Registration Dossier

Administrative data

Description of key information

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
Reliability:
1 (reliable without restriction)
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
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: Elevage Cunicole de Val de Selle, 80160 Prouzel, France
- Age at study initiation: not specified
- Weight at study initiation: the animals had a mean body weight of 2.4 ± 0.1 kg.
- Housing: The animals were housed individually in polystyrene cages (35 cm x 55 cm x 32 cm or 48.2 cm x 58 cm x 36.5 cm). Each cage was equipped with a food container and a water bottle.
- Diet (e.g. ad libitum): During the study, the animals had free access to 112 C pelleted diet (U.A.R., 91360 Villemoisson-sur-Orge, France). Each batch of food was analysed by the supplier for composition and contaminant levels.
- Water (e.g. ad libitum): Drinking water filtered by a F.G. Millipore membrane (0.22 micron) was provided ad libitum. Bacteriological and chemical analysis of the water and diet, including the detection of possible contaminants (pesticides, heavy metals and nitrosamines), are performed regularly by external
laboratories. No contaminants are known to be present in the diet or drinking water at levels which may be expected to interfere with or prejudice the outcome of the study.
- Acclimation period: at least 5 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3
- Humidity (%): 30 to 70
The temperature and relative humidity were under continuous control and recording. The records were checked daily and retained. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment were verified and calibrated at regular intervals.
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air.
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: not specified
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml
- Concentration (if solution): undiluted

VEHICLE
The test substance was used undiluted.
Duration of treatment / exposure:
4 hours
Observation period:
14 days
Number of animals:
3 males
Details on study design:
TEST SITE
- Area of exposure: The day before treatment, the 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.
- % coverage: not specified
- Type of wrap if used: A single dose of 0.5 ml of the test substance was placed on a 6 cm2 dry gauze pad (Coopérative Pharmaceutique Française, 77000 Melun, France), which was then applied to the right flank of the animals for 4 hours.
The test substance and the gauze pad were held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing (Laboratoires de Pansements et d'Hygiène, 21300 Chenove, France) and a restraining bandage (Coheban), Laboratoires 3M Santé, 92245 Malakoff, France).

REMOVAL OF TEST SUBSTANCE
No residual test substance was observed on removal of the dressing.

SCORING SYSTEM:
Dermal irritation was evaluated for each animal according to the following scoring scale:

Erythema and eschar formation:
(0) no erythema
(1) very slight erythema (barely perceptible)
(2) well-defined erythema
(3) moderate to severe erythema
(4) severe erythema (beet redness) to slight eschar formation (injuries in depth)

Oedema formation:
(0) no oedema
(1) very slight oedema (barely perceptible)
(2) slight oedema (edges of area well-defined by definite raising)
(3) moderate oedema (raised approximately 1 millimetre)
(4) severe oedema (raised more than 1 millimetre and extending beyond area of exposure)

Any other lesions were noted.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24h (D2)
Score:
1.3
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 48h (D3)
Score:
1
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 72h (D4)
Score:
1.7
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 1h (D1) and 24h (D2)
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 48h (D3) and 72h (D4)
Score:
2
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 96h (D5)
Score:
1
Max. score:
4
Reversibility:
fully reversible within: D6
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 1h (D1) and 24h (D2)
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 48h (D3)
Score:
1
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 72h (D4), 96h (D5)
Score:
2
Max. score:
4
Reversibility:
fully reversible within: D6
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 1h (D1) and 24h (D2)
Score:
1
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 48h (D3), 72h (D4), 96h (D5)
Score:
2
Max. score:
4
Reversibility:
fully reversible within: D6
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24h (D2), 48h (D3) and 72h (D4)
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal: #1, #2 and #3
Time point:
other: D1 to D6
Score:
0
Max. score:
4
Irritant / corrosive response data:
A very slight or well-defined erythema (grade 1 or 2) was observed in all animals from day 3 to day 5 for two animals, from day 1 to day 5 for the third one.
Dryness of the skin was recorded in one animal from day 6 up to the end of the observation period (day 15).
Mean scores over 24, 48 and 72 hours for each animal were 1.3, 1.0 and 1.7 for erythema and 0.0, 0.0 and 0.0 for oedema.
Other effects:
Dryness of the skin was observed in animal #3 from day 6 to 15.
Interpretation of results:
slightly irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under our experimental conditions, the test substance BUTYLAL is slightly irritant when applied topically to rabbits.
According to the classification criteria laid down in Commission Directive 93/21/E.E.C., the test substance should not be classified as irritating to the skin.
Executive summary:

The potential of the test substance BUTYLAL to induce skin irritation was evaluated in rabbits according to O.E.C.D. (No. 404, 17th July 1992) and E.C. (92/69/E.E.C., B.4, 31st July 1992) guidelines. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.

