hydrolysis products of 3-(triethoxysilyl)propan-1-amine

Endpoint summary

Additional information

The test substance “hydrolysis products of 3-(triethoxysilyl)propan-1-amine” is a complex reaction product obtained from hydrolysis of 3-(triethoxysilyl)propan-1-amine in water. The hydrolysis product of 3-(triethoxysilyl)propan-1-amine where the concentration range of 3-(triethoxysilyl)propan-1-amine is > 0.1% - <16% (w/w) is considered as a substance under REACh and at > 16% 3-(triethoxysilyl)propan-1-amine as a polymer.

The hydrolysis product of 3-(triethoxysilyl)propan-1-amine is an UVCB substance in which the concentration range of each constituent depends on the manufacturing condition (e.g. the ratio of 3-(triethoxysilyl)propan-1-amine and water). As 3-(triethoxysilyl)propan-1-amine is hydrolytically instable in water, rapid hydrolysis produces 3-aminopropylsilanetriol (monomer) and ethanol which are formed directly after hydrolysis and several condensation products such as dimers, trimers as well as polymers of siloxanes.

The hydrolysis product contains ethanol in the concentration range of 0.06 -9.9%. However, ethanol is not further considered in this registration dossier as the generated amounts of ethanol do not pose a potential hazard for human health. 

Typical concentrations of the hydrolysis product obtained from hydrolysis of an aqueous solution of 3-(triethoxysilyl)propan-1-amine (8%) are described below: ca. 0.52% (w/w) 3-aminopropylsilanetriol (monomer, CAS 58160-99-9), ca. 0.7% (w/w) 1,3-bis(3-aminopropyl)disiloxane-1,1,3,3-terol (dimer), ca. 3% (w/w) hydrolysed polymers of 3-(triethoxysilyl)propan-1-amine, ca. 4.99% (w/w) ethanol (CAS64-17-5) and ca. 90.79% water.

There are no experimental studies available in which the toxicokinetic properties of the hydrolysis product were investigated. Therefore, whenever possible, toxicokinetic behaviour was assessed taking into account the available information on physicochemical and toxicological characteristics of hydrolysis product according to “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014)”.

In addition, a read-across approach was used in order to fulfil standard information requirements according to Annex VIII of Regulation (EC) No 1907/2006. Read-across is based on the hypothesis that 3-(triethoxysilyl)propan-1-amine hydrolyses rapidly in water resulting in the test substance. Therefore, it can be expected that both substances have similar behaviour under aqueous conditions and read-across to 3-(triethoxysilyl)propan-1-amine is justified for filling data gaps of the test substance. It is considered that the target and the read-across substance are in one class of compounds and structural differences are not supposed to contribute to significant differences in activity with respect to eco- and human toxicological endpoints. A detailed analogue approach justification is provided in the technical dossier (Please refer to IUCLID Section 13 for further information).

The test substance is produced and marketed as colorless aqueous solutions. Since the hydrolysis product is an UVCB substance, the molecular weight cannot be provided. The molecular weight for the monomer is 137.2 g/mol and 256.4 g/mol for the dimer. The polymers containing trimers and polymers have a molecular weight of ≥ 375.6 g/mol. The test substance exists only in aqueous solutions with high water solubility for the monomer and dimer (10⁶ mg/L).

The test substance is expected to have a very low vapour pressure based on QSAR calculation of its main constituents. The vapour pressure of both the monomer and the dimer is < 0.002 Pa at 25 °C.However, because the substance contains ethanol (in the concentration range of 0.06 - 15%) and only exists under aqueous conditions, the vapour pressure of ethanol and water should also be taken into consideration. According to the theoretical principle of Raoult's law, the vapour pressure of a mixture should be lower than the vapour pressure of its component which has the highest vapour pressure in its pure form. In the case of test substance, the constituent ethanol has the highest vapour pressure. Therefore, based on a weight of evidence approach, the vapour pressure of the test substance should be lower than < 7906 Pa at 25 °C.

Using QSAR models, theoctanol/waterpartition coefficient (log Pow) was calculated to be-2.85 for the monomer and -3.15 for the dimer.

