2,2'-[1,2-ethanediylbis(oxy)]bis(ethanethiol)

Endpoint summary

Description of key information

Acute oral toxicity

The acute toxicity of DIMERCAPTO-1,8-DIOXA-3,6-OCTANE (DMDO) was investigated following a single oral administration to the Sprague-Dawley rat followed by a 14-day observation period (Caruso 2016). Experimental procedures were in agreement with the OECD guideline Number 423 (adopted on 17 December 2001). A first group of 3 female animals was dosed at a level of 300 mg/kg (Step 1), dose level selected on the basis of available information. A second group, similarly composed, was then dosed at the same dose level (Step 2). Since two animals died in Step 2, according to the step-wise procedure foreseen in the relevant guideline, a third group of 3 females was dosed at the lower dose level of 50 mg/kg (Step 3). Finally an additional group, similarly composed, was dosed at the same dose level (Step 4). No further doses were investigated, since the objective of the study had been achieved.

All animals dosed at 300 mg/kg (Step 1) showed tremors, ataxia and piloerection. One animal was found dead and the others recovered from these signs on Day 2 of study. Tremors, ataxia and muscular rigidity were observed in all animals dosed at the same dose level (Step 2). Two animals were found dead, while the third one recovered on Day 2 of study. No mortality occurred and no clinical sign was seen in all animals dosed at 50mg/kg (Step 3 - Step 4). Body weight changes recorded during the study were within the expected range for this strain and age of animals. No abnormalities were observed at necropsy examination performed on termination of the observation period and in the animals found dead.

These results demonstrate the acute toxicity expected (ATE) to be lower than 300 mg/kg body weight, but higher than 50 mg/kg body weight.

Acute dermal toxicity

The acute toxicity of DMDO was investigated following dermal administration of a single dose to the rat (Caruso, 2016). A single dose of 2000 mg/kg was administered to a group of 5 male and 5 female animals for 24 hours. After 14 days, all animals were killed and subjected to necropsy examination. No mortality occurred and no signs of toxicity were observed in male or female animals during the observation period. The body weight changes observed during the study were within the expected range for this species and age of animals. No significant abnormalities were found at necropsy in the animals at termination of the study. No abnormalities were observed at the treated site. These results indicate that the test item has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000 mg/kg. The lack of mortality demonstrates the Lethal Dose to be greater than 2000 mg/kg.

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

Study period:

Start of experimental phase: 05 July 2016 End of experimental phase: 17 August 2016 Study completion :21 October 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

adopted on 17 December 2001

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Species and strain Rat, Hsd: Sprague Dawley SD
Sex: Females (nulliparous and non-pregnant)
Age: 7-8 weeks old; 6-7 weeks old (differently from what specified in the Study Protocol)
Supplier: Envigo RMS s.r.l., San Pietro al Natisone (UD), Italy
Date of arrival: 23 June 2016; 14 July 2016
Weight range at arrival: 170-178 grams; 163.8-168.8 grams
Acclimatisation period: At least 5 days
Veterinary health check: During acclimatisation period

ENVIRONMENTAL CONDITIONS
Animals per cage: 3 during the study; up to 5 during acclimatisation
Housing: Polisulphone solid bottomed cages measuring 59.5×38×20 cm with nesting material provided into suitable bedding bags
Cage control: Daily inspected and changed as necessary (at least 3 times/week)
Water: Drinking water supplied to each cage via a water bottle
Water supply: ad libitum
Diet: 4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy)
Diet supply: ad libitum throughout the study except for the dosing procedure indicated in section 4.2.2
Room lighting: Artificial (fluorescent tubes), daily light/dark cycle of 12/12 hours
Air changes Approximately 15 to 20 air changes per hour
Temperature range: 22 °C±2 °C
Relative humidity range: 55%±15%

Route of administration:

oral: gavage

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 and 5mg/mL
- Amount of vehicle (if gavage): 10 mL/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:

Doses:

300 mg/kg; 50 mg/kg

No. of animals per sex per dose:

6 Females at 300 mg/kg; 6 females at 50 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:Animals were observed for clinical signs the day of dosing: on dosing, approximately 0.5 hour, 2 hours and 4 hours after dosing daily thereafter for a total of 14 days.
All animals were weighed at allocation to the study (Day -1), on the day of dosing (Day 1) and
on Days 2, 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 50 - <= 300 mg/kg bw

Based on:

test mat.

Mortality:

One of the three animals initially dosed at 300mg/kg (Step 1) was found dead on Day 2 of study. Two animals were found dead, in the second group dosed at the same dose level. No mortality occurred in any of six animals dosed at 50 mg/kg.

Clinical signs:

Tremors, ataxia and piloerection were observed in all animals of the step I (dosed at 300 mg/kg). Surviving animals recovered from these signs on Day 2 of study.
Tremors, ataxia and muscular rigidity were observed in all animals of the step II (dosed at 300 mg/kg). Surviving animal recovered from these signs on Day 2 of study.
No clinical sign was seen in all animals dosed at 50 mg/kg.

Body weight:

Changes in body weight observed during the study were within the expected range for this strain and age of animals.

