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Administrative data

Description of key information

4,4'-dithiodimorpholine is of low acute toxicity by the oral and dermal routes. In rats, the acute oral LD50 is 5600 mg/kg and the acute dermal LD0 is higher than 2000 mg/kg. Na data is available by inhalation.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Initial boby weight = 210-240 g (males), 230-235 g (females)
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
DTDM as a 20% suspension in corn oil was administered.
Doses:
3890, 5010, 6310 or 7940 mg/kg bw
No. of animals per sex per dose:
5 animals/dose
Control animals:
no
Details on study design:
Recovery period = 14 days.
Clinical signs of toxicity (activity, food consumption), mortality.. Gross autopsy.
Survivors were sacrified after fourteen days.
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
5 600 mg/kg bw
95% CL:
> 5 320 - < 5 880
Mortality:
Yes, see table
Time of mortality = one to four hours.
Clinical signs:
other: Clinical signs of toxicity included reduced activity and appetite for 3-5 days for survivors, and increasing weakness, collapse and death for decedents in 1-4 days.
Gross pathology:
Gross autopsy findings on decedents were lung and liver hyperemia and acute gastrointestinal inflammation. All viscera of survivors appeared normal.

Table of results

Dose mg/kg

Mortalities male

Mortalities female

Combined

3980

0/2

0/3

0/5

5010

1/3

0/2

1/5

6310

1 /2

2/3

3/5

7940

3/3

2/2

5/5

Interpretation of results:
GHS criteria not met
Conclusions:
In this study, the LD50 (DTDM) was 5600 mg/kg in rats.
Executive summary:

In a pre-guideline acute oral toxicity study, male and female rats were exposed to 4,4 -Dithiodimorpholine at 3980, 5010, 6310 and 7940 mg/kg bw (single exposure), and were observed during 15 days. No mortality was observed at 3980 mg/kg, one rat died at 5010 mg/kg, 3 rats died at 6310 mg/kg and all five rats died at 7940 mg/kg. The LD50 was calculated to be 5600 mg/kg. Clinical signs observed in survivor rats were weakness, collapse, reduced food comsumption and reduced activity.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
5 600 mg/kg bw
Quality of whole database:
Birch study is considered to be reliable with a klimisch score of 2.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
on day 1, body weight of all males was higher than 320 g (up to 401 g) and the female No. 6 has kept its dressing only 22 hours instead of 24 hours
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
see above
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Breeder: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approximately 8 weeks old
- Weight at study initiation: 384 ± 13 g for the males and 248 ± 6 g for the females
- Fasting period before study: none
- Housing: individual polycarbonate cages with stainless steel lid (35.5 cm x 23.5 cm x 19.3 cm). Each cage contained autoclaved sawdust (SICSA, Alfortville, France).
- Diet (e.g. ad libitum): free access to SSNIFF R/M-H pelleted maintenance diet
- Water (e.g. ad libitum): drinking water filtered by a FG Millipore membrane (0.22 micron), provided ad libitum
- Acclimation period: at least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 30 to 70%
- Air changes (per hr): 12 cycles/hour
- Photoperiod (hrs dark / hrs light): 12 h/12 h (7:00 - 19:00)

IN-LIFE DATES: From 11 March 2010 to 25 March 2010
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 5 cm x 7 cm for the males and 5 cm x 6 cm for the females
- % coverage: 10% of the total body surface of the animals
- Type of wrap if used: gauze pad held in contact with the skin for 24 hours by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): any residual test item was removed using a moistened cotton pad.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- For solids, paste formed: yes (substance moistened with 2 mL of purified water)
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
other: historical control data
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the animals were observed frequently during the hours following administration of the test item, and then at least once a day until day 15. Animals were weighed individually just before administration of the test item on day 1 and then on days 8 and 15.
- Necropsy of survivors performed: yes
Statistics:
no
Sex:
male/female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
None.
Clinical signs:
other: None and no cutaneous reactions.
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.
Interpretation of results:
GHS criteria not met
Conclusions:
Under the experimental conditions of this study, the dermal LD0 of the test item, 4,4 Dithiodimorpholine, was higher than 2000 mg/kg in rats.
Executive summary:

The acute dermal toxicity of the test item, 4,4 -Dithiodimorpholine, was evaluated in rats according to OECD (No. 402, 24th February 1987) and Commission Regulation (EC) (No. 440/2008, Part B.3, 30 May 2008) guidelines.

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

 

Methods

The test item, in its original form, was applied for 24 hours to the skin of one group of ten Sprague-Dawley rats (five males and five females) treated at the dose-level of 2000 mg/kg. The test site was covered by a semi-occlusive dressing.

 

Mortality, clinical signs and body weight gain were checked for a period of 14 days following the single application of the test item.

 

On completion of the observation period, the animals were sacrificed then subjected to a macroscopicpost-mortemexamination.

 

Results

No mortality, no clinical signs and no cutaneous reactions were observed during the study.

 

When compared to CIT historical control data, a lower body weight gain was noted in 3/5 males (25 to 33 gvs. 47 ± 7 g in control data base) between day 1 and day 8. The body weight gain of these animals returned to normal thereafter. The body weight gain of the other animals was not affected by the treatment with the test item.

 

No apparent abnormalities were observed at necropsy in any animal.

 

Conclusion

Under the experimental conditions of this study, the dermal LD0of the test item, 4,4 -Dithiodimorpholine, was higher than 2000 mg/kg in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
Birch study is considered to be reliable with a klimisch score of 1.

Additional information

Acute oral

In a pre-guideline acute oral toxicity study similar to OECD guideline # 401 (Birch, 1974a), male and female rats were exposed to 4,4 -Dithiodimorpholine at 3980, 5010, 6310 and 7940 mg/kg bw (single exposure), and were observed during 15 days. No mortality was observed at 3980 mg/kg, one rat died at 5010 mg/kg, 3 rats died at 6310 mg/kg and all five rats died at 7940 mg/kg. The LD50 was calculated to be 5600 mg/kg. Clinical signs observed in survivor rats were weakness, collapse, reduced food consumption and reduced activity.

 

Acute dermal

In an acute dermal toxicity study performed according the OECD guideline # 402 (Rokh, 2010), 4,4 -Dithiodimorpholine, in its original form, was applied at the dose-level of 2000 mg/kg for 24 hours to the skin of one group of ten Sprague-Dawley rats (five males and five females. The test site was covered by a semi-occlusive dressing. Mortality, clinical signs and body weight gain were checked for a period of 14 days following the single application of the test item. No mortality, no clinical signs and no cutaneous reactions were observed during the study. No apparent abnormalities were observed at necropsy in any animal. The dermal LD0was higher than 2000 mg/kg in rats.

 

Justification for classification or non-classification

Based on the available data, no classification for acute toxicity is required for the registered substance according to the Regulation (EC) No 1272/2008.

Justification : the LD50 value for oral and dermal route are higher than 2000 mg/kg bw.

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