Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16 January 2001 to 27 February 2001
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Conducted according to a guideline similar to OECD 412. Original report in Japanese, English translation available.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: Japanese Guidelines on Industrial Chemicals (Kanpogyo no. 5, Yakuhatsu no. 615, 49Kikyoku no. 392, 1971; Revised Kanpogyo no. 700, Yakuhatsu no. 1039, 61Kikyoku no. 1014, 1986
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
full tissue list not examined
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: gas

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Japan Inc
- Age at study initiation: 5 weeks
- Weight at study initiation: males 154 - 202g, females 117 - 155g
- Fasting period before study: no
- Housing: up to 2 of same sex in polycarbonate cages with sterilized hard wood bedding
- Diet (ad libitum): pelleted diet (MF, Oriental Yeast Industry Co.)
- Water (ad libitum): tap water
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.1 - 24.6
- Humidity (%): 33.6 - 61.2
- Air changes (per hr): approx. 12
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 16 January 2001 To: 27 February 2001

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 95 L inhalation chamber
- Method of holding animals in test chamber: individually in wire mesh cages
- Source and rate of air: compressed air at 20 L/min
- Method of conditioning air: not stated
- System of generating vapour: the test substance gas was filled in a high pressure gas cylinder, adjusted to 0.08 MPa, was then diluted with clean compressed air top prepare the gas at a concentration of 5.0 mg/L. This was diluted serially to each target concentration, and each dilution fed into the inhalation chamber by the one-pass method.
- Temperature, humidity, oxygen concentration in chamber: 23.0 - 25.2 degrees C, 32% - 53% RH, 20.6 - 21.0%
- Air flow rate: 20 L/min
- Air change rate: 12.6 air changes/hour
- Method of particle size determination: not applicable - gas
- Treatment of exhaust air: not stated

TEST ATMOSPHERE
- Brief description of analytical method used: hydrocarbon meter (HCM-1B, Shimadzu Corporation) and FID gas chromatography
- Samples taken from breathing zone: no (exhaust gas analysed)

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Hydrocarbon meter and FID gas chromatography (no further details given).
Duration of treatment / exposure:
28 days followed by 14 day recovery period for subgroup of Control and high dose animals
Frequency of treatment:
daily, 6 hours per day
Doses / concentrationsopen allclose all
Dose / conc.:
0.19 mg/L air (analytical)
Remarks:
0.2 mg/L (nominal)
Dose / conc.:
0.87 mg/L air (analytical)
Remarks:
1.0 mg/L (nominal)
Dose / conc.:
4.73 mg/L air (analytical)
Remarks:
5.0 mg/L (nominal)
No. of animals per sex per dose:
12 for Control and high dose, 6 for low and intermediate dose
Control animals:
yes
Details on study design:
- Dose selection rationale: 14-day dose range finding study, no effects noted up to 5 mg/L

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (before and after treatment)

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: once weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/rat/day: Yes
- Time schedule for examinations: once weekly

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to necropsy (Days 29 or 43)
- Anaesthetic used for blood collection: Yes (thiopental sodium)
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table No.1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to necropsy (Days 29 or 43)
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table No.2 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: Day 24
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table No.3 were examined.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)
Statistics:
The significance of differences in mean data was assessed by multiple comparison. The data were tested for homogeneity of variance by Bartlett's test. If the variance was homogenous, possible intergroup differences were assessed by the one-way analysis of variance. If the variance was heterogenous, possible intergroup differences were assessed by the Kruskal-Wallis test. If any significant intergroup differences were detected, the subsequent identification of the groups was carried out by Dunnett's method or Dunnett-type multiple comparison. The significance of differences in counted data was assessed by the a x b Chi-square test. If a significant difference was noted, each dose group was compared with the control group by Armitage's Chi-square test. Differences with P<0.05 were considered statistically significant.

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
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: no effect of treatment.

BODY WEIGHT AND WEIGHT GAIN: no effect of treatment.

FOOD CONSUMPTION: no effect of treatment.

HAEMATOLOGY: lower activated partial thromboplastin time noted in 4.73 mg/L females but was within historical control range and therefore considered unrelated to treatment.

CLINICAL CHEMISTRY: higher potassium and lower urea nitrogen and higher chloride were noted but as none of these changes were noted in the high dose group, were considered unrelated to treatment.

URINALYSIS: no effect of treatment.

ORGAN WEIGHTS: higher relative spleen weight noted at end of recovery period for high dose females. As this was not noted at the end of the treatment period, or in males, it was considered to be unrelated to treatment.

GROSS PATHOLOGY: no effect of treatment.

HISTOPATHOLOGY: NON-NEOPLASTIC: at the end of treatment and recovery, histopathological examination revealed changes including focal myocardial degeneration/fibrosis in the heart, capsulitis and development of germinal centres in the spleen, accumulation of foam cells and osseous metaplasia in the lungs, periportal fatty change in hepatocytes, focal inflammatory cell infiltration and microgranuloma in the liver, basophilic proximal tubules, cysts, dilatation of the pelvis, focal fibrosis, hyaline droplets in the epithelium of proximal tubules, focal lymphocyte infiltration in the interstitum and mineralization in the corticomedullary junction or medulla in the kidneys, diffuse atrophy of seminiferous tubules in the testes and hyperplasia of Rathket's pouch in the posterior lobe of the pituitary. These changes were considered to be unrelated to treatment as they were spontaneous changes in rats and because there was no clear group-related difference in incidence or severity.

Effect levels

Key result
Dose descriptor:
NOAEC
Effect level:
4 730 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects noted up to 4.73 mg/L, the highest concentration tested.

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Repeat-dose inhalation administration of trimethylsilane to rats by whole-body exposure for 28 consecutive days did not result in any findings attributable to treatment. The No-Observed-Adverse-Effect-Concentration (NOAEC) was therefore considered to be 4730 mg/m3 (4.73 mg/L), the highest concentration tested.