Registration Dossier

Administrative data

Description of key information

Two guideline studies are available to evaluate the irritant properties of MTSC : skin irritation (OECD 404) and eye irritation (OECD 405).
The results showed that MTSC is not irritant for skin but slightly irritant for eye. MTSC is not classified for these two endpoints according to the regulation EC no.1272/2008.

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:
2001-04-03 to 2001-04-08
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study (OECD 404)
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
Minor deviations were not considered to have compromised the validity or integrity of the study : the relative humidity recorded in the animal room was sometimes outside of the target ranges ; the animals were given 110 pelleted
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
-Sex: male
- Source: CEGAV (Saint Mars d'Egrenne, France)
- Age at study initiation: no data
- Weight at study initiation: 2.6 ± 0.5 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): no data
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped using electric clippers
Vehicle:
other: none
Controls:
not required
Amount / concentration applied:
undiluted
Purified water (prepared at CIT by reverse osmosis) was used in order to moisten the test substance and ensure a good contact with the skin.
Duration of treatment / exposure:
4 hour(s)
Observation period:
3 days (because no effect were observed at 72 hours)
Number of animals:
3
Details on study design:
ADMINISTRATION:
- Area of exposure: left flank (3-minute exposure) and right flank (4-hour exposure)
- Total quantity applied: 500 mg
- Administration frequency: once
- Removal of test substance: residual is wiped with a dry gauze pad
EXAMINATIONS:
- Scoring system: Draize's score
- Examination time points: 1h, 24 h, 48 h and 72 hours after the patch removal.
Irritation parameter:
erythema score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0.1
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Scores of 3 rabbits were: 0.3, 0.0 and 0.0
Irritation parameter:
edema score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Scores of 3 rabbits were 0.0
Irritant / corrosive response data:
After a 3-minute exposure: No cutaneous reaction were noted in any rabbits.
After a 4-hour exposure: A very slight erythema (grade 1) was observed in one rabbit at 1h and 24h after patch removal. This erythema disappeared thereafter. Other rabbits did not exhibit any cutaneous reactions.
Other effects:
none

Table : 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)

993

Erythema

1

1

0

0

0.3

Oedema

0

0

0

0

0.0

Other

*

*

*

*

 

578

Erythema

0

0

0

0

0.0

Oedema

0

0

0

0

0.0

Other

*

*

*

*

 

993

Erythema

0

0

0

0

0.0

Oedema

0

0

0

0

0.0

Other

*

*

*

*

 

 

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

* : none

D = day, h = hour

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: Regulation EC no.1272/2008
Conclusions:
Under these experimental conditions, the test substance MTSC is non-irritant when applied topically to rabbits.
Executive summary:

The potential of the test substance MTSC to induce skin irritation was evaluated in rabbits according to OECD 404 and in compliance with the principles of Good Laboratory Practice Regulations.

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 500 mg of the test substance in its original form was applied to the closely­clipped 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.

 

After a 3-minute exposure (one animal): No cutaneous reactions were observed.

After a 4-hour exposure (three animals): A very slight erythema was noted in one animal on days 1 and 2. No other cutaneous reactions were observed.

Mean scores over 24, 48 and 72 hours for each animal were 0.3, 0.0 and 0.0 for erythema and 0.0, 0.0 and 0.0 for oedema.

Under these experimental conditions, the test substance MTSC is non-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:
From 2001-04-10 to 2001-04-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study (OECD 405)
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
minor deviations were not considered to have compromised the validity or integrity of the study : relative humidity, animal breeder's and diet.
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: 2.6 ± 0.3 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): no data
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: yes, untreated eye
Amount / concentration applied:
undiluted ; The test substance was used in its original form.
Amount applied: 100 other: mg
Duration of treatment / exposure:
a single exposure
Observation period (in vivo):
6 days (because no effect was observed at day 6)
Number of animals or in vitro replicates:
3 rabbits
Details on study design:
Comment: not rinsed

EXAMINATIONS:
- Ophthalmoscopic examination: Yes
- Scoring system: Draize's scale
- Observation period: 1h, 24h, 48h and 72h after administration of the test substance
- Tool used to assess score: fluorescein
Irritation parameter:
conjunctivae score
Remarks:
(chemosis)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0.87
Max. score:
4
Reversibility:
fully reversible within: 5 days
Remarks on result:
other: Individual scores were : 1.3, 1.0 and 0.3
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
1.47
Max. score:
3
Reversibility:
fully reversible within: 6 days
Remarks on result:
other: Individual scores were : 1.7, 1.0 and 1.7
Irritation parameter:
conjunctivae score
Remarks:
(discharge)
Basis:
mean
Remarks:
6 rabbits
Time point:
other: 24-48-72 hours
Score:
0.2
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Individual scores were: 0.3, 0.3 and 0.0
Irritation parameter:
iris score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0.1
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Individually scores were: 0.3, 0.0 and 0.0
Irritation parameter:
cornea opacity score
Remarks:
(intensity)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0.43
Max. score:
4
Reversibility:
fully reversible within: 5 days
Remarks on result:
other: Individually scores were: 1.3, 0.0 and 0.0
Irritation parameter:
cornea opacity score
Remarks:
(area)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0.43
Max. score:
4
Reversibility:
fully reversible within: 5 days
Remarks on result:
other: Individually scores were: 1.3, 0.0 and 0.0
Irritant / corrosive response data:
Very slight or slight conjunctival reactions were observed in an animals from day 1: a very slight or slight chemosis (grade 1 or 2), a very slight or slight redness of the conjunctiva (grade 1 or 2) and a clear discharge were noted. Some of the se reactions persisted up to day 5 at the latest. A slight iritis (grade 1) was noted in one animal, on day 2 only. A very slight or slight corneal opacity (grade 1 or 2) was recorded in the same animal, from day 2 up to day 4. Mean scores calculated for each animal over 24, 48 and 72 bourg were 1.3, 1.0 and 0.3 for chemosis, 1.7, 1.0 and 1.7 for redness of the conjunctiva, 0.3, 0.0 and 0.0 for iris lesions and 1.3, 0.0 and 0.0 for comeal opacity.
Other effects:
none