The study design was established according to available information on the test substance and the above guidelines. The test substance was applied for 4 hours to three male New Zealand White rabbits. 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. The mean values of the scores for erythema and oedema were calculated for each animal. The interpretation of results was carried out according to the classification criteria laid down in Commission Directive 93/21/E.E.C. (27th April 1993) adapting to technical progress for the eighteenth time Council Directive 67/548/E.E.C.

A very slight or well-defined erythema was observed, from day 3 to day 5 in two animals, from day 1 to day 5 in the third one. Dryness of the skin was recorded in one animal from day 6 up to the end of the observation period (day 15). Mean scores over 24, 48 and 72 hours for each animal were 1.3, 1.0 and 1.7 for erythema and 0.0, 0.0 and 0.0 for oedema.

Under our experimental conditions, the test substance BUTYLAL is slightly irritant when applied topically to rabbits. According to the classification criteria laid down in Commission Directive 93/21/E.E.C., the test substance should not be classified as irritating to the skin.

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
Reliability:
1 (reliable without restriction)
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Elevage Cunicole de Val de Selle, 80160 Prouzel, France.
- Age at study initiation: not specified
- Weight at study initiation: the animals had a mean body weight ± standard deviation of 2.7 ± 0.2 kg.
- Housing: The animals were housed individually in polystyrene cages (35 cm x 55 cm x 32 cm or 48.2 cm x 58 cm x 36.5 cm). Each cage was equipped with a food container and a water bottle.
- Diet (e.g. ad libitum): During the study, the animals had free access to 112 C pelleted diet (U.A.R., 91360 Villemoisson-sur-Orge, France). Each batch of food was analysed by the supplier for composition and contaminant levels.
- Water (e.g. ad libitum): Drinking water filtered by a F.G. Millipore membrane (0.22 micron) was provided ad libitum.
Bacteriological and chemical analysis of the water and diet, including the detection of possible contaminants (pesticides, heavy metals and nitrosamines), are performed regularly by external laboratories. The results of these analyses are archived at C.I.T. No contaminants are known to be present in the diet or drinking water at levels which may be expected to interfere with or prejudice the outcome of the study.
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3
- Humidity (%): 30 to 70
The temperature and relative humidity were under continuous control and recording. The records were checked daily and retained. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment were verified and calibrated at regular intervals.
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: not specified
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution): undiluted

VEHICLE
The test substance was used undiluted.
Duration of treatment / exposure:
72 hours
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
The eyes were not rinsed after administration of the test substance.

SCORING SYSTEM:
Ocular reactions were evaluated for each animal according to the following numerical scale:

CONJUNCTIVAL LESIONS AND DISCHARGES
Chemosis (lids and/or nictitating membranes)
(0) no swelling
(1) any swelling above normal (includes nictitating membranes)
(2*) obvious swelling with partial eversion of lids
(3*) swelling with lids about half-closed
(4*) swelling with lids more than half-closed

Redness (refers to palpebral and bulbar conjunctivae, cornea and iris)
(0) blood vessels normal
(1) a number of blood vessels definitely hyperemic (injected)
(2*) diffuse, crimson colour, individual vessels not easily discernible
(3*) diffuse, beefy red

Discharge
(0) absence of discharge
(1) slight discharge (does not include small amounts normally found in inner canthus)
(2) discharge with moistening of lids and hairs adjacent to lids
(3) discharge with moistening of lids and hairs on wide area around the eye

IRIS LESIONS
(0) normal
(1*) markedly deepened rugae, congestion, swelling, moderate circum-corneal hyperemia, or injection, any of these or combination of any thereof, iris still
reacting to light (sluggish reaction is positive)
(2*) no reaction to light, haemorrhage, gross destruction (any or all of these)

CORNEAL LESIONS
Cornea (direct examination or, if necessary, with an Ultra-Violet lamp)
To determine the presence or absence of corneal opacification and to evaluate the affected area, one or two drops of 0.5% sodium fluorescein solution can be instilled into the eye (however, this must not be performed before the 24-hour reading).
If corneal opacification is difficult to determine, the eye can be examined under a U.V. lamp (a clear fluorescence is visible in the areas of opacification).

Opacity (degree of intensity: area most dense taken for reading)
(0) no ulceration or opacity
(1*) scattered or diffuse areas of opacity (other than slight dulling or normal lustre), details of iris clearly visible
(2*) easily discernible translucent area, details of iris slightly obscured
(3*) nacrous areas, no details of iris visible, size of pupil barely discer
(4*) opaque cornea, iris not discernible through the opacity

Area of opacity
(1) one quarter (or less) but not zero
(2) greater than one quarter but less than a half
(3) greater than one half but less than three quarters
(4) greater than three quarters up to whole area.

Any other lesions observed were noted.

