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Description of key information

The potential of the test substance Vivaldie to induce skin irritation was evaluated in rabbits according to OECD (No. 404, 17th July 1992) and EC (92/69/EEC, B.4, 31st July 1992) guidelines. Mean scores over 24, 48 and 72 hours for each animal were 1.7, 2.0 and 2.0 for erythema and 0.0, 0.0 and 0.0 for oedema. Under the experimental conditions of this study and the evaluation criteria as set out in the DSD 67/548/EC, the test substance Vivaldie is irritant when applied topically to rabbits. 
The potential of the test substance Vivaldie to induce ocular irritation was evaluated in rabbits according to OECD ( No. 405, 24th February 1987 ) and EC (92/69/EEC, B.5, 31st July 1992 ) guidelines. Mean scores calculated for each animal over 24, 48 and 72 hours were 0.0, 1.0 and 0.0 for chemosis, 0.0, 1.0 and 0.0 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity. Under the experimental conditions of this test, the test substance Vivaldie is non-irritant when administered by ocular route to rabbits.

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:
Between 05 December 2000 and 21 December 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with OECD guidelines and in compliance with GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
Animals
Sex, species, strain: male New Zealand White rabbits.
Reason for this choice: species generally accepted by regulatory authorities for this type of study.
Breeder: Elevage Cunicole de Val de Selle, 80160 Prouzel, France.
Number of animals: three animals were used, as recommended by the international guidelines.
Weight on the day of treatment, the animals had a mean body weight ± standard deviation of 2.4 ± 0.1 kg.
Acclimation: at least 5 days before the beginning of the study.
Identification: individual metal ear tag.

Environmental conditions
The conditions in the animal room were set as follows:
temperature: 20 ± 3°C
relative humidity: 30 to 70%
light/dark cycle: 12 hlI2 h
ventilation: approximately 12 cycles/hour of filtered, non-recycled air.
The temperature and relative humidity were under continuous control and recording. The records were checked daily and filed. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment were verified and calibrated at regular intervals.
The animals were housed individually in polystyrene cages (48.2 cm x 58 cm x 36.5 cm).
Each cage was equipped with a food container and a water bottle.

Food and water
During the study, the animals had free access to 110 and 112 C pelleted diet (UAR, 91360 Villemoisson-sur-Orge, France).
Food is analysed regularly by the supplier for composition and contaminant levels.
Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum.
Bacteriological and chemical analyses of water are performed regularly by external laboratories.
These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrosamines).
No contaminants were known to have been present in the diet or drinking water at levels which may be expected to have interfered with or prejudiced the outcome of the study.
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: The untreated skin served as control.
Amount / concentration applied:
0.5 ml of the undiluted test substance
Duration of treatment / exposure:
3 minutes and/or 4 hours
Observation period:
Up to 15 days
Number of animals:
3
Details on study design:
Preparation and selection of the animals
The day before treatment, both flanks of each animal were clipped using electric clippers and the skin of each animal was examined. Only animals with healthy intact skin were used.
Application of the test substance
As possible irritant effects were anticipated, the test substance was evaluated on a single animal (No. 59) in the first instance. The duration of exposure was 3 minutes on one flank and 4 hours on the other flank.
Since the test substance was not severely irritant on this first animal, it was then applied for 4 hours to two other animals (Nos. 71 and 72 ).
Doses of 0.5 ml of the undiluted test substance were placed on a dry gauze pad, which was then applied to the right flank (application for 4 hours) or the left flank (application for 3 minutes) of the animals.
The test substance and the gauze pad were held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage.
The untreated skin served as control.
No residual test substance was observed on removal of the dressing.
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal: 59
Time point:
other: 24, 48 and 72 hours
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: Day 7
Remarks on result:
other: 3 minute exposure
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal: 59
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: No evidence of skin irritation
Remarks on result:
other: 3 minute exposure, dryness of the skin noted at Days 5 to 13
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal: 59
Time point:
other: 24, 48 and 72 hours
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: Day 7
Remarks on result:
other: 4 hour exposure
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal: 71
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: Day 15
Remarks on result:
other: 4 hour exposure
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal: 72
Time point:
other: 24, 48 and 72 hours
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 10 days
Remarks on result:
other: 4 hour exposure
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal: 59
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: No evidence of skin irritation
Remarks on result:
other: 4 hour exposure, dryness of the skin noted at Days 5 to 13
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal: 71
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: No evidence of skin irritation
Remarks on result:
other: 4 hour exposure, dryness of the skin noted at Days 5 to 15
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal: 72
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: No evidence of skin irritation
Remarks on result:
other: 4 hour exposure, dryness of the skin noted at Days 5 to 15
Irritant / corrosive response data:
After a 3-minute exposure (one animal):
A very slight or well-defined erythema (grade 1 or 2) was observed from day 2 to day 6. A dryness of the skin was also noted from day 5 to day 13.

