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EC number: 943-282-9 | CAS number: -
- 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
- Study period:
- 08/04/2016 to 21/10/2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
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)
- Version / remarks:
- 1996
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developm ental Toxicity Screening Test
- Version / remarks:
- 2000
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 1995
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: OPPTS 870.3550, Reproduction/Developmental Toxicity Screening Test
- Version / remarks:
- 2000
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: : EC No 440/2008 B.7: "Repeated Dose (28 days) Toxicity (oral)"
- Version / remarks:
- 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
- Version / remarks:
- 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents
- Version / remarks:
- 2000
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Reaction mass of octadecan-1-ol and trimethyl(octadecyloxy)silane
- Molecular formula:
- CH3(CH2)17OSi(CH3)3
- IUPAC Name:
- Reaction mass of octadecan-1-ol and trimethyl(octadecyloxy)silane
- Test material form:
- other: Off-white waxy solid
Constituent 1
- Specific details on test material used for the study:
- STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability under test conditions: Stability of the test item under test conditions was demonstrated in the analytical method development and validation study.
- Solubility and stability of the test substance in the solvent/vehicle: Corn oil was the selected vehicle at request by the Sponsor.
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Each day of dosing, a stock solution of the test item in vehicle was prepared at the same concentration as the high dose formulation. Aliquots were taken from this stock solution which were further diluted with the vehicle to give the required mid and low dose formulati ons, respectively. These latter formulations were used to treat the mid and low dose group, respectively, and the remaining stock solution was used to treat the high dose group. - Preliminary purification step (if any): no correction factor required
Test animals
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany- Females (if applicable) nulliparous and non-pregnant: yes - Age at study initiation: Approximately 10-12 weeks.
- Weight at study initiation:
- Fasting period before study: none
- Housing: During the pre-mating period animals were housed in groups of 5 animals/sex/cage in Macrolon plastic cages; during mating Main females were caged together with Main males on a one-toone-basis in Macrolon plastic cages; during post-mating Main males were housed in their home cage with a maximum of 5 animals/cage. Main females were individually housed in Macrolon plastic cages; during lactation pups were kept with the dam until termination in Macrolon plastic cages. Recovery animals were housed in groups of 5 animals/sex/cage in Macrolon plastic cages during treatment and recovery period.
- Diet: access to pelleted rodent diet, ad libitum, except during motor activity measurements.
- Water: access to tap-water, ad libitum, except during motor activity measurements. - Acclimation period: At least 5 days prior to start of treatment.
DETAILS OF FOOD AND WATER QUALITY: Diet, water, bedding and cage-enrichment/nesting materia l evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70%
- Air changes (per hr): 10 room air changes/hour
- Photoperiod (hrs dark / hrs light): a 12-hour light/12-hour dark cycle
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Each day of dosing, a stock solution of the test item in v ehicle was prepared at the same concentration as the high dose formulation. Aliquots were taken fro m this stock solution which were further diluted with the vehicle to give the required mid and low dose formulations, respectively. These latter formulations were used to treat the mid and low dose group, respectively, and the remaining stock solution was used to treat the high dose group. The stock solutions were prepared by weighing a required sample of the test item into a clean bottle. The appropriate amoun t of vehicle was added and homogenized to a visibly acceptable level. Adjustment was made for speci fic gravity of the test item (i.e. 0.82) and vehicle (i.e. 0.92). No correction was made for the purity/comp osition of the test item. After homogenizing, aliquots were taken from the stock solution and weighed into a clean bottle. The appropriate amount of vehicle was added and again homogenized to a visibly accep table level. Formulations were prepared daily within 6 hours prior to dosing.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil was the chosen vehicle at request by the Sponsor.
- Concentration in vehicle: not specified
- Amount of vehicle (if gavage): not specified
- Lot/batch no. (if required): not specified
- Purity: not specified - Details on mating procedure:
- - M/F ratio per cage: one to one ratio
- Length of cohabitation: A maximum of 14 days was allowed for cohabitation.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: not specified
- Further matings after two unsuccessful attempts: not specified
- After successful mating each pregnant female was caged (how): Main females were individually housed in Macrolon plastic cages.
- Any other deviations from standard protocol: none - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses were conducted on three occasions during the treatment phase according to a validated metho d. Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and acc uracy of preparation (all concentrations). Stability of formulations over 6 hours at room temperature under normal laboratory light conditions (concentration range 1-200 mg/mL) was determined as part of the analytical method development and validation study.
- Duration of treatment / exposure:
- Main males and Recovery males: 31 days
Main females that delivered: 41-54 days
Main females that failed to deliver: 41 days
Recovery females: 42 days - Frequency of treatment:
- Once daily for 7 days per week
- Details on study schedule:
- - Parental animals not mated until 2 weeks after selection.
