Registration Dossier

Administrative data

Description of key information

There are no repeated dose toxicity data on trimethoxy(propyl)silane available, therefore the structural analogue substance trimethoxy(methyl)silane (CAS1185-55-3) has been used to assess the systemic toxicity of trimethoxy(propyl)silane. (MW ratio: target/source = 1.21).
Repeated dose toxicity:
Inhalation, subchronic:
according to OECD TG 413 in rats: NOAEC = 560 mg/m³ (100 ppm)
MW corrected NOAEC = 677.6 mg/m³
Oral, subacute:
according to OECD TG 422 in rats: NOAEL = 50 mg/kg bw/day
MW corrected NOAEL = 60.5 mg/kg bw/day.
There are no data for the dermal route.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
60.5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study was conducted according to the appropriate OECD guideline and in compliance with GLP and is therefore considered to be reliability 1. Read-across of the study itself is considered to be reliability 2.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
677.6 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study was conducted according to the appropriate OECD guideline and in compliance with GLP and is therefore considered to be reliability 1. Read-across of the study itself is considered to be reliability 2.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
677.6 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study was conducted according to the appropriate OECD guideline and in compliance with GLP and is therefore considered to be reliability 1. Read-across of the study itself is considered to be reliability 2.

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

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(propyl)silane (CAS 1067-25-5) is evaluated point by point.

Read-across hypothesis

After oral and inhalative application, all three substances, trimethoxy(propyl)silane (CAS 1067-25-0), trimethoxy(methyl)silane (CAS 1185-55-3), and triethoxy(isobutyl)silane (CAS 17980-47-1) hydrolyse rapidly to similar silanol hydrolysis products, propylsilanetriol, methylsilanetriol, and (2-methylpropyl)silanetriol, respectively. The non-silanol hydrolysis products, ethanol and methanol, are not expected to contribute to any adverse effects for systemic or reproductive toxicity at the relevant dose levels. This is discussed further below.

The predicted half-lives of trimethoxy(propyl)silane (CAS 1067-25-0), trimethoxy(methyl)silane (CAS 1185-55-3), and triethoxy(isobutyl)silane (CAS 17980-47-1) at 20-25°C and at pH 7 are 2.6, 2.2, and 30 h, respectively, (see Section 4.1.1.1). As the hydrolysis reaction may be acid or base catalysed, the rate of reaction is expected to be slowest at pH 7 and increase as the pH is raised or lowered.

Reaction rate increases with temperature therefore hydrolysis will be faster at physiologically relevant temperatures compared to standard laboratory conditions. Under ideal conditions, hydrolysis rate can be recalculated according to the equation:

DT50 (XºC) = DT50 (T) x e(0.08 (T-X))

Where T = temperature for which data are available and X = target temperature.

Thus, for trimethoxy(propyl)silane (CAS 1067-25-0) the hydrolysis half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is 0.81 h.

For the read-across substances, trimethoxy(methyl)silane (CAS 1185-55-3) and triethoxy(isobutyl)silane (CAS 17980-47-1), the corresponding half-lives are approximately 0.96 h and 11.04 h, respectively.

Analogue approach justification

(a) Structural similarity

Both the registration and read-across substances are structurally similar, containing a silicon moiety and three alkoxy (-OX) groups. The two substances hydrolyse very rapidly in the gut to produce similar silanol hydrolysis products, propylsilanetriol, methylsilanetriol, and isobutylsilanetriol, respectively.

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 and also reflects the worst-case in respect of the effects observed in available studies.

Further information is given in a supporting report attached to Section 13 of the IUCLID5 dossier (PFA, 2013a).

(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

1067-25-0

1185-55-3

17980-47-1

Chemical Name

trimethoxy(propyl)silane

trimethoxy(methyl)silane

triethoxy(isobutyl)silane

Si hydrolysis product

propylsilanetriol

methylsilanetriol

(2-methylpropyl)silanetriol

Molecular weight

164.27 g/mol

136.22 g/mol

220.39 g/mol

log Kow (parent)

1.7

0.7

3.6

log Kow (silanol hydrolysis product)

-1.4

-2.36

-1.0

Water sol (parent)

9200 mg/l

29 000 mg/l

212 mg/l

Water sol (silanol hydrolysis product))

1 000 000 mg/l

1 000 000 mg/l

Miscible

Vapour pressure (parent)

1900 Pa at 25°C

10 680 Pa at 20°C

49 Pa at 25°C

Hydrolysis t1/2 at pH 7 and 25°C

2.6 h

2.2 h

30 h

Hydrolysis t1/2 at pH 2 and 37.5°C

5 sec

5 sec

9 sec

Hydrolysis t1/2 at pH 7 and 37°C

0.81 h

0.96 h

11.04 h

The registered substance, trimethoxy(propyl)silane (CAS 1067-25-0), hydrolyses in contact with water, generating propylsilanetriol and methanol. At pH 7 and 25 °C the rate of hydrolysis is rapid, with a predicted half-life of 2.6 hours. However, at acidic pH the reaction is very rapid; the calculated half-life at pH 2 and 37.5 °C is 5 s. Compared to the typical gastric emptying half-life for liquids in the order of 11–30 min for humans and 77 min in rats (RIVM,http://www.rivm.nl/interspeciesinfo/intra/human/stomach/db_human_stomach.jsp, http://www.rivm.nl/interspeciesinfo/intra/rat/stomach/db_rat_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 read-across substances, trimethoxy(methyl)silane (CAS 1185-55-3) and triethoxy(isobutyl)silane (CAS 17980-47-1), hydrolysis half-lives at pH 7 and 25 °C are 2.2 and 30 h, respectively. At gut pH hydrolysis will occur very rapidly, with calculated half-lives of 5 and 9 sec, respectively.

