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EC number: 921-774-4 | CAS number: 13763-19-4
- 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:
- No data
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Reference substance 002
- Cas Number:
- 112926-00-8
- Test material form:
- solid: particulate/powder
- Remarks:
- powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Germany GmbH
- Age at study initiation: 12-15 weeks
- Weight at study initiation: 195.3- 271g
- Fasting period before study: Not relevant
- Housing: Individually in Macrolon type III cages, with a bedding of dust-free wood shavings and wooden gnawing blocks as environmental enrichment.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 30-70%
- Air changes (per hr): approximately 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: No data
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: highly deionised water containing 10% fetal bovine serum
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Dosing formulations of synthetic amorphous silica were pre-pared with highly deionized water containing 10% fetal bovine serum in order to avoid agglomeration.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The formulations were analysed by scanning electron microscopy after shock freezing and in situ analytical ultracentrifugation.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1-2 untreated females with 1 untreated male
- Length of cohabitation: Not stated but mating occurred between 15:30 and 7.30 on the day after cohousing started.
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Gestation day 6-19
- Frequency of treatment:
- One dose per day
- Duration of test:
- Approximately 21 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 300 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 25 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Highest dose was chosen as the limit dose according to the test guideline.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: described as 'regular'
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: described as 'regular'
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes (described as 'regular')
WATER CONSUMPTION: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus and ovaries - 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, but no data on number examined - Statistics:
- The data for food consumption, maternal, litter weight and body weight change, carcass and gravid uterus weight, number of corpora lutea and implantations, number of resorptions, number of live fetuses, percent pre- and post- implantation loss, percent live fetuses per litter, number of pups per litter, post- implantation loss, and mean placental weights were analysed by the two-sided Dunnett’s test for the hypothesis of equal means. The female mortality, number of pregnant females, and number of litters with fetal findings, were analysed by pairwise comparison of each dose group with the control group using the one-sided Fisher’s exact test for the hypothesis of equal proportions. Proportions of fetuses per litter with findings were analyzed by pairwise comparison of each dose group with the control group by a one-sided Wilcoxon test for the hypothesis of equal medians.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
Results are summarised in Tables 1 and 2. There was no treatment-related mortality or clinical signs of toxicity, and there was no effect on body weight gain or food consumption. Gravid uterine weights were not influenced by treatment with SAS. No treatment-related macroscopic findings were observed at necropsy. The conception rate, mean number of corpora lutea, implantation sites, and post-implantation loss were comparable in all groups. The only minor difference to control values was pre-implantation loss (slightly higher in the groups treated with SAS); however, a compound-related effect can be excluded as treatment started after implantation.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Results are summarised in Table 1. No dead fetuses were noted. The sex distribution of the fetuses was comparable in all groups. Mean fetal weights did not show any biologically relevant differences between the test substance-treated groups and the control. External malformations were recorded for one fetus each in the low- and high- dose group. Both fetuses concerned had multiple malformations. Mandibular micrognathia mirrored the severely malformed skull bones found during skeletal examination in one fetus; these findings were considered related to each other. The cleft palate observed in the other fetus is present in the historical control data at a comparable incidence. Both findings were considered to be spontaneous in nature and without a relation to dosing. The total incidence of external malformations in treated animals did not differ significantly from that of the control group. One soft tissue malformation (i.e. supernumerary liver lobes unilateral) was observed in the control group. Skeletal malformations were noted in single fetuses at 0, 100, and 1000 mg/kgbw/day. Each of them affected individual fetuses and neither statistically significant differences between the test groups nor a dose–response relationship was observed. The overall incidences of skeletal malformations were comparable to those found in the historical control data.
Three soft tissue variations, i.e. short innominate, enlarged atrial chamber of the heart and uni- or bilateral dilation of renal pelvis, were detected. These findings observed in 1–5 fetuses of 1–4 litters at 0, 100, 300 and 1000 mg/kgbw/day showed no dose–response relationship. The observable differences between the groups reflect the usual fluctuation for this parameter and were clearly within the range of the historical control data. For all groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilage. The observed skeletal variations were related to several parts of fetal skeletons and appeared without a relation to dosing. The overall incidences of skeletal variations were comparable to the historical control data. The incidence of the variations observed showed no dosing-related statistical significance and were within historical control ranges. Therefore these observations are not considered toxicologically relevant.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: There were no adverse effects on developmental parameters.
