Registration Dossier

Administrative data

Description of key information

Two studies are available on 1,3 -dibutylthiourea in rabbits to evaluate the irritating potential.

The substance is not irritating to the skin, and slightly irritating to the eyes.

There is no data on respiratory tract irritation.

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:
From 12 Oct 2004 to 19 oct 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
- Source: CEGAV, Saint Mars d'Egrenne, France
- Age at study initiation : 2 to 4 months
- Body weight at study initiation: 2.4 ± 0.2 kg
- Acclimation period: at least 5 days
- Housing: individually in polystyrene cages (48.2 cm x 58 cm x 36.5 cm).
- Diet: free access to 110 pelleted diet (SAFE, Villemoisson, Epinay-sur-Orge, France).
- water: Drinking water ad libidum
- Temperature: 18 ± 3°C
- Humidity: 30 to 70%
- Air changes: approximately 12 cycles/hour of filtered, non-recycled air.
- Photoperiod: 12 h/12 h
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
A single dose of 500 mg of the test item
Duration of treatment / exposure:
4 hour(s)
Observation period:
1 hour, 24, 48, 72 hours after removal of the dressing and then daily until reversibility of cutaneous reactions.
Number of animals:
3
Details on study design:
The test item was first applied for periods of 3 minutes and 4 hours to a single male New Zealand White rabbit. Since the test item was not severely irritant on this first animal, it was then applied for 4 hours to two other animals. A single dose of 500 mg of the test item in its original form was applied to the closely-clipped skin of one flank. The test item was held in contact with the skin by means of a semi-occlusive dressing.
The mean values of the scores for erythema and oedema were calculated for each animal.
Irritation parameter:
erythema score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
After a 3-minute exposure (one animal): a very slight erythema was observed from day 2 to day 5, followed by dryness of the skin on days 6 and 7.
After a 4-hour exposure (three animals) : No cutaneous reactions were observed in any animal. Mean scores over 24, 48 and 72 hours for each animal were 0.0, 0.0 and 0.0 for erythema and 0.0, 0.0 and 0.0 for oedema.
Other effects:
no
Interpretation of results:
GHS criteria not met
Conclusions:
The test item Dibutyl thiourea is non-irritant to skin when applied topically to rabbits
.
Executive summary:

The potential of the test item Dibutyl thiourea 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.

The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.

The test item was first applied for periods of 3 minutes and 4 hours to a single male New Zealand White rabbit. Since the test item was not severely irritant on this first animal, it was then applied for 4 hours to two other animals.

A single dose of 500 mg of the test item in its original form was applied to the closely-clipped skin of one flank. The test item 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 reversibility of cutaneous reactions.

The mean values of the scores for erythema and oedema were calculated for each animal.

After a 3-minute exposure (one animal): a very slight erythema was observed from day 2 to day 5, followed by dryness of the skin on days 6 and 7.

After a 4-hour exposure (three animals) : No cutaneous reactions were observed in any animal. Mean scores over 24, 48 and 72 hours for each animal were 0.0, 0.0 and 0.0 for erythema and 0.0, 0.0 and 0.0 for oedema.

Based on these results, the test item Dibutyl thiourea is non-irritant to skin when applied topically to rabbits.

.

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:
From 19 Oct 2004 to 31 oct 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
minor deviation was not considered to have compromised the validity or integrity of the study : relative humidity
GLP compliance:
yes
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
-Sex: male
- Source: CEGAV (Saint Mars d'Egrenne, France)
- Age at study initiation: on the day of treatment, the animals were 2 to 4 months old
- Weight at study initiation: 2.9 ± 0.1 kg
- Housing: individually in polystyrene cages
- Diet (e.g. ad libitum): free access to 110 pelleted diet (UAR, Villemoisson, Epinay¬sur-Orge, France).
- Water (e.g. ad libitum): Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3°C
- Humidity (%): 30 to 70%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air.
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: yes, untreated eye
Amount / concentration applied:
The test substance was used in its original form.
Amount applied: 100 mg
Duration of treatment / exposure:
a single exposure
Observation period (in vivo):
The eyes were examined approximately 1 hour, 24, 48 and 72 hours after administration of the test item.
The study was ended on day 4 in the absence of persistent ocular reactions.
Number of animals or in vitro replicates:
3 rabbits
Details on study design:
The day before treatment, the eyes of each animal were examined in order to check the absence of any signs of ocular irritation, ocular defects or pre-existing corneal injury.

