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EC number: 214-189-4 | CAS number: 1112-39-6
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 1996
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Dimethoxydimethylsilane
- EC Number:
- 214-189-4
- EC Name:
- Dimethoxydimethylsilane
- Cas Number:
- 1112-39-6
- Molecular formula:
- C4H12O2Si
- IUPAC Name:
- dimethoxydimethylsilane
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl: CD® (SD) IGS BR VAF/Plus®
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC 27610
- Age at study initiation: 9 weeks at experimental start
- Weight at study initiation: 192 to 239 g at experimental start (Females). 283 to 341 g at experimental start (Males)
- Housing: Animals were individually housed in suspended wire-mesh cages elevated above faecal pans containing Bed-O’ Cobs® litter, during quarantine/ acclimation and during the in-life phase of the study. Animals were given Nylabones® and Cozee Pads for environmental enrichment while in standard housing. Environmental enrichment was removed from the toxicity group male and female animals the afternoon/evening prior to necropsy.
- Diet: Lab diet 5002, Certified Rodent Diet (PMI Nutrition International) was provided ad libitum during the quarantine/acclimation period and throughout the study. Food was removed the afternoon/evening prior to necropsy of toxicology animals
- Water: Municipal water, further purified by reverse osmosis was available ad libitum via automatic watering system.
- Acclimation period: 5 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 -21.7
- Humidity (%): 53-59
- Air changes (per hr): 14.3
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 20-10-2008 To: 30-07-2009.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Each dosing solution was prepared individually. Dosing solutions were prepared by adding the appropriate amount of the test article to a tare container and adding the appropriate amount of corn oil to yield the desired dose level. Dosing solutions were administered by oral gavage with a 100 mm, 15 gauge (1.8 mm), plastic feeding tube and syringe. The test article was administered at a dose volume of 4 ml/kg bw and was calculated from the most recent body weight.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based upon the physical and chemical properties of the test article, dried and deacidified corn oil was considered to be the most appropriate vehicle for oral administration.
- Lot/batch no. (if required): 058K0070 - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: Study day 15 up to Study day 28
- Proof of pregnancy: Females rats were evaluated daily for evidence of copulation, by confirming the presence of either vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged (how): Day 0 of gestation was defined as the day evidence of copulation was observed, at which time the female was individually caged. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dosing solution analysis was performed by a GC/FID method to verify concentration, stability, and homogeneity of the test article in carrier. Concentration verification was conducted for the initial and third dose preparations.
- Duration of treatment / exposure:
- Male rats were administered the test substance for 29 consecutive days including a two-week pre-mating phase, while female rats were administered the test substance up to 51 days in total. Female rats were exposed for a two-week pre-mating phase, a 1-14 day mating phase, and through day post-partum, up to 51 days in total.
- Frequency of treatment:
- Daily
- Details on study schedule:
- Not reported
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
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:Clinical observations were performed daily immediately following exposure.
BODY WEIGHT: Yes
- Time schedule for examinations:Individual body weights were determined beginning with randomisation into test groups, on the first day of dosing, at least weekly thereafter, and on the day of euthanasia. During gestation, the reproductive group females were weighed (at a minimum) on gestation days 0, 7, 14 and 20, within 24 hours of parturition and on day 4 post-partum.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes - Oestrous cyclicity (parental animals):
- Not reported
- Sperm parameters (parental animals):
- Parameters examined in [P] male parental generations:
[testis weight, epididymis weight, sperm morphology, ] - Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in [F1 ] offspring:
[number and sex of pups, stillbirths, live births, runts, and the presence any gross anomalies. Live pups were counted, sexed and the sex ratio calculated]
GROSS EXAMINATION OF DEAD PUPS:
[yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead.]- Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals [After a minimum of 28 days on study]
- Maternal animals: All surviving animals were euthanised by CO2 inhalation on post-partum day 4.
GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]
HISTOPATHOLOGY / ORGAN WEIGHTS
Tissues and organ taken for histopathological examination:
Adrenal, Brain (including cerebrum, cerebellum and pons), Cecum, Colon, Duodenum, Epididymis, Heart, Ileum, Jejunum, Kidneys, Liver, Lungs, Lymph nodes, Ovaries, Prostate, Sciatic nerve, Seminal vesicles, Spinal cord, Spleen, Sternum with bone marrow, Stomach, Testes, Thymus, Thyroid, Trachea, Urinary bladder and Uterus (horns and cervix).
