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EC number: 299-135-8 | CAS number: 93857-00-2
- 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:
- 19.11.2003 to 19.05.2005
- 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 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Qualifier:
- according to guideline
- Guideline:
- other: USEPA OPPTS 870.3650
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Trimethoxy(methyl)silane
- EC Number:
- 214-685-0
- EC Name:
- Trimethoxy(methyl)silane
- Cas Number:
- 1185-55-3
- Molecular formula:
- C4H12O3Si
- IUPAC Name:
- trimethoxy(methyl)silane
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: No data
- Age at study initiation: Nine weeks
- Weight at study initiation: Males: 294.2-351.5; Females: 200.2-260.2 g
- Fasting period before study: None
- Housing: individually housed in suspended wire-mesh cages (pregnant rats in shoebox cages)
- Diet (e.g. ad libitum): Ad libitum (except during FOB)
- Water (e.g. ad libitum): Ad libitum (except during FOB)
- Acclimation period: Six days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.2-22.5
- Humidity (%): 36.0-62.0
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 09.02.2004 To: 19.04.2005
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Conducted over nitrogen atmopshere. Test substance was placed into a volumetric flask and corn oil added to achieve the desired volume. The weight of the test substance added to the flask was used to calculate nominal dose solution concentrations. Dosing solutions were prepared at least once every two weeks consistent with the previously determined 15-day stability. The concentration, homogeneity and stability of the test substance in vehicle for at least 15 days.
VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: Various
- Amount of vehicle (if gavage): Up to 3 ml/kg
- Lot/batch no. (if required): 122K0131
- Purity: Considered 100% - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration of methyltrimethoxysilane (MTMS) in corn oil dosing solutions was determined prior to the beginning of the definitive study.
- Duration of treatment / exposure:
- Toxicity group females and males were treated for 28 and 29 days, respectively. Reproductive group females were treated for 14 days prior to the mating period, during the mating period, and then up to and including post partum day 3, for a total of up to 51 days.
- Frequency of treatment:
- Daily, seven days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on a range-finding study
- Rationale for animal assignment (if not random): Weight stratified randomisation process
- Rationale for selecting satellite groups: According to OECD TG 422
- Post-exposure recovery period in satellite groups: None
Examinations
- Observations and examinations performed and frequency:
- Mortality/Morbidity: Animals were observed at least twice daily in their cages for moribundity and mortality throughout the in-life phase of the study.
Daily Observations: General clinical examinations were made at lease once a day and were conducted immediately after dosing. The examinations included, but were not limited to, changes in the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system functions, motor activity and behavior patterns. Findings were recorded for individual animals. General clinical examinations were not performed on days when detailed physical examinations were performed.
Detailed Physical Examinations: All animals received a detailed physical examination once before the first dose administration (to allow for within-subject comparisons), and weekly thereafter. Examinations were made outside the home cage in a standard arena at approximately the same time each day. Observations were detailed and carefully recorded. Examinations included, but were not limited to, changes in skin, fur eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity. Changes in gait, posture and response to handling as well as the presence of clonic or tonic movement, stereotypies, difficult or prolonged parturition or bizarre behavior were recorded. The presence or absence of findings was recorded for individual animals.
Body weights and food consumption were recorded weekly. Additional body weights for reproductive group females were obtained on gestational day 0, 7, 14, and 20, and within 24 hours of parturition, and on postnatal day 4. Individual food consumption was determined for each group following group specific schedules.
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: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: On day of scheduled termination.
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: Males and toxicity phase females
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On day of scheduled termination
- Animals fasted: Yes
- How many animals: Males and toxicity phase females
- Parameters checked in table 1 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to the start of dosing and during the last week of dosing.
- Dose groups that were examined: adult males and all toxicity group females
- Battery of functions tested: Unusual body movements, abnormal behaviour and/or posture, and resistence to removal, palperal closure, lacrimation, pupil size, pupil reactivity, salivation, muscle tone, extensor thrust response, reactivity to handling, level of ambulatory activity including rearing, responsiveness to sharp noise, touch, tail pinch, gait evaluation and quantity of urine and fecal pellets voided, behavior, skin or hair coat, respiration, muscle movements, eyes, urine or feces, soiling, general abnormalities and posture, rectal temperature, hindlimb/forelimb grip strength and landing foot splay. Motor activity assessment involved obtaining baseline motor activity data prior to the first dose administration to assist in evaluating potential treatment-related effects by allowing each rat to act as its own control. - Sacrifice and pathology:
- Males and toxicity group females were sacrificed after they had been treated for 28 days. Reproductive group females and pups were sacrificed
on day 4 postpartum. Complete necropsies were performed on the males and the toxicity group females and selected organs were weighed (adrenals, brain, heart, kidneys, liver, lungs, spleen, thymus, uterus, ovaries, testes, prostate, seminal vesicles, and epididymides). Microscopic examination was performed on protocol-specified tissues from all animals in the control and high dose group males and toxicity group females. Microscopic examination of the liver, thyroid, jejunum and duodenum was extended to males and toxicity group females in the 50 and 250 mg/kg dose groups. In addition, the adrenal gland from these middle dose groups was evaluated for the toxicity group females. - Statistics:
- All data analyses were carried out using SAS version 8.2. Statistically significant probabilities were reported for /-values of <0.05, <0.02 and <0.01.
