Registration Dossier

Administrative data

Description of key information

In a 28-day inhalation study comparable to OECD test guidelines and to GLP (Dow Corning Corporation, 1987) the NOAEC for local effects of tetramethoxysilane in Sprague-Dawley rats was determined to be 10 ppm when exposed by the inhalation route six hours per day, five days per week for four consecutive weeks. The test substance was found to have a steep dose response curve with no effects at 10 ppm, very minimal effects at 15 ppm, moderate to severe effects at 30 ppm and severe effects and lethality at 45 ppm. Exposure-related morphological changes were typical of the local effects of a corrosive agent, and were limited to moist surfaces of the eye (cornea), and respiratory tract (nasal tissues, pharynx, larynx, trachea, bronchi and bronchioles). As all observed significant toxicological effects appeared to be secondary to the local effects the systemic NOAEC is considered to be 45 ppm. However, the overall NOAEC for the study is 15 ppm, based on local effects on the respiratory tract, since the effects at this dose level were minimal. 
There are no oral repeated dose toxicity data on tetramethyl orthosilicate, so good quality data on the structurally-related substance, tetraethyl orthosilicate have been read-across.
In an OECD 422 study conducted to GLP (SEHSC, 2005), 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. Degenerative/necrotic nephropathy was observed among the treated animals at the doses of 50 or 100 mg/kg bw/day.
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:
no adverse effect observed
Dose descriptor:
NOAEC
279 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
93 mg/m³
Study duration:
subacute
Species:
rat

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 is one reliable sub-acute inhalation study on tetramethyl orthosilicate (Dow Corning Corporation, 1987). There are no oral repeated dose toxicity data on tetramethyl orthosilicate, so good quality data on the structurally-related substance, tetraethyl orthosilicate (CAS No. 78-10-4) have been used for read-across for the oral route (SEHSC, 2005).

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 tetramethyl orthosilicate is evaluated point by point.

Read-across hypothesis

The registration substance, tetramethyl 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.

Tetramethyl orthosilicate hydrolyses very rapidly (hydrolysis half-life <3 minutes at pH7) producing silicic acid and methanol.

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, tetramethyl orthosilicate and the read-across substance, tetraethyl orthosilicate, are both tetraalkyl 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

681-84-5

78-10-4

Chemical Name

Tetramethyl orthosilicate

Tetraethyl orthosilicate

Si hydrolysis product

Silicic acid

Silicic acid

Molecular weight

152.22

 208.33

log Kow (parent)

-0.5

3.0

log Kow (silanol hydrolysis product)

N/A (inorganic)

N/A (inorganic)

Water sol (parent)

 4160 mg/l

 78 mg/l

Water sol (silanol hydrolysis product))

1E+06 mg/l

1E+06 mg/l

Vapour pressure (parent)

1800 Pa

110 Pa

Hydrolysis t1/2at pH 7 and 25°C

<3 minutes

6.7 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

<1 minute

2.5 hours

 (c) Toxicokinetics

The log Kow value of the read-across substance favourable for absorption across the skin and the respiratory tract, whereas the registration substance is hydrophilic, therefore the read-across substance represents a worst-case in respect of potential for uptake. Following uptake, hydrolysis to silicic acid and methanol 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) Discussion of repeated systemic toxicity of the non-silanol hydrolysis products

The repeated dose toxicity of the non-silanol hydrolysis products, methanol and 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 2004a and OECD 2004b) are reported here to support read-across arguments.

Methanol

The majority of repeated dose toxicity information for methanol comes from inhalation studies in rats and monkeys.

Generally effects noted include nasal irritation in rats (but not monkeys), CNS depression, effects on body and organ weight and in some cases effects on clinical chemistry parameters. Studies were conducted up to significant doses and generally effects when noted, are considered adverse only at upper end of the dose ranges studied e. g 650 mg/m3 in monkeys, 13000 mg/m3 in rats.

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

Ethanol

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.

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 the repeated inhalation study of longest duration that is available for the registered 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 the repeated inhalation study of longest duration that is available for the registered substance. It was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

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

Justification for classification or non-classification

Based on read-across oral data on tetraethyl orthosilicate, tetramethyl orthosilicate is not classified for specific organ toxicity following repeated oral exposures according to Regulation (EC) No 1272/2008.

The 28-day inhalation NOAEC is 93 mg/m3 but the substance is already classified as Acute Toxicity Category 1 (vapour), irritating to skin and corrosive to eyes. Severe lung damage was the main post-mortem finding of the acute inhalation study (see Section 7.2) and there was evidence of a corrosive effect in the repeated dose study. A separate classification for specific target organ toxicity following repeated exposures is therefore not required.