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EC number: 204-783-1 | CAS number: 126-33-0
- 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 14 Feb 2001 to 10 Aug 2001
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 001
- Report date:
- 2001
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 1998
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Tetrahydrothiophene 1,1-dioxide
- EC Number:
- 204-783-1
- EC Name:
- Tetrahydrothiophene 1,1-dioxide
- Cas Number:
- 126-33-0
- Molecular formula:
- C4H8O2S
- IUPAC Name:
- 1λ⁶-thiolane-1,1-dione
- Test material form:
- liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: CD
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, England
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: 26-30 days on arrival and 39-43 days of age when study commenced.
- Weight at study initiation: 167-215 g (males) and 142-180 g (females)
- Fasting period before study: none
- Housing: 5 per sex in a stainless steel cages.
- Diet (e.g. ad libitum): The animals were allowed free access, except overnight before routine blood sampling, to an expanded rodent diet.
- Water (e.g. ad libitum): water from public supply, as libitum
- Acclimation period: 13 days
DETAILS OF FOOD AND WATER QUALITY: Each batch of diet was routinely analysed by the supplier for various nutritional components and chemical and microbiological contaminants. Supplier's analytical certificates were scrutinised and approved before any batch of diet was released for use. The quality of the water supply is governed by regulations published by the Department of the Environment. Certificates of analysis were routinely received from the supplier.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C
- Humidity (%): 55%
- Air changes (per hr): 15 per hour
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was prepared as a series of graded concentrations in tap water. Each formulation was prepared by dissolving an appropriate amount of Sulfolane with a small volume of vehicle and stirring by hand until a solution formed. Once the material was fully dissolved it was made up to the required final volume and mixed using a magnetic stirrer. Formulations were prepared weekly.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Water was used as vehicle.- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Before treatment commenced, the suitability of the proposed mixing procedure was determined by a trial preparation performed at the lowest highest concentrations (25 and 1600 mg/L). The stability of Sulfolane in the vehicle was assessed for storage at ambient temperature (nominally 21 DC) for 4 and 8 days and in a refrigerator (nominally 40C) for 4, 8 15 days. Analysis at ambient temperature for 15 days was scheduled to be carried out but this was not perforned in error. This deviation did not affect the integrity of the study. In addition, samples of each formulation prepared for administration in Weeks l, 6 and 12 of treatment were analysed for achieved concentration.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily, continuous
Doses / concentrationsopen allclose all
- Dose / conc.:
- 25 mg/L drinking water
- Dose / conc.:
- 100 mg/L drinking water
- Dose / conc.:
- 400 mg/L drinking water
- Dose / conc.:
- 1 600 mg/L drinking water
- Dose / conc.:
- 2.1 mg/kg bw/day (actual dose received)
- Remarks:
- males: equivalent to 25 mg/L
- Dose / conc.:
- 8.8 mg/kg bw/day (actual dose received)
- Remarks:
- males: equivalent to 100 mg/L
- Dose / conc.:
- 35 mg/kg bw/day (actual dose received)
- Remarks:
- males: equivalent to 400 mg/L
- Dose / conc.:
- 131.7 mg/kg bw/day (actual dose received)
- Remarks:
- males: equivalent to 1600 mg/L
- Dose / conc.:
- 2.9 mg/kg bw/day (actual dose received)
- Remarks:
- females: equivalent to 25 mg/L
- Dose / conc.:
- 10.6 mg/kg bw/day (actual dose received)
- Remarks:
- females: equivalent to 100 mg/L
- Dose / conc.:
- 42 mg/kg bw/day (actual dose received)
- Remarks:
- females: equivalent to 400 mg/L
- Dose / conc.:
- 191.1 mg/kg bw/day (actual dose received)
- Remarks:
- females: equivalent to 1600 mg/L
- No. of animals per sex per dose:
- 10 males and 10 females per group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: not selected
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): random - Positive control:
- Not used
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked included: sings of ill health
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a week a more detailed physical examination was performed.
BODY WEIGHT: Yes
- Time schedule for examinations: The bodyweight of each animal was recorded during the acclimatisation period, on the day that treatment commenced (Week O), at weekly intervals during the treatment period and before necropsy.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- The weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded for each week throughout the treatment period. From these records the mean weekly consumption per animal was calculated for each cage.
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: Yes. Group mean food conversion efficiencies were calculated for each week of treatment.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: The amount of water supplied to each cage and that remaining recorded for each week throughout the treatment period. From these records the mean weekly consumption per animal was calculated for each cage.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Before commencement of treatment both eyes of all animals were examined by means of an indirect ophthalmoscope, after the instillation of 0.5% tropicamide. The structures exarnined included the following: adnexa, conjunctivae, cornea and sclera, anterior chamber and iris (pupil dilated), lens and vitreous, ocular fundus. During Week 13 of treatment, all animals from Groups 1 and 5 were similarly examined.
- Dose groups that were examined: All animals
HAEMATOLOGY: Yes
- Time schedule for collection of blood: During week 13 of treatment.
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes, overnight
- How many animals: all animals
- Parameters checked in table [No.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: During week 13 of treatment.
- Animals fasted: Yes, overnight
- How many animals: all animals
- Parameters checked in table [No.1] were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Animals were examined before treatment and on a weekly basis thereafter.
