Registration Dossier

Administrative data

Description of key information

Dimethyl sulphide was found to be not irritating to skin and slightly irritating to eyes in rabbits.

Skin irritation:

The potential corrosive and irritant properties of Dimethyl Sulphide, following dermal application on rabbits was evaluated in a study conducted in compliance with the OECD Guideline No. 404 (Silvano, 2015 c). Dimethyl Sulphide was first applied for periods of 3 minutes, 1 hour and 4 hours to a single male New Zealand White rabbit. After the 4-hour application, since the mean value from grading at 24, 48 and 72 hours after patch removal was < 2.3 for erythema and for edema, the test item was applied on the skin of two other animals for 4 hours. A dosage-volume of 0.5 mL/flank was used. The test item was placed on a gauze pad, which was then applied to a skin area of approximately 6 cm2. The gauze pad was held in place by a non-irritation semi-occlusive dressing and a restraining bandage.After required period of contact with the skin, the dressing was removed. Each animal was observed once a day for mortality and clinical signs. For each exposure period, cutaneous reactions were evaluated approximately 1, 24, 48 and 72 hours after removal of the dressing. The mean values of the scores for erythema and edema were calculated for each animal. Body weight was recorded on the day of treatment and at the end of the evaluation of cutaneous reactions.

No unscheduled deaths occurred during the study and no clinical signs were noted in any animals. The body weight of the animals was unaffected by the test item treatment. No cutaneous reactions were observed during the study. Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:

.         erythema: 0.0, 0.0, 0.0; showing no significant inflammation,

.         edema: 0.0, 0.0; 0.0; showing no significant inflammation.

Dimethyl Sulphide was non-irritant when applied topically to rabbits.

 

Eye irritation:

The potential eye irritant properties of Dimethyl Sulphide, following a single ocular administration to rabbits was evaluated in a study conducted in compliance with the OECD guideline No. 405 (Silvano, 2015d). Dimethyl Sulphide was first administered to a single male New Zealand White rabbit. As mean value from grading at 24, 48 and 72 hours after instillation was [0-2] for conjunctival edema (chemosis) and for conjunctival redness, [0 -1] for iris lesions and for corneal opacity, the test item was administered in the left eye of two other animals. The test item was administered inthe conjunctival sac of the left eye. The right eye remained untreated and acted as control. A dosage-volume of 0.1 mL/animal was used. For the first animal, a local anesthetic was used prior to treatment and the animals were placed under systemic analgesia throughout the study. The eyes were not rinsed before the 24-hour scoring. Each animal was observed once a day for mortality and clinical signs. Ocular reactions were observed approximately 1, 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. Body weight was recorded on the day of treatment and at the end of the evaluation of ocular reactions (Day 4). On completion of the observation period, the animals were sacrificed then discarded without macroscopic post-mortem examination.

No unscheduled deaths occurred during the study and no clinical signs were noted in any animals.The body weight of the animals was unaffected by the test item treatment.In the left treated eye of the first animal, marked chemosis and severe redness of the conjunctiva were recorded 1 hour after test item administration. Chemosis became slight and redness was moderate on Day 2. No iris and corneal lesions were observed. In the left treated eye of the second and third animals, marked chemosis and moderate redness of the conjunctiva were recorded 1 hour after test item administration. Chemosis became moderate on Day 2 and then slight on Day 3. Moderate redness persisted on Day 3 for the third animal or on Day 2 for the second animal, becoming slight on Day 3. No iris and corneal lesions were observed.

Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:

chemosis: 0.3, 1.0 and 1.0,

redness of the conjunctiva: 0.7, 1.0 and 1.3,

iris lesions: 0.0, 0.0 and 0.0,

corneal opacity: 0.0, 0.0 and 0.0.

Dimethyl Sulphidewas slightly 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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: CEGAV, Argenvilliers, France.
- Age at study initiation: 3 to 4 months old
- Weight at study initiation: 3130 g to 3510 g
- Housing: individually housed in noryl cages
- Diet: pelleted breeding diet "type 110C", ad libitum
- Water:. ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): 5 to 15
- Photoperiod (hrs dark / hrs light): 12h/12h
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
3-minute, 1- and 4-hour
Observation period:
1 hour, 24, 48 and 72 hours
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: right and left anterior and/or posterior flanks
- coverage: 6 cm²
- Type of wrap if used: semi-occlusive dressing and restraining bandage

REMOVAL OF TEST SUBSTANCE
- Washing: no

SCORING SYSTEM:
Dermal irritation was graded in each animal according to the following scoring scale:

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


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

STUDY DESIGN
Rationale for design selection
The sequential study design was as follows:
The test item was applied for 3 minutes on the skin of a single animal (D31251):
¿ as no full thickness destruction of skin tissue was observed in the first hour after removal of the pad, the test item was applied on another treatment site for 1 hour.