Gross pathology:

No abnormalities were observed at necropsy examination performed on termination of the observation period and in the animals found dead.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

These results demonstrate the acute toxicity expected (ATE) to be lower than 300mg/kg body weight, but higher than 50mg/kg body weight.

Executive summary:

The acute toxicity of DIMERCAPTO-1,8-DIOXA-3,6-OCTANE (DMDO) was investigated following a single oral administration to the Sprague-Dawley rat followed by a 14-day observation period.

Experimental procedures were in agreement with the OECD guideline Number 423 (adopted on 17 December 2001). A first group of 3 female animals was dosed at a level of 300mg/kg (Step 1), dose level selected on the basis of available information. A second group, similarly composed, was then dosed at the same dose level (Step 2). Since two animals died in Step 2, according to the step-wise procedure foreseen in the relevant guideline, a third group of 3 females was dosed at the lower dose level of 50mg/kg (Step 3). Finally an additional group, similarly composed, was dosed at the same dose level (Step 4). No further doses were investigated, since the objective of the study had been achieved.

All animals dosed at 300mg/kg (Step 1) showed tremors, ataxia and piloerection. One animal was found dead and the others recovered from these signs on Day 2 of study. Tremors, ataxia and muscular rigidity were observed in all animals dosed at the same dose level (Step 2). Two animals were found dead, while the third one recovered on Day 2 of study. No mortality occurred and no clinical sign was seen in all animals dosed at 50mg/kg (Step 3 - Step 4). Body weight changes recorded during the study were within the expected range for this strain and age of animals. No abnormalities were observed at necropsy examination performed on termination of the observation period and in the animals found dead.

These results demonstrate the acute toxicity expected (ATE) to be lower than 300mg/kg body weight, but higher than 50mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

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:

Start of experimental phase: 05 July 2016 End of experimental phase: 20 July 2016 Study completion: 08 August 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted on 24 February 1987

Deviations:

no

GLP compliance:

yes

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
Species and strain: Rat, Hsd: Sprague Dawley SD
Sex: Males and females (nulliparous and non-pregnant)
Age: 6 to 8 weeks old
Weight at order: 176 to 200 grams
Supplier: Envigo RMS s.r.l., San Pietro al Natisone (UD), Italy
Breeder: Envigo RMS s.r.l., San Pietro al Natisone (UD), Italy
Date of arrival: 23 June 2016
Weight range at arrival: 175-182 grams
Acclimatisation period: At least 5 days
Veterinary health check: During acclimatisation period

ENVIRONMENTAL CONDITIONS
Animals per cage: Up to 5 of one sex during acclimatisation; individually caged during the study
Housing: Clear polysulphone H-Temp solid bottomed cages (Tecniplast Gazzada S.a.r.l., Buguggiate, VA, Italy) measuring 59.5×38×20 cm during
acclimatisation period and 42.5×26.6×18.5 cm during the study with nesting material provided into suitable bedding bags.
Cage control: Daily inspected and changed as necessary (at least 3 times/week)
Water Drinking: water supplied to each cage via a water bottle
Water supply: Ad libitum
Diet: 4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy)
Diet supply: Ad libitum throughout the study
Room lighting: Artificial (fluorescent tubes), daily light/dark cycle of 12/12 hours
Air changes: Approximately 15 to 20 air changes per hour
Temperature range: 22 °C±2 °C
Relative humidity range: 55%±15%

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorsal surface of the trunk
- % coverage: Approximately 10% of body surface
- Type of wrap if used: Adhesive bandage and gauze patch

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes, with cotton wool soaked with lukewarmwater.
- Time after start of exposure: 24 hours

Duration of exposure:

The animals remained in contact with the test item for 24 hours.

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for clinical signs the day of dosing: on dosing, approximately 1 hour after dosing, 2 hours
after dosing and 4 hours after dosing, daily thereafter. All animals were weighed at allocation to the study (Day -1), on the day of dosing (Day 1) and
on Days 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

No mortality occurred.

Clinical signs:

No clinical signs were observed in male or female animals after treatment during the observation period.

Body weight:

Body weights and body weight changes were within the expected range for this species and age of animals at the end of the study.

Gross pathology:

No abnormalities were found at necropsy examination performed on all animals at termination of the study.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute toxicity of the test item was investigated following dermal administration of a single dose to the rat at 2000mg/kg.
No mortality occurred following dosing and no signs of toxicity were observed.
These results indicate that the test item has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000mg/kg.
The lack of mortality demonstrates the Lethal Dose to be greater than 2000mg/kg.

Executive summary:

The acute toxicity of Dimercapto-1,8-dioxa-3,6-octane (DMDO) was investigated following dermal administration of a single dose to the rat. A single dose of 2000 mg/kg was administered to a group of 5 male and 5 female animals for 24 hours. After 14 days, all animals were killed and subjected to necropsy examination. No mortality occurred and no signs of toxicity were observed in male or female animals during the observation period. The body weight changes observed during the study were within the expected range for this species and age of animals. No significant abnormalities were found at necropsy in the animals at termination of the study. No abnormalities were observed at the treated site. These results indicate that the test item has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000 mg/kg. The lack of mortality demonstrates the Lethal Dose to be greater than 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw