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Description of key information

The potential of the test substance copper dibutyl dithiocarbamate (CDBC) to induce skin and eye irritation was evaluated in rabbits according to the OECD guideline (OECD 404 and 405). According to these studies, CDBC is slightly irritant for skin and eye, and no classification is required for these endpoints.

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:
3-14 April 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
Minors deviations were observed but not considered to have compromised the validity or integrity of the study.
Principles of method if other than guideline:
Minor deviations observed: relative humidity recorded in the animal room was sometimes outside of the target ranges specified in the protocol, the animal's breeder was CEGAV, the animals were given 110 pelleted diet (instead of 112).
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
-sex: male
- Source: CEGAV, 61350 Saint Mars d'Egrenne, France
- Age at study initiation: no data
- Weight at study initiation: 3.2 ± 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): water filtered, ad libitum
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18+/-3°C
- Humidity (%): 30-70%
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
undiluted
Duration of treatment / exposure:
3 minutes and 4 hour(s)
Observation period:
14 days
Number of animals:
3
Details on study design:
ADMINISTRATION:
- Area of exposure: application for 4 hours on the right flank and for 3 minutes on the left flank
- Total quantity applied: 500 mg
- Administration frequency: once
- Removal of test substance: residual was wiped off by means of moistened cotton pad.

EXAMINATIONS:
- Scoring system: Draize's score
- Examination time points: 1h, 24 h, 48 h and 72 hours after the patch removal. When persistent irritation reactions were noted at 72 hours, the observation period was extended up daily to their complete reversibility (day 10).
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 10 days
Remarks on result:
other: not evaluated in the two other animals
Irritation parameter:
edema score
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
AFTER 3-MINUTE EXPOSURE: No cutaneous reaction was observed but a brown coloration of the skin which could have masked a possible very slight erythema between days 1 and 3.
AFTER 4-HOUR EXPOSURE:
- A brown coloration of the skin was noted in all animals. It could have masked a possible very slight or a well-defined erythema in 2 animals, up to day 3 (72h) or 5 but no cutaneous reaction was noted afterwards. In these two animals, no oedema was observed. However, it should be noted that in worst case, the mean irritation scores would have remained lower than 2, for these 2 animals.
- In the third rabbit, the brown coloration was resolved by the 24-hour scoring interval and a well-defined erythema was recorded: grade 2-erythema from day 2 up to day 5 and a grade 1 up to day 9. Moreover, a slight oedema (grade 2) was noted on day 3.
MEAN SCORES OVER 24, 48 AND 72h:
- For erythema: not calculable for 2 animals because of the skin coloration and 2.0 in the third animal.
- For oedema: 0.0, 0.0 and 0.7.

Table 1: individual cutaneous examinations and mean values of the scores recorded at each reading (24, 48 and 72 hours) for the first animal (application for 3 minutes)

 

Rabbit number

Dermal irritation

scores

Mean irritation score (1)

1h (D1)

24h (D2)

48h (D3)

72h (D4)

994

Erythema

C1

C1

C1

0

(2)

Oedema

0

0

0

0

0.0

Other

*

*

*

C

 

(1)  mean of scores on days 2, 3 and 4, (2): not calculated

* : none, D = day, h = hour

C = Brown coloration of the skin

C1 = brown coloration of the skin which could have masked a possible very slight erythema

 

 

Table 2: individual cutaneous examinations and mean values of the scores recorded at each reading (24, 48 and 72 hours) for each animal (application for 4 hours)

 

Rabbit number

Dermal irritation

scores

Mean irritation score (1)

1h (D1)

24h (D2)

48h (D3)

72h (D4)

994

Erythema

C2

C2

C1

C1

(2)

Oedema

0

0

0

0

0.0

Other

*

*

*

*

 

576

Erythema

C2

C2

C1

0

(2)

Oedema

0

0

0

0

0.0

Other

*

*

*

C

 

577

Erythema

C2

2

2

2

2.0

Oedema

0

0

2

0

0.7

Other

*

C

C

C

 

 

Rabbit number

Dermal irritation

Scores

D5

D6

D7

D8

D9

D10

994

Erythema

C1

0

-

-

-

-

Oedema

0

0

-

-

-

-

Other

*

C

-

-

-

-

576

Erythema

-

-

-

-

-

-

Oedema

-

-

-

-

-

-

Other

-

-

-

-

-

-

577

Erythema

2

1

1

1

1

0

Oedema

0

0

0

0

0

0

Other

C

C

C

C

C

C

(1)  mean of scores on days 2, 3 and 4, (2): not calculated

* : none, D = day, h = hour

C = Brown coloration of the skin

C1 = brown coloration of the skin which could have masked a possible very slight erythema

C2= brown coloration of the skin which could have masked a possible well-defined erythema

Interpretation of results:
GHS criteria not met
Remarks:
not skin irritating
Conclusions:
Under these experimental conditions, the test substance CDBC is slightly irritant when applied topically to rabbits.
Executive summary:

The potential of the test substance CDBC to induce skin irritation was evaluated in rabbits according to OECD (404) and EC guidelines, and in compliance with the principles of GLP.

