1,5,2,4-dioxadithiane 2,2,4,4-tetraoxide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

15 June 2011 to 31 July 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was performed according to EC and OECD guidelines and according to GLP principles.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Principles of method if other than guideline:

no additional information provided

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1,5,2,4-dioxadithiane 2,2,4,4-tetraoxide

EC Number:

700-464-0

Cas Number:

99591-74-9

Molecular formula:

C2H4O6S2

IUPAC Name:

1,5,2,4-dioxadithiane 2,2,4,4-tetraoxide

Details on test material:

- Name of test material (as cited in study report): MMDS
- Substance type: organic
- Physical state: White powder
- Analytical purity: Not indicated by the sponsor; treated as 100% pure
- Purity test date: no data
- Lot/batch No.: 100910
- Expiration date of the lot/batch: 20 April 2012
- Stability under test conditions: hydrolyses rapidly, handle in nitrogen environment in glovebox
- Storage condition of test material: In refrigerator (2-8°C) in the dark under nitrogen

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 9 weeks
- Weight at study initiation:
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available ad libitum
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material and paper as cage-enrichment
- Diet: Free access to pelleted rodent diet
- Water: Free access to tap water
- Acclimation period: at least 5 days before start of treatment under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Remarks:

dewatered and specific gravity 0.92

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2000 mg/kg; 300 mg/kg
- Amount of vehicle (if gavage): 10 mL/kg b.w.
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at NOTOX and on test substance data supplied by the sponsor

DOSAGE PREPARATION: The test substance and formulation were handled under nitrogen as much as possible, using a glove box. The test substance formulations (w/w) were prepared within 15 minutes prior to dosing. No adjustment was made for specific gravity of the vehicle. Homogeneity was obtained to visually acceptable levels.

CLASS METHOD
- Rationale for the selection of the starting dose: The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups

Doses:

2000 mg/kg (10 mL/kg) body weight.
300 mg/kg (10 mL/kg) body weight.

No. of animals per sex per dose:

3

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily. The time of death was recorded as precisely as possible.
Body weights: Days 1 (pre-administration), 8 and 15 and at death (if found dead after Day 1).
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.

- Necropsy of survivors performed: yes. The animals surviving to the end of the observation period were sacrificed by oxygen/carbon dioxide procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.

Statistics:

The oral LD50 value of the test substance was ranked within the following ranges: 0-5, 5-50, 50-300 or 300-2000 mg/kg b.w. or as exceeding 2000 mg/kg b.w. The LD50 cut-off value was established based on OECD guideline 423. No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).

Results and discussion

Preliminary study:

not applicable

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

300 mg/kg bw

Based on:

test mat.

Mortality:

At 2000 mg/kg, two females were found dead on Day 1 and one female was found dead on Day 2.
At 300 mg/kg, all animals survived up to scheduled necropsy.

Clinical signs:

At 2000 mg/kg, lethargy, lateral recumbency, hunched posture, slow breathing, general blue discolouration, ptosis, dark eyes and/or piloerection were noted among all animals on Day 1.

At 300 mg/kg, one animal showed piloerection on Day 1, whilst no clinical signs were noted among the other two animals.

Body weight:

The body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.

Gross pathology:

At 2000 mg/kg, many black(-brown) foci in the stomach were noted among all animals. One of these animals showed an advanced stage of autolysis.

At 300 mg/kg, no macroscopic abnormalities were noted.

Other findings:

no additional information provided

Any other information on results incl. tables

no additional information provided

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information harmful if swallowed (Category 4) for acute toxicity by the oral route Criteria used for interpretation of results: OECD GHS

Conclusions:

The oral LD50 value of MMDS in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.

Executive summary:

Assessment of acute oral toxicity with MMDS in the rat (Acute Toxic Class Method).

 

The study was carried out based on the guidelines described in: OECD No.423 (2001) "Acute Oral Toxicity, Acute Toxic Class Method"

Commission Regulation (EC) No 440/2008, B1 tris: "Acute Oral Toxicity, Acute Toxic Class Method" EPA, OPPTS 870.1100 (2002), "Acute Oral Toxicity" JMAFF guidelines (2000) including the most recent partial revisions.

 

Initially, MMDS was administered by oral gavage to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure additional groups of females were dosed at 300 mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).

 

At 2000 mg/kg, two females were found dead on Day 1 and one female was found dead on Day 2.

At 300 mg/kg, all animals survived up to scheduled necropsy.

 

At 2000 mg/kg, lethargy, lateral recumbency, hunched posture, slow breathing, general blue discolouration, ptosis, dark eyes and/or piloerection were noted among all animals on Day 1.

At 300 mg/kg, one animal showed piloerection on Day 1, whilst no clinical signs were noted among the other two animals.

The body weight gain shown by the animals over the study period was considered to be normal.

 

At 2000 mg/kg, many black(-brown) foci in the stomach were noted among all animals. One of these animals showed an advanced stage of autolysis. At 300 mg/kg, no macroscopic abnormalities were noted.

 

The oral LD50value of MMDS in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.

 

According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.

 

Based on these results:

-       according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007), MMDS should be classified as: harmful if swallowed (Category 4) for acute toxicity by the oral route.

-      according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, MMDS should be classified as Category 4 and should be labeled as H302: Harmful if swallowed.