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EC number: 219-154-7 | CAS number: 2374-14-3
- 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:
- 2002
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 2,4,6-trimethyl-2,4,6-tris(3,3,3-trifluoropropyl)cyclotrisiloxane
- EC Number:
- 219-154-7
- EC Name:
- 2,4,6-trimethyl-2,4,6-tris(3,3,3-trifluoropropyl)cyclotrisiloxane
- Cas Number:
- 2374-14-3
- Molecular formula:
- C12H21F9O3Si3
- IUPAC Name:
- 2,4,6-trimethyl-2,4,6-tris(3,3,3-trifluoropropyl)cyclotrisiloxane
- Reference substance name:
- 2, 4, 6-trimethyl-2, 4, 6-tris(3, 3, 3-trifluoropropyl)cyclotrisiloxane
- IUPAC Name:
- 2, 4, 6-trimethyl-2, 4, 6-tris(3, 3, 3-trifluoropropyl)cyclotrisiloxane
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)IGS BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, NC
- Age at study initiation: approximately 7 weeks
- Weight at study initiation: Males 225 - 309g Females 160 - 214g
- Fasting period before study: No
- Housing: individually in wire mesh cages
- Diet: Certified Rodent Lab Diet 5002, PMI Nutrition Inc., ad libitum except overnight prior to blood collection
- Water: Reverse osmosis treated on-site drinking water ad libitum
- Acclimation period: 15 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.1 - 22.7
- Humidity (%): 33.3 - 68.1
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: To: 24 October 2000 to 25 January 2001
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: sesame oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: prepared weekly by weighing appropriate amount of test article and adding sufficient vehicle
VEHICLE
- Concentration in vehicle: 0, 0.4, 2, 10, 25/17.5 mg/mL
- Amount of vehicle: 2mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity and stability established before start of study.
Weekly for first 4 weeks then monthly analysis of formulations for test article concentration during the study - Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- 5 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.8 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 4 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 20 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 35 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 20 per sex in Control and high dose (50/35 mg/kg/day) groups
10 per sex in intermediate dose groups - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: not stated
Initial high dose of 50 mg/kg/day not tolerated and reduced to 35 mg/kg/day from Day 5.
- Post-exposure recovery period in satellite groups: 28-day recovery period initially included but due to excessive mortality at high dose, no recovery period conducted.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-dose and Week 12
- Dose groups that were examined: All
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 4 and 13
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table No. 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 4 and 13
- Animals fasted: Yes / No / No data
- How many animals: all
- Parameters checked in table No. 2 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Week 12
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity ( see table No. 3)
LOCOMOTOR ACTIVITY: Yes
- Time schedule for examinations: Week 12
- Dose groups that were examined: all
- Parameters: ambulatory and total motor activity
OTHER:
BODY TEMPERATURES: recorded from 5 animals/sex/group approx 1 hour after dosing during first 2 weeks of treatment. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 3)
ORGAN WEIGHT : Yes (see table 3)
HISTOPATHOLOGY: Yes (see table 3) - Statistics:
- All analyses were two-tailed for significance levels of 5% and 1%. Body weights, body weight changes, food consumption, clinical pathology values and organ weights were subjected to a one-way analysis of variance (ANOVA) followed by Dunnett's Test if the ANOVA revealed statistical significance (p<0.05). Continuous Functional Observational Battery (FOB) and Locomotor Activity data were analysed using one-way ANOVA. If significant effects were observed at a given timepoint, Dunnett's test was conducted to determine significant treatment differences from the control group. Discontinuous (ordinal or descriptive) FOB data were analysed using Fisher's Exact test to determine significant treatment differences from the control group.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Test-article related clinical signs were noted at 50/35 and 20 mg/kg/day and primarily included ataxia, impaired use of hindlimbs, hindlimb tremors, walking on metatarsus, increased salivation and red or yellow material on body surfaces. Other clinical signs noted during the study included prostration, head bobbing, body cool to touch, shallow respiration, lethargy and piloerection.
During detailed clinical observations slight to total impaired mobility was observed at 50/35 mg/kg/day generally throughout the study. Abnormal gait was also noted and included ataxia, dragging hindlimbs, walking on metatarsus and hunched gait.
