[3-(triethoxysilyl)propyl]urea

Endpoint summary

Description of key information

Oral (OECD TG 407): NOAEL = 1228 mg/kg bw (highest dose tested)
Dermal: no data available
Inhalation: no data available

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

1 228 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was conducted according to an appropriate OECD test guideline and in compliance with GLP. Since this study is a read-across from CAS 116912-64-2, the reliability downgraded from RL1 to RL2.

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 information about repeated dose exposure is available for the registered substance, however, reliable data is available for the closely related substance ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2). The read-across is justified as follows:

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 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 [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0) is evaluated point by point.

Read-across hypothesis

After oral application, both [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0 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 adverse effects for systemic toxicity at the relevant dose levels. Therefore read-across from ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) to [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0) is appropriate for the oral route.

Analogue approach justification

(a) Structural similarity

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) being one of the constituents.

Both substances are part of an analogue group of 3-(trialkoxysilyl)propylurea substances containing propylurea and alkoxy groups. The read-across substance was 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).

(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	23779-32-0	116912-64-2
Chemical Name	[3-(Triethoxysilyl) propyl]urea	Ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters
Composition	Mono-constituent substance	Multi-constituent substance
Constituents	n. a.	1. [3-(Trimethoxysilyl) propyl]urea 2. [3-(Dimethoxyethoxysilyl) propyl]urea 3. [3-(Methoxydiethoxysilyl) propyl]urea 4. [3-(Triethoxysilyl) propyl]urea
Si hydrolysis product	[3-(trihydroxysilyl) propyl]urea	[3-(trihydroxysilyl) propyl]urea
Molecular weight (parent)	264.39 g/mol	1. 222.31 g/mol 2. 236.34 g/mol 3. 250.36 g/mol 4. 264.39 g/mol
Molecular weight (silanol hydrolysis product)	180.23 g/mol	180.23 g/mol
log Kow (parent)	1.3	1. -0.2 2. 0.3 3. 0.8 4. 1.3
log Kow (silanol hydrolysis product)	-3.3	-3.3
Water sol (parent)	7 000 mg/l	1.      240 000 mg/l 2.        74 000 mg/l 3.        23 000 mg/l 4.          7 000 mg/l
Water sol (silanol hydrolysis product)	1 000 000 mg/l	1 000 000 mg/l
Vapour pressure (parent)	0.0031 PA (20 °C)v	30.3±1.5 Pa (20 °C) (mixture)
Hydrolysis t1/2 at pH 7 and 25°C	16.4 h (20-25°C)	1. <2.4 h 2. <2.4 h 3. ≥2.4 h 4. 16.4 h (20-25°C)
Hydrolysis t1/2 at pH 4 and 25°C	0.3 h (20-25°C)	1. <<2.4 h 2. <<2.4 h 3. <<2.4 h 4. 0.3 h (20-25°C)
Hydrolysis t1/2 at pH 2 and 25°C	10.8 s (20-25°C)	1. <<1.44 min 2. <<1.44 min 3. <<1.44 min 4. 10.8 s (20-25°C)
Hydrolysis t1/2 at pH 7 and 37.5°C	6.04 h	1. 0.88 h 2. 0.88 h 3. 0.88 h 4. 6.04 h
Hydrolysis t1/2 at pH 2 and 37.5°C	4.0 s	1. <<31.8 s 2. <<31.8 s 3. <<31.8 s 4. 4.0 s
Dermal penetration rate of parent substance (DERMWIN 2012)	0.00272 mg/cm²/h	1. 0.01453 mg/cm²/h 2. 0.00833 mg/cm²/h 3. 0.00481 mg/cm²/h 4. 0.00272 mg/cm²/h
Dermal penetration rate of hydrolysis products (DERWIN 2012)	0.00069 mg/cm²/h	0.00069 mg/cm²/h

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-lifeof [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.

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, 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.

(c) Similar toxicokinetics

The predicted water solubility of [3-(trimethoxysilyl)propyl]urea, [3-(dimethoxyethoxysilyl)propyl]urea, [3-(methoxydiethoxysilyl)propyl]urea, and [3-(triethoxysilyl)propyl]urea range from 70 000 mg/l to 240 000 mg/l, depending on the alkoxy groups bond to the silanol moiety. Together with the moderate log Kow of all four parent substances (-0.2 to 1.3) this suggests that they will all readily dissolve in the gastrointestinal fluids while they are still lipophilic enough to be absorbed by passive diffusion. Since hydrolysis is expected to occur rapidly in the gut, exposure is assumed nearly exclusively to the common hydrolysis product. The strong hydrophilicity of the hydrolysis product (water solubility of 1 000 000 mg/l), the low log Kow (-3.3) and the low molecular weight (180.23 g/mol) suggest that the hydrolysis product will have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. However, fast renal excretion of the hydrolysis product must also be taken into account.

(d) Similar acute toxicity

No acute toxicity data are available for the registered substance, however, reliable data is available for the read-across substance.

Ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) is of no acute systemic toxicity and the acute oral and dermal LD50 exceed the highest dose tested (both >2457 mg/kg bw). No mortality occurred and no test material related clinical findings were reported. Since the submission substance is one of the constituents of ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2), comparable toxicological behaviour can be expected.

 

(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 ethanol and the NOAEC from methanol are greater than the dose that is expected to be generated from hydrolysis of ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) in the stomach. Therefore the effects observed of ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) following oral exposure are not attributable to methanol or ethanol.

It is therefore considered to be appropriate, to read-across the repeated oral toxicity from ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) to the registered substance [3-(triethoxysilyl) propyl]urea (CAS 23779-32-0).

Discussion

A 28 -day repeated dose oral toxicity study is available to assess the repeated dose toxicity of ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (NOTOX, 2000b). In the study according to OECD 407 (adopted 1995) and in compliance with GLP, male and female Wistar rats (5 per sex and dose group) were treated with 61, 184, 1228 mg/kg bw test substance by oral gavage for 28 days. No mortality occurred in the study. Salvation was observed in the animals of the high dose group, but was not considered to be a sign of adverse systemic toxicity. No other clinical signs were evident. Slightly lower body weight gain was observed in the mid and high dose males, but was not statistically significant. Decrease of RBC, HB, relative number of lymphocytes and an increase of relative number of neutrophils in the female mid-dose group were considered to have occurred by chance, as there was no dose-response relationship and the values were within the range of historical control data. In two females of the mid-dose group the total motor activity was increased. Moreover, in one of these females the ratio between upper and lower sensor recordings was reverse to what is expected. These effects were considered to have occurred by chance because no corroborative findings in the animals and no dose-response relationship was observed. A decrease in the thymus: body weight ratio of high dose males was not supported by histological examination of the thymus. In view of the very small variation in the thymus weights of the male high dose group and the fact that all thymus weights were within the range of the historical control data, the toxicological significance of this effect was doubted. Thickening of the limiting ridge was observed in the stomach of 2/5 females of the high dose group. Microscopically a minimal squamous hyperplasia was observed. These effects were attributed to an irritative effect of the substance and are also commonly seen in gavage studies. In conclusion, exposure to up to 1228 mg/kg bw test substance did not results in any substance-related adverse effects. Thus, a NOAEL of 1228 mg/kg bw/day was deduced.

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

Justification for classification or non-classification

The available data are reliable and suitable for classification. Based on this data, classification for repeated dose toxicity according to Regulation (EC) 1272/2008 is not warranted.