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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:
2003-04-30 to 2003-11-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
1995
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
002897-60-1
Cas Number:
002897-60-1
IUPAC Name:
002897-60-1
Constituent 2
Reference substance name:
[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane
IUPAC Name:
[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane
Constituent 3
Chemical structure
Reference substance name:
[3-(2,3-epoxypropoxy)propyl]diethoxymethylsilane
EC Number:
220-780-8
EC Name:
[3-(2,3-epoxypropoxy)propyl]diethoxymethylsilane
Cas Number:
2897-60-1
Molecular formula:
C11H24O4Si
IUPAC Name:
diethoxy(methyl){3-[(oxiran-2-yl)methoxy]propyl}silane
Test material form:
other: liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Ltd, UK
- Age at study initiation: 5-6 weeks old
- Weight at study initiation: males 109 to 154g; females 110 to 152g
- Housing: in groups of 5 in polypropylene grid-floor cages
- Diet: pelleted diet (Rodent 5LF2 (Certified) Diet), ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2°C
- Humidity (%): 55 ± 15%
- Air changes (per hr): 15/ hour
- Photoperiod (hrs dark / hrs light): 12/ 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test material was prepared at the appropriate doses as a suspension in dried Arachis Oil BP. Formulations were stable for at least 14 days. Formulations were prepared weekly and stored at approximately +4°C in the dark under silica gel.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of test material in the formulations was determined by gas chromatography (GC) using an external standard technique. The test material formulations were extracted with acetonitrile to give a final, theoretical test material concentration of approximately 0.05 mg/ml. Standard solutions of test material was prepared in acetonitrile at a nominal concentration of 0.05 mg/mI. The test material formulations were mixed thoroughly and samples were taken from the top, middle and bottom ofthe container. Sampling was performed in triplicate. The test material formulations were sampled and analysed initially and then after storage at approximately +4°C in the dark for fourteen days. The test material formulations were sampled and analysed within two days of preparation.
Duration of treatment / exposure:
28 days.
Frequency of treatment:
7 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Dose / conc.:
150 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:
5 male and 5 female rats per dose
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on dose range finding test



Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: immediately before dosing and at 1 and 5 hours post-administration during the working week; immediately before dosing and at 1 hour after dosing during the weekends.

BODY WEIGHT: Yes
- Time schedule for examinations: individual body weights were recorded on days 0 (before the start of the treatment), 7, 14, 21 and 28. Also recorded at terminal kill.

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: Yes

FOOD CONSUMPTION:
- Food consumption was recorded for each cage group at weekly intervals throughout the study.

WATER CONSUMPTION:
- Water intake was observed daily, for each cage group, by visual inspection of the water bottles.

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 28 (the end of the study)
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: all test and control animals
- Parameters checked in table [No.2] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day 28 (the end of the study)
- Animals fasted: No
- How many animals: all test and control animals
- Parameters checked in table [No. 1] were examined.

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to the start of the treatment, on days 7, 13, 20 and 27
- Dose groups that were examined: all test and control animals
- Battery of functions tested: Motor activity; forelimb/ hindlimb grip strength; sensory reactivity

Sacrifice and pathology:
GROSS PATHOLOGY: Yes. When the dosing period was completed, all animals were killed by intravenous overdose injection of sodium pentobarbitone. Macroscopic abnormalities were recorded (Table 3).

HISTOPATHOLOGY: Yes. Tissue samples were taken from all the animals and preserved in buffered 10 % formalin. The examined tissues were: adrenals, aorta, bone and bone marrow, brain (including cerebellum, cerebrum and pons), caecum, colon, duodenum, epididymides, eyes, gross lesions, heart, oesophagus, ovaries, pancreas, pituitary, prostate, rectum, salivary glands, sciatic nerve, seminal vesicles, skin, spinal cord, spleen, ileum, jejunum, kidneys, liver, lungs, lymph nodes, muscle, stomach, testes, thymus, thyroid/parathyroid, urinary bladder, uterus, trachea (Table 3).
Other examinations:
ORGAN WEIGHTS:
The organs examined at the end of the study were dissected free from fat and weighed before fixation. The examined organs were: adrenals, brain, epididymides, heart, kidneys, liver, ovaries, spleen, testes, thymus (Table 3).
Statistics:
Group mean values were calculates. Appropriate standard deviations were included. Haematological, blood chemical, organ weight, weekly body weight gain, quantitative functional performance and sensory reactivity data were assessed for dose response relationship linear regression analysis, followed by one way analysis of variance (ANOVA) incorporating Levene's test for homogeneity of variance. Where variances were shown to be homogenous, pairwise comparison were conducted using Dunnett's test. Where Levene's test showed unequal variances, the data were analysed using non-parametric methods: Kruskal-Wallis ANOVA and Mann-Whitney 'D' test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Slight reduction in food consumption in female group, in comparison with the control group. No clear dose relationship, thus considered not to be toxicologically important. Food consumption in males was similar to the control group.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No intergroup differences
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related changes were detected
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment-related differences were detected in the blood
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No treatment-related changes were detected
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No treatment-related orgain weights changes were detected
Gross pathological findings:
no effects observed
Description (incidence and severity):
No abnormalities were noted
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: No mortality was noted during the 28-day study period.

BODY WEIGHT AND WEIGHT GAIN: No adverse effect on body weight gain was observed.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Slight reduction in food consumption in females, in comparison with the control group. No clear dose relationship, thus considered not to be toxicologically important. Food consumption in males was similar to the control group.

FOOD EFFICIENCY: No treatment-related changes in food efficiency were observed.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No treatment-related changes in water consumprion were observed.

HAEMATOLOGY: No treatment-related changes were detected in the haematological parameters measured.

CLINICAL CHEMISTRY: There were no treatment-related or statistically significant differences detected in the blood chemical parameters measured.

NEUROBEHAVIOUR: During the open-field assessment, hunched posture was noted in one female treated with 1000 mg/kg/day. The isolated finding was associated with the dosing procedure. No such observations were reported in any other test animal.

Males treated with 1000 mg/kg/day showed a statistically significant increase (p<0.05) in forelimb grip strength compared with controls. No such changes were detected in females treated with 1000 mg/kg/day or in animals from the remaining treatment groups. In the absence of any associated changes an increase in this parameter was considered unlikely to be toxicologically significant.

There were no treatment-related changes in sensory reactivity.

ORGAN WEIGHTS: Statistically significant findings were confined to males treated with 1000 mg/kg/day and involved a reduction (p<0.001) in relative thymus weight compared with controls. However, all individual values were within the historical ranges for rats of this strain and age and in the absence of any histopathological evidence of a treatment-related effect, this reduction was considered to be without toxicological importance. No toxicologically significant organ weight changes were detected.

GROSS PATHOLOGY: No treatment-related macroscopic abnormalities were noted.

HISTOPATHOLOGY: All morphological changes detected were those commonly observed in laboratory maintained rats of the age and strain employed, and there were no differences in incidence or severity between control and treatment groups that were considered to be of toxicological significance.

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 28-day oral repeated dose toxicity study, conducted according to OECD TG 407, and in compliance with GLP, a NOAEL value of >= 1000 mg/kg/bw was reported for [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane.