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Diss Factsheets

Administrative data

Description of key information

In the key acute oral study conducted according to OECD Test Guideline 423 and in compliance with GLP (Bayer AG 2001, reliability score 1), the LD50 for tetraethyl orthosilicate (CAS No. 78-10-4, EC No. 201-083-8) in the rat was >2000 mg/kg bw.

 

In the key acute inhalation study conducted according to OECD Test Guideline 403 and in compliance with GLP (Hoechst AG 1991, reliability score 1), the LC50 for tetraethyl orthosilicate was 10.0 mg/L aerosol in male rats and >16.8 mg/L aerosol in female rats.

 

For the acute dermal route, there were no reliable data, and thus no key study identified.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001/01/29 - 2001/04/02
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: Wistar HsdCpb:WU
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, Districts of Paderborn

- Age at study initiation: ca. 8 weeks

- Weight at study initiation: 185-187g males, 159-175g females

- Housing: During the acclimatization period the animals were kept conventionally in polycarbonate cages type III (animals <180 g bw - five animals, of >180 g - max three animals per cage). The cages were changed at least three times a week. Feed racks and water bottles were not changed. During the test period the animals were kept conventionally in polycarbonate cages type III (three animals per cage). The cages were changed at least once a week. Feed racks and water bottles were not changed. The bedding consisted of low dust wood granules type BK 8/15.

- Diet: "NAFAG No.9439 Long Life W 10", ad libitum (approx. 2 hours after administration)

- Fasting: 17 hours +/- 2 before administration

- Water: tap water, ad libitum

- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 22 +/- 2

- Humidity (%): 55 +/- 5

- Air changes (per hr): ca. 15-20

- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
DOSE VOLUME ADMINISTERED: 5 mL/kg bw

DOSAGE PREPARATION (if unusual): The test substance was formulated in polyethylene glycol 400 before administration. The applied formulations were well mixed by pumping the syringe several times.
Doses:
2000 mg/kg bw, single dose
No. of animals per sex per dose:
3M, 3F
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: appearance and behaviour were recorded several times on the day of treatment, and at least once a day thereafter. Where sign occurred, the type, period and intensity were determined individually. The body weights of the rats were recorded on day 1 before administration and then weekly. Additionally, all animals that died or were sacrificed were weighed.

- Necropsy of survivors performed: yes

- Examinations performed: clinical signs, body weight, gross pathology, other: During clinical observation all abnormal findings were registered and particular attention was paid to the following organ systems, localizations and physiological functions: appearance - fur, skin colour, edemas, eyes, lacrimation, nasal discharge, salivation; behaviour - grooming, vocalization, excitement, aggression, digging and preening movements, cannibalism; nervous system - reactivity, motility, reflexes, gait, paralysis, spasms, tremors; where accessible - respiration frequency and heart rate, pallor; posture, and gastrointestinal functions - appearance of feces, etc.
Statistics:
No statistical analysis was carried out.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
other: There were no clinical signs.
Gross pathology:
No gross pathologic changes were observed in animals sacrificed at the end of the study period.
Other findings:
No other findings reported.
Interpretation of results:
GHS criteria not met
Conclusions:
In the key acute oral study for tetraethyl orthosilicate (reliability score 1), the LD50 value of >2000 mg/kg bw in the rat was determined in a reliable study conducted according to OECD Test Guideline 423 and in compliance with GLP. There were no clinical signs or effects on body weight or gross pathology observed.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Klimisch score of 1, based on the acute oral toxicity (reliability score 1) data for tetraethyl orthosilicate

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991/07/19 - 1991/10/16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
traditional method
Limit test:
no
Species:
rat
Strain:
other: Wiskf(SPF71)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: HOECHST AG, Kastengrund, SPF-Zucht

- Age at study initiation: 8-10 weeks

- Weight at study initiation: Male rats weighed 193-234 g at the time of dosing and female rats weighed 190-202 g at dosing 

- Housing: In an airconditioned room in Makrolon type 4 cages, 5 animals per cage

- Diet: Rat diet Altromin 1324, ad libitum

- Water: Tap water, ad libitum

- Acclimation: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2

- Humidity (%): 50 +/- 20

- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The test substance was injected into the chamber at constant velocity through an infusion apparatus at one end of the chamber.

- Exposure chamber volume: 60 L

- Method of holding animals in test chamber: The animals were in a stainless steel and glass cylinder, with plastic tubes leading to the exposure cylinder designed so that the animal's noses fit inside.

- Source and rate of air: The air supply was kept constant at 800 L/h through a calibrated rotameter.

- Method of conditioning air: A suction device at the bottom of the inhalation chamber enabled the air to be passed through, attached to a water bottle, a Buehler filter and a bottle of calcium chloride.

- System of generating particulates/aerosols: The primary aerosol formation took place in the generation flasks, and the smaller particles were passed into the inhalation chamber through a riser pipe.

