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Diss Factsheets

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:
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/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

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 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)

Formulation analysis showed that the formulations were prepared accurately and homogenously.

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.