Di(morpholin-4-yl) disulphide

Endpoint summary

Description of key information

4,4'-dithiodimorpholine is not skin or eye irritant in rabbits.
However 4,4'-dithiodimorpholine is irritating for the respiratory tract.

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:

1974

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Draize method

GLP compliance:

no

Species:

rabbit

Strain:

other: New Zealand Albino

Details on test animals or test system and environmental conditions:

no

Type of coverage:

occlusive

Preparation of test site:

other: shaved and abraded

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g of DTDM, as a finely groud powder moistened with water

Duration of treatment / exposure:

24 hr

Observation period:

24, 48, 72 and 168 hours after topical application.

Number of animals:

6 animals / dose

Details on study design:

TEST SITE
- Area of exposure: to the shaved dorsal of rabbits
- % coverage: DTDM was applied to the skin under 1'' square gauze patches
- Type of wrap if used: an occlusive wrap latex rubber secured by bandaging and elastic tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data
- Time after start of exposure: 24 hr

SCORING SYSTEM:
Dermal irritation was scored by Draize Method.

The primary irritation Index was calculated by averaging the mean scores at 24 and 72 hours.

Irritation parameter:

erythema score

Basis:

mean

Remarks:

6 rabbits

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: Intact skin

Irritation parameter:

edema score

Basis:

mean

Remarks:

6 rabbits

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: n/a

Remarks on result:

other: Intact skin

Irritation parameter:

erythema score

Basis:

mean

Remarks:

6 rabbits

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: Abraded skin

Irritation parameter:

edema score

Basis:

mean

Remarks:

6 rabbits

Time point:

24/48/72 h

Score:

0.05

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: Abraded skin

Irritant / corrosive response data:

Small effects were observed at 24 hours (score of 1 of each animal).
Similar effects is observed on intact skin and on abraded skin.

Interpretation of results:

GHS criteria not met

Conclusions:

DTDM was not irritating to the intact or abraded skin.

Executive summary:

In a pre-guideline study, 0.5 grams of 4,4'-dithiodimorpholine, as a finely ground powder moistened with water, was applied to the shaved or abraded dorsal areas of six albino rabbits. The test material was applied to the skin under 1” square gauze patches and held in contact with the skin by means of an occlusive wrap of latex rubber secured by bandaging and elastic tape. The occlusive wrap and gauze patches were removed after 24 hours. Dermal irritation was scored by the Draize Method, and results were recorded 24, 48, 72 and 168 hours after topical application. All six rabbits showed a very slight reaction (erythema) with a score of 1 at 24 hours on both the intact or abraded skin, effects were fully reversible at 48 hours (score of 0 at 48 hours). Oedema (score 1) was recorded in one rabbit at 24 hours on the abraded skin. According to these results, 4,4'-dithiodimorpholine is considered as not skin irritant.

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:

1974

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method of Draize (1944)

GLP compliance:

no

Species:

rabbit

Strain:

other: New Zealand Albino

Details on test animals or tissues and environmental conditions:

no

Vehicle:

unchanged (no vehicle)

Controls:

yes

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg of DTDM, as a finely ground powder

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

6

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 24 hr

SCORING SYSTEM: The Draize Method

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

8.4

Max. score:

20

Reversibility:

fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

80

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

10

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

3

Remarks on result:

other: "conjunctivae score" not detailed in the report

Irritant / corrosive response data:

Immediate = slight discomfort ; At 1 hour = moderate erythema, slight edema, copious discharge; At 24 hours = moderate to severe erythema, very slight edema, copious discharge containing whitish exudate ; At 48 hours and at 72 hours = gradual improvement; At 168 hours = all animals scored "0".

Interpretation of results:

GHS criteria not met

Conclusions:

4,4'-dithiodimorpholine was not irritating for the eyes.

Executive summary:

In a pre-guideline study, 100.0 mg of 4,4'-dithiodimorpholine, as a finely ground powder, was applied to one eye of six albino rabbits. The other eye was not treated and served as a control. The cornea, iris and conjuntivea were examined immediately after treatment, and then at intervals of 1 hour, and at 24, 48, 72 and 168 hours. The Draize Method was used for scoring eye irritation. A slight discomfort was observed immediately after the instillation. At 1 hour, moderate erythema, slight edema and copious discharge were observed. At 24 hours, moderate to severe erythema, very slight edema, and copious discharge containing whitish exudate were still observed. At 48 and 72hours, the effects gradually improved. At 168 hours, all animals scored “0”. The average Draize score for 24, 48 and 72 hours was calculated for each animal and then averaged over the six animals. The average Draize score was 8.4 on a scale from 0-110. 4,4'-dithiodimorpholine is considered as not eye irritant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin irritation

In a pre-guideline study (Birch, 1974b), 0.5 grams of 4,4'-dithiodimorpholine, as a finely ground powder moistened with water, was applied to the shaved or abraded dorsal areas of six albino rabbits. The test material was applied to the skin under 1” square gauze patches and held in contact with the skin by means of an occlusive wrap of latex rubber secured by bandaging and elastic tape. The occlusive wrap and gauze patches were removed after 24 hours. Dermal irritation was scored by the Draize Method, and results were recorded 24, 48, 72 and 168 hours after topical application. All six rabbits showed a very slight reaction (erythema) with a score of 1 at 24 hours on both the intact or abraded skin, effects were fully reversible at 48 hours (score of 0 at 48 hours). Oedema (score 1) was recorded in one rabbit at 24 hours on the abraded skin. According to these results, 4,4'-dithiodimorpholine is considered as not skin irritant.

Eye irritation

In a pre-guideline study (Birch, 1974c), 100.0 mg of 4,4'-dithiodimorpholine, as a finely ground powder, was applied to one eye of six albino rabbits. The other eye was not treated and served as a control. The cornea, iris and conjuntivea were examined immediately after treatment, and then at intervals of 1 hour, and at 24, 48, 72 and 168 hours. The Draize Method was used for scoring eye irritation. A slight discomfort was observed immediately after the instillation. At 1 hour, moderate erythema, slight edema and copious discharge were observed. At 24 hours, moderate to severe erythema, very slight edema, and copious discharge containing whitish exudate were still observed. At 48 and 72hours, the effects gradually improved. At 168 hours, all animals scored “0”. The average Draize score for 24, 48 and 72 hours was calculated for each animal and then averaged over the six animals. 4,4'-dithiodimorpholine is considered as not eye irritant.

Respiratory tract irritation

Respiratory tract irritation could be studied in the 90 -day repeated toxicity study performed with DTDM by inhalation (Sieber 2014). In this study, histopathological changes in the larynx of both sexes were noted in a concentration-related manner. These findings included focal squamous metaplasia, focal hyperplasia of squamous epithelium, submucosal inflammation and focal erosion/ulceration. The latter finding was noted in group 4 only. After the end of the recovery period, complete recovery was observed in groups 2 and 3 and partial recovery in group 4.

There were no further findings that were considered to be related to treatment.  Based on the findings in the larynx, the NOAEC (No-Observed-Adverse-Effect-Concentration) for local effects was considered to be 0.507 mg 4,4’-Dithiodimorpholine/m3 air.

Justification for classification or non-classification

Based on the available data, no classification for skin or eye irritation is required for the registrated substance according to the Regulation (EC) No 1272/2008. However, the registered substance is considered as irritating for the respiratory tract : STOT SE 3, H335 “May cause respiratory irritation”.