After the 1-hour application on animal D31251:
¿ as no full thickness destruction of skin tissue was observed in the first hour after removal of the pad, the test item was applied on another treatment site for 4 hours.

After the 4-hour application on animal D31251:
¿ as mean value from grading at 24, 48 and 72 hours after patch removal was < 2.3 for erythema and for edema, the test item was applied on the skin of two other animals for 4 hours (D31252 and D31253).

For each animal, the day of dose application was recorded as Day 1 of its observation period.
Irritation parameter:
erythema score
Basis:
animal: #1, 2 and 3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal: #1, 2 and 3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
No cutaneous reactions were observed during the study.

Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:
¿ erythema: 0.0, 0.0, 0.0; showing no significant inflammation,
¿ edema: 0.0, 0.0; 0.0; showing no significant inflammation.
Other effects:
MORTALITY
No unscheduled deaths occurred during the study.

BODY WEIGHT
The body weight of the animals was unaffected by the test item treatment.
Interpretation of results:
GHS criteria not met
Conclusions:
Dimethyl Sulphide was non-irritant when applied topically to rabbits.
Executive summary:

The potential corrosive and irritant properties of Dimethyl Sulphide, following dermal application on rabbits was evaluated in a study conducted in compliance with the OECD Guideline No. 404. Dimethyl Sulphidewas first applied for periods of 3 minutes, 1 hour and 4 hours to a single male New Zealand White rabbit. After the 4-hour application, since the mean value from grading at 24, 48 and 72 hours after patch removal was < 2.3 for erythema and for edema, the test item was applied on the skin of two other animals for 4 hours. A dosage-volume of 0.5 mL/flank was used. The test item was placed on a gauze pad, which was then applied to a skin area of approximately 6 cm2. The gauze pad was held in place by a non-irritation semi-occlusive dressing and a restraining bandage.After required period of contact with the skin, the dressing was removed. Each animal was observed once a day for mortality and clinical signs. For each exposure period, cutaneous reactions were evaluated approximately 1, 24, 48 and 72 hours after removal of the dressing. The mean values of the scores for erythema and edema were calculated for each animal. Body weight was recorded on the day of treatment and at the end of the evaluation of cutaneous reactions.

No unscheduled deaths occurred during the study and no clinical signs were noted in any animals. The body weight of the animals was unaffected by the test item treatment. No cutaneous reactions were observed during the study. Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:

.         erythema: 0.0, 0.0, 0.0; showing no significant inflammation,

.         edema: 0.0, 0.0; 0.0; showing no significant inflammation.

Dimethyl Sulphide was 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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: CEGAV, Argenvilliers, France.
- Age at study initiation: 3 to 4 months old
- Weight at study initiation: 3130 g to 3510 g
- Housing: individually housed in noryl cages
- Diet: pelleted breeding diet "type 110C", ad libitum
- Water:. ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): 5 to 15
- Photoperiod (hrs dark / hrs light): 12h/12h
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
not rinced
Observation period (in vivo):
1, 24, 48 and 72 hours
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing : no
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
other: #1 and 2
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
1.3
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
iris score
Basis:
animal: #1, 2 and 3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Irritation parameter:
cornea opacity score
Basis:
animal: #1, 2 and 3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
No ocular reactions were observed in the right untreated control eye.

First animal (D31531)
In the left treated eye of male D31531, marked chemosis (grade 3) and severe redness (grade 3) of the conjunctiva were recorded 1 hour after test item administration.
Chemosis became slight (grade 1) and redness became moderate (grade 2) on Day 2.
No iris and corneal lesions were observed.

Second and third animals (D31532 and D31533)
In the left treated eye of males D31532 and D31533, marked chemosis (grade 3) and moderate redness (grade 2) of the conjunctiva were recorded 1 hour after test item administration.
Chemosis became moderate (grade 2) on Day 2 and then slight (grade 1) on Day 3.
Moderate redness (grade 2) persisted on Day 3 for male D31533 or on Day 2 for male D31532, becoming slight (grade 1) on Day 3.
No iris and corneal lesions were observed.

Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:
¿ chemosis: 0.3, 1.0 and 1.0,
¿ redness of the conjunctiva: 0.7, 1.0 and 1.3,
¿ iris lesions: 0.0, 0.0 and 0.0,
¿ corneal opacity: 0.0, 0.0 and 0.0.
Other effects:
No unscheduled deaths occurred during the study and no clinical signs were noted in any animals. The body weight of the animals was unaffected by the test item treatment.