The following organs were weighed:
Adrenal, Brain (including cerebrum, cerebellum and pons), Epididymis, Heart, Kidneys, Liver, Seminal vesicles, Spleen, Testes, Thymus,and Uterus (horns and cervix). - Postmortem examinations (offspring):
- Not applicable
- Statistics:
For reproductive endpoints that involve occurrence up to birth (corpora lutea counts, total implants, post-implantation losses, day’s gestation) and for the total number of pups in the litter and total live pups in the litter, an ANOVA was done. If a statistically significant difference across treatment groups was seem pair-wise comparisons are made between the control group and the treated groups using Dunnett’s tests. For the remaining endpoints an ANOVA with the treatment and total litter size as independent variables was done. For all these analyses total litter size is defined as the total number of pups, both alive and dead. If the treatment was a significant variable in the analysis, then pair-wise comparisons were made between the control and each treated group using Dunnett’s test and adjusting for the litter sizes.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Reproductive performance:
- effects observed, treatment-related
Details on results (P0)
All but one animal survived to their scheduled necropsy. For the males at 1000 mg/kg bw/day, significant abnormal observations (p<0.01) were noted and included soiling of the chin and urogenital area. Abdominal, chin, muzzle and urogenital soiling were significant abnormal observations (p<0.01) in the reproductive group females at 1000 mg/kg bw/day.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no statistically significant differences between controls and treatment groups in the mean body weights on any of the test groups.
There were no differences in the average daily food consumption between controls and the males groups for any of the measured time periods. In the reproductive group females, at 1000 mg/kg bw/day, there was a significant decrease (35%) in food consumption from control s during the intervals post-partum days 0-4.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
In the testes there was moderate to marked seminiferous tubule degeneration observed in all 1000 mg/kg bw/day male rats that was characterised by degeneration of spermatocytes. A downstream effect was observed in the epididymides of the same rats. This is an adverse finding.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
In the reproductive group females, there was no statistically significant difference across treatment groups for corpora lutea and total implants. However, there was statistically significant difference at 1000 mg/kg bw/day for post-implantation losses, days of gestation, total pups and total live pups with the 1000 mg/kg bw/day groups having significantly more post-implantation losses, a longer gestation period, fewer pups in the litter and fewer live pups in the litter than were seen in the control.
ORGAN WEIGHTS (PARENTAL ANIMALS)
The increased liver weights in males and females at 1000 mg/kg bw/day correlated with the histopathologic finding of panlobular hypertrophy and centrilobular hypertrophy in females at 250 mg/kg bw/day. In males, adrenal cortical atrophy was accompanied by a decrease in absolute and relative adrenal weights at 1000 mg/kg bw/day, seminiferous tubule degeneration was accompanied by a decrease in absolute and relative testes weights at 1000 mg/kg bw/day, epididymal effects were accompanied by a decrease in absolute and relative decreases in epididymal weights, and kidney nephropathy findings were accompanied by an increase in relative kidney weights.
GROSS PATHOLOGY (PARENTAL ANIMALS)
The ovaries appeared enlarged in one female/group administered ≥50 mg/kg bw/day. The seminal vesicles appeared small in 4 males administered 1000 mg/kg bw/day, and in one animal each at the 50 and 250 mg/kg bw/day dosage levels.
Testes:
There was moderate to marked seminiferous tubule degeneration observed in all 1000 mg/kg bw/day male rats, significant at p<0.01. Minimal seminiferous tubule degeneration was recorded for one male rat dosed at 250 mg/kg bw/day (not statistically significant). The finding was not observed in control rats or those administered 50 mg/kg bw/day. The finding was characterised by degeneration of spermatocytes that appeared to be arrested and dying while in meiotic division (to become spermatids) or degenerating at earlier spermatocytes stages. Because of cell death at the meiotic spermatocytes stage, meiotic spindles were observed much more commonly in the high-dose males than in controls.
Epididymides:
The beginning of the downstream effect of the spermatocyte degeneration in the testes was observed in the epididymides of all 1000 mg/kg bw/day male rats. A mild increase in immature spermatids was observed throughout the epididymides in 10/10 animals, significant at p<0.01 however they were especially common in the head portion. A minimal number of immature spermatids were observed in one 250 mg/kg bw/day male rat. Mild to moderate hypospermia, statistically significant at p<0.01, in 9/10 animals was also observed at the highest dosage, but it should be noted that this was largely confined to the head of the epididymides. Sperm numbers appeared to be near normal in the remainder of the epididymides.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: At 1000 mg/kg bw/day- in males: hepatic protoporphyrin accumulation, adrenal cortical atrophy, kidney protein droplet nephropathy, testicular seminiferous tubule degeneration with epididymides involvement and in females rats, periportal vacuolation
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
Details on results (F1)
The number of day 4 viable pups and the ratio of the number of viable pups to the total litter size was significantly different, with the 1000 mg/kg bw/day group having fewer viable pups by day 4 and a smaller viable/total ratio than did the control group. The percentage of post-natal loss was significantly different, with the 1000 mg/kg bw/day having a significantly higher loss than did the control group.