As possible irritant effects were anticipated, the test item was first administered to a single animal (No. 198). Since the test item was not severely irritant on this first animal, it was then evaluated on two other animals (Nos. 22 and 23).
A single dose of 100 mg of the test item in its original form was introduced 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 item. The right eye, which remained untreated, served as control.
The eyes were not rinsed after administration of the test item.

Conjunctival reactions, iritis and corneal opacification were evaluated daily for each animal.
For the evaluation of corneal opacification (presence or absence, affected area), the eyes were examined under a UV lamp after instillation of one or two drops of 0.5% sodium fluorescein solution (a clear fluorescence is visible in the areas of opacification). This evaluation was performed on day 2 and repeated thereafter whenever necessary.

Ocular reactions were scored according to the following numerical scale:
Conjunctival lesions and discharge
Chemosis (lids and/or nictitating membranes)
. no swelling ...............................................................................................................................0
. any swelling above normal (includes nictitating membranes) .................................................1
. obvious swelling with partial eversion of lids..........................................................................2
. swelling with lids about half-closed.........................................................................................3
. swelling with lids more than half-closed .................................................................................4
Redness (refers to palpebral and bulbar conjunctivae, cornea and iris)
. blood vessels normal ................................................................................................................0
. a number of blood vessels definitely hyperemic (injected)......................................................1
. diffuse, crimson colour, individual vessels not easily discernible ...........................................2
. diffuse, beefy red......................................................................................................................3
Discharge
. absence of discharge ................................................................................................................0
. slight discharge (does not include small amounts normally found in
inner canthus) ...........................................................................................................................1
. discharge with moistening of lids and hairs adjacent to lids....................................................2
. discharge with moistening of lids and hairs on wide area around the eye...............................3
Iris lesions
. normal ......................................................................................................................................0
. 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) ........................................................................1
. no reaction to light, haemorrhage, gross destruction (any or all of these) ...............................2
Corneal lesions
Degree of opacity (area most dense taken for reading)
. no ulceration or opacity............................................................................................................0
. scattered or diffuse areas of opacity (other than slight dulling or normal lustre),
details of iris clearly visible .....................................................................................................1
. easily discernible translucent area, details of iris slightly obscured ........................................2
. nacreous areas, no details of iris visible, size of pupil barely discernible ...............................3
. opaque cornea, iris not discernible through the opacity...........................................................4
Area of opacity
. one quarter (or less) but not zero..............................................................................................1
. greater than one quarter but less than a half.............................................................................2
. greater than one half but less than three quarters.....................................................................3
. greater than three quarters up to whole area. ...........................................................................4
Irritation parameter:
conjunctivae score
Remarks:
(chemosis)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0.43
Max. score:
4
Reversibility:
fully reversible within: 4 days
Remarks on result:
other: Individual scores were : 1.0, 0.3 and 0.0
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0.87
Max. score:
3
Reversibility:
fully reversible within: 4 days
Remarks on result:
other: Individual scores were : 1.3, 1.0 and 0.3
Irritation parameter:
conjunctivae score
Remarks:
(discharge)
Basis:
mean
Remarks:
6 rabbits
Time point:
other: 24-48-72 hours
Score:
0.23
Max. score:
3
Reversibility:
fully reversible within: 3 days
Remarks on result:
other: Individual scores were: 0.7, 0.0 and 0.0
Irritation parameter:
iris score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0.2
Max. score:
2
Reversibility:
fully reversible within: 3 days
Remarks on result:
other: Individually scores were: 0.3, 0.3 and 0.0
Irritation parameter:
cornea opacity score
Remarks:
(intensity)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 3 days
Remarks on result:
other: Individually scores were: 0.3, 0.3 and 0.0
Irritation parameter:
cornea opacity score
Remarks:
(area)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 3 days
Remarks on result:
other: Individually scores were: 0.3, 0.3 and 0.0
Irritant / corrosive response data:
Very slight to moderate conjunctival reactions, including a very slight or slight chemosis (grade 1 or 2), a very slight to moderate redness of the conjunctiva (grades 1 to 3) and a clear discharge, were observed in all animals from day 1 up to day 2 (1/3 animals) or 3 (2/3 animals). An iritis (grade 1) and a very slight corneal opacity (grade 1) were noted in 2/3 animals on day 2.
Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 0.3 and 0.0 for chemosis, 1.3, 1.0 and 0.3 for redness of the conjunctiva, 0.3, 0.3 and 0.0 for iris lesions and 0.3, 0.3 and 0.0 for corneal opacity.
Other effects:
Any other lesions observed were noted.
Interpretation of results:
GHS criteria not met
Conclusions:
Under these experimental conditions, the test substance Dibutyl thiourea is slightly irritant when administered by ocular route to rabbits.
Executive summary:

The potential of the test item Dibutyl thiourea 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. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.

As possible irritant effects were anticipated, the test item was first administered to a single male New Zealand White rabbit. Since the test item was not severely irritant on this first animal, it was then evaluated in two other animals.

A single dose of 100 mg of the test item in its original form was introduced 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 item. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration.

Very slight to moderate conjunctival reactions (very slight or slight chemosis, very slight to moderate redness of the conjunctiva and/or clear discharge) were observed in all animals from day 1 up to day 2 (1/3 animals) or 3 (2/3 animals). An iritis and a very slight corneal opacity were noted in 2/3 animals on day 2.

Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 0.3 and 0.0 for chemosis, 1.3, 1.0 and 0.3 for redness of the conjunctiva, 0.3, 0.3 and 0.0 for iris lesions and 0.3, 0.3 and 0.0 for corneal opacity.

Under our experimental conditions, the test item dibutyl thiourea is slightly irritant when administered by ocular route to

rabbits, but not classified according to the CLP regulation.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In vivo skin irritation study (2005)

The potential of the test item Dibutyl thiourea 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.

The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.

The test item was first applied for periods of 3 minutes and 4 hours to a single male New Zealand White rabbit. Since the test item was not severely irritant on this first animal, it was then applied for 4 hours to two other animals.

A single dose of 500 mg of the test item in its original form was applied to the closely-clipped skin of one flank. The test item 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 reversibility of cutaneous reactions.

The mean values of the scores for erythema and oedema were calculated for each animal.

After a 3-minute exposure (one animal): a very slight erythema was observed from day 2 to day 5, followed by dryness of the skin on days 6 and 7.

Based on these results, the test item Dibutyl thiourea is non-irritant to skin when applied topically to rabbits.

In vivo eye irritation study (2006)

The potential of the test item Dibutyl thiourea 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. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.

As possible irritant effects were anticipated, the test item was first administered to a single male New Zealand White rabbit. Since the test item was not severely irritant on this first animal, it was then evaluated in two other animals.

A single dose of 100 mg of the test item in its original form was introduced 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 item. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration.

Very slight to moderate conjunctival reactions (very slight or slight chemosis, very slight to moderate redness of the conjunctiva and/or clear discharge) were observed in all animals from day 1 up to day 2 (1/3 animals) or 3 (2/3 animals). An iritis and a very slight corneal opacity were noted in 2/3 animals on day 2.

Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 0.3 and 0.0 for chemosis, 1.3, 1.0 and 0.3 for redness of the conjunctiva, 0.3, 0.3 and 0.0 for iris lesions and 0.3, 0.3 and 0.0 for corneal opacity.

Under the experimental conditions, the test item dibutyl thiourea is slightly irritant when administered by ocular route to rabbits, but not classified according to the CLP regulation.

Justification for classification or non-classification

Based on the available data, no classification is required for skin or eye irritation according to the Regulation EC.1272/2008.