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Additional information

No information about genetic toxicity is available for the registered substance, however, reliable data is available for the closely related substances Ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) and 3-(trimethoxysilyl)propyl]urea (CAS 23843-64-3).

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 genetic toxicity relevant properties are structural similarity as well as physical-chemical and basic toxicological parameters in the same range. Especially functional groups that are associated with genetic toxicity have to be compared. In the following paragraphs the read-across approach for [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0) is evaluated point by point.

Read-across hypothesis

No data on genotoxicity are available for the registered substance [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0), however, reliable read-across data are available for the structural analogue substance [3-(trimethoxysilyl)propyl]urea (CAS 23843-64-3; Ames Test) and the related substance ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2; Ames Test, Mammalian Chromosome Aberration Test in vitro, Mammalian Erythrocyte Micronucleus Test in vivo).

The registration and read-across substances are structurally similar, containing a silicon bound ureidopropyl moiety and three alkoxy (-OX) groups. The substances hydrolyse rapidly to produce the same silanol hydrolysis product [3-(trihydroxysilyl)propyl]urea. The read-across substance ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) is a multi-constituent substance, with the submission substance [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0) and the read-across substance [3-(trimethoxysilyl)propyl]urea (CAS 23843-64-3) being two of the constituents.

These substances are part of an analogue group of 3-(trialkoxysilyl)propylurea substances containing propylurea and alkoxy groups. The read-across substances were selected as the most appropriate based on chemical structure. Further information is given in a supporting report attached to Section 13 of the IUCLID5 dossier (PFA 2013a).

After oral application, [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0), [3-(trimethoxysilyl)propyl]urea (CAS 23843-64-3), and ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) hydrolyse rapidly to the common silanol hydrolysis product [3-(trihydroxysilyl)propyl]urea. The non-silanol hydrolysis products, ethanol and methanol, are not expected to contribute to any genotoxic effects at the relevant dose levels.

The predicted half-life of [3-(triethoxysilyl)propyl]urea is 16.4 h at pH 7 and 20-25°C, the measured half-lives of [3-(trimethoxysilyl)propyl]urea, [3-(dimethoxyethoxysilyl)propyl]urea, and [3-(methoxydiethoxysilyl)propyl]urea are approximately 2.4 h at 25°C and at pH 7 (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 increases as the pH is raised or lowered. The calculated half-life of [3-(triethoxysilyl)propyl]urea is therefore 10.8 s at 20-25°C, and for [3-(trimethoxysilyl)propyl]urea, [3-(dimethoxyethoxysilyl)propyl]urea, and [3-(methoxydiethoxysilyl)propyl]urea the half-lives at pH 2 and 25°C are <<1.44 min, respectively.

Reaction rate increases with temperature therefore hydrolysis will be faster at physiologically relevant temperatures compared to standard laboratory conditions. Thus, for [3-(triethoxysilyl)propyl]urea the hydrolysis half-lives at 37.5ºC and pH 7 (relevant for lungs and blood) are approximately 6.04 h at pH 7 and approximately 4.0 s at pH 2, respectively. For the constituents [3-(trimethoxysilyl)propyl]urea, [3-(dimethoxyethoxysilyl)propyl]urea, and [3-(methoxydiethoxysilyl)propyl]urea, the corresponding half-lives are approximately 0.88 h at pH 7 and at pH 2 <<31.8 s, respectively..

Hydrolysis is therefore expected to occur during testing and following exposure, and it is considered appropriate to read-across data from ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) and 3-(trimethoxysilyl)propyl]urea (CAS 023843-64-3) to the registered substance.

None of the Ames tests available showed a positive result, indicating that the test materials do not exhibit a mutagenic potential. In contrast, the available Mammalian Chromosome Aberration Test in vitro conducted with ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) was positive with and without metabolic activation, indicating clastogenic properties of at least one of the constituents. However, this result could not be confirmed in vivo, since the Mammalian Erythrocyte Micronucleus Test in vivo revealed a negative result. Thus, it can be concluded, that the substances of this analogue group are not genotoxic.

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

The genetic toxicity data available for the substances of the analogue group III-23 are summarised in Table 1.

 

Table 1: Summary of available genotoxicity data for substances in the analogue group III-23.

