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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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2004-06-29 to 2005-01-24
- 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 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- adopted 27 July 1995
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- 30 May 2008
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
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:
- rat
- Strain:
- other: Crl: CD® (SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 5-7 weeks
- Weight at study initiation: 126-164 g (males); 123-151 g (females)
- Housing: in groups of five by sex in polypropylene grid-floor cages suspended over trays lined with absorbent paper
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days
DETAILS OF FOOD AND WATER QUALITY: The diet and drinking water were considered not to contain any contaminant at a level that might have affected the purpose or integrity of the study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- arachis oil
- Remarks:
- BP
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: For the purpose of this study the test material was prepared at the appropriate concentrations as a solution in dried Arachis oil BP. After extensive method development it was found that only the high dose level could be analysed due to interference from the vehicle at lower levels. The formulations were found to be stable for at least four weeks. They were therefore prepared weekly and stored at approximately +4ºC in the dark.
VEHICLE
- Justification for use and choice of vehicle (if other than water): The vehicle was found appropriate to obtain an applicable solution with the described concentrations.
- Concentration in vehicle: 0, 1.25, 3.75, 12.5 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration of the test item in the test material formulations was determined by high performance liquid chromatography mass selective detection (HPLC/MSD) using an external standard technique. After extensive method development it was found that only the high dose level could be analysed due to interference from the vehicle.
The test material formulations were extracted with acetonitrile to give a final, theoretical test material concentration of approximately 5 mg/L.
Standard solutions of test material were prepared in acetonitrile at a nominal concentration of 5 mg/L.
The standard and sample solutions were analysed by HPLC. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 5 mg/kg bw/day (nominal)
- Remarks:
- the sample results have not been corrected for recovery, because 99% of the nominal concentration was found after HPLC analysis
- Dose / conc.:
- 15 mg/kg bw/day (nominal)
- Remarks:
- the sample results have not been corrected for recovery, because 99% of the nominal concentration was found after HPLC analysis
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- the sample results have not been corrected for recovery, because 99% of the nominal concentration was found after HPLC analysis
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on results from a preliminary study
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: before dosing, one hour after and 5 hours after dosing during working week and before dosing and one hour after dosing at weekends and on public holidays
BODY WEIGHT: Yes
- Time schedule for examinations: body weights were recorded on Day 0 (the day before the start of treatment) and on Days 7, 14, 21 and 28. Bodyweights were also recorded at terminal kill.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Food consumption was recorded for each cage group at weekly intervals throughout the study.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION : Yes
- Time schedule for examinations: Water intake was observed daily, for each cage group, by visual inspection of the water bottles for any overt changes.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on Day 28
- Anaesthetic used for blood collection: Not specified
- Animals fasted: No
- How many animals: all animals
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on Day 28
- Animals fasted: No
- How many animals: all animals
- Parameters checked in table [No.1] were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Prior to the start of treatment and on Days 3, 10, 17 and 24 all animals were observed for signs of functional/behavioural toxicity.
- Dose groups that were examined: all animals
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
Gait, Hyper/Hypothermia, Tremors ,Skin colour, Twitches, Respiration, Convulsions, Palpebral closure, Bizarre/Abnormal/Stereotypic behaviour, Urination, Salivation, Defecation, Pilo-erection, Transfer arousal, Exophthalmia, Tail elevation, Lachrymation, Motor activity, For/Hindlimb Grip Strength,
Sensory Reactivity: Grasp response, Touch escape, Vocalisation, Pupil reflex, Toe pinch, Blink reflex, Tail pinch, Startle reflex, Finger approach
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see tables 2 & 3) - Statistics:
- Haematological, blood chemical, organ weight (absolute and relative to terminal bodyweight), weekly bodyweight gain and quantitative functional performance and sensory reactivity data were assessed for dose response relationships by linear regression analysis, followed by one way analysis of variance (ANOVA) incorporating Levene’s test for homogeneity of variance. Where variances were shown to be homogenous, pairwise comparisons were conducted using Dunnett’s test. Where Levene’s test showed unequal variances the data were analysed using non-parametric methods: Kruskal-Wallis ANOVA and Mann-Whitney ‘U’ test.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Animals of either sex treated with 50 mg/kg/day showed increased salivation up to ten minutes after dosing from Day 10 onwards. Males from this treatment group showed prolonged incidents of salivation, up to one and five hours after dosing on Days 22 and 24 respectively. One female treated with 15 mg/kg/day developed a bulging left eye on Day 23, which continued until Day 28. This is a slight physical injury and of no toxicological significance. No such effects were detected in animals of either sex treated with 15 or 5 mg/kg/day.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No adverse effect on bodyweight development was detected.