- Selection of parents from F1 generation when pups were [...] days of age: not applicable, F1 not mated
- Age at mating of the mated animals in the study: approximately 12-14 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:
- Vehicle control: 10 males and 10 females; 5 recovery males and 5 recovery females
100 mg/kg bw/day: 10 males and 19 females
300 mg/kg bw/day: 10 males and 10 females
1000 mg/kg bw/day: 10 males and 10 females; 5 recovery males and 5 recovery females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were based on the results of the dose range finding study.
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: Recovery animals were included for all control and high dose groups to track reversibility of effects.
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random): random
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily for mortality.
- Cage side observations checked in table included mortality and viability.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily
BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of treatment (prior to dosing) and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 postcoitum and during lactation on PND 1 and 4. - Oestrous cyclicity (parental animals):
- Estrous cycle determination at 14 days prior to treatment, 14 days of treatment and during mating until evidence of mating, and on the day of necropsy.
- Sperm parameters (parental animals):
- Parameters examined in [P] male parental generations: testis weight, epididymis weight
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in F1 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: yes, for external and internal abnormalities
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: No
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: No - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals were sacrificed after at least 28 days of dose administration
- Maternal animals: All female rats which delivered were sacrificed on lactation day 5-7. All females which failed to deliver were sacrificed on post-coitum days 25-27
GROSS PATHOLOGY: Yes (see table No 1)
HISTOPATHOLOGY: Yes (see table No 1) - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed at 5-7 days of age.
- These animals were subjected to postmortem macroscopic examinations
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY
- Not performed - Statistics:
- Dunnett-test: comparison of the treated groups and the control groups for each sex;
Steel-test: if the data could not be assumed to follow a normal distribution;
Fisher Exact-test: frequency data;
Kruskal-Wallis nonparametric ANOVA test: motor activity data to determine intergroup differences - Reproductive indices:
- Mating index, fertility index, conception index, gestation index
- Offspring viability indices:
- Viability index
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs of toxicity were noted during the observation period.
Salivation seen at a dose related incidence after dosing among animals of the 300 and 1000 mg/kg bw/day dose groups for prolonged periods during treatment period was considered to be a physiological response rather than a sign of systemic toxicity considering the nature and minor severity of the effect and its time of occurrence. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- No treatment related mortality occurred during the study period.
One recovery female from the control group was sacrificed for ethical reasons after it was accidentally injured during blood sampling at start of the recovery period.
Incidental findings that were noted included rales, red discolouration around the mouth, alopecia and scabs on the cheek. These findings occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study. Temporary chromodacryorrhoea and a dark eye observed in some recovery animals were considered to be related to the blood sampling via the orbit at start of recovery period. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weights gain in males at 1000 mg/kg bw/day was slightly lower over the treatment period, achieving a level of statistical significance on day 15 of treatment (the day of the start of mating) when compared to the control ls. The body weight gain in high dose recovery males at start of recovery (when compared to study day 1), was statistically significantly lower than in control recovery males. The increase in difference in the mean body weights between control and high dose males over one day (from the end of treatment to the start of recovery) was due to relatively low body weights of the high dose males that continued in the recovery period compared to those of the whole group. The terminal body weights determined at necropsy, after overnight fasting, still indicated a similar difference in mean body weights between control and high dose recovery males. Based on these data, it was assumed that body weight gain was comparable for controls and high dose recovery males also over the second week of the recovery period.
Over the two weeks premating period, body weights and body weight gain of treated females remained in the same range as controls.
In the non-mating, control and high dose recovery females, body weights and body weight gain remained similar until termination of treatment and during the subsequent two weeks recovery period. In the main high dose females, the body weight gain was slightly lower over the post coitum phase in comparison with controls, resulting in slightly lower body weights in these females immediately after delivery (lactation day 1). The difference in body weights between the main control and high dose females had diminished on lactation day 4.
Body weights and body weight gain in main females treated at 100 and 300 mg/kg bw/day remained in the same range as controls during the post coitum and lactation phases.
The statistically significant differences observed for (lower) body weight gain over the first four days of the post coitum phase in main females treated at 300 and 1000 mg/kg bw/day were considered to have occurred by chance. As body weight increase was noted to be within normal limits for pregnant rats during the post coitum phase, these statistical significances were not indicative for a treatment related effect. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No toxicologically relevant changes in food consumption before or after allowance for body weight were noted in the main and recovery animals during the treatment and recovery phases.
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- A statistically significantly lower number of white blood cells (WBC) was observed in males treated at 1000 mg/kg bw/day. These values were within the normal limits, no clear changes in their differential white blood cells counts and the fact that the difference in number of WBC between control and high dose males had disappeared at the end of the recovery phase, this change in number of WBC in high dose males was considered to be non-adverse. Treatment related changes in the values of WBC were not observed in females either at the end of treatment and end of recovery.
