[3-(triethoxysilyl)propyl]urea

Endpoint summary

Description of key information

Oral (OECD 401, rat): LD50 > 5000 mg/kg bw
Inhalation: No data available (data waiving according to Column 2 of REACH Annex VIII, Section 8.5.2)
Dermal (OECD 402, rat): LD50 > 2457 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 mg/kg bw

Quality of whole database:

The study was conducted according to an appropriate OECD test guideline, and in compliance with GLP. Since this is a read-across from a structural analogue substance, the reliability was changed from RL1 to RL2.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 457 mg/kg bw

Quality of whole database:

The study was conducted according to an appropriate OECD test guideline, and in compliance with GLP. Since this is a read-across from a structural analogue substance, the reliability was changed from RL1 to RL2.

Additional information

No acute toxicity data are available for the submission substance [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0). However, reliable data via the oral route are available from the structural analogue substance [3-(trimethoxysilyl)propyl]urea (CAS 2384 -64-3). Additionally, reliable information on toxicity via the dermal route is available from [3-(trimethoxysilyl)propyl]urea (CAS 23843-64-3) and 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 acute 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, all three substances [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 adverse effects for systemic toxicity at the relevant dose levels. Therefore read-across from [3-(trimethoxysilyl)propyl]urea (CAS 23843-64-3) and 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) 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).

(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	23843-64-3
Chemical Name	[3-(Triethoxysilyl) propyl]urea	Ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters	[3-(trimethoxysilyl) propyl]urea
Composition	Mono-constituent substance	Multi-constituent substance	Mono-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	n. a.
Si hydrolysis product	[3-(trihydroxysilyl) propyl]urea	[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	222.31 g/mol
Molecular weight (silanol hydrolysis product)	180.23 g/mol	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	-0.2
log Kow (silanol hydrolysis product)	-3.3	-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	240 000 mg/l
Water sol (silanol hydrolysis product)	1 000 000 mg/l	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)	0.03 Pa at 25°C
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)	<2.4 h
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)	<<2.4 h
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)	<<1.44 min
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	0.88 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	<<31.8 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	0.01453 mg/cm²/h
Dermal penetration rate of hydrolysis products (DERWIN 2012)	0.00069 mg/cm²/h	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.

For an acid-base catalysed reaction in buffered solution, the measured rate constant is a linear combination of terms describing contributions from the uncatalysed reaction as well as catalysis by hydronium, hydroxide, and general acids or bases.

k_obs= k₀+ k_H3O+[H₃O⁺] + k_OH-[OH^-] + k_a[acid] + k_b[base]

At extremes of pH and under standard hydrolysis test conditions, it is reasonable to suggest that the rate of hydrolysis is dominated by either the hydronium or hydroxide catalysed mechanism. This is supported by studies for various organosilicon compounds in which calculation of k_H3O+ and k_OH- from the experimental results at pH 4 and 9, respectively, resulted in reasonable estimates of the half-life at pH 7 (Peter Fisk Associates, 2011 and Peter Fisk Associates, 2013).

Therefore, at low pH:

k_obs≈ k_H3O+[H₃O⁺]

At pH 4 [H₃O⁺] = 10^-4 mol dm^-3 and at pH2 [H₃O⁺]=10^-2 mol dm^-3; therefore, k_obs at pH 2 should be approximately 100 times greater than k_obs at pH 4.

The half-life of a substance at pH 2 is calculated based on:

t_1/2(pH 2) = t_1/2(pH 4) / 100

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. Under ideal conditions, hydrolysis rate can be recalculated according to the equation:

DT₅₀(X°C) = DT₅₀(T) x e^{(0.08 (T-X))}

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

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

Oral absorption: 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 sianol 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 common 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.

Dermal absorption: QSAR based dermal permeability prediction (DERMWIN, 2012) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 00272 mg/cm²/h for the submission substance and 0.01453, 0.00833, and 0.00481 mg/cm²/h, respectively, for [3-(trimethoxysilyl)propyl]urea, [3-(dimethoxyethoxysilyl)propyl]urea, and [3-(methoxydiethoxysilyl)propyl]urea. These data indicate that dermal absorption may be low to moderate (20-50%) for all four substances, increasing with the amount of ethoxy groups bond to the silanol moiety together with increasing lipophilicity. In contrast, the common hydrolysis product exhibits a very low dermal absorption (0.00069 mg/cm²/h, 10%). However, hydrolysis is considered to be of minor importance due to the low presence of water on the skin surface.

