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EC number: 213-668-5 | CAS number: 999-97-3
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 17 April 2013 to 19 November 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Study was conducted according to an appropriate guideline and in compliance with GLP
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2014
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1998
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Hydroxytrimethylsilane
- EC Number:
- 213-914-1
- EC Name:
- Hydroxytrimethylsilane
- Cas Number:
- 1066-40-6
- Molecular formula:
- C3H10OSi
- IUPAC Name:
- Trimethylsilanol
- Test material form:
- other: liquid
- Details on test material:
- - Name of test material (as cited in study report): Trimethylsilanol
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD IGS
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Germany
- Age at study initiation: 12 weeks
- Weight at study initiation: 230 to 316g
- Fasting period before study: no
- Housing: In groups of three to five animals in Makrolon type-4 cages with wire mesh tops up to the day of mating and afterwards individually in Makrolon type-3 cages with wire mesh tops with sterilized standard softwood bedding (‘Lignocel’) with paper enrichment (ISO-BLOX).
- Diet (ad libitum): Pelleted standard Harlan Teklad 2018C
- Water (ad libitum): community tap water
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.2 - 23.5
- Humidity (%): 27.2 - 70.3
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 22 April 2013 To: 23 May 2013
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Trimethylsilanol was weighed into a glass beaker on a tared precision balance and the vehicle (corn oil) was added. Using an appropriate homogenizer, a homogeneous suspension was pre-pared. Separate formulations were prepared for each concentration
Dose formulations were devided into daily aliquots.
Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
VEHICLE
- Concentration in vehicle: 0, 10, 30, 90 mg/mL
- Amount of vehicle: 5 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- On the first treatment day samples from the control group as well as three samples (top, middle and bottom) of about 1 g of each concentration were taken prior to dosing for analysis of concentration and homogeneity. Samples of about 1 g of each concentration were taken from the middle only to confirm the stability (4 hrs at room temperature and 8 days in refrigerator). During the last week of the treatment, samples were taken from the middle to confirm concentration. The aliquots for analysis of dose formulations were frozen (-20 ± 5 °C) and delivered on dry ice to the person responsible for formulation analysis and stored there at -20 ± 5 °C until analysis.
The samples were analyzed by Headspace GC-Method The test item was used as the analytical standard.
Duplicates were taken of all samples and were stored. - Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Length of cohabitation: until evidence of copulation observed
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 post coitum
- Any other deviations from standard protocol: no - Duration of treatment / exposure:
- Day 6 to Day 20 post coitum
- Frequency of treatment:
- daily
- Duration of test:
- 21 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Group 1 - Control Group
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Remarks:
- Group 2
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Remarks:
- Group 3
- Dose / conc.:
- 450 mg/kg bw/day (actual dose received)
- Remarks:
- Group 4
- No. of animals per sex per dose:
- 22 female
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected based on a previous dose range-finding toxicity study in Sprague Dawley rats using dose levels of 0, 50, 150 and 600/400 mg/kg bw/day.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 3 times daily during treatment
BODY WEIGHT: Yes
- Time schedule for examinations: daily
FOOD CONSUMPTION: Yes
- Time schedule for examinations: recoreded at 3-day intervals, days 0-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post coitum
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
WATER CONSUMPTION: No
- Time schedule for examinations:
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- liver weight recorded - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter - Statistics:
- The following statistical methods were used to analyze food consumption, body weights, reproduction and skeletal examination data:
• Means and standard deviations of various data were calculated and included in the report.
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Fisher's exact-test was applied if the variables could be dichotomized without loss of information. - Historical control data:
- Data from test facility derived during 1992 to 2005 included
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical signs such as uncoordinated movement, decreased activity and/or prostrate appearance and/or ruffled fur occurred after dosing the animals with dose levels of 150 and/or 450 mg/kg bw/day during the treatment period. These were considered to be related to the treatment with the test item. Due to the full recovery of the animals, slight severity grade and frequency at 150 mg/kg bw/day, this dose level was considered to cause treatment-related but not adverse effects in pregnant rats. Due to the nature, frequency and severity of the findings and the observation that one animal did not fully recover from the symptoms, the dose level of 450 mg/kg bw/day was considered to cause treatment-related and adverse effects in pregnant rats.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- All females survived until the scheduled necropsy.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 450 and 150 mg/kg bw/day, mean absolute body weight and body weight gain were decreased statistically significantly and were considered to be related to the treatment with the test item. At 450 mg/kg bw/day, the corrected body weight gain was also affected by treatment with the test item.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- At 450 and 150 mg/kg bw/day, test item-related statistically significant decreases were observed for mean food consumption.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- Uncoordinated movement, decreased activity with dose levels of 150 and/or 450 mg/kg bw/day during the treatment period. These were considered to be related to the treatment with the test item.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No effects on liver weights were noted.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No findings were observed at any dose level during macroscopical examination.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The relevant reproduction data (pre-and post-implantation loss and number of fetuses per dam) were not affected by treatment with the test item.