In the first instance, the test substance was applied for periods of 3 minutes and 4 hours to a single male rabbit. Since the test substance was not severely irritant on the first animal, it was than applied for 4 hours to two other animals. A single dose of 500 mg of CDBC in its original form was applied to the closely-clipped skin of one flank. 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 animals.

After a 3-minute exposure (one animal): no cutaneous reactions were observed. A brown coloration of the skin was noted; it could have masked a possible very slight erythema between days 1 to 3.

After a 4 -hour exposure (three animals): A brown coloration of the skin was noted in all animals; it could have masked a possible very slight or well-defined erythema up to day 3 (one animal) or 5 (one animal). No cutaneous reactions were observed afterwards in these two animals. In the third animal, a well-defined erythema was noted from day 2 to day 5, then a very slight erythema was recorded up to day 9. A slight oedema was noted on day 3.

Mean scores over 24, 48 and 72 hours were not calculable for eryhtema because of the skin coloration for two animals. In the third animal, mean scores were 2.0 for erythema and 0.7 for oedema.

Under these experimental conditions, the test substance CDBC is slightly irritant 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:
10-15 April 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
Minors deviations were observed but not considered to have compromised the validity or integrity of the study.
Principles of method if other than guideline:
Minor deviations observed: relative humidity recorded in the animal room was sometimes outside of the target ranges specified in the protocol, the animal's breeder was CEGAV, the animals were given 110 pelleted diet (instead of 112).
GLP compliance:
yes
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: no data
- Weight at study initiation: 3.4 ± 0.2 kg
- Housing: individually in polystyrene cages.
- Diet (e.g. ad libitum): 110 pelleted diet (UAR, Villemoisson, Epinay sur orge, France), free access
- Water (e.g. ad libitum): water filtered, ad libitum
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18+/-3°C
- Humidity (%): 30-70%
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: control = untreated right eye
Amount / concentration applied:
A sinlge dose of 100 mg of the test substance first ground to a fine powder 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 held together for about one second to avoid any loss of test substance.
Duration of treatment / exposure:
one administration only
Observation period (in vivo):
10 days
Number of animals or in vitro replicates:
3
Details on study design:
Comment: not rinsed

ADMINISTRATION:
- Administration frequency: once
EXAMINATIONS:
- Ophthalmoscopic examination: Yes
- Scoring system: Draize's score
- Observation period: 1h, 24h, 48h and 72h after administration of the test substance
- Tool used to assess corneal opacification: examination under UV lamp after instillation of 1 or 2 drops of fluorescein (on day 2 and whenever if necessary).
Irritation parameter:
chemosis score
Remarks:
(chemosis)
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
0.8
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Mean individual scores : 1.0, 0.7 and 0.7
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
0.8
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Mean individual scores : 1.0, 0.7 and 0.7
Irritation parameter:
conjunctivae score
Remarks:
(discharge)
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Mean individual scores : 0.3, 0.3 and 0.3
Irritation parameter:
iris score
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
0.1
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
cornea opacity score
Remarks:
(intensity)
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Mean individual scores : 0.0, 0.3 and 0.3
Irritation parameter:
cornea opacity score
Remarks:
(area)
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Mean individual scores : 0.0, 0.3 and 0.3
Irritant / corrosive response data:
CONJUNCTIVAE:
- very slight or slight chemosis and redness (grade 1 or 2) were observed from day 1, in all animals and were completely resolved by 72-hour scoring interval
- a clear discharge (grade 1 or 2) was noted too from day 1 in all animals and were completely resolved by 48h-hour scoring interval.

IRIS: A slight iritis (grade 1) was noted in 1 animal on days 1 and 2.

CORNEAL OPACITY: A very slight corneal opacity (grade 1) was observed in 2 animals on day 2 only.

MEANS SCORES CALCULATED FOR EACH ANIMAL:
- For chemosis: 1.0, 0.7 and 0.7
- For redness of conjunctiva: 1.0, 0.7 and 0.7
- For iris lesions: 0.3, 0.0 and 0.0
- For corneal opacity: 0.0, 0.3 and 0.3.