Mean body temperature was lower for 50/35 mg/kg/day females on Day 2. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Twenty-two animals were found dead or killed due to poor clinical condition during the study. One male and 3 females were found dead or killed following administration of 50 mg/kg/day. After reduction in the dose to 35 mg/kg/day, 7 males and 7 females were killed or found dead. At 20 mg/kg/day 1 female was found dead and 1 killed. The majority of animals died during the first 5 weeks of dosing and the deaths were considered test-article related. Two control males were also found dead in weeks 4 and 5 respectively.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean body weight and body weight gain were lower than control for 50/35 mg/kg/day animals and 20 mg/kg/day males generally throughout the study. Overall weight gain was up to 16% lower than control during the dosing period.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Mean food consumption was lower than control for the 50/35 mg/kg/day group generally throughout the study.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No effect of treatment.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No effect of treatment.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Test-article related increases in urea nitrogen were noted at 50/35 and 20 mg/kg/day at weeks 4 (males only) and 13 (males and females). Mean phosphorus levels were increased for 20 mg/kg/day males and 50/35 mg/kg/day animals at both evaluations during the study. Mean potassium levels were increased for 20 mg/kg/day and 50/35 mg/kg/day males during the study and for 50/35 mg/kg/day females in Week 13. Mean cholesterol was lower in 50/35 mg/kg/day males at Week 13.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- When evaluating results it should be noted that many of the high dose animals with the most severe hindlimb effects did not survive until the evaluation in week 12.
There were no test-article effects on home cage observations.
An increased number of animals at 50/35 mg/kg/day were noted to have hard and tense muscle tone during the handling observations.
Slightly impaired mobility and abnormal gait was noted for 50/35 mg/kg/day females during the open field observations.
There were no test-article effects on sensory observations.
One female at 50/35 mg/kg/day was noted with exceptionally low hindlimb grip strength during the neuromuscular observations.
There were no remarkable differences apparent between control and treated groups for physiological parameters.
When evaluating results, it should be noted that many of the high dose animals with the most severe hindlimb effects did not survive until the evaluation in week 12.
Overall no remarkable differences between control and treated animals, one female at 50/35 mg/kg/day was noted with the lowest combined motor activity counts. - Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased mean absolute and relative (to final body weight and brain weight) liver weights were noted at 20 and 50/35 mg/kg/day. Lower seminal vesicle (absolute and relative) weights were also noted for males in these groups and lower prostate (absolute and relative) weights were noted in 50/35 mg/kg/day males.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No findings related to treatment.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Test-article related microscopic changes were noted in the liver, skeletal muscle and heart and were generally comparable between decedent animals and those surviving to scheduled necropsy.
In the liver, periportal vacuolar change (hepatocytes enlarged by a variably distinct micro- to macro vacuolated cytoplasm) was noted with dose-related incidence in all treated groups. In the absence of correlating clinical chemistry findings, these hepatic changes was considered not to be adverse.
In the skeletal muscle (rectus femoris), minimal to moderate degeneration (hyaline and basophilic cytoplasm, shape and size variations of myocytes, loss of cross striations and increased cellularity) was noted in the 20 and 50/35 mg/kg/day groups.
In the heart, treatment-related or treatment-exacerbated subacute (accumulations of mononuclear cells, primarily macrophages within and surrounding degenerative myocytes) or chronic (mononuclear inflammatory cells and/or fibroplasia and scattered degeneration and necrosis of myocytes) myopathy was noted in 4, 20 and 50/35 mg/kg/day groups. This finding was morphologically similar to spontaneously developing cardiomyopathy typically seen in older rats, however, it was considered to be test-article related in this case. - Histopathological findings: neoplastic:
- no effects observed
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 0.8 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 4 mg/kg bw/day (actual dose received)
- System:
- other: gastrointestinal; cardiovascular; musculoskeletal
- Organ:
- heart
- liver
- other: skeletal muscle
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
Any other information on results incl. tables
Table 1 - survival
Dose |
Control |
0.8 |
4 |
20 |
50/35 |
Males |
|||||
Number in group |
20 |
10 |
10 |
10 |
20 |
Found dead |
2 |
0 |
0 |
0 |
4 |
Killed |
0 |
0 |
0 |
0 |
4 |
Survived until scheduled termination |
18 |
10 |
10 |
10 |
12 |
Females |
|||||
Number in group |
20 |
10 |
10 |
10 |
20 |
Found dead |
0 |
0 |
0 |
1 |
4 |
Killed |
0 |
0 |
0 |
1 |
6 |
Survived until scheduled termination |
20 |
10 |
10 |
8 |
10 |
Applicant's summary and conclusion
- Conclusions:
- Oral administration of 2,4,6-trimethyl-2,4,6-tris(3,3,3-trifluoropropyl)cyclotrisiloxane to rats at 0.8, 4, 20 or 50/35 mg/kg/day for 13 weeks was not tolerated at the highest dose and resulted in a number of mortalities, 2 animals also died at 20 mg/kg/day. Pathological changes were noted in the liver, heart and skeletal muscle and several clinical findings were noted consistent with the skeletal muscle toxicity. Generally, effects were primarily noted at 20 or 50 mg/kg/day and also included body weight, food consumption, clinical chemistry and organ weight effects.
Based on mortality at 20 or 50/35 mg/kg/day, clinical signs, body weight, food consumption, clinical chemistry, FOB and organ weight effects at 20 and/or 50/35 mg/kg/day and pathology findings in the skeletal muscle and heart at 4, 20 or 50/35 mg/kg/day, the NOAEL was considered to be 0.8 mg/kg/day.
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