Mean numbers of corpora lutea and implantation sites were similar across all groups. - Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- not specified
- Details on maternal toxic effects:
- Statistically significantly decreased mean food consumption, body weight, body weight gain and corrected body weight gain were affected by the treatment with the test
item and were considered to be adverse maternal toxic effects.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Maternal General Toxicity
- Effect level:
- ca. 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 450 mg/kg bw/day, there were statistically significantly decreased fetal body weights both on litter and individual basis and this was related to the treatment with the test item.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- No test item-related effects on the sex ratio of the fetuses were noted in any group.
- Changes in litter size and weights:
- effects observed, treatment-related
- Description (incidence and severity):
- At 450 mg/kg bw/day, there were statistically significantly decreased fetal body weights both on litter and individual basis and this was related to the treatment with the test item.
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- No test item-related findings were noted during skeletal examination of the fetuses. Non-ossified cervical vertebral bodies (1 - 7), some non-ossified caudal vertebrae, incompletely ossified sternebra 5, non-ossified metatarsalia 1 and non-ossified digits on fore and hind limbs were seen in fetuses at 450 mg/kg bw/day. These findings indicated a slight delay in ossification at 450 mg/kg bw/day which correlated with the lower fetal body weight in this dose group and this was related to the treatment with the test item.
At 450 mg/kg bw/day, statistically significantly increased incidence of supernumerary rudimentary ribs, long ventral plate and long or interrupted costal cartilage occurred both on an individual
and litter basis and these indicated a slight disturbance in development.
These observations were only variations with high spontaneous incidence of this strain. - Visceral malformations:
- no effects observed
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- The mean fetal body weight was statistically significantly lower at 450 mg/kg bw/day and was considered to be related to the treatment with the test item. In correlation with the lower fetal weights a slight delay in ossification was noted in the high dose group (450 mg/kg bw/day). An increased incidence of long or interrupted costal cartilages or long ventral plate indicated a slight disturbance in development at this dose level.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- ca. 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- other:
- Remarks on result:
- other: Effects seen are considered secondary to maternal toxicity or variations only
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: forelimb
- skeletal: rib
- skeletal: vertebra
- skeletal: hindlimb
- Description (incidence and severity):
- An increased incidence of long or interrupted costal cartilages or long ventral plate indicated a slight disturbance in development at this dose level. However these observations are variations only, and not reported as malformations.
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 450 mg/kg bw/day (actual dose received)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 1: Results for Formulation Analysis
Dose Group |
Sample taken from |
Nominal Conc (mg/mL) |
Actual Conc |
Relative to Nominal |
Mean |
Control |
vehicle |
0.0 |
ND |
- |
- |
2 |
top |
10.0 |
9.273 |
92.7 |
|
3 |
top |
30.0 |
31.61 |
105.4 |
|
4 |
top |
90.0 |
89.91 |
99.9 |
|
ND = not detected
In addition, the test item was found to be stable in application formulations when kept four hours at room temperature and eight days at in the refrigerator (5 ± 3 °C) due to recoveries which met the variation limit of 10% from the time-zero (homogeneity) mean value.
Table 2 - Summary of Performance of Mated Females
Group |
1 |
2 |
3 |
4 |
Female numbers |
1 - 22 |
23 - 44 |
45 - 66 |
67 - 88 |
Number of mated females |
22 |
22 |
22 |
22 |
Non-pregnant females (A) |
1 |
0 |
1 |
1 |
Number of pregnant females |
21 |
22 |
21 |
21 |
Number of females with live fetuses at termination* |
21 |
22 |
21 |
21 |
* Only dams with at least one live fetus at caesarean section were used for the calculations of food consumption, body weight gain and corrected body weight gain data.
(A) Female no. 10 from group 1 (control), female no. 57 from group 3 and female no. 79 from group 4 were not pregnant.
Applicant's summary and conclusion
- Conclusions:
- In the pre-natal developmental toxicity study conducted according to OECD Test Guideline 414 and in compliance with GLP, administration of trimethylsilanol (CAS 1066-40-6) by oral gavage to Sprague-Dawley rats from Day 6 to 20 of pregnancy at 0, 50, 150 or 450 mg/kg/day resulted in clinical signs and reduced food consumption and body weight gain in dams at 150 and 450 mg/kg bw/day. The effects on food consumption and body weight were considered to be adverse at 450 mg/kg/day, therefore the maternal NOAEL for general toxicity was considered to be 150 mg/kg/day. There was no maternal developmental effects observed but reduced foetal weight, delayed ossification and increased incidence of some cartilaginous variations were noted in foetuses at 450 mg/kg/day. The skeletal findings are reported to be variations only and are not considered to be adverse effects as such. The reduced foetal weight is considered secondary to maternal toxicity. Therefore the developmental NOEL is considered to be 150 mg/kg bw/day based on findings observed in the pups.
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