* indicates positive effect

TOOL USED TO ASSESS SCORE: fluorescein (batch 8617)
Irritation parameter:
conjunctivae score
Remarks:
- Mean scores - CHEMOSIS
Basis:
animal: #1 and #3
Time point:
other: Days 2 (24h), 3 (48h) and 4 (72h)
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: Day 3
Remarks on result:
other: non-irritating according to EEC criteria
Irritation parameter:
conjunctivae score
Remarks:
- Mean scores - CHEMOSIS
Basis:
animal #2
Time point:
other: Days 2 (24h), 3 (48h) and 4 (72h)
Score:
0
Max. score:
4
Remarks on result:
other: non-irritating according to EEC criteria
Irritation parameter:
conjunctivae score
Remarks:
- Mean scores - REDNESS
Basis:
animal: #1, #2 and #3
Time point:
other: Days 2 (24h), 3 (48h) and 4 (72h)
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: Day 3
Remarks on result:
other: non-irritating according to EEC criteria
Irritation parameter:
conjunctivae score
Remarks:
- Mean scores - DISCHARGE
Basis:
animal: #1, #2 and #3
Time point:
other: Days 2 (24h), 3 (48h) and 4 (72h)
Score:
0
Max. score:
3
Remarks on result:
other: non-irritating according to EEC criteria
Irritation parameter:
iris score
Remarks:
- Mean scores
Basis:
animal: #1, #2 and #3
Time point:
other: Days 2 (24h), 3 (48h) and 4 (72h)
Score:
0
Max. score:
2
Remarks on result:
other: non-irritating according to EEC criteria
Irritation parameter:
cornea opacity score
Remarks:
- Mean scores - INTENSITY
Basis:
animal: #1, #2 and #3
Time point:
other: Days 2 (24h), 3 (48h) and 4 (72h)
Score:
0
Max. score:
4
Remarks on result:
other: non-irritating according to EEC criteria
Irritation parameter:
cornea opacity score
Remarks:
- Mean scores - AREA
Basis:
animal: #1, #2 and #3
Time point:
other: Days 2 (24h), 3 (48h) and 4 (72h)
Score:
0
Max. score:
4
Remarks on result:
other: non-irritating according to EEC criteria
Irritant / corrosive response data:
Very slight to slight conjunctival reactions were observed in all animals on days 1 and 2: very slight or slight chemosis (grade 1 or 2), very slight or slight redness of the conjunctiva (grade 1 or 2) and clear discharge were noted.
No other ocular reactions were observed.
Mean scores calculated for each animal over 24, 48 and 72 hours were 0.3, 0.0 and 0.3 for chemosis, 0.3, 0.3 and 0.3 for redness of the conjunctiva, and 0.0 for iris lesions and corneal opacity.
Other effects:
None
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under our experimental conditions, the test substance BUTYLAL is non-irritant when administered by ocular route to rabbits.
According to the classification criteria laid down in Commission Directive 93/21/E.E.C., the test substance should not be classified as irritating to the eyes.
Executive summary:

The test substance BUTYLAL to induce ocular irritation was evaluated in rabbits according to O.E.C.D. (No. 405, 24th February 1987) and E.C. (92/69/E.E.C., B.5, 31st July 1992) guidelines. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.

The study design was established according to available information on the test substance and the above guidelines. As possible irritant effects were anticipated, a first assay was conducted in one male New Zealand White rabbit. Since the test substance did not show severe irritant properties in the first assay, it was evaluated in two other male New Zealand White rabbits in a second assay.

A single dose of 0.1 ml of the test substance was instilled into the left conjunctival sac. The right eye served as control. The test substance was used undiluted. The eyes were not rinsed after administration of the test substance. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal. The interpretation of results was carried out according to the classification criteria laid down in Commission Directive 93/21/EEC (27th April 1993) adapting to technical progress for the

eighteenth time Council Directive 67/548/EEC.

Very slight to slight conjunctival reactions (very slight or slight chemosis, very slight or slight redness of the conjunctiva and clear discharge) were observed in all animals on days 1 and 2. No other ocular reactions were observed. Mean scores calculated for each animal over 24, 48 and 72 hours were 0.3, 0.0 and 0.3 for chemosis, 0.3, 0.3 and 0.3 for redness of the conjunctiva, and 0.0 for iris lesions and corneal opacity.

Under our experimental conditions, the test substance BUTYLAL is non-irritant when administered by ocular route to rabbits.

According to the classification criteria laid down in Commission Directive 93/21/E.E.C., the test substance should not be classified as irritating to the eyes.

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:

This test was selected as the only one available and is reliable as performed according to OECD TG 404 and GLP.

Justification for selection of eye irritation endpoint:

This test was selected as the only one available and is reliable as performed according to OECD TG 405 and GLP.

Justification for classification or non-classification

The test substance is not classified as dermal or eye irritant according to the CLP criteria.