Registration Dossier

Administrative data

Description of key information

Skin irritation: not irritating (OECD 404 (modified), GLP)
Eye irritation: severe irritant to the eye (OECD 405; GLP)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation / corrosion, other
Remarks:
in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-06-22 to 2012-06-25
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP guideline study reliable without restrictions The following deviations from the guideline OECD 404 (2002) occured, but they had no effect on the results of the study: - the animals were observed 30 minutes after the removal of the test item instead of 60 minutes after test item removal - the animals were not observed for systemic adverse effects, but only for the skin irritation listed in the Draize scoring system
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
2002-04-24
Deviations:
yes
Remarks:
please refer to "Rationale for reliability incl. deficiencies" above
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kuiper Rabbitry, Gary, Indiana
- Age at study initiation: approximately ten to twelve weeks old
- Weight at study initiation: 2.67 to 2.82 kg
- Housing: the rabbits were individually housed in stainless steel cages.
- Diet (ad libitum): Purina Laboratory Rabbit Chow
- Water (ad libitum): water
- Acclimation period: at least five days prior to study initiation

ENVIRONMENTAL CONDITIONS
- Temperature: 20 ± 3°C
- Relative humidity: 30-70%
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g aliquot of the test material was slightly moistened with distilled water

Duration of treatment / exposure:
4 hours
Observation period:
30 minutes, 24, 48 and 72 hours after removal of the test substance
Number of animals:
3 male rabbits
Details on study design:
INITIAL TEST
One animal was screened by applying the test substance for a 3 minute and 1 hour topical exposure. No irritation was observed in either exposure; therefore the four hour exposure was conducted. Following the 4 hour exposure of the one animal, two additional animals were tested for four hours.

TEST SITE
- Area of exposure: the day before study initiation, electric clippers were used to remove the hair from the left side of the trunk, from the midline of the back to the abdomen. The following day an aliquot of the test material with the vehicle was applied to an area approximately 6 square centimeters on the side of the test animal. The application site is located approximately 5-7 centimeters down from the backbone.
- Type of wrap if used: the test substance was covered with a 2.5 cm² - 2 layer gauze patch held in place with non-irritating Kendall Curity Standard Porous Tape and the patch was then covered with a semi-occlusive plastic overwrap secured in place with Kendall Curity Standard Porous Tape for the duration of the exposure period.

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: at the end of the 4 hour contact period, excess material was removed from the site; the site being observed and scored.

SCORING SYSTEM: according to the Draize scale
Other adverse changes at the skin sites will be recorded if present
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
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
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
There were mild irritation reactions (grade 1 - very slight erythema (barely perceptible)) in two of the test subjects at the 30 minute observation which cleared by the 24 hour observation.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item is not a skin irritant.
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is not classified as 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
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
January 2013
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 (incl. certificate)
Remarks:
signed 2011-08-31
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS - New Zealand White (Hsdlf:NZW) strain rabbits
- Source: Harlan Laboratories UK Ltd., Leicestershire, UK
- Age at study initiation: twelve to twenty weeks old
- Weight at study initiation: 2.72 kg
- Housing: the animals were individually housed in suspended cages.
- Diet (ad libitum): 2930 Teklad Global Certified Rabbit diet supplied by Harlan Laboratories UK Ltd., Oxon, UK
- Water (ad libitum): mains drinking water
- Acclimation period: at least five days

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

ENVIRONMENTAL CONDITIONS
- Temperature: 17 to 23°C
- Relative humidity: 30 to 70%
- Air exchange: at least fifteen changes per hour
- 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): a volume of 0.1 ml of the test item was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball. The upper and lower eyelids were held together for about one second immediately after treatment, to prevent loss of the test item, and then released. The left eye remained untreated and was used for control purposes.
Duration of treatment / exposure:
not applicable
Observation period (in vivo):
approximately 1 hour and 24, 48 and 72 hours following treatment
Number of animals or in vitro replicates:
1 male rabbits
Details on study design:
Immediately before the start of the test, both eyes of the provisionally selected test rabbits were examined for evidence of ocular irritation or defect with the aid of a light source from a standard ophthalmoscope. Only animals free of ocular damage were used.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
7 d
Score:
2
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 8 days
Score:
3
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not reversible
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not reversible
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 8 days
Score:
3
Max. score:
3
Reversibility:
not reversible
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Irritant / corrosive response data:
Diffuse corneal opacity was noted in the treated eye one hour after treatment, at the 24, 48 and 72-Hour observations with translucent corneal opacity at the 7-Day observation and opalescent corneal opacity at the additional 8-Day observation.

