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EC number: 254-751-6 | CAS number: 40018-26-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2005-01-26 to 2005-03-31
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 005
- Report date:
- 2005
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- adopted 21 July, 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- 8 June 2000
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- other: In Vivo Mammalian Micronucleus Test
Test material
- Reference substance name:
- 1,4-dithiane-2,5-diol
- EC Number:
- 254-751-6
- EC Name:
- 1,4-dithiane-2,5-diol
- Cas Number:
- 40018-26-6
- Molecular formula:
- C4H8O2S2
- IUPAC Name:
- 1,4-dithiane-2,5-diol
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- other: Crl:CD-1™(ICR)BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 5-8 weeks
- Weight at study initiation: 20 - 27 g
- Assigned to test groups randomly: yes
- Housing: in groups of up to seven in solid-floor polypropylene cages with wood-flake bedding.
- Diet (e.g. ad libitum): ad libitum (Certified Rat and Mouse Diet Code 5LF2, BCM, IPS Limited, London, UK)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 25
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- - Vehicle(s)/solvent(s) used: Arachis oil
- Justification for choice of solvent/vehicle: required for a suspension at the appropriate concentrations.
- Concentration of test material in vehicle: 25, 30, 40 mg/mL for the range finding toxicity test and 5, 7.5, 15 and 30 mg/mL for the main test
- Amount of vehicle (if gavage or dermal): 10 mL/kg bw - Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: For the purpose of this study the test material was freshly prepared as required as a suspension at the appropriate concentration in arachis oil.
- Duration of treatment / exposure:
- 24 h in the range finding toxicity test
24 h (in one vehicle control and in the 75, 150, 300 and positive control groups) and 48 h (at the dose level of 300 mg/kg bw and in the vehicle control) in the main test - Frequency of treatment:
- single exposure
Doses / concentrationsopen allclose all
- Dose / conc.:
- 75 mg/kg bw/day (nominal)
- Remarks:
- main test
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Remarks:
- main test
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- range finding toxicity test
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- range finding toxicity test and main test
- Dose / conc.:
- 400 mg/kg bw/day (nominal)
- Remarks:
- range finding toxicity test
- No. of animals per sex per dose:
- 2 animals (1 female and 1 male) for 250 mg/kg bw, 2 animals (2 males) for three 300 mg/kg bw groups and 9 male animals for 400 mg/kg bw in the range finding test
7 in the main test - Control animals:
- yes, concurrent vehicle
- Positive control(s):
- cyclophosphamide
- Justification for choice of positive control(s): Cyclophosphamide is a positive control material known to produce micronuclei under the conditions of the test.
- Route of administration: oral gavage
- Doses / concentrations: 50 mg/kg bw / 5 mg/mL
Examinations
- Tissues and cell types examined:
- 2000 premature erythrocytes were evaluated after termination (i.e. 24 or 48 hours following dosing) of the exposure. Both femurs were dissected from each animal, aspirated with foetal calf serum and bone marrow smears prepared following centrifugation and re-suspension. The smears were air-dried, fixed in absolute methanol, stained in May-Grünwald/Giemsa, allowed to air-dry and cover-slipped using mounting medium.
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION: The dose level selected should ideally be the maximum tolerated dose level or that which produces some evidence of toxicity up to a maximum recommended dose of 2000 mg/kg. The range-finding toxicity test was also used to determine if the main test was to be performed using both sexes or males only. It was considered to be unnecessary to investigate either the intraperitoneal route of administration or dose levels above 400 mg/kg based on the results of preliminary tests.
TREATMENT AND SAMPLING TIMES (in addition to information in specific fields): The test material was administered orally to 7 male mice (main study) each group, the animals were observed for 24 or 48 h and then killed by cervical dislocation
DETAILS OF SLIDE PREPARATION: Immediately following termination (i.e. 24 or 48 hours following dosing), both femurs were dissected from each animal, aspirated with foetal calf serum and bone marrow smears prepared following centrifugation and re-suspension. The smears were air-dried, fixed in absolute methanol, stained in May-Griinwald/Giemsa, allowed to air-dry and cover-slipped using mounting medium.
METHOD OF ANALYSIS: Stained bone marrow smears were coded and examined blind using light microscopy at x1000 magnification. The incidence of micronucleated cells per 2000 polychromatic erythrocytes (PCB-blue stained immature cells) per animal was scored. Micronuclei are normally circular in shape, although occasionally they may be oval or half-moon shaped, and have a sharp contour with even staining. In addition, the number of normochromatic erythrocytes (NCE-pink stained mature cells) associated with 1000 erythrocytes was counted; these cells were also scored for incidence of micronuclei. The ratio of polychromatic to normochromatic erythrocytes was calculated together with appropriate group mean values and standard deviations. - Evaluation criteria:
- A comparison was made between the number of micronucleated polychromatic erythrocytes occurring in each of the test material groups and the number occurring in the corresponding vehicle control group.