- Dose groups that were examined: all animals
- Battery of functions tested: sensory activity, grip strength, motor activity, startle reflex, pupil reflex, touch response, approach response, body temperature, body weight, landing footsplay, tail pinch response, tighting reflex
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table No 2)
HISTOPATHOLOGY: Yes (see table No 2) - Statistics:
- The significance of inter-group differences in hematology and blood chemistry was first assessed by Bartlett's test. Using tests dependent on the outcome of Bartlett's test, treated groups were then compared with the Control group, incorporating adjustment for multiple comparisons where necessary.
For organ weights and bodyweight changes, homogeneity of variance was tested using Bartlett's test. Whenever this was found to be statistically significant a Behrens-Fisher test was used to perform pairwise comparisons, otherwise a Dunnett's test was used. Inter-group differences in macroscopic and microscopic pathology were assessed using Fishers Exact test. Unless stated, group mean values or incidences for the treated groups were not significantly different
from those of the Controls (p>0.05).
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs related to treatment were observed.
- Mortality:
- no mortality observed
- Description (incidence):
- No animals died during the treatment.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Bodyweight gain in the first week of treatment was lower in high dose (1600 mg/L) animals than the control group. Bodyweight gain thereafter was unaffected, resulting in similar overall bodyweight gain. Bodyweight gain in the rest of the groups was unaffected.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption was not affected in any of the treatment groups.
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- Food conversion efficiency was slightly low, compared with Controls, during Week I in animals receiving 1600 mg/L. Thereafter food conversion efficiency was unaffected in these animals resulting in similar overall food conversion efficiency.
Food conversion efficiency in animals receiving 25, 100 or 400 mg/L was not affected by treatment. - Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- Water consumption was unaffected.
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects observed in any of the animals.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Haematological examination in Week 13 revealed low lymphocyte, monocyte and large unstained cell counts, compared with the controls, in females receiving 100, 400 or 1600 mg/L, resulting in a concomitant reduction in the total white blood cell count in these animals. Though the effect was greatest in females receiving 1600 mg/L, overall there was no strong trend with administered concentration of Sulfolane. There was no similar finding in males. There was no evidence of any chronic inflammatory change or of compromised immune function in females, or any effect upon bone marrow, thymus or spleen that would account for the reduced numbers of these leucocytes. Other inter-group differences that attained statistical significance were considered minor or lacked dosage relationship and so were considered to represent normal biological variation. Such differences included the slightly prolonged prothrombin times in males receiving 1600 mg/L, slightly high mean cell volumes and reduced activated partial thromboplastin times in females receiving 1600 mg/L, slightly low basophil counts in females receiving 100 mg/L and in animals receiving 400 or 1600 mg/L and slightly low large unstained cell counts in males receiving 400 or 1600 mg/L which was attributed to high values in two control animals.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Biochemical examination of the plasma in Week 13 revealed, compared with the Controls, slightly low alanine amino-transferase activities and slightly high creatinine concentrations in males receiving 1600 mg/L. The cause of the slight reduction of plasma alanine amino-transferase activities in males receiving 1600 mg/L was not established in this study. Toxicological significance is usually associated with increased plasma alanine amino-transferase activities and therefore this finding is not considered biologically significant.
Other inter-group differences that attained statistical significance such as the variations in sodium concentrations were minor or lacked dosage relationship and so were considered to represent normal biological variation. Such changes included, in males receiving 1600 mg/L, low aspartate amino-transferase activities, which was attributed to a raised mean value for the controls due to unusually high values in two animals and reduced sodium concentration which was attributed to a markedly low value in one animal. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No treatment-related changed in the in hand observations. Salivation was observed throughout the treatment in all dose groups, including control group. Behaviour in the arena was unaffected by treatment. No treatment-related effects were noted during manipulation. No treatment-related changes in motor activity was noticed in any of the animals.
- 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 organ weights in any of the animals.
Absolute and bodyweight relative uterus weights were higher than Controls in females receiving 100 or 1600 mg/L; however these changes were considered to represent the slightly increased incidence of uterine fluid distension, due to the stage of oestrus in some of these animals. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related macroscopic changes were noted in any of the animals.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- The only findings considered related to treatment were seen in the kidneys of males given Sulfolane at 400 mg/L or above. There was an increase in the incidence and severity of cortical tubules with hyaline droplets, compared with controls, in males receiving 400 or 1600 mg/L. This is related to the toxicological syndrome known as "hydrocarbon nephropathy" which results from an accumulation of alpha-2µ-globulin in the cortical tubules of affected kidneys. This finding is specific to the male rat and is therefore of no toxicological significance to man. There was an increase in the incidence and severity of cortical tubular basophilia in males receiving 1600 mg/L. The incidence of granular casts of the medulla was slightly high in males receiving 1600 mg/L.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 100 mg/L drinking water
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other: equivalent to 8.8 mg/kg bw/day
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 25 mg/L drinking water
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- haematology
- Remarks on result:
- other: equivalent to 2.9 mg/kg bw/day
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 100 mg/L drinking water
- System:
- immune system
- Organ:
- other: reduction in immunological parameters
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
See attachment for result tables.
Applicant's summary and conclusion
- Conclusions:
- In the 90-day repeated dose oral toxicity study with Sulfolane, conducted according to the appropriate OECD 408 Test Guideline and in compliane with GLP, it was concluded the NOEL level for females and males to be 25 mg/L and 100 mg/L, respectively. The overall NOAEL is 2.9 mg/kg bw/day based on reduced immunological parameters in females.
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