Trimethoxy(2-methylpropyl)silane

Endpoint summary

Description of key information

There are no repeated dose toxicity data on trimethoxy(2-methylpropyl)silane or its hydrolysis product, (2-methylpropyl)silanetriol, so good quality data for the related substance triethoxyisobutylsilane (CAS 17980-47-1) have been used to assess the general systemic toxicity of trimethoxy(2-methylpropyl)silane. 
In a rat 28-day oral gavage study conducted using a protocol similar to OECD 407 and to GLP (Huntingdon Research Centre, 1988) the NOAEL for triethoxyisobutylsilane was at least 1000 mg/kg bw/day, as there were no adverse toxicological findings at this the only dose tested. 
In a repeated nose-only inhalation study, conducted to OECD 413 and to GLP (Safepharm Laboratories, Ltd., 1992a) the NOAEC for triethoxyisobutylsilane was at least 2.54 mg/l in rats. 
The key and supporting studies for triethoxyisobutylsilane show that this substance has a low potential to cause adverse health effects.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 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

2 540 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

2 540 mg/m³

Study duration:

subchronic

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 are no repeated dose toxicity data on trimethoxy(2-methylpropyl)silane or its hydrolysis product, (2-methylpropyl)silanetriol, so good quality data for the related substance triethoxyisobutylsilane (CAS 17980-47-1) have been used to assess the general systemic toxicity of trimethoxy(2-methylpropyl)silane. (Isobutyl and 2-methylpropyl are synonyms).

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 trimethoxy(2-methylpropyl)silane is evaluated point by point.

Read-across hypothesis

After oral application, trimethoxy(2-methylpropyl)silane and triethoxy(2-methylpropyl)silane both hydrolyse very rapidly (half-life in the order of a few seconds) to a common silanol hydrolysis product, (2-methylpropyl)silanetriol, which is thus the systemically relevant species after oral application. It is concluded that both parent substances behave in a very similar way by this route of exposure. After inhalation exposure the parent substance is seen as most relevant for the toxicological evaluation. Based on the physico-chemical parameters the read-across substance is seen as the worst case. The non-silanol hydrolysis products, methanol and ethanol, are not expected to contribute to any adverse effects for systemic or reproductive toxicity at the relevant dose levels. This is discussed further below.

Analogue approach justification

(a) Structural similarity

The registration and read-across substances are structurally similar, containing a branched butyl chain bound to silicon and three alkoxysilane (-SiOX) groups. They share a common silanol hydrolysis product, (2-methylpropyl)silanetriol.

These substances are part of an analogue group of alkoxysilane substances containing alkyl groups. The read-across substance was selected as the most appropriate based on chemical structure.

(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	18395 -30 -7	17980 -47 -1
Chemical Name	Trimethoxy(2-methylpropyl)silane	Triethoxy(2-methylpropyl)silane
Si hydrolysis product	(2-methylpropyl)silanetriol	(2-methylpropyl)silanetriol
Molecular weight	178.31	220.39
log Kow (parent)	2.1	3.6
log Kow (silanol hydrolysis product)	-1.0	-1.0
Water sol (parent)	4900 mg/l	212 mg/l
Water sol (silanol hydrolysis product))	1E+06 mg/l	1E+06 mg/l
Vapour pressure (parent)	190 Pa	33 Pa
Hydrolysis t1/2 at pH 7 and 25°C	4.1 hours	30 hours
Hydrolysis t1/2 at pH 2 and 37.5°C	ca. 5 seconds	9 seconds
Hydrolysis t1/2 at pH 7 and 37.5°C	1.5 hours	11 hours

  (c) Similar toxicokinetics

The registered substance, trimethoxy(2-methylpropyl)silane, hydrolyses in contact with water, generating (2-methylpropyl)silanetriol and methanol. The calculated half-life at pH 2 and 37.5°C is approximately 5 seconds (see Section 5.1.2). Compared to the typical gastric emptying half-life for liquids in the order of 11 - 30 minutes for humans and 77 minutes in rats (RIVM, http: //www. rivm. nl/interspeciesinfo/intra/human/stomach/db_human_stomach. jsp), several to many hydrolysis half-lives would therefore have occurred and absorption in the intestine would almost exclusively relate to hydrolysis products.

For the triethoxy read-across substances, gut pH hydrolysis will occur very rapidly, with a half-life of approximately 9 seconds, but due to the higher lipophilicity and lower water solubility of the parent substance it is possible that some unhydrolysed material is absorbed onto food present in the stomach and thus the true rate of degradation in the stomach is difficult to predict. Nevertheless, reading across from ethoxy to methoxy can be considered as worst case since uptake in the intestine would be higher for the ethoxy compared to either methoxy or silanol species.

With respect to the inhalation route, the log K_owof both substances is favourable for absorption across the respiratory tract. Following uptake, rapid hydrolysis of the registration substance followed by excretion via urine will occur (calculated half-life 1.5 hours, as discussed in Section 5.1.2). For the read-across substance, hydrolysis at blood temperature and pH is slower (half-life 11 hours) therefore the potential for systemic distribution is greater and can be considered a worst case i.e. hydrolysis is a detoxification step.

The existing 90-day repeated inhalation study with triethoxy(2-methylpropyl)silane was performed at the highest achievable vapour concentration for the substance. Although the more volatile registration substance could achieve higher concentrations in air than this value, additional testing at higher concentrations are not considered to be appropriate since the available data clearly demonstrate no adverse effects at a concentration that is in excess of classification cut-offs for repeated inhalation toxicity according to Regulation (EC) No 1272/2008. The low toxicity of the substance is also demonstrated by the absence of effects in a repeated oral study.

 (d) Similar acute toxicity

Acute oral and inhalation toxicity studies are available for the registered substance and the read-across substance. Clinical signs were observed at high dose levels indicating systemic availability. In addition, an acute dermal toxicity study is available for the read-across substance. In all cases, the test data demonstrated that the substances were not acutely hazardous by any exposure route.

The available data are summarised in the table below:

CAS Number	18395-30-7	17980-47-1
Chemical Name	Trimethoxy(2-methylpropyl)silane	Trimethoxy(2-methylpropyl)silane
Acute oral toxicity LD50(mg/kg bw)	>2000 (Hüls, 1993a)	>5000 (Huntingdon Research Centre, 1987a)
Acute dermal toxicity LD50(mg/kg bw)	-	>2000 (Huntingdon Research Centre, 1987b)
Acute inhalation toxicity LC50(mg/l)	>11 (Dow Corning Corporation, 1984)	>5.9 (Huntingdon Research Centre, 1990)

 Additional information is given in a supporting report attached in Section 13 of the IUCLID 5 dossier (PFA, 2013t).

 (e) 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/m³in monkeys, 13000 mg/m³in 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

Based on the similar chemical structure, toxicokinetics and acute toxicity properties, it is considered appropriate to read-across existing data from triethoxy(2-methylpropyl)silane to trimethoxy(2-methylpropyl)silane. The non-silanol hydrolysis products would not contribute toxic effects in rats at the dose levels tested.

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

Justification for classification or non-classification

Based on the available oral and inhalation read-across repeated dose toxicity studies, trimethoxy(2-methylpropyl)silane is not classified for specific target organ toxicity following repeated exposure according to Regulation (EC) No 1272/2008.