Tetraethyl orthosilicate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

No-effect level of subacute tetraethoxysilane inhalation on the mouse kidney.

Author:

Omae K, Nakashima H, Takebayashi T, Uemura T, Ishizuka C, Yamazaki K, Sakurai H

Year:

1995

Bibliographic source:

Journal of occupational health, 37(1): pp. 1-4; Jan 1995.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

yes

Remarks:

limited examinations, males only, limited information on exposure conditions.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetraethyl orthosilicate

EC Number:

201-083-8

EC Name:

Tetraethyl orthosilicate

Cas Number:

78-10-4

Molecular formula:

C8H20O4Si

IUPAC Name:

tetraethyl orthosilicate

Test animals

Species:

mouse

Strain:

ICR

Remarks:

SPF grade

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan, Inc.
- Age at study initiation: Four weeks
- Weight at study initiation: Not specified
- Fasting period before study: Not specified
- Housing: Five per transparent plastic cages with stainless steel wire mesh ceiling
- Diet (e.g. ad libitum): Pelleted rodent food (CRF-1), ad libitum
- Water (e.g. ad libitum): Distilled water, ad libitum
- Acclimation period: One week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 60
- Air changes (per hr): Not specified, filtered air, ventilated
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: Not specified

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Chamber: Tightly sealed 500 Lstainless steel exposure chamber
- Tetraethyl orthosilicate was supplied from an organic solvent vapour generator

TEST ATMOSPHERE
- Brief description of analytical method used: GC
- Samples taken from breathing zone: Not specified

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

monitored at 10 minute intervals by means of GC

Duration of treatment / exposure:

6 hours/day for 2 or 4 weeks

Frequency of treatment:

5 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 ppm (analytical)

Doses / concentrations 2

Dose / conc.:

100 ppm (analytical)

No. of animals per sex per dose:

10M

Control animals:

other: filtered room air

Details on study design:

- Dose selection rationale: Not specified
- Rationale for animal assignment (if not random): Not specified
- Rationale for selecting satellite groups: No satellite groups
- Post-exposure recovery period in satellite groups: No post-exposure recovery period

Positive control:

None

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Behaviour and external appearance checked daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Weighed on Monday, Wednesday, and Friday prior to exposure

FOOD CONSUMPTION: No

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Not specified
- Anaesthetic used: Not specified
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked in Table 1 below were determined

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Not specified
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked in Table 1 below were determined

URINALYSIS: Yes
- Time schedule for collection of urine: Every Friday night
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Not specified
- Parameters checked in Table 1 below were determined

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

SACRIFICE
The mice were sacrificed by exsanguination 2 days after the final exposure.

GROSS PATHOLOGY: Yes
As described, their organs were examined grossly.

HISTOPATHOLOGY: Yes
The tissues identified in Table 2 below were subjected to microscopic examination.

Statistics:

Student's t test or Welch's methods were adopted for the statistical test of difference between means of the effects indices.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

Immediately after being exposed on each day, most mice began to perform face-washing movements and lick the lower abdomen for short periods more frequently than non-exposed mice. Finding is considered non-adverse.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No differences were observed between the exposed and non-exposed groups in body weight gain.

Food consumption and compound intake (if feeding study):

not examined

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):

RBC, Hb and Ht values were lower in exposed mice than in non-exposed mice, mixed statistical results (see Table 3 below). The proportion of neutrophils were significantly higher at 50 and 100 ppm in the 2-week study, but not in the 4-week. The neutrophil count (not shown) was significantly higher at 100 ppm in the 4-week study.

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

Description (incidence and severity):

Kidney weights were slightly lower at 50 and 100 ppm, after 2- or 4-weeks of exposure (not significant). No trends reported for lung, liver, or spleen weight.