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1 Summary of reproductive and developmental results
Dose (mg/kg bw/d) | 0 (vehicle control) | 100 | 300 | 1000 | |
Females mated | N | 25 | 25 | 25 | 25 |
Pregnant | N | 22 | 21 | 25 | 23 |
Conception rate | % | 88 | 84 | 100 | 92 |
Aborted | N | 0 | 0 | 0 | 0 |
Premature births | N | 0 | 0 | 0 | 0 |
Dams with viable fetuses | N | 22 | 21 | 25 | 23 |
Dams with total litter loss | N | 0 | 0 | 0 | 0 |
Female mortality | N | 0 | 0 | 0 | 0 |
Pregnant at terminal sacrifice | N | 22 | 21 | 25 | 23 |
% | 88 | 84 | 100 | 92 | |
Corpora luteaD | mean ± SD | 14.2 ± 2.4 | 13.9 ± 2.08 | 14.0 ± 1.99 | 14.7 ± 2.03 |
Implantation sitesD | mean ± SD | 13.5 ± 2.56 | 12.5 ± 2.8 | 12.8 ± 1.62 | 13.4 ± 2.27 |
Pre-implantation loss (%)D | mean ± SD | 4.9 ± 7.31 | 9.4 ± 17.69 | 7.7 ± 11.81 | 8.4 ± 12.31 |
Post-implantation loss (%)D | mean ± SD | 8.3 ± 9.96 | 5.2 ± 5.22 | 9.9 ± 16.2 | 6.0 ± 3.56 |
Early resorptions (%)D | 7.6 ± 9.27 | 5.2 ± 5.22 | 9.9 ± 16.2 | 5.6 ± 3.75 | |
Late resorptions (%)D | 0.7 ± 2.26 | 0 | 0 | 0.3 ± 1.49 | |
Dead fetuses | 0 | 0 | 0 | 0 | |
Dams with viable fetuses | N | 22 | 21 | 25 | 23 |
Live fetusesD | mean ± SD | 12.4 ± 2.59 | 11.8 ± 2.71 | 11.5 ± 2.47 | 12.7 ± 2.23 |
Live fetuses (% implantation)D | mean ± SD | 91.7 ± 9.96 | 94.8 ± 5.22 | 90.1 ± 16.2 | 94.0 ± 3.56 |
MalesD | mean ± SD | 5.9 ± 1.7 | 5.5 ± 1.91 | 6.5 ± 1.85 | 5.7 ± 1.79 |
Males (%)D | mean ± SD | 43.7 ± 10.64 | 46.5 ± 18.79 | 50.9 ± 14.23 | 43.2 ± 13.09 |
FemalesD | mean ± SD | 6.5 ± 1.95 | 6.3 ± 2.76 | 5.0 ± 2.34 | 6.9 ± 2.21 |
Females (%)D | mean ± SD | 48.0 ± 11.17 | 48.3 ± 18.55 | 39.2 ± 15.98 | 50.9 ± 11.85 |
Sex ratio (% males) | 47.4 | 46.8 | 56.3 | 45.4 | |
Placental weightsD | mean ± SD | 0.47 ± 0.040 | 0.47 ± 0.042 | 0.46 ± 0.038 | 0.47 ± 0.038 |
N | 22 | 21 | 25 | 23 | |
Of male fetusesD | mean ± SD | 0.49 ± 0.038 | 0.48 ± 0.036 | 0.47 ± 0.043 | 0.48 ± 0.037 |
N | 22 | 21 | 25 | 23 | |
Of female fetusesD | mean ± SD | 0.46 ± 0.042 | 0.46 ± 0.052 | 0.46 ± 0.044 | 0.46 ± 0.041 |
N | 22 | 20 | 25 | 23 | |
Fetal weightsD | mean SD | 3.4 ± 0.26 | 3.4 ± 0.15 | 3.4 ± 0.24 | 3.4 ± 0.14 |
N | 22 | 21 | 25 | 23 | |
MalesD | mean SD | 3.5 ± 0.27 | 3.4 ± 0.18 | 3.5 ± 0.24 | 3.5 ± 0.14 |
N | 22 | 21 | 25 | 23 | |
FemalesD | mean SD | 3.3 ± 0.25 | 3.3 ± 0.17 | 3.4 ± 0.28 | 3.3 ± 0.15 |
N | 22 | 20 | 25 | 23 |
*p<0.05; **p<0.01 (D, two-sided Dunnett's test)
Table 2 Summary of fetal malformations
Dose (mg/kg bw/d) | 0 (vehicle control) | 100 | 300 | 1000 | |
Litters evaluated | N | 22 | 21 | 25 | 23 |
Fetuses evaluated | N | 272 | 248 | 288 | 291 |
Total Malformations | |||||
Fetal incidence | N | 3 | 1 | 0 | 1 |
% | 1.1 | 0.4 | 0.0 | 0.3 | |
Litter incidenceF | N | 2 | 1 | 0 | 1 |
% | 9.1 | 4.8 | 0.0 | 4.3 | |
Affected fetuses per litterW | mean% ± SD | 1.3 ± 4.07 | 0.4 ± 1.98 | 0.0 ± 0.00 | 0.3 ± 1.60 |
*<0.05; **p<0.01 (F, one-sided Fisher's exact test; W, one-sided Wilcoxon)
Applicant's summary and conclusion
- Conclusions:
- Based on a prenatal developmental toxicity study in Wistar rats conducted in accordance with OECD TG 414 and to GLP the NOAEL for developmental toxicity was ≥1000 mg/kg bw/day as no adverse effects on developmental parameters were observed up to the highest dose tested. The NOAEL for general systemic toxicity was also ≥1000 mg/kg bw/day as there were no signs of adverse effects in any of the maternal animals up to the highest dose tested.
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