N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine

Endpoint summary

Description of key information

The available information showed some evidence that N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine, is expected to be absorbed via the gastro-intestinal and respiratory tract and by the dermal route. Once absorbed, the substance may be distributed systemically in the water compartment of the body. The substance is considered to be excreted via the urine without being further metabolised.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of the substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2017). There are no studies available in which the toxicokinetic behaviour of N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine (CAS 35141-30-1) has been investigated.

 

Therefore, the toxicokinetic behaviour assessment of the substance and its hydrolysis product was assessed from its physicochemical properties and from the available toxicology studies on the substance itself and on the read-across substance, N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3).  

 

N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine hydrolyses in contact with water (half-life is 4.3 h at pH 7 and 20-25°C), generating methanol and N-(2-aminoethyl)-N'-[3-(trihydroxysilyl)propyl]ethylenediamine. Acid environments are known to catalyse this abiotic and enzyme-independent reaction and enhance the reaction rate, which is further increased by the body temperature of approximately 37 °C present in mammals. Thus, the predicted half-lives at pH 4, 5, and 9 are 0.3, 0.3, and 0.1 h at 20-25 °C, and at pH 2 at 37.5 °C, which is the condition found in the stomach, N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine is predicted to hydrolyse within 4.5 minutes. This suggests that systemic exposure to both the parent, N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine, and to the hydrolysis product, N-(2 -aminoethyl)-N'-[3-(trihydroxysilyl)propyl]ethylenediamine, is possible. Hence, this toxicokinetic behaviour assessment will try to predict the behaviour of both these substances. The toxicokinetics of methanol is discussed elsewhere and is not included in this summary.

The molecular weight and the predicted water solubility of N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine are 265 g/mol and 1E+06 mg/L, respectively. The molecular weight and predicted water solubility of the hydrolysis product, N-(2-aminoethyl)-N'-[3-(trihydroxysilyl)propyl]ethylenediamine, are 222 g/mol and 1E+06 mg/L, respectively. This shows that the hydrolysis product is smaller in size and, thereby, suggests that it will have greater potential to be absorbed through biological membranes than the parent substance. However, the predicted log Kow values of -0.8 for the parent substance and -3.9 for the hydrolysis product indicate that the hydrolysis product, unlike the parent, is not lipophilic enough to efficiently pass through biological membranes by passive diffusion.

 

Absorption

 

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Kow) value and the water solubility. The log Kow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

 

Absorption, oral

 

In general, molecular weights below 500 g/mol and log Kow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Kow> 4), in particular for those that are poorly soluble in water (= 1 mg/L) which would otherwise be poorly absorbed (ECHA, 2017).

Based on the physicochemical data absorption of the parent substance and hydrolysis product is expected. The parent substance may be absorbed by passive diffusion, based on the log Kowof -0.8, low molecular weight and the high water solubility. In case of the hydrolysis product passage through aqueous pores or being carried through the epithelial barrier by the bulk passage of water could be possible based on the low molecular weight and the high water solubility.

These assumptions are supported by the results of the acute oral toxicity study in rats where dosage of above 2000 mg/kg bw test substance provoked mortality and clinical signs of toxicity, showing systemic availability of the substance.

 

Absorption, dermal

 

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Kow< 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Kow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Kow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Kow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).

The physicochemical properties of the parent substance suggest it has the potential to be absorbed through the skin. In contrast, the low Kow of its hydrolysis product suggests a lower absorption through the skin. The high water solubility and log Kow of < 0 may limit the ability of the hydrolysis product to cross the stratum corneum. This is further supported by QSAR based dermal permeability prediction (DERMWIN V2.00.2009) using molecular weight, log Kow and water solubility, calculated a dermal penetration rate of 15.3 µg/cm²/h for N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine which leads to an estimated high dermal absorption potential. In contrast, the calculated dermal penetration rate for the hydrolysis product is 0.593 µg/cm²/h, which is a medium to low dermal absorption potential. These values are considered as an indicator for a dermal absorption of 80% for the parent substance and 20% for the hydrolysis product.

 

However, a reliable acute dermal toxicity study is available (DCC, 2000) for the structural analogue substances, N-(3-(triethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3), it was shown that the substance was of low toxicity and/or had low potential to be absorbed by the dermal route.

 

Absorption, inhalation

 

N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine has a calculated vapour pressure of 1.5E-02 Pa at 25 °C (PFA, 2014). Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours and gases is not significant.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). In humans, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. Particles with aerodynamic diameters below 50 µm may reach the thoracic region and those below 15 µm may reach the alveolar region of the respiratory tract (ECHA, 2017).

As for oral absorption, the molecular weight, log Kow and water solubility indicate that absorption via inhalation is possible.

These assumptions are supported by the results of the acute inhalation toxicity study with the structural analogue substance, N-(3-(triethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3), where rats exposed to concentrations of up to 5.75 mg/L test substance (aerosol) provoked mortality and clinical signs of toxicity, showing systemic availability of the substance.

 

Distribution and accumulation

 

Any absorbed test substance is likely to be in the form of the hydrolysis product, N-(2-aminoethyl)-N'-[3-(trihydroxysilyl)propyl]ethylenediamine.

Distribution of a compound within the body depends on the physicochemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2017).

Once absorbed, the substance is likely to be distributed within the water compartment of the body due to the high water solubility.The molecular weight (223 g/mol) and high water solubility (1E+06 mg/L) of the hydrolysis product suggests it will diffuse through aqueous channels, pores and will be widely distributed in the body. However, the log Kow of - 3.9 indicates the hydrolysis product is not lipophilic enough to distribute into cells and the extracellular concentration may be higher than the intracellular concentration. Accumulation in the body is not favourable for the substance.

 

Metabolism

 

There are no data regarding the metabolism of N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for the substance N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine itself.

 

Excretion

 

The low molecular weight (below 300 g/mol) and good water solubility of the parent and hydrolysis product suggest that they are likely to be excreted by the kidneys into urine.

 

Conclusion

 

The available information showed some evidence that N-(2-aminoethyl)-N'-[3-(trimethoxysilyl)propyl]ethylenediamine is expected to be absorbed via the gastro-intestinal and respiratory tract. Once absorbed, the substance may be distributed systemically in the water compartment of the body. The substance is considered to be excreted via the urine without being further metabolised.