The other haematological parameters in males were considered not to be affected by treatment. The statistically significant changes in relative number of eosinophils in low dose males and in relative number of lymphocytes and platelets in low dose females were not considered to be toxicologicall y relevant as they occurred in the absence of a treatment-related distribution and remained within the range considered normal for rats of this age and strain.
No toxicologically relevant changes occurred in haematological parameters of the main females and recovery females treated with the test item when compared to controls.
Higher values were observed for red blood cell distribution width (RDW) in main females at 1000 mg/kg bw/day and for mean corpuscular haemoglobin concentration (MCHC) in recovery females at 1000 mg/kg bw/day, achieving statistical significance when compared to controls. all individual values for both parameters in the respective high dose females were well within the normal range these changes were considered to have occurred by chance and of no toxicological significance. Moreover, no changed were noted in red blood cell parameters haemoglobin and haematocrit. - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No toxicologically relevant changes occurred in clinical biochemistry parameters of treated rats.
No toxicologically relevant changes occurred in haematological parameters of the main females and recovery females treated with the test item when compared to controls.
Any statistically significant changes apparent in males for sodium and chloride in males at 300 mg/kg bw/day and calcium at 1000 mg/kg bw/day (at the end of treatment) and for ASAT at 1000 mg/kg bw/day (at the end of recovery) were considered not to be toxicologically significant as they occurred in the absence of a treatment-rel ated distribution and/or remained within the range considered normal for rats of this age and strain. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Hearing ability, pupillary reflex and static righting reflex were normal in all selected animals.
No toxicologically relevant effects were observed in fore and hind limb grip strength in selected male and female rats.
The increased mean value for fore limp grip strength in males treated at 300 mg/kg bw/day, achieving a level of statistical significance when compared to controls, was a fortuitous finding and in the absence of a dose related effect considered of no toxicological significance.
The total movements and ambulations determined in the motor activity test in main males and females were similar in all groups.
In recovery animals, relatively high values for total movements and ambulations were observed in the recovery control males when compared to main control males, whereas those values were comparable be tween recovery high dose main and recovery males. These values were within the normal limits and were considered to be of no toxicological significance.
The motor activity in recovery females was considered to be similar between controls and the high dose group, but slightly lower than seen in the main females. The difference between main and recovery females might be related to the fact that the main females were pregnant at the moment of motor activity assessment and the recovery females not. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no test item-related morphologic alterations following treatment of Wistar (Han) rats up to 1000 mg/kg bw/day for at least 28 days.
- Histopathological findings: neoplastic:
- 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
- Description (incidence and severity):
- Fertility and conception index were considered not to be affected by treatment.
A total of three females, one control, one at 100 mg/kg bw/day and one at 300 mg/kg bw/day, were not pregnant. In the absence of a dose-related incidence of non-pregnancy, this was not considered to be related to treatment.
Details on results (P0)
Effect levels (P0)
- 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 effects on reproduction observed.
Target system / organ toxicity (P0)
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs occurred among pups that were considered to be related to treatment.
The nature and incidence of clinical signs observed remained within the range considered normal for pups of this age, and were therefore not considered to be toxicologically relevant. - Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- No mortality occurred among pups that was considered to be related to treatment with the test item.
Two pups, one in a litter of the 300 mg/kg bw/day group and one in a litter of the 1000 mg/kg bw/day group, were found dead at first litter check and five pups went missing during the lactation phase, i.e. two in control litters, one in a litter at 100 mg/kg bw/day, one in a litter at 300 mg/kg bw/day and one in a litter at 1000 mg/kg bw/day. Pups missing were most likely cannibalised.
No toxicological relevance was attributed to these dead and missing pups since the mortality rate remained within the range considered normal for this type of studies with rats of this age and strain. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weights of pups were not considered to be affected by treatment.
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No macroscopic findings were noted among pups that were considered to be related to treatment.
The few macroscopic findings in pups surviving to termination were confirmations of the (incidental) clinical signs observed in these pups during lactation. Macroscopic findings in pups that were found dead included partial cannibalism and absence of milk in the stomach. The nature and incidence of all these macroscopic findings remained within the range considered normal for this type of studies with rats of this age and strain, and were therefore not considered to be toxicologically relevant. - Histopathological findings:
- not examined
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 observed.
Target system / organ toxicity (F1)
- Critical effects observed:
- no
Overall reproductive toxicity
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- In the Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, conducted according to an appropriate OECD test guideline and in compliance with GLP, the reported NOAEL for the test substance, trimethyl(octadecyloxy)silane in stearyl alcohol, for reproductive toxicity was ≥ 1000 mg/kg bw/day, which was the highest dose tested. No adverse effects were observed in any of the animals.
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