A positive mutagenic response was demonstrated when a statistically significant, dose-responsive, toxicologically relevant increase in the number of micronucleated polychromatic erythrocytes was observed for either the 24 or 48-hour kill times when compared to their corresponding control group. If these criteria were not fulfilled, then the test material was considered to be non-genotoxic under the conditions of the test.
A positive response for bone marrow toxicity was demonstrated when the dose group mean polychromatic to norrnochromatic ratio was shown to be statistically significantly lower than the concurrent vehicle control group. - Statistics:
- All data were statistically analysed using appropriate statistical methods as recommended by the UKEMS Sub-committee on Guidelines for Mutagenicity Testing Report, Part III (1989). The data was analysed using Student's t-test (two tailed) and any significant results were confirmed using the one-way analysis of variance.
Results and discussion
Test resultsopen allclose all
- Key result
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- yes
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Sex:
- female
- Genotoxicity:
- negative
- Toxicity:
- yes
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
- Dose range: 250, 300 and 400 mg/kg bw
- Clinical signs of toxicity in test animals: Clinical signs were observed at and above 250 mg/kg and included lethargy, ptosis, decreased respiratory rate, hunched posture and ataxia.
- Rationale for exposure: existing toxicology data
RESULTS OF DEFINITIVE STUDY
- Ratio of PCE/NCE (for Micronucleus assay): No increase in micronucleated PCEs observed as compared to the concurrent vehicle control
- Appropriateness of dose levels and route: The dose levels were determined in a preliminary dose range finding test
Any other information on results incl. tables
Table 1: Relative Group Frequency Categories of Micronuclei Per 1000 PCEs
48-Hour Control Group (60 Groups)
Frequency Categories |
Groups |
|
0.0-0.4 |
21
|
35% |
0.5-0.9 |
18
|
30% |
1.0-1.4 |
14 |
23% |
1.5-2.0 |
7
|
12% |
2.1-2.5 |
0 |
0% |
Table 2: Relative Group Frequency Categories of Micronuclei Per 1000 PCEs
24-Hour Control Group (60 Groups)
Frequency Categories |
Groups |
|
0.0-0.4 |
15 |
25% |
0.5-0.9 |
25 |
42% |
1.0-1.4 |
14 |
23% |
1.5-2.0 |
3 |
12% |
2.1-2.5 |
3 |
0% |
Combined 24 and 48-Hour Groups (120 Groups)
Frequency Categories |
Groups |
|
0.0-0.4 |
36 |
30% |
0.5-0.9 |
43 |
36% |
1.0-1.4 |
28 |
23% |
1.5-2.0 |
10 |
8% |
2.1-2.5 |
3 |
3% |
Table 3
Micronucleus Test - Summary of Group Mean Data
|
Treatment Group |
Number of PCE with Micronuclei per 2000 PCE |
PCE/NCE Ratio |
||
Group Mean |
SD |
Group Mean |
SD |
||
l. |
Vehicle Control 10 ml/kg 48-hour Sampling Time |
2.0 |
3.2 |
1.45 |
0.46 |
2. |
Vehicle Control 10 ml/kg 24-hour Sampling Time |
1.3 |
1.0 |
1.32 |
0.36 |
3. |
Positive Control 50 mg/kg 24-hour Sampling Time |
58.4** |
23.5 |
1.32 |
0.39 |
4. |
1 ,4-dithane-2,5-diol 300 mg/kg 48-hour Sampling Time |
3.3 |
2.1 |
0. 89 * |
0.34 |
5. |
1 ,4-dithane-2,5-diol 300 mg/kg 24-hour Sampling Time |
2.0 |
1.5 |
2.21 |
0.49 |
6. |
1 ,4-dithane-2,5-diol 150 mg/kg 24-hour Sampling Time |
1.9 |
1.2 |
1.70 |
0.50 |
7. |
1 ,4-dithane-2,5-diol 75 mg/kg 24-hour Sampling Time |
1.0 |
1.2 |
1.60 |
0.58 |
PCE: Polychromatic erythrocytes
NCE: Normochromatic erythrocytes
SD: Standard deviation
* = p < 0.05
** = p < 0.001
Applicant's summary and conclusion
- Conclusions:
- The present test was conducted according to OECD guideline 474 (adopted 21 July 1997). Each 7 male mice of the Crl:CD-1™(ICR)BR strain were orally administered 50, 75, 150 or 300 mg/kg bw of the test material. After 24h or 48h bone marrow smear was prepared from both femur of each animal. Micronuclei from polychromatic, premature erythrocytes were scored. Based on the obtained results the test substance is considered non-genotoxic under the conditions of the test. Thus, the test item does not need to be classified according to (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS) with respect to genotoxicity.
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