- Method of particle size determination: Determination of the particle size was only possible at the highest concentration because the test substance was mostly in the gaseous phase as the concentrations decreased.

- Treatment of exhaust air: Exhaust air was extracted and neutralised.

- Temperature, humidity, pressure in air chamber: An air monitoring system (Hartmann & Braun) continuously recorded CO, CO2, O2, humidity and temperature in the exposure chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: For the determination of the test material concentration in the inhalation chamber, 31 L of the test atmosphere during a 60-minute period of the exposure period was analysed by passing it through a series of connected gas wash bottles which were completely filled with 70, 60 and 50 mL absolute ethanol residing in a cold bath. The distribution of aerosol particle size was determined using an Anderson-Cascade Impactor 3 (Anderson Samples Inc, Atlanta). Mean relative abundances of aerodynamic diameter were determined. The device was operated at a vacuum flow rate of 9.5 L/min, from which a flow velocity of 1.25 m/s was calculated.

- Samples taken from breathing zone: Yes

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 0.8 micrometers / 1.7.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Gas chromatography using an FID as a detector.
Duration of exposure:
4 h
Concentrations:
5.74, 9.98, 10.40 and 16.83 mg/L
No. of animals per sex per dose:
5M, 5F per dose, except no females in the 5.74 mg/L dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Rats were observed for clinical symptoms during the 4-hour exposure period and then twice per day for 14 days post exposure. Body weights were determined prior to dosing and on days 8 and 15 of the study.

- Necropsy of survivors performed: Yes
Statistics:
The LC50 and 95% confidence limits were calculated according to Fieller and Sidak and probit analysis was carried out on the mortality data according to Finney and Weber.
Sex:
male
Dose descriptor:
LC50
Effect level:
10 mg/L air
Exp. duration:
4 h
Remarks on result:
other: aerosol
Sex:
female
Dose descriptor:
LC50
Effect level:
> 16.8 mg/L air
Exp. duration:
4 h
Remarks on result:
other: aerosol
Mortality:
Deaths first occurred on or just before the 3rd test day. Please see Table 1.
Clinical signs:
other: The animals showed reactions involving motor behavior and respiration, palpebral stenosis extending to full lid closure with encrusted blood covered eyelid rims, shivering and tonic cramping. Cyanosis and decreased reflexes occurred in individual animals.
Body weight:
Body weights were decreased during the study but by the completion of the study, all the animals exceeded their initial weight.
Gross pathology:
Necropsy results from animals which died during the study showed red and orange coloured lungs, release of froth upon incision of the lungs and lung spotting. Spotting or light colouration of the lungs were found in every female rat sacrificed at the end of the study. There were no macroscopic findings in the male rats sacrificed at the end of the study.

Table 1: Concentrations, exposure conditions and mortality per animals treated

 

Analytical Conc. (mg/L)

Mortality (# dead/total)

Males

Females

Combined

 5.74

 1/5

 -

1/5 

 9.98

 2/5

 0/5

 2/10

 10.40

3/5

1/5

4/10

 16.83

4/5 

 1/5

 5/10

- = Not tested

Value [LC50]: 10.0 mg/L for male rats and >16.8 mg/L for female rats. 

Interpretation of results:
GHS criteria not met
Conclusions:
In a study conducted according to OECD Test Guideline 403 and GLP compliant (reliability score 1), tetraethyl orthosilicate was determined to have a 4-hour LC50 of 10.0 mg/L aerosol in male rats and >16.8 mg/l aerosol in female rats.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
10 000 mg/m³ air
Quality of whole database:
Klimisch score of 1, based on the acute inhalation toxicity (reliability score 1) data for tetraethyl orthosilicate

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

ORAL ROUTE

For the acute oral route, the tetraethyl orthosilicate data consist of:

- Key OECD Test Guideline 423 (Bayer AG 2001, reliability score 1)

- Supporting OECD Test Guideline 401 (Degussa-Huls AG 1992, reliability score 1)

- Multiple additional supporting studies with reliability score 4. However, these studies either pre-date OECD guidelines and GLP, or the studies are either non-guideline (or not specified) and the GLP status is not indicated.

 

For the key acute oral study conducted according to OECD Test Guideline 423 and in compliance with GLP (Bayer AG 2001, reliability score 1), the tetraethyl orthosilicate LD50 was >2000 mg/kg bw in the Wistar rat. There were no clinical signs or effects on body weight or gross pathology observed.

 

In a supporting acute oral study conducted according to OECD Test Guideline 401 and in compliance with GLP (Degussa-Huls AG 1992, reliability score 1), an acute oral LD50 value of >2000 mg/kg bw for tetraethyl orthosilicate in the Wistar rat was determined. Rats were administered 2000 mg/kg bw of tetraethyl orthosilicate (no vehicle). There were no deaths, remarkable body weight changes, or gross necropsy findings. Limited clinical signs were observed 24 and 48 hours after dosing, with all animals normal by day 3. The result supports the key study findings.