Iridial inflammation was noted in the treated eye one hour after treatment, at the 24, 48 and 72-Hour, 7 and 8-Day observations Moderate conjunctival irritation was noted in the treated eye one hour after treatment with severe conjunctival irritation noted at the 24, 48 and 72-Hour observations and moderate conjunctival irritation noted at the 7-Day observation. Severe conjunctival irritation was noted at the 8-Day observation.

A conjunctival bulla was noted inside the lower eyelid, approximately 3 mm x 3 mm in size, at the 7 and 8-Day observations. Sloughing of the nictitating membrane and white appearance of the majority of the nictitating membrane were noted in the treated eye at the 8-Day observation.

Due to worsening reactions and signs of pain and discomfort the animal was killed for humane reasons immediately after the 8-Day observation, in accordance with Company policy and current UK Home Office guidelines.
Other effects:
- Bodyweight: both animals showed expected gain in bodyweight during the study.
Interpretation of results:
Category 1 (irreversible effects on the eye)
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item is classified as Irreversible effects on the eye (Category 1) according to regulation (EC) No. 1272/2008 and R41 according to directive 67/548/EEC.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin corrosion

One reliable in vitro skin corrosion study described in Heppenheimer (2010) (OECD 431; GLP compliant is considered to be reliable without restrictions. the substance was determined to be corrosive to the skin.

Skin irritation

One reliable in vivo skin irritation study described in Kukulinski (2012) (OECD 404 (modified), GLP compliant) is considered to be reliable without restrictions. The substance was determined to be not irritating to the skin.

In an initial testing programme cobalt, borate propionate was tested for skin corrosion in an in vitro system (according to OECD 431, Heppenheimer 2010). Following this test, cobalt, borate propionate needed to be classified as skin irritating category 1A.

In another regulatory context a re-test with cobalt, borate propionate for in vivo skin irritation was required (according to US EPA TG OPPTS 870.2500 and OECD 404, Kukulinski 2011). The outcome did not show any skin corrosion or irritation potential of cobalt, borate propionate, thus no classification required.

Since in vivo test results should take precedence over in vitro test results, the results received from this in vivo test are taken forward for the chemical hazard assessment.

Eye irritation

One reliable in vivo study described by Sanders (2013) (OECD 405; GLP compliant) is considered to be reliable without restrictions. The substance was determined to be severely irritating to the eye.


Justification for selection of skin irritation / corrosion endpoint:
Key study.

Justification for selection of eye irritation endpoint:
Key study

Effects on eye irritation: corrosive

Justification for classification or non-classification

Skin corrosion

Reference Heppenheimer (2010) is considered as disregarded study for skin corrosion, since an in vivo skin irritation test is available.

The overall irritation results in an in vitro human skin model test (according to OECD 431) are as follows:

Relative viability 3 min after treatment: 48.4 %

Relative viability 60 min after treatment: 19.3 %

Testing requirements in other international schemes necessitated an in vivo test. Since in vivo test results should take precedence over in vitro test results, the results received from this in vivo test are taken forward for the chemical hazard assessment.

 

Skin irritation

Reference Kukulinski (2012) is considered as the key study for in vivo skin irritation and will be used for classification. The skin irritation was scored according to the Draize scale. The mean score (24, 48, 72h) for erythema and oedema was 0 for all animals. The study was terminated after the 72 hour observation. According toregulation (EC) 1272/2008 and subsequent amendments the substance will not be classified as skin irritant.

In an initial testing programme cobalt, borate propionate was tested for skin corrosion in an in vitro system (according to OECD 431, Heppenheimer 2010). Following this test, cobalt, borate propionate needed to be classified as skin irritating category 1A.

In another regulatory context a re-test with cobalt, borate propionate for in vivo skin irritation was required (according to US EPA TG OPPTS 870.2500 and OECD 404, Kukulinski 2011). The outcome did not show any skin corrosion or irritation potential of cobalt, borate propionate, thus no classification required.

Since in vivo test results should take precedence over in vitro test results, the results received from this in vivo test are taken forward for the chemical hazard assessment.

 

Eye irritation

Reference Sanders (2013) is considered as the key study for eye irritation and will be used for classification. The test item showed severe irritating effects in cornea, iris and conjunctivae. The classification criteria according to regulation (EC) 1272/2008 as severe eye irritation are met, hence the substance will be classified as severe eye irritant (Category 1, R41).

 

Respiratory irritation

The justification for classification as respiratory irritant is covered under the endpoint specific target organ toxicity- single exposure: inhalation as given in the acute toxicity section.