CLINICAL SIGNS (OFFSPRING)
No data
BODY WEIGHT (OFFSPRING)
The initial litter weight and average pup weight (defined using the live pup litter weight divided by the total number of live pups on day 0) were significantly different only for the 250 mg/kg bw/day group having a significantly increased litter weight and average pup weight compared to that in the control group after adjusting for litter size. The litter size was also a significant variable for these two endpoints with larger litters having litter weights but smaller average pup weights. For the final litter weight and average pup weights, there was also a significant difference, but it was the 1000 mg/kg bw/day group that was significantly different from the control group with both smaller overall litter weights and smaller average pup weight than in the control groups. There were no grossly external abnormalities observed in the pups.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 250 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 2. Summary of Mean Reproductive Parameters for Reproductive Group Female Rats.
|
|
Control (0 mg/kg bw/day) |
50 mg/kg bw/day |
250 mg/kg bw/day |
1000 mg/kg bw/day |
Litter Size |
||||
Corpora Lutea Counts |
Mean |
21 |
|
18 |
|
17 |
|
22 |
|
N/A |
Std |
5 |
|
5 |
|
3 |
|
5 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Total Implants |
Mean |
15 |
|
16 |
|
14 |
|
13 |
|
N/A |
Std |
1.2 |
|
2.0 |
|
2.0 |
|
3.7 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Post-Implantation Loss (%) |
Mean |
9.8 |
*** |
4.3 |
|
8.6 |
|
23.5 |
** |
N/A |
S td |
5.9 |
|
7.7 |
|
10.2 |
|
14.3 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Days Gestation |
Mean |
22 |
|
22 |
|
22 |
|
23 |
*** |
N/A |
Std |
1 |
|
1 |
|
1 |
|
1 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Total Pups |
Mean |
13.7 |
*** |
16.0 |
|
13.0 |
|
10.3 |
*** |
N/A |
Std |
0.8 |
|
2.3 |
|
1.8 |
|
2.8 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Total Live Pups Day 0 |
Mean |
13.4 |
*** |
15.6 |
|
12.7 |
|
9.8 |
*** |
N/A |
Std |
0.8 |
|
2.8 |
|
1.7 |
|
2.7 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Male pups |
Mean |
7 |
|
8 |
|
6 |
|
5 |
|
*** |
Std |
2 |
|
3 |
|
2 |
|
3 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Female pups |
Mean |
6 |
|
8 |
|
6 |
|
5 |
|
* |
Std |
1 |
|
2 |
|
2 |
|
2 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Males/Females |
Mean |
1.4 |
|
1.1 |
|
1.2 |
|
1.2 |
|
|
Std |
0.8 |
|
0.7 |
|
0.7 |
|
0.9 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Day 4 Viable pups |
Mean |
13 |
*** |
15 |
|
13 |
|
7 |
*** |
*** |
Std |
1 |
|
3 |
|
2 |
|
4 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Viable/total |
Mean |
0.97 |
*** |
0.96 |
|
0.97 |
|
0.74 |
*** |
|
Std |
0.04 |
|
0.04 |
|
0.05 |
|
0.31 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Initial Litter Weight (g) [Live Pups only] |
Mean |
88 |
*** |
100.0 |
|
93.1 |
* |
64.4 |
|
|
Std |
7.4 |
|
13.8 |
|
11.8 |
|
14.1 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Initial Average pup Weight (g) [Live Pups only] |
Mean |
6.6 |
*** |
6.5 |
|
7.4 |
*** |
6.8 |
|
*** |
Std |
0.5 |
|
0.6 |
|
0.4 |
|
0.7 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
|
Final Litter weight (g) |
Mean |
145.5 |
*** |
160.6 |
|
142.0 |
|
72.9 |
*** |
*** |
Std |
12.6 |
|
18.8 |
|
16.0 |
|
15.5 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
7 |
|
|
|
Final Average pup (g) |
Mean |
11.0 |
*** |
10.5 |
|
11.3 |
|
8.9 |
*** |
|
Std |
0.9 |
|
1.0 |
|
1.0 |
|
1.3 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
7 |
|
|
|
Post-Natal Loss (%) |
Mean |
0.7 |
*** |
1.3 |
|
0.7 |
|
24.0 |
*** |
* |
Std |
2.3 |
|
3.7 |
|
2.3 |
|
32.6 |
|
|
|
N |
10 |
|
8 |
|
10 |
|
8 |
|
|
Note: Asterisks next to the control indicates a significant treatment effects in the ANOVA, asterisks in the litter column indicates a significant litter effect in the ANOVA with p–values of *<0.05, ** <0.02 or *** <0.01 in the control column and significance in the litter sizes with p-values of *<0.05, **<0.02 or *** <0.01 in the litter significance column. N/A is the litter column indicates that the litter was not used as a covariate in the analysis of that endpoint.
% Post-Implantation Loss = ((# Implantations - # Live at First Litter Check) # Implantations)* 100
% Post-Natal Loss = ((#Live pups Day 0 - # Live pups Day 4) # live pups Day 0)* 100
Applicant's summary and conclusion
- Conclusions:
- The study was conducted according to OECD 422 test guideline, and in compliance with GLP for the registered substance. Based on observations at 1000 mg/kg bw/day (an increase in post-implantation loss, an increase in days of gestation, a decrease in live pups, a decrease in the total viable pups/total, a decrease in final litter weight, a decrease in final average pup weight and an increase in the % of post-natal loss), the NOAEL for reproductive toxicity is 250 mg/kg bw/day.
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