The potential eye irritant properties of Dimethyl Sulphide following a single ocular administration to rabbits was evaluated in a study conducted in compliance with the OECD guideline No. 405. Dimethyl Sulphide was first administered to a single male New Zealand White rabbit. As mean value from grading at 24, 48 and 72 hours after instillation was [0-2] for conjunctival edema (chemosis) and for conjunctival redness, [0 -1] for iris lesions and for corneal opacity, the test item was administered in the left eye of two other animals. The test item was administered in the conjunctival sac of the left eye. The right eye remained untreated and acted as control.A dosage-volume of 0.1 mL/animal was used.For the first animal, a local anesthetic was used prior to treatment and the animals were placed under systemic analgesia throughout the study. The eyes were not rinsed before the 24-hour scoring. Each animal was observed once a day for mortality and clinical signs.Ocular reactions were observed approximately 1, 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. Body weight was recorded on the day of treatment and at the end of the evaluation of ocular reactions (Day 4). On completion of the observation period, the animals were sacrificed then discarded without macroscopic post-mortem examination.

No unscheduled deaths occurred during the study and no clinical signs were noted in any animals.The body weight of the animals was unaffected by the test item treatment.In the left treated eye of the first animal, marked chemosis and severe redness of the conjunctiva were recorded 1 hour after test item administration. Chemosis became slight and redness was moderate on Day 2. No iris and corneal lesions were observed. In the left treated eye of the second and third animals, marked chemosis and moderate redness of the conjunctiva were recorded 1 hour after test item administration. Chemosis became moderate on Day 2 and then slight on Day 3. Moderate redness persisted on Day 3 for the third animal or on Day 2 for the second animal, becoming slight on Day 3. No iris and corneal lesions were observed.

Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:

.       chemosis: 0.3, 1.0 and 1.0,

.       redness of the conjunctiva: 0.7, 1.0 and 1.3,

.       iris lesions: 0.0, 0.0 and 0.0,

.       corneal opacity: 0.0, 0.0 and 0.0.

Dimethyl Sulphide was slightly irritant when administered by ocular route to rabbits.

Interpretation of results:
GHS criteria not met
Conclusions:
Dimethyl Sulphide was slightly irritant when administered by ocular route to rabbits.
Executive summary:

The potential eye irritant properties of Dimethyl Sulphide, following a single ocular administration to rabbits was evaluated in a study conducted in compliance with the OECD guideline No. 405. Dimethyl Sulphide was first administered to a single male New Zealand White rabbit. As mean value from grading at 24, 48 and 72 hours after instillation was [0-2] for conjunctival edema (chemosis) and for conjunctival redness, [0 -1] for iris lesions and for corneal opacity, the test item was administered in the left eye of two other animals. The test item was administered inthe conjunctival sac of the left eye. The right eye remained untreated and acted as control.A dosage-volume of 0.1 mL/animal was used.For the first animal, a local anesthetic was used prior to treatment and the animals were placed under systemic analgesia throughout the study. The eyes were not rinsed before the 24-hour scoring. Each animal was observed once a day for mortality and clinical signs. Ocular reactions were observed approximately 1, 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. Body weight was recorded on the day of treatment and at the end of the evaluation of ocular reactions (Day 4). On completion of the observation period, the animals were sacrificed then discarded without macroscopic post-mortem examination.

No unscheduled deaths occurred during the study and no clinical signs were noted in any animals.The body weight of the animals was unaffected by the test item treatment.In the left treated eye of the first animal, marked chemosis and severe redness of the conjunctiva were recorded 1 hour after test item administration. Chemosis became slight and redness was moderate on Day 2. No iris and corneal lesions were observed. In the left treated eye of the second and third animals, marked chemosis and moderate redness of the conjunctiva were recorded 1 hour after test item administration. Chemosis became moderate on Day 2 and then slight on Day 3. Moderate redness persisted on Day 3 for the third animal or on Day 2 for the second animal, becoming slight on Day 3. No iris and corneal lesions were observed.

Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:

chemosis: 0.3, 1.0 and 1.0,

redness of the conjunctiva: 0.7, 1.0 and 1.3,

iris lesions: 0.0, 0.0 and 0.0,

corneal opacity: 0.0, 0.0 and 0.0.

Dimethyl Sulphidewas 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

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008:

Dimethyl sulphide is not irritating to the skin of the rabbit, therefore, no classification is warranted.

Dimethyl sulphide is slightly irritating to the rabbit eye, therefore, no classification is warranted.