Females treated with 50 or 5 mg/kg/day showed a statistically significant reduction in bodyweight gain during week 2 of the study. The dose response was unconvincing and, in isolation, the intergroup difference were considered to be without toxicological importance. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No adverse effect on dietary intake was detected. Food efficiency (the ratio of bodyweight gain to dietary intake) in test animals was similar to that of controls.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- Daily visual inspection of water bottles revealed no intergroup differences.
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- There were no adverse effects detected in the haematological parameters measured.
Statistical analysis of the data revealed no significant intergroup differences. - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- There were no adverse effects detected in the blood chemical parameters measured.
Females treated with 50, 15 or 5 mg/kg/day showed a statistically significant reduction in total plasma protein and plasma urea when compared to controls. All individual values were within the normal ranges for rats of the strain and age used and the intergroup differences were considered to be of no toxicological importance. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- There were no treatment-related changes in the functional performance parameters measured.
Statistical analysis of the data revealed no significant intergroup differences.
All inter and intra group differences in sensory reactivity scores were considered to be a result of normal variation for rats of the strain and age used, and were of no toxicological importance. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related changes in the organ weights measured.
Females treated with 50 mg/kg/day showed a statistically significant increase in adrenal weight relative to bodyweight. In the absence of histopathological correlates this minimal (p<0.05) increase was considered to be fortuitous and of no toxicological importance. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related macroscopic abnormalities were detected.
One male treated with 50 mg/kg/day showed red lungs. In the absence of any histopathological correlates, this was considered incidental and of no toxicological importance. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- STOMACH: Agglomeration of gastric secretion with associated mucosal atrophy and erosion were seen as an effect of treatment for animals of either sex treated with 50 mg/kg/day. Agglomeration of secretion was also seen for two males and for one female treated with 15 mg/kg/day and although this condition is occasionally encountered among control rats as a spontaneous entity, the possibility of a relationship to treatment in this instance cannot be excluded. All remaining morphological changes were those commonly observed in laboratory maintained rats of the age and strain employed, and there were no differences in incidence or severity between control and treatment groups that were considered to be of toxicological significance.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 15 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- stomach
- Treatment related:
- yes
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 2: Summary Incidence of Histopathological Findings - Males
Histopathological Finding |
Dose Level (mg/kg bw/day) |
|||
0 |
5 |
15 |
50 |
|
Number of animals examined at terminal kill |
5 |
5 |
5 |
5 |
Bone marrow |
||||
Adipose infiltration |
|
|
|
|
no data |
0 |
5 |
5 |
0 |
(minimal) |
4 |
0 |
0 |
5 |
(slight) |
1 |
0 |
0 |
0 |
Heart |
||||
Focal myocarditis |
||||
no data |
0 |
5 |
5 |
0 |
absent |
2 |
0 |
0 |
2 |
(minimal) |
3 |
0 |
0 |
3 |
Pericarditis |
|
|
|
|
no data |
0 |
5 |
5 |
0 |
absent |
4 |
0 |
0 |
5 |
present |