 

INHALATION ROUTE

In the case of acute inhalation, the tetraethyl orthosilicate data set includes:

- Key OECD Test Guideline 403 (Hoechst AG 1991a, reliability score 1)

- Supporting OECD Test Guideline 403 (Hoechst AG 1991b, reliability score 1, but with a single concentration)

- Supporting study similar to OECD Test Guideline 403 (Nakashima et al. 1994, reliability score 2)

- Multiple supporting studies with reliability score 4. However, most of these studies pre-date OECD guidelines and GLP, with one study non-guideline and the GLP status not specified.

 

In the key study conducted according to OECD Test Guideline 403 and GLP compliant (Hoechst AG 1991a, reliability score 1), Wistar rats were exposed to 5.74, 9.98, 10.4, and 16.8 mg/L tetraethyl orthosilicate aerosol for 4 hours. Deaths in one or more males occurred starting at 5.74 mg/L, and at 10.4 mg/L in females. The animals showed reactions involving motor behaviour and respiration, palpebral stenosis extending to full lid closure with encrusted blood covered eyelid rims, shivering and tonic cramping. Cyanosis and decreased reflexes occurred in individual animals. By day 8, all the surviving animals were clinically symptom free. Body weights were decreased during the study but by the completion of the study, all the animals exceeded their initial weight. Necropsy results from animals which died during the study showed red- and orange-coloured lungs, release of froth upon incision of the lungs, and lung spotting. Spotting or light colouration of the lungs were found in every female rat sacrificed at the end of the study. There were no macroscopic findings in the male rats sacrificed at the end of the study. Tetraethyl orthosilicate was determined to have a 4-hour LC50 of 10.0 mg/L aerosol in male rats and >16.8 mg/L in female rats.

 

In a supporting acute inhalation study conducted according to OECD Test Guideline 403 and GLP compliant (Hoechst AG 1991b, reliability score 1), Wistar rats were exposed to 5.03 mg/L aerosol for 4 hours. There were no deaths or effects on body weight or gross pathology. The clinical signs noted involved the motor and respiratory systems and some sneezing, with all animals symptom free after the 3rd day post-exposure. In this study, tetraethyl orthosilicate had a 4-hour LC50 value of >5.03 mg/L aerosol in male and female rats. The result supports the key study findings.

 

In a supporting acute inhalation study similar to OECD Test Guideline 403 (GLP not specified) (Nakashima et al. 1994, reliability score 2), groups of 10 male mice were exposed to 1000 ppm vapour for 1, 2, 4, or 8 hours. One, one, and six mice died after the 2-, 4- and 8-hour exposures. Tetraethyl orthosilicate did not seem to influence breathing behaviour, while most of the mice that died exhibited weakness and piloerection during the observation period. In the 2-, 4- and 8-hour groups, body weight decreased up to 4 days after tetraethyl orthosilicate exposure and did not reach the level of control mice until the end of observation. All dead mice developed acute tubular necrosis (ATN) of the kidney and acute splenic atrophy (ASA). Tubulointerstitial nephritis (TIN) was frequently found in the surviving mice. However, blood biochemical examinations revealed no evidence of renal dysfunction. Pulmonary congestion, pulmonary oedema and hepatic congestion were observed in the dead mice. The olfactory epithelium of mice that died was necrotic. Effects on the olfactory epithelium were also seen in the surviving mice. There was no hyperplasia due to inhalation. The 4-hour LC50 for tetraethyl orthosilicate in the mouse was >1000 ppm vapour (approximately >8.5 mg/L).

 

DERMAL ROUTE

For acute dermal exposure, no key study with tetraethyl orthosilicate is identified, but three studies that pre-date OECD guidelines and GLP (all reliability score 4) are available. In two of these studies, the LD50 for tetraethyl orthosilicate in the rabbit was 6.3 mL/kg bw (approximately 5900 mg/kg bw). In the third, the rabbit and mouse TDLo units (pph) and the study details are insufficient to estimate the mg/kg bw dosing.

Justification for classification or non-classification

The acute oral and dermal toxicity data on tetraethyl orthosilicate do not indicate that this substance should be classified for acute toxicity for the oral and dermal routes according to Regulation (EC) No. 1272/2008.

 

Although the key reliable acute inhalation LC50 is >10 mg/L aerosol (supportive of non-classification), tetraethyl orthosilicate is currently classified in Annex VI of Regulation (EC) No. 1272/2008 as Acute Inhalation Category 4 (H332, Harmful if inhaled). Clinical signs were reported in the key study but resolved by day 8. Some lung discoloration was also noted.