Registration Dossier

Administrative data

Description of key information

No data are available for repeated dose toxicity for the registered substance. 3-[Tris(acetoxy)silyl]propyl methacrylate hydrolyses forming acetic acid, which would cause corrosion in repeated dose toxicity studies. This is supported by

a repeated dose toxicity study via the oral route which has been read across from the analogous substance triacetoxyethylsilane (CAS 17689-77-9) which has the hydrolysis product, acetic acid, in common with the registered substance. Only a range finding study is available (Dow Corning Corporation, 2004); the main study was not conducted due to the severe corrosive effects of acetic acid in the oesophagus and stomach. The LOAEL was 20 mg/kg bw/day based on occasional salivation during/shortly after dosing the animals.

The requirement for repeated dose toxicity studies has therefore been waived and the risk assessment based on the local effects of the hydrolysis product, acetic acid, using the EU IOEL for acetic acid. The overall NOAEC for local effects is based on the IOEL for acetic acid which is calculated to be 46 mg/m3 expressed as the proportion of the registered substance.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
20 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study is a range-finding study with the analogous substance triacetoxyethylsilane (CAS 17689-77-9) which has the hydrolysis product acetic acid, in common with the registered substance. The main study was not conducted due to severe corrosive effects in the early digestive tract.

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

No data are available for repeated dose toxicity of the registered substance. It is considered not to be either ethical or technically feasible to perform repeated dose toxicity testing with 3-[tris(acetoxy)silyl]propyl methacrylate by any route of exposure due to its known corrosive properties. The available data for a surrogate substances, triacetoxyethylsilane (CAS 17689-77-9), are used as read-across to demonstrate corrosivity.

Oral route

Data are available from a seven-day range-finding study conducted with another acetoxysilane substance, triacetoxyethylsilane (CAS 17689-77-9). Oral gavage administration of the substance caused erosion and ulceration of the oesophagus and stomach at dose levels as low as 20 mg/kg bw/day (Dow Corning Corporation, 2004). The results indicated that a maximum dose level of less than 20 mg/kg/day would be required for a longer duration repeated dose study in order to avoid death or obvious suffering due to the corrosivity of the hydrolysis product, acetic acid. The data provided in this range-finder study indicated that a practical and humane dose range for subsequent longer term studies was below the limit of technical practicality and toxicological significance.

Inhalation route

It is the requirement of a guideline-compliant repeated-dose inhalation study to elicit systemic toxicity at the highest test concentration. Since the local corrosive effects of 3-[tris(acetoxy)silyl]propyl methacrylate would be significant, a valid inhalation study according to the relevant guidelines is technically not feasible to do. Acetic acid has an EU 8-hour Indicative Occupational Exposure Level (IOEL) of 25 mg/m3 (Commission Directive 91/322/EEC). This value may be taken as a reasonable starting point for the maximum test concentration that would not cause undue suffering to test animals in a repeated dose inhalation study with exposure for six hours per day. Since the registered substance produces three moles of acetic acid per mole of starting material, the equivalent test concentration expressed as parent would be:

MW (acetic acid) = 60 g/mol;

MW (3-[tris(acetoxy)silyl]propyl methacrylate) = 332 g/mol;

Amount acetic acid produced by 1 mole 3-[tris(acetoxy)silyl]propyl methacrylate = 3*(60 g/mol) = 180 g;

Concentration of 3-[tris(acetoxy)silyl]propyl methacrylate required to produce 25 mg/m3 acetic acid, = (332/180)*25 = 46 mg/m3.

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 rate and the physical-chemical parameters in the same range. In the following paragraphs the proposed read-across from triacetoxyethylsilane (CAS 17689-77-9) is evaluated point by point.

Read-across from triacetoxyethylsilane (CAS 17689-77-9) for the oral route

Read-across hypothesis

Testing of the registered substance is neither ethical nor technically feasible because of the production of acetic acid. The read-across hypothesis is that the source substance (read-across) and target (registration) substance have similar local toxicological properties based on their rapid hydrolysis to acetic acid, which is corrosive (RAAF scenario 1). The production of acetic acid prevents repeated dose toxicity testing at relevant doses.

Read-across justification

The predicted hydrolysis half-lives of the registered substance, 3-[tris(acetoxy)silyl]propyl methacrylate, are <1 minute at 25°C and pH 4, 7 and 9. The products of hydrolysis are 3-(trihydroxysilyl)propyl methacrylate and acetic acid.

The read-across substance triacetoxyethylsilane (CAS 17689-77-9) has measured hydrolysis half-lives of <13 s (0.2 min) at pH 4, 7 and 9 and 25°C. The hydrolysis products are ethylsilanetriol and acetic acid.

Both substances hydrolyse very rapidly to produce three moles of acetic acid for each mole of parent substance.

The available 7-day oral range-finding study for triacetoxyethylsilane shows clear evidence of corrosive effects (erosion and ulceration of the oesophagus and stomach) at dose levels down to 20 mg/kg bw/day. These effects are attributable to the rapid formation of acetic acid.

Further testing by the oral route is therefore considered to be inappropriate since a humane dose range for subsequent longer term studies was below the limit of technical practicality and toxicological significance.

Discussion of the toxicity of the non-silanol hydrolysis product

Acetic acid

NOAELs following repeated exposure to acetic acid and its salts, reported in the SIAR for triacetoxymethylsilane (CAS 4253-34-3; SIAR, 2005) range from 210 mg/kg bw/day (2-4 month acetic acid drinking water study; systemic toxicity) to 3600 mg/kg bw/day (acetic acid, sodium salt, 4 week dietary study; no effects reported). Signs of irritation/corrosion at the site of contact as well as systemic toxicity have been reported. Prolonged inhalation exposure to acetic acid results in muscle imbalance, increase in blood cholinesterase activity, decreases in albumins and decreased growth at concentrations greater than 0.01 mg/m3. There is no clear evidence to determine if systemic effects were secondary to corrosion, but this is likely to be the case. Since in these studies the test material was administered via drinking water or the diet, corrosive effects would be less severe than if neat test substance were administered by gavage. There are no dermal studies.


Justification for classification or non-classification

Based on the available data 3-[tris(acetoxy)silyl]propyl methacrylate does not require classification for repeated dose toxicity according to Regulation (EC) No 1272/2008.