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Description of key information

There are no reliable studies on repeated dose toxicity on 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane, so good quality data for a related substance has been used to assess the oral repeated dose toxicity. 

In an oral subchronic toxicity study (NOTOX, 1998) with rats which was conducted according to OECD Guideline 408, the NOAEL for beta-(3,4-epoxycyclohexyl)ethyltriethoxysilane (CAS 10217-34-2) was found to be at least 1000 mg/kg bw/day.

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:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

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 reliable repeated dose toxicity data on 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane, however a reliable repeated dose toxicity study was available for the analogoius substance beta-(3,4-epoxycyclohexyl)ethyltriethoxysilane (CAS 10217-34-2), which has been used as read across for the registered substance. There were no clinical signs of toxicity or behavioural changes over the 90-day observation period that were considered to be relevant to treatment.No statistically significant differences were noted in body weights and body weight gain of treated animals versus controls. There were no differences in food consumption before or after allowance for body weight between treated and control animals. No remarkable findings were reported in haematological or clinical biochemistry parameters. Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment. Organ weights and relative organ weights of treated animals were considered to be similar to those of control animals.There were no microscopic findings noted that were considered to be treatment-related. A No Observed Adverse Effect Level (NOAEL) of 1000 mg/kg/day was concluded for repated dose oral exposure to the test material.

A reliability 4 supporting study with the tregistered substance is also included in the data set (TRC 1996). To determine if the potential for systemic toxicity following cumulative dermal exposure to the test material, two groups of male albino rabbits each received 8 inunctions of the clipped skin of the trunk over a 19-day period. Two dosage levels (1.0 and 2.0 ml/kg/inunction) were tested.  None of the rabbits died, but there were significant body weight and kidney weight changes at the 2 ml/kg dosage level.  Severe scaling and minor erythema were noted at 2 ml/kg, with only severe scaling at 1.0 ml/kg.  A no-observed-effect-level (NOEL) of 1.0 ml/kg was determined in this study.

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, the relevant properties are structural similarity, hydrolysis half-life and the physical-chemical parameters in the same range. In the following paragraphs the proposed read-across from beta-(3,4-epoxycyclohexyl)ethyltriethoxysilane (CAS 10217-34-2) to 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane is evaluated point by point.

Read-across hypothesis

The hypothesis is that the target (registration) substance and the source (read-across) substance have similar toxicological properties because they are structurally similar and hydrolyse after oral application, to the common silanol hydrolysis product [2-(3,4-epoxycyclohexyl)ethyl]silanetriol and methanol and ethanol, respectively. Based on publically available information, methanol and ethanol are not known to contribute to toxicity at the relevant dose levels (OECD, 2004a and 2004b), which is discussed further below.

Read-across justification

The predicted hydrolysis half-lives of the registered substance, 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane (CAS 3388-04-3), are 0.2 hours at pH 4, 0.3 hours at pH 5, 4 hours at 7 and 0.1 hours at pH 9 at 20-25°C. At 37.5°C and pH 2 (relevant for conditions in the stomach following oral exposure), the hydrolysis half-life is less than 5 seconds. The ultimate products of hydrolysis are [2-(3,4-epoxycyclohexyl)ethyl]silanetriol and methanol.

The read across substance [2-(3,4-epoxycyclohexyl)ethyl]triethoxysilane (CAS 010217-34-2) has measured hydrolysis half-lives of 0.7 hours at pH 4, 31 hours at pH 7 and 0.4 hours at pH 9 and 25°C. At 37.5°C and pH 2 (relevant for conditions in the stomach following oral exposure), the hydrolysis half-life is 9 seconds The products of hydrolysis are [2-(3,4-epoxycyclohexyl)ethyl]silanetriol and ethanol.

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.

Analogue approach justification

(a) Structural similarity

The registration and read-across substances are structurally similar and are members of an analogue group of epoxyalkyl alkoxysilanes. Both substances are trialkoxysilanes that have a 2-(3,4-epoxycyclohexyl)ethyl side group attached to the silicon atom. In the structure of the registration substance, the three alkoxy groups are methoxy, whereas in the structure of the read-across substance, the three alkoxy groups are ethoxy. The silanol hydrolysis product in both cases is 2-(3,4-epoxycyclohexyl)ethylsilanetriol. The non-silicon-containing hydrolysis products are ethanol and methanol respectively.

(b) Similar physicochemical characteristics

The similarity of the physicochemical properties and hydrolysis half-life at pH relevant to oral exposure is important. The parent substances hydrolyse at slightly different rates but both hydrolyse to the same silanol hydrolysis product. The key physicochemical parameters are summarised below.

Table 5.2.3: Key physicochemical parameters

 

Target (registration substance)

Source (read-across substance)

CAS number

3388-04-3

10217-34-2

 

EC number

222-217-1

425-050-4

Chemical Name

2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane

[2-(3,4-epoxycyclohexyl)ethyl]triethoxysilane

Molecular weight

 (gmol-1)

246.38

288.46

log Kow(parent)

2.5 at 20°C

3.9 at 20°C (predicted)

log Kow(silicon-containing hydrolysis product)

-0.6 at 20°C

-0.6 at 20°C

Water solubility (parent)

1400 mg/l at 20-25°C

830/860 mg/l (two isomers)

Water solubility (silicon-containing hydrolysis product)

1.0E+06 mg/l at 20-25°C

 

1.0E+06 mg/l at 20-25°C

 

Hydrolysis at pH2, 37.5°C

5 seconds

9 seconds

Vapour pressure (parent)

0.46 Pa at 25°C

0.3 Pa at 25°C

Hydrolysis at pH 7, and 37.5°C

1.5 h

11 hours

Vapour pressure (silicon-containing hydrolysis product)

7.5E-06 Pa at 25°C

7.5E-06 Pa at 25°C

(c) Acute toxicity

The acute toxicity of the registered substance and the read across substance is similar, supporting the notion that the toxicological profiles of the two substances are similar. The acute oral LD50 values are reported to be 17220 mg/kg (Mellon, 1962) and >5000 mg/kg (WIL, 1996) for the registered substance and read-across substance, respectively.

(d) Discussion of the toxicity of the hydrolysis products

The predicted half-life for the registration substance 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane (CAS 3388-04-3) and read-across substance [2-(3,4-epoxycyclohexyl)ethyl]triethoxysilane (CAS 010217-34-2) at neutral pH and body temperature (pH 7, 37.5°C) differ between the registered substance (1.5 h) and the read across substance (ca. 11 hours). However under the acidic conditions of the stomach, the hydrolysis half-lives are short (< 1 minute) and therefore comparable, as both substances will be rapidly hydrolysed to their common hydrolysis product [2-(3,4-epoxycyclohexyl)ethyl]silanetriol.

The repeated dose toxicity of the non-silanol hydrolysis product, methanol, 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) are reported here to support read-across arguments.

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 high doses and generally effects when noted, are considered adverse only at the upper end of the dose ranges studied e. g 650 mg/m3 in monkeys, 13000 mg/m3 in rats.

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 (OECD, 2004b).

Therefore the repeated dose toxicity studies would reflect the properties of the common silanol hydrolysis product.

Methanol and ethanol are not considered to contribute to overall effects in rats.


Justification for classification or non-classification

There are no data to suggest that 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane should be classified for STOT-RE following repeated exposure according to Regulation (EC) No 1272/2008.

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