Registration Dossier

Administrative data

Description of key information

Skin irritation/ corrosion: not irritating/corrosive

Eye irritation: not irritating

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:
26 October 2012 to 12 November 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Skin Irritation (2-1-4), 12 Nohsan No. 8147, Agricultural Production Bureau, November 24, 2000.
Version / remarks:
2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Stock supply
- Age at study initiation: 36 weeks
- Weight at study initiation: 3.98 to 4.19 kg
- Housing: The rabbits were housed individually in plastic cages with perforated floors.
- Diet: Each rabbit was offered 125 g of a standard laboratory rabbit diet per day
- Water: Drinking water was provided ad libitum.
- Acclimation period: 22 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 16 to 20°C
- Humidity: 40 to 70%
- Air changes (per hr): no data
- Photoperiod: Lighting was controlled by means of a time switch to give 12 hours of artificial light (06:00 to 18:00 GMT) in each 24 hour period.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Approximately 0.5 g.

VEHICLE
- Amount(s) applied (volume or weight with unit): not applicable
Duration of treatment / exposure:
3 min, 1 h and 4 h
Observation period:
24, 48 and 72 hours after administration
Number of animals:
3, all female.
Details on study design:
TEST SITE
- Area of exposure: no data
- % coverage: no data
- Type of wrap if used: 2-ply 25 mm x 25 mm porous gauze pad secured with ‘Blenderm’ surgical tape.

REMOVAL OF TEST SUBSTANCE
- Washing : the treatment site was washed with lukewarm water (30-40°C) to remove any residual test substance. The treated area was blotted dry with absorbent paper.
- Time after start of exposure: 3 min, 1 and 4 h

SCORING SYSTEM:
Local dermal irritation was assessed using the prescribed numerical system:
Erythema and eschar formation:
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) or eschar formation (injuries in depth) preventing grading of erythema 4

Oedema formation:
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) 4
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
0
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
0
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
0
Irritant / corrosive response data:
Clinical signs
There was no sign of toxicity or ill health in any rabbit during the observation period.

Dermal responses
No dermal reaction was observed in any animal throughout the duration of the study. One hour after bandage removal test substance was present on each test site; this was not present on the next day.
Other effects:
None
Interpretation of results:
GHS criteria not met
Conclusions:
The Primary Irritation Index was calculated to be 0.0; Rikabinol HB was classified as ‘non-irritant’ according to the criteria of the ECETOC and did not require labelling in accordance with Commission Regulation 1272/2008.
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:
08 November 2012 to 26 November 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Eye Irritation (2-1-5), 12 Nohsan No. 8147, Agricultural Production Bureau, November 24, 2000.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Commercial laboratory animal supplier.
- Age at study initiation: 38 to 41 weeks
- Weight at study initiation: 3.48 to 4.18 kg
- Housing: Each animal was housed individually in a plastic cage with perforated floors
- Diet: 125 g of a standard laboratory rabbit diet per day
- Water: drinking water was provided ad libitum
- Acclimation period: All rabbits were acclimatised to the experimental environment for a period of 15 or 24 weeks prior to the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature: 16 to 20°C
- Humidity: 40 to 70%
- Air changes (per hr): No data
- Photoperiod: Lighting was controlled by means of a time switch to give 12 hours of artificial light (06:00 to 18:00 GMT) in each 24 hour period.

IN-LIFE DATES: From: To:
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mg
Duration of treatment / exposure:
Ocular reactions to treatment were assessed 1, 24, 48 and 72 hours
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
4
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): A single animal received an instillation of test substance which irrigated with copious quantities of physiological saline.
- Time after start of exposure: 30 seconds