Body weight, body weight changes, organ weight, organ to body weight ratios, food consumption, hematology data, clinical chemistry and prothrombin times were analyzed using a one-way Analysis of Variance (ANOVA) if the data satisfied the requirements of normality of the residuals and homogeneity of variance as determined using the Shapiro-Wilk test for normality and Levene’s test for homogeneity of variance. If the data did not satisfy the parametric requirements, a Kruskal-Wallis test was used. If the ANOVA or Kruskal-Wallis test was significant, pair-wise comparisons of the dosed groups to control were made using the Dunnett’s Test or a Wilcoxon test, respectively.
The red blood morphology findings in the hematology data that were reported by severity grade; polychromasia, anisocytes, poikilocytosis, and ananthocytes were analyzed using a Cochran-Armitage trend test to indicate an increasing incidence trend regardless of grade with Fisher’s Exact tests used to indicate increased incidence (non-grade specific) over the control. To determine shifts in severity, analysis using the Kruskal-Wallis test was performed on the graded data only if there was at least once incidence of severity grade seen in the controls group. If the overall Kruskall-Wallis test was significant, pair wise comparisons of the graded animals between the control and treated groups was done using the Kruskal-Wallis.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- There were two unscheduled deaths (one female each at 0 and 50 mg/kg bw/day); both were related to dosing errors. Clinical signs included
transient inactivity or salivation following dosing. Statistically significant decreases in body weight gain and food consumption were noted
for 1000 mg/kg bw/day group males. Increased liver weight was observed for male and female animals at 250 and 1000 mg/kg bw/day.
Exposure to MTMS was associated with organ weight and/or histomorphological changes in males (liver, thymus, thyroid, duodenum,
jejunum) and females (liver, thyroid, duodenum, jejunum, and adrenal gland) at dose levels at or above 250 mg/kg bw/day.
A marked increase in prothrombin time was observed for males at 250 and 1000 mg/kg bw/day whereas females were unaffected. Exposure
was also associated with increased blood platelet concentration for males and females, and increased red blood cell concentration in males at 1000 mg/kg bw/day. The NOAEL for systemic toxicity was 50 mg/kg bw/day.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- haematology
- histopathology: non-neoplastic
Target system / organ toxicity
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- System:
- other: gastrointestinal and cardiovascular
- Organ:
- liver
- thymus
- Treatment related:
- yes
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Any other information on results incl. tables
Toxic Response/Effects by Dose Level:
50 mg/kg bw/day Methyltrimethoxysilane:
Males: None
Females: None
250 mg/kg bw/day Methyltrimethoxysilane:
Males:
Increased liver weight (absolute(relative): 19%* (25%*)
Thyroid gland follicular cell hyperplasia/hypertrophy: (incidence 6*/10)
Decreased thymus weight (absolute(relative): 28%*(24%*)
Increased prothrombin time: 2-fold*
Females:
Increased liver weight (absolute(relative): 37%* (41%*)
Centrilobular hepatocellular hypertrophy (incidence 5*/10)
Periportal vacuolation (incidence 10*/10)
Thyroid gland follicular cell hyperplasia/hypertrophy:
(incidence 10*/10)
1000 mg/kg bw/day Methyltrimethoxysilane:
Males:
Increased liver weight (absolute(relative): 33%* (47%*)
Diffuse hepatocellular hypertrophy (incidence 10*/10)
Thyroid gland follicular cell hyperplasia/hypertrophy: (incidence 10*/10)
Mucosal lipidosis: duodenum (incidence 4*/10)
Mucosal lipidosis: jejunum (incidence 7*/10)
Decreased thymus weight (absolute(relative): 35%*(29%*)
Ancanthocytosis (incidence 5*/10)
Increased red blood cell concentration: 16%*
Increased prothrombin time: 2-fold*
Increased serum alanine aminotransferase (48%*)
Increased blood platelet concentration: 16*
Females (Toxicity Phase):
Increased liver weight (absolute(relative)): 197%* (200%*)
Centrilobular hepatocellular hypertrophy (incidence 10*/10)
Periportal vacuolation (incidence 8*/10)
Thyroid gland follicular cell hyperplasia/hypertrophy:(incidence 10*/10)
Adrenal gland hyperplasia/hypertrophy (incidence 10*/10)
Adrenal gland apoptosis (incidence 9*/10)
Adrenal gland lymphocytic infiltration: zona reticularis:(incidence 5*/10)
Mucosal lipidosis: duodenum (incidence 5*/10)
Mucosal lipidosis: jejunum (incidence 5*/10)
Ancanthocytosis (incidence 4*/10)
Increased blood platelet concentration: 21%*
Where "*" denotes statistically different from control (p<0.05)
Applicant's summary and conclusion
- Conclusions:
- Exposure to methyltrimethoxysilane was associated with organ
weight and/or histomorphological changes in males (liver,
thymus, thyroid, duodenum, jejunum, and red blood cell) and females (liver, thyroid, duodenum, jejunum, and adrenal
gland) at dose levels at or above 250 mg/kg bw/day. A marked increase in prothrombin time was observed for males at 250
and 1000 mg/kg bw/day whereas females were unaffected. Exposure was also associated with increased blood platelet
concentration for males and females at 1000 mg/kg bw/day. These data support a NOAEL for the toxicity phase of the
study of 50 mg/kg bw/day.
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