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EC number: 236-704-1 | CAS number: 13465-77-5
- 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:
- two-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- 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 guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Reference substance 001
- Cas Number:
- 112926-00-8
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland (Sulzfeld, Germany)
- Age at study initiation: (P) no data (4-5 weeks at purchase); (F1): 22 days
- Weight at study initiation: No data
- Fasting period before study: Not relevant
- Housing: Macrolon cages with a bedding of wood shavings and strips of paper as environmental enrichment. During mating a single female and male were housed together. Once mated the females were housed individually, and later they were housed individually with their litters.
- Diet : Ad libitum
- Water: Ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 45-65%
- Air changes (per hr): approximately 10 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: Once per week throughout the study, seven bottles per dosing group were prepared, each containing the relevant amount of test substance. On each day, the required amount of vehicle was added to achieve concentrations of 0, 10, 30 and 100 mg/ml test substance and stirred for at least 60 minutes.
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: Up to 2 weeks
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): Individually (no further details) - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- At various weeks during the study, samples were taken from each of the dosing formulations for analytical investigation of hydrodynamic diameters of the silica particles.
- Details on study schedule:
- - F1 parental animals not mated until at least 10 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 22 days of age.
- Age at mating of the mated animals in the study: at least 10 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 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:
- 28 (F0), 4 (F1, F2)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Random
- Positive control:
- None
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes, throughout the study, all animals were checked daily for clinical signs and abnormal behaviour.
DETAILED CLINICAL OBSERVATIONS: No data
- Limited information on this.
BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of all males and females was recorded weekly during premating, and for males, weekly thereafter. Mated females were weighed on gestation days 0, 4, 7, 10, 14, 17 and 21 and during lactation on post-natal days 1, 4, 7, 10, 14, 17 and 21. Animals were also weighed on their scheduled necropsy day.
FOOD CONSUMPTION: During the premating period, food consumption was measured weekly for each cage. Individual food consumption of all mated females were recorded from gestation days 0-4, 4-7, 7-10, 10-14, 14-17 and 17-21 and for all females with live pups on post-partum days 1-4, 4-7, 7-10, 10-14, 14-17 and 17-21.
WATER CONSUMPTION: No - Oestrous cyclicity (parental animals):
- Three weeks prior to the end of the premating period of the F0 and F1 generation, vaginal smears were made from each female to evaluate the estrous cycle length and normality.
- Sperm parameters (parental animals):
- Parameters examined in F0 and F1 male parental generations: testes weight, epididymis weight, caudal epididymal sperm count, sperm motility and testicular sperm count
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- Maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities
GROSS EXAMINATION OF DEAD PUPS: a necropsy was performed on stillborn pups and pups that died during lactation. - Postmortem examinations (parental animals):
- SACRIFICE
It is not clear from the publication when scheduled sacrifices occurred. The study is stated to be according to OECD TG 416, so timings are assumed to follow this guideline, i.e. F0 and F1 males dosed until they are no longer needed for assessment of reproductive effects and females are sacrificed after weaning of their litter.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations
HISTOPATHOLOGY / ORGAN WEIGHTS
The adrenals, brain, epididymides, kidneys, liver, ovaries, pituitary gland, prostate, seminal vesicles with coagulating glands, spleen, testes, thyroid, uterus with cervix (after counting of implantation sites), vagina and all gross lesions were weighed (except vagina) and preserved for microscopic examination for the control and the highest dose groups and on macroscopic abnormalities of all groups. Also, reproductive organs of F0 and F1 males who failed to sire, and of the non-mated/non-pregnant females from the low and mid dose groups were examined microscopically. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 21 days of age.
- Of the remaining F1 pups, one male and one female from each litter were selected for a thorough necropsy, and the brain, spleen and thymus were weighed. Sexual maturation was studied by scoring the day of vaginal opening in females and testes descent and preputial separation in males from post-natal days 31, 21 and 39, respectively.
HISTOPATHOLOGY / ORGAN WEIGHTS
As for parental animals. - Statistics:
- For some offspring viability data, sexual maturation, some sperm parameters and organ weights: Anova followed by Dunnett's multiple comparison test.
For some offspring data: Fisher's exact test.
For precoital time, gestation time and post-implantation loss per animal: Kruskal-Wallis + Mann-Whitney U test.
For some offspring data: Kruskal-Wallis followed by Dunnett's multiple comparison.
For some sperm parameters: Kruskal-Wallis non-parametric analysis of variance followed by Mann-Whitney U test. - Reproductive indices:
- Mating, fertility, fecundity, gestation
- Offspring viability indices:
- Live birth, viability (day 4), viability (day 21)
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- 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:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): No adverse effects.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): No adverse effects.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): No adverse effects.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): No adverse effects.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): No adverse effects.
ORGAN WEIGHTS (PARENTAL ANIMALS): Except for a statistically significant decrease in the relative weight of the thyroid of male animals of the mid-dose group (F1 generation), no statistically significant differences were observed for absolute and relative organ weights.
GROSS PATHOLOGY (PARENTAL ANIMALS): No adverse effects.
HISTOPATHOLOGY (PARENTAL ANIMALS): No adverse effects.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- Reproduction
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects on reproductive parameters were observed in any generation.
- Remarks on result:
- other: Generation: All (migrated information)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects were observed in parental animals.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
VIABILITY (OFFSPRING): No adverse effects.
CLINICAL SIGNS (OFFSPRING): No adverse effects.
BODY WEIGHT (OFFSPRING): No adverse effects.
SEXUAL MATURATION (OFFSPRING): No adverse effects.
ORGAN WEIGHTS (OFFSPRING): No adverse effects.
GROSS PATHOLOGY (OFFSPRING): No adverse effects.
HISTOPATHOLOGY (OFFSPRING): No adverse effects.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects were observed in any of the F1 offspring.
Results: F2 generation
Effect levels (F2)
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects were observed in any of the F2 offspring.
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 1 Reproductive Performance of female rats receiving NM-200
NM-200 dose (mg/kg bw/day) | |||||
Parameter of reproductive performance | Generation | 0 | 100 | 300 | 1000 |
Mating index (%) | F0 | 96 | 100 | 100 | 100 |
F1 | 100 | 100 | 100 | 100 | |
Fertility index (%) | F0 | 96 | 100 | 96 | 96 |
F1 | 98 | 93 | 93 | 89 | |
Fecundity index (%) | F0 | 100 | 100 | 96 | 96 |
F1 | 89 | 93 | 93 | 89 | |
Gestation index (%) | F0 | 100 | 96 | 100 | 100 |
F1 | 100 | 100 | 96 | 96 | |
Precoital time (days) | F0 | 2.7±0.21 | 2.8±0.25 | 2.3±0.19 | 2.5±0.21 |
F1 | 2.8±0.27 | 2.5±0.2 | 2.4±0.2 | 2.4±0.26 | |
Gestation time (days) | F0 | 21.7±0.09 | 21.6±0.11 | 21.6±0.1 | 21.6±0.1 |
F1 | 21.3±0.09 | 21.2±0.08 | 21.4±0.12 | 21.3±0.09 | |
Postimplantation loss per animal (%) | F0 | 8.6±2.66 | 10.5±3.72 | 9.5±2.54 | 10.1±2.52 |
F1 | 8.9±1.48 | 13.6±3.68 | 17.6±5.47 | 14.8±4.91 |
Table 2 Offspring data from rats receiving NM-200
NM-200 dose (mg/kg bw/day) | |||||
Generation | 0 | 100 | 300 | 1000 | |
Pups delivered (total) | F0 | 10.3±2.9 | 10.7±2.3 | 11.3± 2.0 | 11.0±1.5 |
F1 | 11.5 ±1.6 | 10.7±2.8 | 10.4±2.8 | 11.0± 2.6 | |
Live birth index (%) | F0 | 97.3±9.9 | 94.8± 19.1 | 96.5±12.7 | 98.7± 4.9 |
F1 | 96.2±6.1 | 90.7± 17.3 | 94.2±12.7 | 93.5± 16.1 | |
Pup mortality day 1 (%) | F0 | 2.7±9.9 | 5.2± 19.1 | 3.5±12.7 | 1.3± 4.9 |
F1 | 3.8±6.1 | 9.3± 17.3 | 5.8 ±19.0 | 6.5± 16.1 | |
Viability index day 4 (%) | F0 | 99.3±2.5 | 99.6± 2.0 | 98.9±4.2 | 98.8± 3.5 |
F1 | 84.7±28.0 | 83.8± 34.6 | 95.3 ± 20.0 | 73.8±42.3 | |
Viability index day 21 (%) | F0 | 100±0 | 100±0 | 100±0 | 100±0 |
F1 | 100±0 | 99.5 ±2.6 | 98.6 ±6.8 | 100±0 | |
Whole litter losses (litters lost/total number of litters) | F0 | 2/27 | 2/28 | 2/27 | 0/27 |
F1 | 1/25 | 3/26 | 1/25 | 4/24 | |
Sex ratio day 1 (% males) | F0 | 51.9±17.6 | 43.9± 12.2 | 50.8 ±15.6 | 51.1± 10.9 |
F1 | 47.4± 16.2 | 52.6±21.4 | 45.3± 19.6 | 42.3± 15.4 |
Applicant's summary and conclusion
- Conclusions:
- Based on a two-generation reproductive toxicity study in Wistar rats conducted in accordance with OECD TG 416 and to GLP the NOAEL for reproductive toxicity of synthetic amorphous silica was ≥1000 mg/kg bw/day as no adverse effects on reproductive 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 parental animals in any generation up to the highest dose tested.
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