(c) Similar toxicokinetics

Repeated inhalation toxicity data are available for trimethoxy(methyl)silane (CAS 1185-55-3), reporting increased incidences of grossly observed urinary bladder calculi along with the kidney dilation at 2200 mg/m³ after subchronic exposure duration. Given the low vapour pressures of trimethoxy(propyl)silane (CAS 1067-25-0) as compared to trimethoxy(methyl)silane (CAS 1185-55-3), this read-across is a worst case and therefore considered appropriate.

Among repeated inhalation toxicity data, information on systemic toxicity after repeated oral administration of trimethoxy(methyl)silane (CAS 1185-55-3) and triethoxy(isobutyl)silane (17980-47-1) to rats are available, indicating systemic availability of the silanol compound. In view of the rapid hydrolysis following oral dosing and based on the fact that closely related silanol-containing products of hydrolysis are formed by trimethoxy(propyl)silane (CAS 1067-25-0) and trimethoxy(methyl)silane (CAS 1185-55-3), it is considered appropriate to read-across the available oral data from trimethoxy(methyl)silane (CAS 1185-55-3) and triethoxy(isobutyl)silane (17980-47-1) to trimethoxy(propyl)silane (CAS 1067-25-0).

(d) Similar acute toxicity

Acute toxicity data are available for the registered substance and the read-across substances. The acute oral LD50 in rats was 5170 mg/kg bw for trimethoxy(propyl)silane (CAS 1067-25-0) and 11 685 mg/kg bw and > 5000 mg/kg bw for trimethoxy(methyl)silane (CAS 1185-55-3) and triethoxy(isobutyl)silane (CAS 17980-47-1), respectively. There was evidence of systemic toxicity for all three substances, indicating absorption and systemic availability is high. It is therefore considered appropriate to read-across the toxicity data after oral administration from trimethoxy(methyl)silane (CAS 1185-55-3) and triethoxy(isobutyl)silane (CAS 17980-47-1) to trimethoxy(propyl)silane (CAS 1067-25-0). The acute LC50 in rats was for all three substances high, with 22 200 mg/m³ for the submission substance and > 42 100 and > 5880 mgm³ for the read-across substances trimethoxy(methyl)silane (CAS 1185-55-3) and triethoxy(isobutyl)silane (CAS 17980-47-1), respectively. Treatment with both trimethoxy(propyl)silane (CAS 1067-25-0) and trimethoxy(methyl)silane (CAS 1185-55-3) resulted in clinical signs, indicating systemic availability of the test item, whereas exposure to triethoxy(isobutyl)silane (CAS 17980-47-1) resulted predominantly in local irritating effects. It is therefore considered appropriate to read- across the inhalation data from trimethoxy(methyl)silane (CAS 1185-55-3) to trimethoxy(propyl)silane (CAS 1067-25-0).

(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/m³ in monkeys, 13 000 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 conclusion, the oral NOAEL in rats for methanol is greater than the dose that is expected to be generated from hydrolysis of trimethoxy(methyl)silane in the stomach. Therefore the general effects of trimethoxy(methyl)silane following a dose of 1000 mg/kg bw/day are not attributable to methanol. Similarly, ethanol generated from hydrolysis of triethoxy(isobutyl)silane is not contributed to the observed toxicity in rats at the dose levels used.

The molecular weight difference between target trimethoxy(propyl)silane (CAS 1067-25-0) and source chemical trimethoxy(methyl)silane (CAS 1185-55-3) is 164.27/136.22 = 1.21.

Studies were chosen as key when the available study was of relevance and of sufficient quality for classification, labelling and for risk assessment.  

A key reliable OECD TG 422 combined repeated dose/ reproductive and developmental screening study (Dow Corning Corporation, 2005) is available by the oral route for the structural analogue substance trimethoxymethylsilane (CAS 1185-55-3). Exposure to trimethoxymethylsilane was associated with organ weight and/or histomorphological changes in males (liver, thymus, thyroid, duodenum, jejunum, and red blood cell) and females (liver, thyroid, duodenum, jejunum, and adrenal gland) at dose levels at or above 250 mg/kg bw/day. A marked increase in prothrombin time was observed for males at 250 and 1000 mg/kg bw/day whereas females were unaffected. Exposure was also associated with increased blood platelet concentration for males and females at 1000 mg/kg bw/day. These data support a NOAEL for the toxicity phase of the study of 50 mg/kg bw/day. The NOAEL for the target chemical is 60.5 mg/kg bw/day.

A key reliable sub-chronic inhalation toxicity study is available for the structural analogue substance trimethoxymethylsilane (CAS 1185-55-3), according to OECD TG 413. Based on the increased incidence of grossly observed urinary bladder calculi along with the kidney dilation at the 400 ppm exposure level, the No Observable Adverse Effect Level (NOAEL) for trimethoxymethylsilane vapour administered six hours per day, five days per week for a 90 -day interval via whole-body inhalation exposure to male and female Sprague-Dawley rats, was 100 ppm (560 mg/m³) (Dow Corning Corporation, 2008). Based on the molecular weight difference, the NOAEC for the target chemical is 677.6 mg/m³.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The key study was selected for assessment.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The key study was selected for assessment.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Reliable data are available for the oral and inhalation routes.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Reliable data are available for the oral and inhalation routes.

Repeated dose toxicity: via oral route - systemic effects (target organ) glandular: thyroids

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

Justification for classification or non-classification

The available data on repeated dose toxicity of the structural analogue substance, trimethoxymethylsilane (CAS 1185 -55 -3), do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification of the registered substance.