(d) Similar acute toxicity

Acute toxicity data are available for the registered substance and the read-across substances. An overview of the available key acute toxicity data of the test substance and the analogue substances is given below:

CAS Number	23779-32-0	116912-64-2	23843-64-3
Chemical Name	[3-(Triethoxysilyl) propyl]urea	Ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters	[3-(Trimethoxysilyl) propyl]urea
Acute oral toxicity (LD50)	no data	>2457 mg/kg bw	>5000 mg/kg bw
Acute inhalation toxicity (LC50)	no data	no data	no data
Acute dermal toxicity (LD50)	no data	>2457 mg/kg bw	>2000 mg/kg bw

Both read-across substances show no acute systemic toxicity and the acute oral and dermal LD50 exceed the highest dose tested. 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) and a close structural analogue substance to [3-(trimethoxysilyl)propyl]urea (CAS 23843-64-3), comparable toxicological behaviour can be expected.

In conclusion, read-across from ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) and [3-(trimethoxysilyl)propyl]urea (CAS 23843-64-3) to the registered substance [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0) for acute oral and dermal toxicity is considered to be appropriate.

Acute Toxicity: oral

In the available key study (WIL Research Laboratories, Inc., 1996a) 1-[3-(trimethoxysilyl)propyl]urea (CAS 23843-64-3) was investigated for acute oral toxicity according to the OECD TG 401, and in compliance with GLP. The undiluted test material was administered once via oral gavage to Crl:CD BR rats. Prior to initiation of the main study, a range-finding study was conducted in which groups of one male and one female rat were dosed at levels of 500, 1000, 2000, 3500 and 5000 mg/kg bw. There were no deaths during the range-finding study. Based on these results, 5000 mg/kg was selected as the first level on the main study using 5 rats per sex. No mortality occurred and no clinical signs were noted throughout the study period. There were no remarkable changes or differences in body weights and no test material related findings at necropsy. Based on these results, the LD50 was set at >5000 mg/kg bw, and classification for acute oral toxicity according to 67/584/EEC and EC/1272/2008 is not warranted.

Acute Toxicity: inhalation

In accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the inhalation route (required in Section 8.5.2 of REACH Annex VIII) does not need to be conducted as reliable data via the oral and dermal routes are available.

Acute Toxicity: dermal

In the key dermal toxicity study, which was conducted in compliance with GLP and according to the OECD TG 402, an LD50>2457 mg/kg bw was reported for ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) (NOTOX, 1999a). Five male and female Wistar rats were treated with a limit dose of 2.17 ml/kg bw (equivalent to 2457 mg/kg bw) for 24 h under occlusive conditions. No mortality occurred and no necropsy findings were observed within the observation time of 14 days. Red staining of the snout, head or neck was observed among several animals on days 1 and 2. These findings were not considered to be substance-related as they are typically noted in association with the bandage application procedures. Focal erythema was seen in the treated skin-area of three females during the observation period. Signs of necrosis and scabs were also seen in one of these animals. The animals had recovered from the symptoms between day 6 and 11.

Supporting company data (TRC Environmental Corp., 1996) report that 1-[3-(trimethoxysilyl)propyl]urea (CAS 23843-64-3) was investigated for acute dermal toxicity in rats at a dose of 2000 mg/kg bw. No test guideline and no information on GLP compliance are given. No deaths were observed during the study and no clinical signs were observed, except minor reversible desquamation. The LD50 reported is >2000 mg/kg bw. Based on these results, classification for acute dermal toxicity according to 67/584/EEC and EC/1272/2008 is not warranted.

Justification for selection of acute toxicity – oral endpoint
The key study was selected for assessment.

Justification for selection of acute toxicity – inhalation endpoint
In accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the inhalation route (required in Section 8.5.2 of REACH Annex VIII) does not need to be conducted as reliable data via the oral and dermal routes are available.

Justification for selection of acute toxicity – dermal 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 acute toxicity according to 67/584/EEC and EC/1272/2008 is not warranted.