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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
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:
2017
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/Developmental Toxicity Screening Test
Version / remarks:
2000
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: OECD 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:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study 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

Constituent 1
Chemical structure
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
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 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.
- 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-to-one-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 material 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
Details on route of administration:
Oral gavage, using a plastic feeding tube. Formulations were placed on a magnetic stirrer during dosing.
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: 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 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 amount of vehicle was added and homogenized to a visibly acceptable level. Adjustment was made for specific gravity of the test item (i.e. 0.82) and vehicle (i.e. 0.92). No correction was made for the purity/composition 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 acceptable 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
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 method. Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy 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
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
Positive control:
Not used

Examinations

Observations and examinations performed and frequency:
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 post-coitum and during lactation on PND 1 and 4.

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples were collected at the end of the treatment period on the day of scheduled necropsy. Blood samples were also collected at the end of recovery period.
- Anaesthetic used for blood collection: Yes (isoflurane )
- Animals fasted: Yes
- How many animals: 5 Main animals/sex/group
- Parameters checked in table [No.1 Haematology and clinical chemistry parameters] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood samples were collected at the end of the treatment period on the day of scheduled necropsy. Blood samples were also collected at the end of recovery period.
- Animals fasted: Yes
- How many animals: 5 Main animals/sex/group
- Parameters checked in table [No.1 Haematology and clinical chemistry parameters] were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during Week 4 of treatment
- Dose groups that were examined: Main males and all Recovery males
- Battery of functions tested: sensory activity / grip strength / motor activity

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table No 2 Gross necropsy and tissue preparation (checked (X) collected (column C), weighed (column W) and examined for histopathology)

HISTOPATHOLOGY: Yes (see table No 2 Gross necropsy and tissue preparation (checked (X) collected (column C), weighed (column W) and examined for histopathology)
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

Results and discussion

Results of examinations

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 controls. The body weight gain in high dose recovery males at the start of recovery (when compared to study day 1), was statistically significantly lower than in the control recovery males. The increase in difference in mean body weights between control and high dose males over one day (from 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-mated, 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. Based on there being no clear changes in the differential white blood cells counts and 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 1000 mg/kg bw/day 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 toxicologically 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 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-related 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 between 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
Description (incidence and severity):
Organ weights and organ to body weight ratios of treated animals were considered to be similar to those of control animals.
Statistically significantly higher relative kidney and adrenals weights were found in males treated at 1000 mg/kg bw/day. As the increases were minimal, all individual values were within the normal range and the absence of microscopic findings in the organs, these findings were considered of no toxicological significance.
A minimally increased splenic weight was observed in females at 1000 mg/kg bw/day, achieving levels of statistical significance for absolute and relative weights. Since all individual spleen weights were within the normal range for female rats of this strain and age and in the absence of any microscopic observation in this organ, this finding was considered of no toxicological relevance.
The statistically significant difference between thymic weights in males treated at 300 mg/kg bw/day and control animals had occurred by chance and in the absence of a dose effect relationship considered not to be a sign of toxicity. Moreover, all individual thymic weight values were within the normal limits.
In recovery high dose males, the absolute weight of the seminal vesicles were statistically significantly lower than in the controls. As the relative weights of the seminal vesicles were comparable, this difference in mean absolute weight of the seminal vesicles was related to the difference also noted in body weights between the two groups and a relation to treatment was not suspected.
In recovery females, a difference in mean splenic weights between controls and the high dose group was apparent at the end of the recovery period, achieving a level of statistical significance for the absolute as well the relative weights. Similar as noted in the main females all individual spleen weights were within the normal range for female rats of this strain and age and this finding was considered of no toxicological relevance.

Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment.
The incidence of other incidental findings among control and treated animals was within the background range of findings that are encountered among rats of this age and strain, and did not show a dose-related incidence trend.
Neuropathological findings:
not examined
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
Details on results:
Formulation analysis showed that the formulations were prepared accurately and homogenously.

Effect levels

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 observed.

Target system / organ toxicity

Critical 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 (OECD 422) and in compliance with GLP, the reported NOAEL for the test substance, trimethyl(octadecyloxy)silane in stearyl alcohol, for repeated dose toxicity was greater than 1000 mg/kg bw/day, which was the highest dose tested. No adverse effects were observed in any of the test or recovery animals.