CAS

Name

Group

Bacterial Mutagenicity

In Vitro Mammalian Cytogenicity

In Vitro Mammalian Mutagenicity

In Vivo Genotox

23843-64-3

[3-(trimethoxysilyl)

propyl]urea

III-23

Negative

 

 

 

116912-64-2

Ureudopropyl

trialkoxysilane,

 mixed methoxy

and ethoxy esters

 

III-23

Negative

Positive

 

Negative in micro-nucleus

One in vitro (chromosome aberration) and one in vivo (micronucleus assay) study are available for assessment of the genetic toxicity of ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters and one in vitro (Ames) study is available for assessment of the genetic toxicity of 3-(trimethoxysilyl)propyl]urea.

 

In vitro:

An Ames test according to OECD TG 471 and in compliance with GLP was performed with the structural analogue [3 -(trimethoxysilyl)propyl] urea (CAS 23843 -64 -3) to assess the mutagenic properties of the test substance (Microbiological Associates Inc., 1996). S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2 uvr A were treated with 100 - 5000 µg/plate of the test substance in the presence or absence of a metabolic activation system. No increase of the mutation frequency was observed in any tester strain at any dose level. No toxicity and no precipitation were observed up to the maximum dose of 5000 mg/kg bw. The controls were valid and were within the historical control data. The use of 2 -Aminoanthracene as a sole indicator for the efficacy of the metabolic activation system is not recommended in the actual OECD TG 471 (adopted 1997), as each batch of S9 should be characterised with a second substance, but was supposed not to affect the validity of the test. In conclusion, the test substance is not proposed to be mutagenic in the Ames test.

In a second in vitro test, performed according to OECD TG 473 and in compliance with GLP, ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters was investigated on its ability to induce chromosome aberrations (NOTOX, 2000c). Cultured peripheral human lymphocytes were treated for 3 hours (main test) with 100, 180, 333, 420, 560 µg/ml (without S9 -mix) and 333, 560, 1000, 1300, 1800 µg/ml (with S9 -mix) and were fixed after 24 h. A genotoxic effect was observed for the test substance tested in a 3 h treatment in two independent experiments without and with metabolic activation. Appropriate solvent and positive controls were included and showed expected results. The test substance is genotoxic under the test conditions applied.

 

In vivo:

For assessment of genetic toxicity in vivo a micronucleus test with Wistar rats according to OECD TG 474 and in compliance with GLP is available (NOTOX, 2001).Five male and female animals were treated once per gavage with 500, 1000, 2000 mg/kg bw test substance. After 24 or 48 h (high dose group only) the animals were killed and the bone marrow was prepared for investigation of erythrocytes. No significant increase in the incidence of micronucleated polychromatic erythrocytes was observed in the bone marrow of male or female rats 24 or 48 hours after a single oral dose of up to and including 2000 mg/kg bw. A reduction in the PCE/total erythrocyte ratio was only observed in the 48 hour positive control group. It is concluded that the test substance is negative for the induction of micronuclei under the conditions of the study. Although no bioavailability of the test substance was proven, the study was evaluated as valid, because it was tested up to the limit concentration of 2000 mg/kg bw.

 

In conclusion, the test substance should not be classified in the category "genetic toxicity", as there is no indication for mutagenicity from an Ames test, and no chromosome aberration was observed in the in vivo micronucleus test (according to ECHA, guidance on information requirements and chemical safety assessment, chapter R7a, November 2012 (ECHA, 2012a)).


Justification for selection of genetic toxicity endpoint
No study was selected, since the positive result observed in the in vitro mammalian cytogenicity study could not be confirmed in the in vivo micronucleus assay, and thus, the test material was concluded to be not genotoxic.

Short description of key information:
In vitro:
Ames test (OECD TG 471, GLP): negative with and without metabolic activation.
Chromosome aberration assay (OECD TG 473, GLP): positive with and without metabolic activation.
In vivo:
Micronucleus test (OECD TG 474, GLP): negative

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the available in vitro and in vivo data on mutagenicity of the test substance, ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters is not classified for mutagenicity according to Regulation (EC) 1272/2008 or Directive 67/548/EEC.

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