1 |
0 |
0 |
0 |
Kidneys |
||||
Groups of basophilic tubules |
||||
no data |
0 |
5 |
5 |
0 |
absent |
3 |
0 |
0 |
2 |
(minimal) |
2 |
0 |
0 |
3 |
Hydronephrosis |
||||
no data |
0 |
5 |
5 |
0 |
absent |
4 |
0 |
0 |
5 |
(minimal) |
1 |
0 |
0 |
0 |
Liver |
||||
Mononuclear cell foci |
||||
no data |
0 |
5 |
5 |
0 |
absent |
1 |
0 |
0 |
0 |
(minimal) |
4 |
0 |
0 |
4 |
(slight) |
0 |
0 |
0 |
1 |
Lungs |
||||
Perivascuolar/Peribronchiolar |
||||
lymphoid aggregations |
|
|
|
|
no data |
0 |
5 |
5 |
0 |
absent |
1 |
0 |
0 |
0 |
(minimal) |
4 |
0 |
0 |
5 |
Spleen |
||||
Extramedullary haemopoiesis |
||||
no data |
0 |
5 |
5 |
0 |
(minimal) |
5 |
0 |
0 |
4 |
(slight) |
0 |
0 |
0 |
1 |
Stomach |
||||
Agglomeration secretion gastric mucosa |
||||
absent |
5 |
5 |
3 |
0 |
(minimal) |
0 |
0 |
2 |
4 |
(slight) |
0 |
0 |
0 |
1 |
Mucosal atrophy/erosion |
||||
absent |
5 |
5 |
5 |
2 |
(minimal) |
0 |
0 |
2 |
4 |
(slight) |
0 |
0 |
0 |
1 |
Thyroids |
||||
Follicular cell hypertrophy |
||||
no data |
0 |
5 |
5 |
0 |
absent |
4 |
0 |
0 |
4 |
(minimal) |
1 |
0 |
0 |
1 |
Urinary Bladder |
||||
Epithelial hyperplasia |
||||
no data |
0 |
5 |
5 |
0 |
absent |
5 |
0 |
0 |
4 |
(minimal) |
0 |
0 |
0 |
1 |
Statistical information |
||||
Mode of death |
||||
Terminal kill |
5 |
5 |
5 |
5 |
Table 3:
Summary Incidence of Histopathological Findings - Females
Histopathological Finding |
Dose Level (mg/kg bw/day) |
|||
0 |
5 |
15 |
50 |
|
Number of animals examined at terminal kill |
5 |
5 |
5 |
5 |
Bone marrow |
||||
Adipose infiltration |
||||
no data |
0 |
5 |
5 |
0 |
(minimal) |
5 |
0 |
0 |
4 |
(slight) |
0 |
0 |
0 |
1 |
Heart |
||||
Focal myocarditis |
||||
no data |
0 |
5 |
5 |
0 |
absent |
4 |
0 |
0 |
5 |
(minimal) |
1 |
0 |
0 |
0 |
Kidneys |
||||
Groups of basophilic tubules |
||||
no data |
0 |
5 |
5 |
0 |
absent |
4 |
0 |
0 |
3 |
(minimal) |
1 |
0 |
0 |
2 |
Corticomedullary mineralisation |
||||
no data |
0 |
5 |
5 |
0 |
absent |
2 |
0 |
0 |
4 |
(minimal) |
3 |
0 |
0 |
1 |
Liver |
||||
Mononuclear cell foci |
||||
no data |
0 |
5 |
5 |
0 |
(minimal) |
5 |
0 |
0 |
5 |
Periportal lipid vacuolation |
||||
no data |
0 |
5 |
5 |
0 |
absent |
3 |
0 |
0 |
5 |
(minimal) |
2 |
0 |
0 |
0 |
Lungs |
||||
Perivascuolar/Peribronchiolar lymphoid aggregations |
||||
no data |
0 |
5 |
5 |
0 |
absent |
|
|
|
|
(minimal) |
5 |
0 |
0 |
5 |
Spleen |
||||
Extramedullary haemopoiesis |
||||
no data |
0 |
5 |
5 |
0 |
(minimal) |
5 |
0 |
0 |
5 |
Stomach |
||||
Agglomeration secretion gastric mucosa |
||||
absent |
5 |
5 |
4 |
1 |
(minimal) |
0 |
0 |
1 |
2 |
(slight) |
0 |
0 |
0 |
2 |
Mucosal atrophy/erosion |
||||
absent |
5 |
5 |
5 |
1 |
(minimal) |
0 |
0 |
1 |
2 |
(slight) |
0 |
0 |
0 |
2 |
Urinary Bladder |
||||
Epithelial hyperplasia |
||||
no data |
0 |
5 |
5 |
0 |
absent |
5 |
0 |
0 |
4 |
(minimal) |
0 |
0 |
0 |
1 |
Uterus/Cervix |
||||
Dilatation horn1 |
||||
no data |
0 |
5 |
5 |
0 |
absent |
5 |
0 |
0 |
4 |
(slight) |
0 |
0 |
0 |
1 |
Dilatation horn2 |
||||
no data |
0 |
5 |
5 |
0 |
absent |
5 |
0 |
0 |
4 |
(minimal) |
0 |
0 |
0 |
1 |
Applicant's summary and conclusion
- Conclusions:
- In the present study conducted according to OECD guideline 407 (adopted 27 July 1995), 5 female and 5 male Sprague-Dawley rats per group were daily administered 0, 5, 15 or 50 mg/kg bw of the test substance for an experimental time of 28 days. No Mortality occurred during the experimental time, clinical signs observed were mainly salivation. Histopathological examinations at the end of the study revealed an agglomeration of gastric secretion with associated mucosal atrophy and erosion in the high dose group and in the mid dose group. The possibility of a relationship to treatment in this instance could not be excluded. Based on the obtained results the NOAEL of the test substance was established to be 5 mg/kg bw/day.
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