Registration Dossier

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Administrative data

Description of key information

There are no repeated dose toxicity studies, therefore good quality data on the structurally-related substance, tetraethyl orthosilicate have been read-across for the oral and inhalation routes. 
In a good quality OECD 422 study (CIT, 2005) conducted to GLP, the parental NOAEL for tetraethylorthosilicate in rats was 50 mg/kg bw/day for the females and 10 mg/kg bw/day for the males, based on adverse effects on the kidneys (tubular nephropathy).
In a repeated inhalation study which was similar to OECD 412 (no information on GLP status) the LOAEC for tetraethoxysilane was 50 ppm (426 mg/m3 based on a molecular weight of 208.33) in mice, based on haematological changes (lower haemoglobin, red blood cell count and haematocrit values in exposed mice than in non-exposed mice, but not there was no dose-response). Effects on the kidney (tubulo-interstitial nephritis) were observed at 100 ppm when exposure was over two or four weeks. There were also signs of irritation in the nasal mucosa. (Omae et al., 1995).
There are no dermal data.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
426 mg/m³
Study duration:
subacute
Species:
mouse

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
426 mg/m³
Study duration:
subacute
Species:
mouse

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no repeated dose toxicity studies for tetrapropyl orthosilicate, therefore good quality data on the structurally-related substance, tetraethyl orthosilicate have been read-across for the inhalation and oral routes.

Read-across justification

To reduce animal testing REACH recommends to make use of a read-across approach where appropriate based on the high accordance in properties relevant for the specific endpoint. In the case of repeated dose toxicity and reproductive toxicity relevant properties are structural similarity as well as physical-chemical and basic toxicological parameters in the same range. In the following paragraphs the read-across approach for tetrapropyl orthosilicate is evaluated point by point.

Read-across hypothesis

The registration substance, tetrapropyl orthosilicate and the read-across substance, tetraethyl orthosilicate, are both tetralkyl silicates. Both hydrolyse rapidly at physiological pH producing silicic acid.

Tetraethyl orthosilicate hydrolyses rapidly (hydrolysis half-life 4.4 h at pH 7 (measured) producing silicic acid and ethanol.

Tetrapropyl orthosilicate hydrolyses rapidly (hydrolysis half-life 6.7 h at pH 7 (measured) producing silicic acid and n-propanol.

The rate is considerably faster under both acidic and basic pH conditions (refer to Section 5.1.2) indicating a much shorter half-life in vivo, particularly when exposure is via the oral route. Therefore, the hydrolysis products of these substances are also of relevance in the chemical safety assessment.

Analogue approach justification

(a) Structural similarity

The registration substance, tetrapropyl orthosilicate and the read-across substance, tetraethyl orthosilicate, are both tetralkyl silicates. Both hydrolyse rapidly at physiological pH producing silicic acid and low molecular weight alcohols.

(b) Similar physicochemical characteristics

A data matrix is attached in Section 13 of the IUCLID dossier, and the key physicochemical parameters are summarised below.

 

CAS Number

682-01-9

78-10-4

Chemical Name

Tetrapropyl orthosilicate

Tetraethyl orthosilicate

Si hydrolysis product

Silicic acid

Silicic acid

Molecular weight (g/mol)

264.44 

 208.33

log Kow (parent)

3.4

3.0

log Kow (silanol hydrolysis product)

N/A (inorganic)

N/A (inorganic)

Water sol (parent)

 78 mg/l

 1500 mg/l

Water sol (silanol hydrolysis product))

1E+06 mg/l

1E+06 mg/l

Vapour pressure (parent)

0.26 Pa

110 Pa

Hydrolysis t1/2at pH 7 and 25°C

6.7 hours

4.4 hours

Hydrolysis t1/2at pH 2 and 37.5°C

ca. 5 seconds

ca. 5 seconds

Hydrolysis t1/2at pH 7 and 37.5°C

2.5 hours

1.6 hours

 (c) Similar toxicokinetics

The log Kow values of both parent substances are similar and are favourable for absorption across the skin and the respiratory tract. Following uptake, hydrolysis to silicic acid and propanol or ethanol is rapid. In contact with the skin at pH 5, hydrolysis may also occur in the presence of sufficient moisture, in which case the potential for uptake will be significantly reduced.

Following oral exposure to the parent substance, very rapid hydrolysis will occur for both substances, with a predicted half-life of approximately 5 seconds (see Section 5.1.2), forming the common hydrolysis product, silicic acid and either propanol or ethanol for the registered and read-across substances, respectively.

(d) Similar acute toxicity

Acute oral toxicity studies are available for both the registered substance (LPT, 2002a) and the read-across substance (Krotlinger, 2001). The LD50 was >2000 mg/kg bw in both cases and there were no mortalities, clinical signs or other adverse findings in either study. An acute inhalation (Hoescht AG, 1991) study for the read-across substance also showed no evidence of acute systemic toxicity at dose levels relevant to current guideline limits. No reliable dermal toxicity studies are available although a number of results are available for tetraethyl orthosilicate for which reliability was unassignable; there was no evidence of dermal toxicity in those studies.

(e) Discussion of repeated systemic toxicity of the non-silanol hydrolysis products

n-Propanol

The limited information available on the repeat dose toxicity of propanol comes from studies in rats from a few days in duration generally up to 3-months and most of these studies are designed for research purposes to investigate specific endpoints. However, the limited data available indicates that propanol is hepatoxic at high doses, with a No Observed Adveerse Effect level in the region of 3000 mg/kg/day.

Ethanol

The repeated dose toxicity of ethanol, has been extensively studied. It is beyond the scope of this assessment to review all of the available data in detail. However, the key findings from the disseminated REACH dossiers and OECD SIAR reports (OECD 2004) are reported here to support read-across arguments.

Generally in repeat dose studies in animals with ethanol very large doses are used, and often specific endpoints relating to known effects in humans are the primary focus of such studies. However, adverse effects on the liver have been noted in animals but only at very high doses >8 g/kg/day.

Ethanol is not classified for repeated dose toxicity in Annex VI of Regulation (EC) No 1272/2008.

The hydrolysis product silicic acid is essentially systemically non-toxic via oral or inhaled routes. A data summary exists for synthetic amorphous silica (ECETOCJACC (Joint Assessment of Commodity Chemicals) Report 051- Synthetic Amorphous Silica, Brussels, September 2006;http: //www. ecetoc. org/jacc-reports)which supports this conclusion.

Conclusion

In view of the very rapid hydrolysis of both the registration and read-across substances at pH2, it is appropriate to read-across toxicological data for the oral route between the two.The non-silanol hydrolysis products will not contribute any effects in tests with rodents at the relevant dose levels.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The selected study is a reliable repeated dose oral toxicity study with a relevant surrogate substance. It was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The selected study is a reliable repeated dose inhalation toxicity study with a relevant surrogate substance. It was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The selected study is a reliable repeated dose inhalation toxicity study with a relevant surrogate substance. It was conducted in accordance with a protocol that was similar to OECD 412. No information is available on GLP-status.

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

Based on read-across oral and inhalation data on tetraethyl orthosilicate, tetrapropyl orthosilicate is not classified for specific organ toxicity following repeated exposures according to Regulation (EC) No 1272/2008, in accordance with the EU harmonised classification for tetraethyl orthosilicate in Annex VI of the Regulation.

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