SCORING SYSTEM: Kay and Calandra

TOOL USED TO ASSESS SCORE: No data
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 1h
Score:
7.3
Max. score:
7.3
Reversibility:
fully reversible
Remarks on result:
other: The total mean scores according to the system of Kay and Calandra (1962)
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 24h
Score:
4.7
Max. score:
4.7
Reversibility:
fully reversible
Remarks on result:
other: The total mean scores according to the system of Kay and Calandra (1962)
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 48h
Score:
1.3
Max. score:
1.3
Reversibility:
fully reversible
Remarks on result:
other: The total mean scores according to the system of Kay and Calandra (1962)
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 72h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks on result:
other: The total mean scores according to the system of Kay and Calandra (1962)
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
0
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 1
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0.7
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0.3
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 0.3
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0.3
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0.3
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Rikabinol HB did not require labelling in accordance with European Commission regulation 1272/2008.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The in vitro study was performed (Huntingdon Life Sciences, 2014, Study MOG0006) to assess the irritation potential of HBPA by means of the Human Skin Model Test. The test was conducted in accordance with the Standard Operating Procedure, In Vitro Skin Irritation Test: Human Epidermis Model and the OECD TG 439, and in compliance with GLP.

The test substance was applied to EPISKIN human epidermis skin constructs. The cell viability was determined by mitochondrial dehydrogenase activity, assessed by the reduction of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to a soluble, coloured, formazan product. The prediction model uses the percentage viability values (compared to negative control viability) to identify irritant and non-irritant substances.

 

It was concluded that HBPA was not compatible with this test system as it was not possible to obtain a reliable prediction due to the adherent nature of the test substance to the tissues.

 

A study was performed (Huntingdon Life Sciences, 2014, Study MOG0007) to assess the skin irritation potential of HBPA. The study was performed according to EC Method B.4, OECD test guideline 404, EPA test guideline OPPTS 870.2500 and Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Skin Irritation (2-1-4), 12 Nohsan No. 8147, and in compliance with GLP.

 

Three New Zealand White rabbits received a single, semi-occlusive, dermal administration of approximately 0.5 g of the test substance as supplied and were observed for four days. A single animal received three exposures of three minutes, one or four hours duration in a step-wise manner and acted as a preliminary screen. In the absence of a severe effect on removal of the dressings, the next exposure was initiated. In the absence of a severe effect in this animal, two further animals were committed to the study.

 

No dermal reaction was observed in any animal throughout the duration of the study. The Primary Irritation Index was calculated to be 0. HBPA was classified as ‘non-irritant’ according to the criteria of the ECETOC and did not require labelling in accordance with Commission Regulation 1272/2008

The Bovine Corneal Opacity and Permeability (BCOP) test (Huntingdon Life Sciences Ltd, 2012, Study MOG0008) was used to identify if HBPA could induce serious eye damage. The test was conducted according to the OEDC test guideline 437, and in compliance with GLP.

 

The undiluted HBPA was applied and incubated for 4 hours ± 5 minutes at 32 ± 1 °C. Negative and positive control items were tested concurrently. The decreased light transmission through the cornea (opacity) and increased passage of sodium fluorescein dye through the cornea (permeability) were combined in an empirically derived formula to generate an In Vitro Irritancy Score (IVIS).

 

HBPA elicited an In Vitro Irritancy Score of 0.5 ± 1.6 and was predicted to be a non-corrosive/ non-severe eye irritant. According to OECD 437 HBPA does not require classification under the GHS.

A study was performed (Huntingdon Life Sciences, 2014, Study MOG00018) to assess the eye irritation potential of HBPA to the rabbit. The test was conducted in accordance with the EC Method B.5, OECD test guideline 405, EPA test guideline OPPTS 870.2400 and Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Eye Irritation (2-1-5), 12 Nohsan No. 8147, Agricultural Production Bureau, and in compliance with GLP.

 

Four New Zealand White rabbits were each administered a single ocular dose of a volume of 0.1 mg and were observed for three days after instillation.

 

HBPA did not require labelling in accordance with European Commission regulation 1272/2008.

Justification for classification or non-classification

Based on the above studies, HBPA does not meet the criteria for classification as irritating/corrosive to skin does not require classification under the CLP.

As noted above studies HBPA did not cause a relevant increase of the corneal opacity or permeability, therefore does not require classification under the CLP.