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Diss Factsheets

Administrative data

Endpoint:
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:
other: 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:
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:
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)
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, re spectively, 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
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.
Details on mating procedure:
- Impregnation procedure: cohoused
- 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
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

Examinations

Maternal 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.
POST-MORTEM EXAMINATIONS: Yes
- 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
- Organs examined: See table 1
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: Not examined
- Number of late resorptions: Not examined
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [all per litter]
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
Indices:
Mating index, fertility index, conception index, gestation index, viability index.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

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):
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 w ith 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.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
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 changes 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.
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 total movements and ambulations determined in the motor activity test in main males and females were similar in all groups.
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.
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.
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

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
Examination of cage debris of pregnant females revealed no signs of abortion or premature birth. No deficiencies in maternal care were observed.
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
not examined
Early or late resorptions:
not examined
Dead fetuses:
no effects observed
Description (incidence and severity):
Examination of cage debris of pregnant females revealed no signs of abortion or premature birth. No deficiencies in maternal care were observed.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Gestation index and duration of gestation were not considered to be affected by treatment.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): Gestation index and duration of gestation were not considered to be affected by treatment.
Changes in number of pregnant:
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 maternal toxic effects:
Formulation analysis showed that the formulations were prepared accurately and homogenously.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed.

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Body weights of pups were not considered to be affected by treatment.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Body weights of pups were not considered to be affected by treatment.
Reduction in number of live offspring:
no effects observed
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 group and one in a litter of the 1000 mg/kg 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, one in a litter at 300 mg/kg and one in a litter at 1000 mg/kg. 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.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratio was not considered to be affected by treatment.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
No mortality occurred among pups that was considered to be related to treatment with the test item.
External malformations:
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.
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental 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 developmental toxicity was ≥ 1000 mg/kg bw/day, which was the highest dose tested. No adverse effects were observed in any of the animals.