Table 1: Individual ocular examination and mean values of the scores recorded at each reading (24, 48 and 72 hours) for each animal

 

Rabbit number

Region of eye

Description of ocular reactions

scores

Mean irritation score (1)

1h (D1)

24h (D2)

48h (D3)

72h (D4)

 

994

conjunctivae

Chemosis

2

2

1

0

1.0

Redness

2

2

1

0

1.0

Discharge

2

1

0

0

0.3

Iris

1

1

0

0

0.3

Corneal opacity

Intensity

0

0

0

0

0.0

Area

0

0

0

0

0.0

Other

Su

*

*

*

 

Fluorescein

/

U

/

/

 

 

576

conjunctivae

Chemosis

1

1

1

0

0.7

Redness

1

1

1

0

0.7

Discharge

2

1

0

0

0.3

Iris

0

0

0

0

0.0

Corneal opacity

Intensity

0

1

0

0

0.3

Area

0

1

0

0

0.3

Other

Su

Su

*

*

 

Fluorescein

/

U

U

/

 

 

577

conjunctivae

Chemosis

1

1

1

0

0.7

Redness

2

1

1

0

0.7

Discharge

2

1

0

0

0.3

Iris

0

0

0

0

0.0

Corneal opacity

Intensity

0

1

0

0

0.3

Area

0

1

0

0

0.3

Other

Su

Su

*

*

 

Fluorescein

/

U

U

/

 

 

(1)  mean of scores on days 2, 3 and 4

* : none

U: fluorescein batch No.D616

/: fluorescein not used

Su: residual test substance

Interpretation of results:
GHS criteria not met
Remarks:
not eye irritating
Conclusions:
Under these experimental conditions, the test substance CDBC is slightly irritant when administered by ocular route to rabbits.
Executive summary:

The potential of the test substance CDBC to induce ocular irritation was evaluated in rabbits according to OECD (405) and EC guidelines, and in compliance with the principles of GLP.

As possible irritant effects were anticipated, the test substance was administered to a single male rabbit in the first instance. Since the test substance was not severely irritant on this first animal, it was evaluated in twho other animals.

A single dose of 100 mg of the test substance, first ground to a fine powder, was introduced into the left conjunctival sac. The right eye was not rinsed after administration of the test substance. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after administration. The mean values of the scores for chemosis, redness of the conjunctivae, iris lesions and corneal opacity were calculated for each animal.

Very slight or slight conjunctival reactions (slight chemosis, slight redness of the conjunctivae and clear discharge) were observed in all animals from day 1: some of these reactions persisted up to day 3. A slight iritis was noted in one animal on days 1 and 2. A very slight corneal opacity was recorded in two animals, on day 2 only. Mean scores calculared for each animal aver 24, 48 and 72 hours were 1.0, 0.7 and 0.7 for chemosis, 1.0, 0.7 and 0.7 for redness of the conjunctiva, 0.3, 0.0 and 0.0 for iris lesions and 0.0, 0.3 and 0.3 for corneal opacity.

Under these experimental conditions, the test substance CDBC is slightly 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

Skin irritation study (Manciaux 2001):

The potential of the test substance CDBC to induce skin irritation was evaluated in rabbits according to OECD (404) and EC guidelines, and in compliance with the principles of GLP.

In the first instance, the test substance was applied for periods of 3 minutes and 4 hours to a single male rabbit. Since the test substance was not severely irritant on the first animal, it was than applied for 4 hours to two other animals. A single dose of 500 mg of CDBC in its original form was applied to the closely-clipped skin of one flank. 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.

After a 3-minute exposure (one animal): no cutaneous reactions were observed. A brown coloration of the skin was noted; it could have masked a possible very slight erythema between days 1 to 3.

After a 4 -hour exposure (three animals): A brown coloration of the skin was noted in all animals; it could have masked a possible very slight or well-defined erythema up to day 3 (one animal) or 5 (one animal). No cutaneous reactions were observed afterwards in these two animals. In the third animal, a well-defined erythema was noted from day 2 to day 5, then a very slight erythema was recorded up to day 9. A slight oedema was noted on day 3.

Mean scores over 24, 48 and 72 hours were not calculable for eryhtema because of the skin coloration for two animals. In the third animal, mean scores were 2.0 for erythema and 0.7 for oedema.

Under these experimental conditions, the test substance CDBC is slightly irritant when applied topically to rabbits.

Eye irritation study (Manciaux 2001):

The potential of the test substance CDBC to induce ocular irritation was evaluated in rabbits according to OECD (405) and EC guidelines, and in compliance with the principles of GLP.

A single dose of 100 mg of the test substance, first ground to a fine powder, was introduced into the left conjunctival sac. The right eye was not rinsed after administration of the test substance. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after administration.

Very slight or slight conjunctival reactions (slight chemosis, slight redness of the conjunctivae and clear discharge) were observed in all animals from day 1: some of these reactions persisted up to day 3. A slight iritis was noted in one animal on days 1 and 2. A very slight corneal opacity was recorded in two animals, on day 2 only. Mean scores calculared for each animal aver 24, 48 and 72 hours were 1.0, 0.7 and 0.7 for chemosis, 1.0, 0.7 and 0.7 for redness of the conjunctiva, 0.3, 0.0 and 0.0 for iris lesions and 0.0, 0.3 and 0.3 for corneal opacity.

Under these experimental conditions, the test substance CDBC is slightly irritant when administered by ocular route to rabbits.


Justification for classification or non-classification

Proposed self-classification according to the Regulation (EC) No 1272/2008: not classified