Table 1: Individual ocular examinations 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)

(D5)

(D6)

 

993

conjunctivae

Chemosis

1

2

1

1

0

-

1.3

Redness

1

2

2

1

0

-

1.7

Discharge

1

1

0

0

0

-

0.3

Iris

0

1

0

0

0

-

0.3

Corneal opacity

Intensity

0

2

1

1

0

-

1.3

Area

0

2

1

1

0

-

1.3

Other

*

*

*

*

*

-

 

Fluorescein

/

U

U

U

U

-

 

 

579

conjunctivae

Chemosis

1

1

1

1

0

-

1.0

Redness

1

1

1

1

0

-

1.0

Discharge

1

1

0

0

0

-

0.3

Iris

0

0

0

0

0

-

0.0

Corneal opacity

Intensity

0

0

0

0

0

-

0.0

Area

0

0

0

0

0

-

0.0

Other

*

*

*

*

*

-

 

Fluorescein

/

U

/

/

/

-

 

 

566

conjunctivae

Chemosis

2

1

0

0

0

0

0.3

Redness

2

2

2

1

1

0

1.7

Discharge

1

0

0

0

0

0

0.0

Iris

0

0

0

0

0

0

0.0

Corneal opacity

Intensity

0

0

0

0

0

0

0.0

Area

0

0

0

0

0

0

0.0

Other

Su

*

*

*

*

*

 

Fluorescein

/

U

/

/

/

/

 

 

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

* : none

U: fluorescein batch No.D616

/: fluorescein not used

Su: residual test substance

-         : ocular examination not performed

 

Interpretation of results:
slightly irritating
Remarks:
Migrated information but not classified Criteria used for interpretation of results: other: Regulation EC n°1272/2008
Conclusions:
Under these experimental conditions, the test substance 4 -methylthiosemicarbazide is slightly irritant when administered by ocular route to rabbits.
Executive summary:

The potential of the test substance 4 -methylthiosemicarbazide to induce ocular irritation was evaluated in rabbits according to OECD 405 and with the principles of Good Laboratory Practice Regulations.

A single dose of 100 mg of the test substance in its original form was introduced into the left conjunctival sac of three male New Zealand White rabbits. The right eye was not treated andserved as control. 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 and then daily until reversibility of the ocular reactions. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal.

Very slight or slight conjunctival reactions (very slight or slight chemosis, very slight or slight redness of the conjunctiva and clear discharge) were observed in all animals from day 1: some of these reactions persisted up to day 5 at the latest.

A slight iritis was noted in one animal, on day 2 only. A very slight or slight corneal opacity was recorded in the same animal, from day 2 up to day 4.

Mean scores calculated for each animal over 24, 48 and 72 hours were 1.3, 1.0 and 0.3 forchemosis, 1.7, 1.0 and 1.7 for redness of the conjunctiva, 0.3, 0.0 and 0.0 for iris lesions and 1.3,0.0 and 0.0 for corneal opacity.

Under these experimental conditions, the test substance 4 -methylthiosemicarbazide 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 (Manciaux 2001) : The potential of the test substance MTSC to induce skin irritation was evaluated in rabbits according to OECD 404 and in compliance with the principles of Good Laboratory Practice Regulations.

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 500 mg of the test substance in its original form was applied to the closely­clipped 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.

After a 3-minute exposure (one animal):No cutaneous reactions were observed.

After a 4-hour exposure (three animals):A very slight erythema was noted in one animal on days 1 and 2.No other cutaneous reactions were observed.

Mean scores over 24, 48 and 72 hours for each animal were 0.3, 0.0 and 0.0 for erythema and 0.0, 0.0 and 0.0 for oedema.

Under these experimental conditions, the test substance MTSC is non-irritant when applied topically to rabbits.

Eye irritation (Manciaux 2001) : The potential of the test substance 4 -methylthiosemicarbazide to induce ocular irritation was evaluated in rabbits according to OECD 405 and with the principles of Good Laboratory Practice Regulations. A single dose of 100 mg of the test substance in its original form was introduced into theleft conjunctival sac of three male New Zealand White rabbits. The right eye was not treated and served as control. 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 and then daily until reversibility of the ocular reactions. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal. Very slight or slight conjunctival reactions (very slight or slight chemosis, very slight or slight redness of the conjunctiva and clear discharge) were observed in all animals from day 1: some of these reactions persisted up to day 5 at the latest. A slight iritis was noted in one animal, on day 2 only. A very slight or slight corneal opacity wasrecorded in the same animal, from day 2 up to day 4. Mean scores calculated for each animal over 24, 48 and 72 hours were 1.3, 1.0 and 0.3 forchemosis, 1.7, 1.0 and 1.7 for redness of the conjunctiva, 0.3, 0.0 and 0.0 for iris lesions and 1.3,0.0 and 0.0 for corneal opacity. Under these experimental conditions, the test substance 4 -methylthiosemicarbazide is slightly irritant when administered by ocular route to rabbits.


Justification for selection of skin irritation / corrosion endpoint:
Only one study is available for this endpoint.

Justification for selection of eye irritation endpoint:
Only one study is available for this endpoint.

Effects on eye irritation: slightly irritating

Justification for classification or non-classification

Proposed self-classification

- Regulation (EC) No 1272/2008 :Not classified

- Directive 67/548/EEC :Not classified