2,11-Dioxa-3,10-disiladodecane, 3,3,10,10-tetramethoxy-

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1996-02-20 to 1996-06-07

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study was conducted according to the appropriate OECD test guideline and in compliance with GLP.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reference substance 001

Cas Number:

87135-01-1

Molecular formula:

C12H30O6Si2

Constituent 2

Reference substance name:

3,3,10,10-tetramethoxy-2,11-dioxa-3,10-disiladodecane

EC Number:

617-969-6

Cas Number:

87135-01-1

Molecular formula:

(CH3O)3Si(CH2)6Si(OCH3)3 C12 H30 O6 Si2

IUPAC Name:

3,3,10,10-tetramethoxy-2,11-dioxa-3,10-disiladodecane

Test material form:

other: liquid

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan Inc
- Age at study initiation: 5 wk
- Weight at study initiation: 131.1-152.4 (m); 105.1-133.0 (f)
- Housing: 1/stainless steel hanging cage with wire mesh floor
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: apparently 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/-2
- Humidity (%): 55 +/-10
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: 1996-02-20 From: To: 1996-04-09 (including recovery group)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The test substance was accurately weighed and mixed with olive oil to make 10.0 w/v% solution once per week. Three concentrations of 2.0, 0.4 and 0.08 w/v% were diluted from 10.0 w/v% just before dosing.

VEHICLE
- Justification for use and choice of vehicle (if other than water): none given
- Concentration in vehicle: 2.0, 0.4 and 0.08 w/v% were diluted from 10.0 w/v% just before dosing.
- Amount of vehicle (if gavage): 10 ml/kg bw total volume administered in each case
- Lot/batch no. (if required): 002RNQ, Astra Japan Co., Ltd.
- Purity: not given

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

treatment for 28 days

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 8, 40, 200, 1000 mg/kg bw/day (main groups)
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 200, 1000 mg/kg bw/day (satellite recovery groups)
Basis:
actual ingested

No. of animals per sex per dose:

6

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
- Rationale for animal assignment (if not random): body weight-stratified randomization
- Rationale for selecting satellite groups: none given
- Post-exposure recovery period in satellite groups: 14 days

Positive control:

No

Examinations

Observations and examinations performed and frequency:

[Treatment day is day 1, the day before is day -1, recovery days are also specified]

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: days -2, 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 28. On recovery days 1, 3, 5, 8, 10, 12, 14

FOOD CONSUMPTION AND COMPOUND INTAKE
- Food consumption: Yes - before dosing and twice weekly during dosing and recovery periods.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of dosing and end of recovery
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: all survivors
- Parameters checked in table No.1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of dosing and end of recovery
- Animals fasted: Yes
- How many animals: all survivors
- Parameters checked in table No.1 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: end of dosing (day 28) and recovery day 14
- Metabolism cages used for collection of urine: Yes
- Parameters checked: volume, colour, pH, protein, ketone bodies, bilirubin, occult blood, glucose, urobilinogen, urinary sediment.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 2) - a slightly more limited range of organ weights is provided than is specified in the current guideline.
HISTOPATHOLOGY: Yes (see table 2)

Statistics:

Data regarding body weights, food consumption, haematological examinations, blood chemical examinations, urine volume and organ weights were analysed using Bartlett’s test for homogeneity of variance. If the variances were homogeneous at a significance level of 5%, one way analysis of variance was performed. When there was a significant difference in this analysis, the difference between the vehicle control group and each of the treatment group was analysed by Dunnett‘s test (equal number of data) or Scheff3 test (unequal number of data). If the variances were not homogeneous in the Bartlett’s test, Kruskal-Wallis’s test was used. When there was a significant difference in this test, the difference between the vehicle control group and each of the treatment group was analysed by nonparametric Dunnett’s test (equal number of data) or nonparametric Scheffe’s test (unequal number of data).

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

see below

Mortality:

mortality observed, treatment-related

Description (incidence):

see below

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

see below

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

see below

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

see below

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

see below

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No treatment related deaths. Salivation reported in various groups including the controls was not considered related to the test substance.
BODY WEIGHT AND WEIGHT GAIN
No treatment-related effect on body weight.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No treatment-related effect on food consumption
HAEMATOLOGY
Reported changes: decreased platelet count (1000 mg/kg bw/day females after treatment but no longer evident after recovery); decreased segmented neutrophil ratio (200 and 1000 mg/kg bw/day females after treatment and remaining statistically significant at 200 mg/kg bw/day after recovery); increased haematocrit value (8 and 1000 mg/kg bw/day females after treatment but no longer statistically significant after recovery).
CLINICAL CHEMISTRY
No treatment-related effect.
URINALYSIS
Turbid urine with irregular granules noted at 40, 200 and 1000 mg/kg bw/day males and 200 and 1000 mg/kg bw/day females at the end of dosing.
After the recovery phase no abnormalities were noted in urinalysis.
ORGAN WEIGHTS
No treatment-related effect.
GROSS PATHOLOGY
The kidneys of 1000 mg/kg bw/day males had white regions. These were also noted after the recovery phase in this group
Spleen nodules present in 1000 mg/kg bw/day females were not associated with any histopathological changes and were not considered to be related to treatment. Hydrocephalus also noted in 1000 mg/kg bw/day females was also not considered treatment-related because it was said to have occurred spontaneously.
HISTOPATHOLOGY: NON-NEOPLASTIC
Kidney: interstitial round cell infiltration, fibrosis, pyelitis, basophilic tubules, degeneration and necrosis of the tubules with neutrophils and multinucleate giant cells were noted in the 1,000 mg/kg bw/day males at the end of the dosing period. Increased eosinophilic bodies in the kidney in 200 and 1,000 mg/kg bw/day males were not considered treatment-related as a similar change was also observed in the vehicle control group at the end of the recovery period.
These kidney changes persisted to the end of the recovery period, their extent similar, but fibrosis was then slightly increased.
HISTORICAL CONTROL DATA (if applicable)
Data provided from these laboratories
Segmented neutrophil ratio, eosinophilic bodies in the kidney, degeneration of the tubules and interstitial round cell infiltration in the kidney.

Effect levels

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Urinary effects particularly in males.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

A generally well reported 28-day rat oral study, conducted in accordance with GLP and the current guideline, identified a NOAEL of 8 mg/kg bw/day, based on changes to the urine particularly of male rats at 40 mg/kg bw/day.