Triethoxy(2,4,4-trimethylpentyl)silane

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Triethoxy(2,4,4-trimethylpentyl)silane

EC Number:

252-558-1

EC Name:

Triethoxy(2,4,4-trimethylpentyl)silane

Cas Number:

35435-21-3

Molecular formula:

C14H32O3Si

IUPAC Name:

triethoxy(2,4,4-trimethylpentyl)silane

Test material form:

liquid

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Age at study initiation: males: 7-8 weeks old, females: 7-8 weeks old.
- Weight at study initiation: males: 151.1 – 184.6 g; females: 122.0 – 148.1 g
- Fasting period before study: not indicated
- Housing: Animals of the same sex were housed in groups of up to five in type IV polysulphone cages on Altromin saw fibre bedding (lot no. 02102140605)
- Diet (e.g. ad libitum): Free access to Altromin 1324 maintenance diet for rats and mice (lot no. 1526)
- Water (e.g. ad libitum): Free access to tap water, sulphur acidified to a pH of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals)
- Acclimation period: minimum 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 10 x / hour
- Photoperiod (hrs dark / hrs light): Artificial light, sequence being 12 hours light, 12 hours dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

The test item formulation or vehicle was administered at a single dose to the animals by oral gavage. The application volume for all groups was 5 mL/kg body weight.

For each animal the individual dosing volume was calculated on the basis of the body weight most recently measured.

The doses were selected in consultation with the sponsor.

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Stability of the dosing formulations was tested once at the beginning of the treatment period. In the first week of treatment, at the beginning of the second month of treatment and at the end of the treatment period, samples for the testing of homogeneity were taken from the top, middle and bottom of the freshly prepared high and low-dose formulations and stored between -15 and -35 °C.

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily, 7 days per week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

15 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

150 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10/sex/dose

Details on study design:

The highest dose level was chosen with the aim of inducing toxic effects, but no death or severe suffering. Thereafter, a descending sequence of dose levels was selected with a view to demonstrate any dosage related response and NOAEL.
The animals in the control group were handled in an identical manner to the test group subjects and received corn oil using the same volume as used for the high dose group.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once before the first administration and at least once a week thereafter

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Minimum once a day, twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily.

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight was recorded once before the assignment to the experimental groups, on the first day of administration and weekly during the treatment and recovery period.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No, food consumption was measured weekly during the treatment and recovery period.

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmological examination, using an ophthalmoscope was made at the first administration and in the last week of the treatment period.
- Dose groups that were examined: All animals, as well as at the end of the recovery period in the recovery animals.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the treatment and recovery period, prior to or as part of the sacrifice of the animals.
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- Parameters checked: haematocrit, haemoglobin content, red blood cell count, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular concentration, reticulocytes, platelet count, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, large unstained cells, coagulation parameters (prothrombin time, activated partial thromboplastin time)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment and recovery period prior to or as part of the sacrifice of the animals
- Animals fasted: No data
- Parameters checked: alanine aminotransferase, aspartate-aminotransferase, alkaline phosphatase, creatinine, total protein, albumin, urea, total bilirubin, total bile acids, total cholesterol, glucose, potassium, sodium

URINALYSIS: Yes
- Time schedule for collection of urine: prior to or as part of the sacrifice of the animals
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: specific gravity, nitrite, pH, protein, glucose, ketone bodies, urobilinogen, bilirubin, blood, leukocytes.

FUNCTIONAL OBSERVATIONS: Yes
- Time schedule for examinations: Once before the first exposure and once in the last week of the recovery period.
- Dose groups that were examined: All animals
- Battery of functions tested: other: sleep, moving around cage, piloerection, vocalisation, grooming, grip strength, visual palcing, positional passivity, equilibrium reflex, startle response, sterotypical behaviour, unusual behaviour, seizures, twitches, tremors, gait etc.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes.

-Organs weighed at necropsy: liver, kidneys, adrenals, testes, epididymides, prostate, seminal vesicles, coagulating glands, ovaries, uterus with cervix, thymus, thyroid/parathyroid glands, spleen, brain, pituitary gland, heart. The wet weight of the organs of all sacrificed animals was taken from sacrificed animals as soon as possible. Paired organs were weighed together.

-Preserved and examined tissues: brain, spinal cord, eye, liver, kidneys, adrenal glands, stomach, heart, ovaries, uterus with cervix, vagina, testes, apididymides, prostrate and seminal vescles with coagulating glands as a whole. Small and large intestines, thymus, thyroid glands, spleen, lung and trachea, mammary glands, skin, urinary bladder, lymphnodes, perpheral nerve with skeletal muscle, sternum with bone marrow, pituitary gland, oesophagus

HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No test item related clinical findings were observed in this study. The clinical findings were either rare incidental findings or were observed in similar frequency also in control animals. The effects are not considered to be adverse.

Mortality:

no mortality observed

Description (incidence):

No mortality occurred in the control or any of the dose groups during the treatment period of this study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

The body weight development of all groups was within the expected range of variation with no test item related effects. In accordance to the body weight development no effects on food consumption were recorded.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Description (incidence and severity):

No influence of triethoxy(2,4,4-trimethylpentyl)silane on any of the analysed parameters of hematology and blood coagulation independent of the gender of the animals was observed at the end of the treatment and after the recovery period.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

All clinical biochemistry parameters analyzed at the end of the treatment and recovery phase did not indicate toxicologically relevant findings which are related to the test item.

Urinalysis findings:

no effects observed

Description (incidence and severity):

Abnormalities observed in urinalysis were incidental findings and are not assumed to be toxicologically relevant. Therefore the test item is assumed to show no effects on parameters of urinalysis.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

No relevant effects were observed in any of the parameters of the functional observation battery with no biologically relevant differences in body temperature between the groups.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Changes in organ weights were either related to female cycle, rare single cases or within normal range of variation with no toxicological relevance.

Gross pathological findings:

no effects observed

Description (incidence and severity):

The recorded pathological changes were either isolated findings, were observed in control animals or were related to female cycle and are therefore considered to be normal background alterations.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathologically adaptive and therefore non-adverse urothelial hyperplasia with minor degree was found in the urinary bladder of males and females receiving 50 mg/kg/day and 150 mg/kg/day.

Histopathological findings: neoplastic:

no effects observed

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse systemic effects were observed in any of the test animals at doses of 15, 50 and 150 mg/kg bw/day.

Target system / organ toxicity

Critical effects observed:

no

Any other information on results incl. tables

Formulation analytics revealed that all samples were stable; the nominal concentrations were confirmed for all dose groups and that all samples were homogenous.

Applicant's summary and conclusion

Conclusions:

In the 90-day oral repeated dose toxicity study, conducted according to OECD Test Guideline 408 and in compliance with GLP, a systemic NOAEL of 150 mg/kg bw/day was concluded based on no treatment-related effects in any of the test animals.