After a 4-hour exposure (three animals):
A very slight or well-defined erythema (grade 1 or 2) was noted in all animals from day 1 up to day 6, 10 or to the end of the observation period (day 15).
A dryness of the skin was also recorded in all animals from day 5 to day 13 (one animal) or 15.

Mean scores over 24, 48 and 72 hours for each animal were 1.7, 2.0 and 2 .0 for erythema and 0.0, 0.0 and 0 .0 for oedema.
Other effects:
None
Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study and the evaluation criteria as set out in the DSD 67/548/EC, the test substance Vivaldie is irritant when applied topically to rabbits .
Executive summary:

The potential of the test substance Vivaldie to induce skin irritation was evaluated in rabbits according to OECD (No. 404, 17th July 1992) and EC (92/69/EEC, B.4, 31st July 1992) guidelines. In the first instance, the test substance was applied for periods of 3 minutes and 4 hours to a single male New Zealand White rabbit. Since the test substance was not severely irritant on this first animal, it was then applied for 4 hours to two other animals. A single dose of 0.5 ml of the undiluted test substance was applied to the closely-clipped skin of one flank.

The test substance was held in contact with the skin by means of a semi-occlusive dressing. Cutaneous reactions were observed approximately 1 hour, 24, 48 and 72 hours after removal of the dressing and then daily until the end of the observation period. Mean scores over 24, 48 and 72 hours for each animal were 1.7, 2.0 and 2.0 for erythema and 0.0, 0.0 and 0.0 for oedema. Under the experimental conditions of this study and the evaluation criteria as set out in the DSD 67/548/EC, the test substance Vivaldie is irritant when applied topically to rabbits.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (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:
Between 19 December 2000 and 25 December 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with OECD guidelines and in compliance with GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Animals
Sex, species, strain: male New Zealand White rabbits.
Reason for this choice: species generally accepted by regulatory authorities for this type of study.
Breeder: Elevage Cunicole de Val de Selle, 80160 Prouzel, France.
Number of animals: three animals were used, as recommended by the international guidelines.
Weight: on the day of treatment, the animals had a mean body weight ± standard deviation of 2.8 ± 0.1 kg.
AccIimation: at least 5 days before the beginning of the study.
Identification: individual metal ear tag.

Environmental conditions
The conditions in the animal room were set as follows:
temperature: 20 ± 3°C
relative humidity: 30 to 70%
light/dark cycle: 12 h/12 h
ventilation: approximately 12 cycles/hour of filtered, non-recycled air.
The temperature and relative humidity were under continuous control and recording. The records were checked daily and filed. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment were verified and calibrated at regular intervals.
The animals were housed individually in polystyrene cages (48.2 cm x 58 cm x 36.5 cm).
Each cage was equipped with a food container and a water bottle.

Food and water
During the study, the animals had free access to 112C pelleted diet (UAR, 91360 Villemoissonsur -Orge, France).
Each batch of food is analysed by the supplier for composition and contaminant levels.
Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum.
Bacteriological and chemical analyses of water are performed regularly by external laboratories.
These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrosamines).
No contaminants were known to have been present in the diet or drinking water at levels which may be expected to have interfered with or prejudiced the outcome of the study.
Vehicle:
unchanged (no vehicle)
Controls:
other: The right eye remained untreated and was used for control purposes.
Amount / concentration applied:
0.1 ml of the undiluted test substance
Duration of treatment / exposure:
Up to 1 hour
Observation period (in vivo):
Up to 5 days
Number of animals or in vitro replicates:
3
Details on study design:
TREATMENT

Selection of the animals
The day before treatment, the eyes of each animal were examined in order to use only animals without any signs of ocular lesions. Animals showing signs of ocular irritation, ocular defects or pre-existing corneal injury were not used.

