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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
7 April 2016 to 21 July 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
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:
EU Method 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: 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: OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents
Version / remarks:
2000
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane
EC Number:
241-881-3
EC Name:
1,1,1,3,5,5,5-heptamethyl-3-octyltrisiloxane
Cas Number:
17955-88-3
Molecular formula:
C15H38O2Si3
IUPAC Name:
2,2,4,6,6-pentamethyl-4-octyl-3,5-dioxa-2,4,6-trisilaheptane
Test material form:
liquid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Expiration date of the lot/batch: 04 June 2017
- Purity test date: no data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: In refrigerator (2-8°C)
- Stability under test conditions: stable
- Solubility and stability of the test substance in the solvent/vehicle: Predicted solubility = 2.8E-05 mg/L at 20°C

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and test substance.
- Preliminary purification step (if any): No correction was made for the purity/composition of the test item.

FORM AS APPLIED IN THE TEST: diluted in corn oil

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: 10 weeks males and 11 weeks females
- Weight at study initiation: all animals within ± 20% of the sex mean
- Fasting period before study: none
- Housing: During pre-mating the animals were housed in groups of 5 animals/sex/cage in Macrolon plastic cages. During mating main group females were caged together with main group males on a oneto-one-basis in Macrolon plastic cages. During post-mating period main group males were housed in their home cage with a maximum of 5 animals/cage; main group females were individually housed in Macrolon plastic cages.
- Diet: pelleted rodent diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days

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 - 24°C
- Humidity (%): 40 - 70%
- Air changes (per hr): 10/ hour
- Photoperiod (hrs dark / hrs light): 12/ 12

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: Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and test substance. No correction was made for the purity/composition of the test item.

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil was the chosen vehicle
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses were conducted during the treatment phase in Week 1 and Week 6, according to a validated method. Samples of formulations were analysed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations).
Duration of treatment / exposure:
Main and recovery males: 29 days
Main females: 41 to 47 days
Recovery females: 43 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:
Main group: 10 males and 10 females
Recovery group: 5 males and 5 females (control and high dose)
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based on toxicity results of a 14-day dose range finding study.
- Rationale for animal assignment (if not random): The animals were assigned randomly.
- Rationale for selecting satellite groups: Recovery groups were selected for the control and high dose group.
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random): random

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at lest once daily for clinical signs and twice daily for mortality and viability
- Cage side observations checked included: clinical signs of toxicity, mortality, viability

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once prior to start of treatment and at weekly intervals during the treatment period this was also performed outside the home cage in a standard arena.

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of exposure (prior to first exposure) and weekly thereafter. Mated Main females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 postcoitum and during lactation on Days 1 and 4.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the treatment period on the day of scheduled necropsy
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (deprived from food overnight)
- How many animals: 5 animals/sex/group
- Parameters checked in table [No.1] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment period on the day of scheduled necropsy
- Animals fasted: Yes (deprived from food overnight)
- How many animals: 5 animals/sex/group
- Parameters checked in table [No.1] were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: The selected main males and all recovery males were tested during Week 4 of treatment, and the selected main females were tested towards the last week of lactation (from lactation Day 4 onwards) and all recovery females were tested on the first day a main female was tested. These tests were performed after observation for clinical signs (incl. arena observation, if applicable) at no specific time point, but within similar time period after dosing for the respective animals.
- Dose groups that were examined: all test animals
- Battery of functions tested: sensory activity / grip strength / motor activity / other: hearing ability; pupillary reflex; static righting reflex; ambulations

IMMUNOLOGY: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table No. 2)

HISTOPATHOLOGY: Yes (see table No. 2)
Statistics:
• If the variables could be assumed to follow a normal distribution, the Dunnett-test based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
• The Steel-test was applied if the data could not be assumed to follow a normal distribution.
• The Fisher Exact-test was applied to frequency data.
• The Kruskal-Wallis nonparametric ANOVA test was applied to motor activitydata to determine intergroup differences.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs or abnormalities during weekly arena observations were noted during the observation period that were considered to be related to treatment.
Any clinical signs noted during the treatment period 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 and did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment.
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No toxicologically relevant changes in body weight were noted.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
At 1000 mg/kg, an elongated mean activated partial thromboplastin time (APTT) was recorded for males at the end of treatment. The mean remained within the range considered normal for rats of this age and strain and at the end of the recovery period, mean activated partial thromboplastin time was similar to controls.
The statistically significant lower red blood cell counts and haematocrit of females at 300 mg/kg at the end of treatment occurred in the absence of a dose-related trend. As such this was considered to be unrelated to treatment.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No toxicologically relevant changes occurred in clinical biochemistry parameters of treated rats.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No toxicologically relevant effects on hearing ability, pupillary reflex, static righting reflex and grip strength were observed in selected animals. Motor activity was similar between treated and control groups. All groups showed a similar motor activity habituation profile with a decreasing trend in activity over the duration of the test period. One male at 100 mg/kg had an absent pupillary reflex of the right eye and had a white stain on the eye. Given the incidental nature of this finding, this was considered unrelated to treatment with the test item.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No toxicologically relevant changes in organ weights were recorded. There was a minimal statistically significant increase in liver weights (absolute only) in main group females treated at 300 and 1000 mg/kg/day without any correlating findings at necropsy or after microscopic evaluation. Also, the liver weights were all within the range expected for female rats of this age and strain treated in this type of study and therefore not considered to be toxicologically relevant.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test item-related gross observations. All of the recorded macroscopic findings were within the range of background gross observations encountered in rats of this age and strain.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no test item-related microscopic observations. Slight vacuolation in the zona fasiculata of the adrenal glands was recorded in 1 male of the 100 mg/kg/day main group and 1 male of the 1000 mg/kg/day main group and in 2 males of the 1000 mg/kg/day recovery group. Based on the absence of a clear dose-relationship and the fact that slight vacuolation in the zona fasciculata can be observed as a background finding in control rats (although this was not the case in the present study), the adrenal gland finding is not considered to be test item related.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified

Effect levels

Key result
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 28-day repeated dose toxicity study with the reproduction/ developmental toxicity screening test, the reported NOAEL was greater than 1000 mg/kg bw. No treatment-related changes were observed in any of the test animals.