h observations. During the 72 h observation one quarter or less but not zero.
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Diffuse redness, crimson colour, individual vessels not easily discernible (grade 2) was observed at the 1 h observation. Discharge with moistening of the adjacent lids and hairs (grade 2) was observed at the 1 h observation.
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Obvious swelling with partial eversion of lids (grade 2) was observed at the 1 h observation.
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Diffuse redness, crimson colour, individual vessels not easily discernible (grade 2) was observed at the 1 h observation. Discharge with moistening of the adjacent lids and hairs (grade 2) was observed at the 1 h observation.
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Obvious swelling with partial eversion of lids (grade 2) was observed at the 1 h observation.
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Diffuse redness, crimson colour, individual vessels not easily discernible (grade 2) was observed at the 1 h observation. Discharge with moistening of the adjacent lids and hairs (grade 2) was observed at the 1 h observation.
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Obvious swelling with partial eversion of lids (grade 2) was observed at the 1 h observation.
Irritant / corrosive response data:
The single instillation of 0.1 g Flußmittel Degussa h-Paste into the conjunctival sac of the rabbit eye caused slight changes in cornea and conjunctiva.
In the cornea signs of irritation with the grading 1 (scattered or diffuse opacity) occurred in 1 of 3 test animals already 1 hour after exposure of the test product. Firstly less than half of the corneal area and subsequently approximately one quarter of the corneal area were involved. This finding persisted up to day 14 of the observation period.
In the Iris no changes occurred due to the contact with the test product.
The conjunctiva reacted with redness, swelling, and discharge. These findings occurred in all 3 animals already after 1 hour of exposure of the test product. Redness was diffuse with the grading 2. Obvious swelling with partial eversion of lids (grade 2) occurred. The observed discharge led to moistening of adjacent lids and hairs. The changes were detectable up to 48 hours at the longest after exposure of the test product into the conjunctival sac.
Other effects:
Systemic toxic effects did not occur after conjunctival application of the test substance. The general condition of the test animals was undisturbed.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test material is non-irritating to the eyes.
According to 67/548/EC and subsequent regulations, the substance is not classified as an eye irritant.
According to the EC Regulation No. 1272/2008 and subsequent regulations, the substance is not classified as an eye irritant.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Assessment entity approach

"Brazing fluxes" are mixtures of boron-containing constituents (potassium(fluoro)borates), which undergo chemical exchanges (anion exchange) and condensation reactions (e.g. formation of oligoborates, polyborates) upon mixing and further manufacturing. This results in a complex mixture of potassium borates, which cannot be fully chemically characterised for substance identity. Thus, according to the definition under REACH, such brazing fluxes must be described as a UVCB substance.

 

An assessment entity approach is followed based on the transformation products of this UVCB uppon dissolution in aqueous media. The substance is highly soluble and forms complex boron, potassium and fluoride constituents. The quantitatively predominant transformation productof this UVCB is represented by boric acid, which is assumed to be the determinant of human health effects because of its classification and its toxicity. For this reason, the assessment is based on information for “borates” (including potassium borate, boric acid and other borate substances).

 

Based on the information provided below, it may safely be assumed that under physiological conditions the chemical speciation of most of the unknown potassium boron compounds corresponds to boric acid. Thus, from a chemical point of view, there is no reason to assume that brazing fluxes would behave differently than boric acid and/or borates under physiological conditions.

 

The basis of this assessment entity approach is further justified by the following reasoning:

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 below.

 

Substance

Formula

Conversion factor for equivalent dose of B (multiply by)

Boric acid

H3BO3

0.1748

Boric Oxide

B2O3

0.311

Disodium tetraborate anhydrous

Na2B4O7

0.2149

Disodium tetraborate pentahydrate

Na2B4O7•5H2O

0.1484

Disodium tetraborate decahydrate

Na2B4O7•10H2O

0.1134

Disodium octaborate tetrahydrate

Na2B8O13·4H2

0.2096

Sodium metaborate (anhydrous)

NaBO2

0.1643

Sodium metaborate (dihydrate)

NaBO2·2H2O

0.1062

Sodium metaborate (tetrahydrate)

NaBO2·4H2O

0.0784

Sodium pentaborate (anhydrous)

NaB5O8

0.2636

Sodium pentaborate (pentahydrate)

NaB5O8∙5H2O

0.1832

 Dipotassium tetraborate (anhydrous)

 

 K2B4O7

 

 0.185

 

 Dipotassium tetraborate (tetrahydrate)

 

 K2B4O7.4H2O

 

 0.1415

 

 Potassium pentaborate (anhydrous)

 

 B5KO8

 

 0.244

 

 Potassium pentaborate (tetrahydrate)

 

 B5KO8.4H2O

 

 0.1843

 

 

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

 

 

Discussion:

Skin Irritation

In vivo skin irritation studies were performed with the analogous substance potassium tetraborate (Young & Doyle, 1973), as well as with brazing fluxes (Zechel, 1983). Both tests showed no potential for skin irritation.

Eye Irritation

An eye irritation study in rabbits according to OECD 405 was carried out with 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).

One eye irritation study in rabbits according to OECD 405 was carried out with brazing fluxes (Zechel, 1983). No positive irritation scores were observed in any animal throughout the study for iris lesions. Conjunctival redness scores were 0.44 for all animals (mean), and conjunctival chemosis scores ranged from 0 to 0.33.

 

Supplementary data on other borate substances

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 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-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.

Because borates are considered the transformation product driving the human health effects for brazing fluxes, respiratory irritation effects are similarly not anticipated for brazing fluxes.


Effects on respiratory irritation: irritating

Justification for classification or non-classification

Skin irritation:

In vivo testing with brazing fluxe paste (Zechel, 1983) showed no skin irritating potential. Therefore, according to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item does not require classification for as skin irritation. Likewise, the test item also does not require classification for as skin irritation according to EC Regulation No. 1272/2008 and subsequent regulations.

Eye irritation:

An eye irritation study in rabbits according to OECD 405 was carried out for the brazing fluxe paste and showed no eye irritating potential.

According to the criteria specified by Directive 67/548/EEC and subsequent regulations as well as EC Regulation No. 1272/2008 and subsequent regulations, the test item does not require classification for eye irritation.