Administration of the test substance
As possible irritant effects were anticipated, the test substance was administered to a single animal (No. 59) in the first instance. Since the test substance was not severely irritant on this first animal, it was then evaluated on two other animals (Nos. 71 and 72).
A single dose of 0.1 ml of the undiluted test substance was instilled into the conjunctival sac of the left eye after gently pulling the lower lid away from the eyeball.
The lower and upper eyelids were held together for about one second to avoid any loss of test substance. The right eye, which remained untreated, served as control.
The eyes were not rinsed after administration of the test substance.
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal: 59
Time point:
other: Score at 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: No effects observed
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal: 71
Time point:
other: Score at 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
not specified
Remarks:
No effects observed
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal: 72
Time point:
other: Score at 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: No effects observed
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal: 59
Time point:
other: Score at 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: No effects observed
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal: 71
Time point:
other: Score at 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: No effects observed
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal: 72
Time point:
other: Score at 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: No effects observed
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal: 59
Time point:
other: Score at 24, 48 and 72 hours
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 24 hours
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal: 71
Time point:
other: Score at 24, 48 and 72 hours
Score:
1
Max. score:
3
Reversibility:
fully reversible within: Day 5
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal: 72
Time point:
other: Score at 24, 48 and 72 hours
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 24 hours
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal: 59
Time point:
other: Score at 1, 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 hours
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal: 71
Time point:
other: Score at 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: Day 5
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
72
Time point:
other: Score at 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 hours
Irritant / corrosive response data:
Slight conjunctival reactions were observed in all animals on day 1: a very slight chemosis (grade 1) and a slight redness of the conjunctiva (grade 1) were noted. These ocular reactions persisted up to day 4 in 1/3 animals.
No other ocular reactions were recorded during the study.
Mean scores calculated for each animal over 24, 48 and 72 hours were 0.0, 1.0 and 0.0 for chemosis, 0.0, 1.0 and 0.0 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under our experimental conditions, the test substance Vivaldie is non-irritant when administered by ocular route to rabbits.
Executive summary:

The potential of the test substance Vivaldie to induce ocular irritation was evaluated in rabbits according to OECD ( No. 405, 24th February 1987 ) and EC (92/69/EEC, B.5, 31st July 1992 ) guidelines. As possible irritant effects were anticipated, the test substance was administered to a single male New Zealand White rabbit in the first instance. Since the test substance was not severely irritant on this first animal, it was then evaluated in two other animals. A single dose of 0.1 rnl of the undiluted test substance was instilled into the left conjunctival sac. The right eye was not treated and served as control. The eyes were not rinsed after administration of the test substance. Slight conjunctival reactions (very slight chemosis and slight redness of the conjunctiva) were observed in all animals on day 1; they persisted up to day 4 in 1/3 animals.

No other ocular reactions were noted during the study. Mean scores calculated for each animal over 24, 48 and 72 hours were 0.0, 1.0 and 0.0 for chemosis, 0.0, 1.0 and 0.0 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity. Under the experimental conditions of this test, the test substance Vivaldie is non-irritant when administered by ocular route to rabbits.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of skin irritation / corrosion endpoint:
Key study at reliability 1

Justification for selection of eye irritation endpoint:
Key study at reliability 1

Effects on skin irritation/corrosion: irritating

Justification for classification or non-classification

Based on the in vivo skin irritation study Vivaldie needs to classified as irritating to skin R38 under the DSD 67/548/EC as a mean score of 2 for erythema in two animals was seen. However, the substance does not need to be classified for skin irritation anymore under CLP as the mean score for erythema and oedema is between 1.5 and 2.3 which would lead under GHS to classification as skin irritant 3 (mild irritant). This category, however, is not taken up in the CLP Regulation.

Based on the results of the in vivo eye irritation study Vivaldie does not need to be classified for ocular irritation under the DSD 67/548/EC or the CLP Regulation EC 1272/2008.

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