Gross pathological findings:

no effects observed

Description (incidence and severity):

“Organs were examined,” but no findings reported.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In the kidney, 2/10 mice exposed to 100 ppm for 2 weeks and 2/10 mice exposed to 100 ppm for 4 weeks developed histopathological lesions (tubulo-interstitial nephritis). The lesions were wedge-shaped and extended from the cortex into the medulla. In the affected regions, small numbers of neutrophils and mononuclear inflammatory cells had infiltrated interstitial tissue, and some tubules were dilated, exhibiting atrophy and obliteration. No kidney lesions were observed in mice exposed to 50 ppm.

Inflammation of the nasal mucosa was observed in almost all the mice (9/10 to 10/10) exposed to 50 ppm or 100 ppm, for 2 or 4 weeks. Exudates containing inflammatory cells and necrotic epithelial cells were observed in the nasal cavity, inflammatory cell infiltration in submucosal tissue, and eosinophilic hyaline droplets predominantly in the olfactory epithelium. The findings were slightly more severe in the mice exposed to 100 ppm.

In the bone marrow, increases in the M: E ratio were observed, no further details provided.

No lesions were observed in the liver, lungs, respiratory tract, spleen, pancreas, thymus, thyroid, or cornea.

Effect levels

Key result

Dose descriptor:

NOAEC

Effect level:

< 50 ppm (analytical)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Nasal cavity histopathology (inflammation) and haematology findings, noting renal histopathology at 100 ppm

Target system / organ toxicity

1

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

100 ppm (analytical)

System:

urinary

Organ:

kidney

Treatment related:

yes

2

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

50 ppm (analytical)

System:

respiratory system: upper respiratory tract

Organ:

nasal cavity

Treatment related:

yes

Any other information on results incl. tables

Concentrations of tetraethyl orthosilicate (Mean +/- SD):
Exposure level of 100 ppm:
2 weeks: 100 +/- 4
4 weeks: 101 +/- 5

Exposure level of 50 ppm:
2 weeks: 51 +/- 3
4 weeks: 51 +/- 3

 

Table 3 Summary of haematological findings following two and four weeks exposure.

 

Exposure Concentration (ppm)	Two week exposure			Four week exposure
	100	50	0	100	50	0
RBC (x10000/µ l)	823± 60*	866± 51	895± 60	840± 39	815± 36*	859± 35
Hg (g/dl)	-	-	-	14.1± 0.5*	13.7± 0.5**	14.7± 0.6
Ht (%)	42.9± 3.2**	45.1± 2.7	47.5± 3.2	43.1± 1.4	42.3± 1.6**	44.6± 1.8
WBC (x100 µ l)	-	-	-	36± 13	21± 6	28± 14
Neutrophil (%)	30± 10**	27± 5*	13± 7	34± 9	24± 11	25± 18
Lymphocyte (%)	68± 10**	72± 5**	85± 7	64± 9	75± 12	74± 19

 

Table 4 Number of mice with significant histopathological findings on the kidney and nasal cavity.

 

Exposure concentration (ppm)	100		50		0
Exposure duration	2	4	2	4	2	4
Kidney TIN	2	2	0	0	0	0
Nasal cavity
SIN	10	10	7	10	0	0
All positive findings	10	10	9	10	0	0

TIN: tubulo-interstitial nephritis.

SIN: submucosal infiltration of neutrophilic leukocytes.

Applicant's summary and conclusion

Conclusions:

In the key repeated inhalation study which was similar to OECD 412 (no information on GLP status), the LOAEC for tetraethyl orthosilicate was 50 ppm vapour (ca. 0.4 mg/L) in male mice after a 2- or 4-week exposure, based primarily on histopathological (inflammatory) findings in the nasal mucosa and with some haematological changes noted. Histopathology findings in the kidney were observed at 100 ppm (ca. 0.9 mg/L) when mice were exposed over 2 or 4 weeks. Kidney weights were slightly lower at 50 and 100 ppm after 2 or 4 weeks, but this renal result was not significant. A NOAEC is not identified. The published study is well documented, meets generally accepted scientific principles, is acceptable for assessment, and thus is assigned reliability score 2.