 

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 log Pow and the water solubility. The log Pow provides information on the relative solubility of the substance in water and lipids (ECHA, 2014).

Oral

In general, the smaller the molecule, the more easily it will be taken up. Molecular weights below 500 g/mol are favorable for oral absorption (ECHA, 2014). As the molecular weight of the hydrolysed monomer, dimer and polymer ranges from 137.2 g/mol to ≥ 375.6 g/mol, oral absorption in the gastrointestinal (GI) tract is likely for the monomer, the dimer and to some extent also for the polymer.

Absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the GI fluid. However, if the molecular weight is low (less than 200) the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water (Renwick, 1994). Negative log P values indicate that a substance is more soluble in water than in octanol. In general, log Pow values between -1 and 4 are favourable for absorption.

The test substance exists only in aqueous solutions and the log Pow is estimated to be -2.85 for the monomer and -3.15 for the dimer, indicating that absorption from the GI tract may be limited. However, based on its molecular weight, the monomer could pass through aqueous pores.

The available data on oral toxicity of the read-across substance 3-(triethoxysilyl)propan-1-amine is considered for assessment of oral absorption. An acute oral toxicity study with 3-(triethoxysilyl)propan-1-amine revealed that single doses between 1340 and 3800 mg/kg bw caused deaths and signs of toxicity in rats (Myers and Christopher, 1989). The kidney seems to be a target organ for acute toxicity after oral exposure. The LD50 was calculated to be 1492 mg/kg bw for females and 2689 mg/kg bw for males. With respect to the dose administered and due to the systemic effects observed, it can be suggested that 3-(triethoxysilyl)propan-1-amine or its hydrolysis product possess either a low toxic potency or a low absorption in combination with a low systemic toxicity.

Based on the fact that the test substance is formed in aqueous solutions of 3-(triethoxysilyl)propan-1-amine where the concentration range of 3-(triethoxysilyl)propan-1-amine is > 0.1 - < 16% (w/w), the available acute oral toxicity study represents a worst case assumption. With respect to mixture rules, the LD50 value for hydrolysis products of 3-(triethoxysilyl)propan-1-amine (15%) is 9946 mg/kg bw for females and 17927 mg/kg bw for males. Therefore, it can be suggested that the target substance possesses a lower toxic potency than the read-across substance 3-(triethoxysilyl)propan-1-amine. 

An oral repeated dose toxicity study performed in rats according to OECD 408 showedtreatment-related effects in the highest dose group tested with the read-across substance 3-(triethoxysilyl)propan-1-amine (WIL Research, 2001).The animals were treated at dose levels of 70, 200 and 600 mg/kg bw/day. At 600 mg/kg bw/day, pathological and histopathological findings were noted in the liver. Also an increase in the level of alanine aminotransferase and aspartate aminotransferase was observed in the high dose group. The animals showed labored respiration, gasping, partial closure of the eyes, general paleness, hypothermia, dermal atonia and/or tremors at 600 mg/kg bw/day. As the treatment-related effects were limited to the high dose group, the NOAEL was therefore 200 mg/kg bw/day. The study indicates that 3-(triethoxysilyl)propan-1-amine or its hydrolysis product is systemically bioavailable after repeated oral administration. With respect to mixture rules, the NOAEL for hydrolysis products of 3-(triethoxysilyl)propan-1-amine (15%) is 1333 mg/kg bw/day.

Also a prenatal developmental toxicity study with 3-(triethoxysilyl)propan-1-amine is available. Thirty female rats per group were exposed by gavage from day 6 of gestation through day 20 of gestation to doses of 20, 100 or 600 mg/kg bw/day of 3-(triethoxysilyl)propan-1-amine (Breslin, 1998). Increased incidences of mortality and clinical observations, as well as slight decreases in body weight gain and food consumption, were observed at 600 mg/kg bw/day. The occurrence of maternal toxicity at 600 mg/kg bw/day was accompanied by slight fetal toxicity, as exhibited by 27 presacral vertebrae and sternebra unossified. No significant maternal or developmental effects were observed at 20 or 100 mg/kg bw/day. Therefore, the maternal and developmental NOAEL was 100 mg/kg bw/day. With respect to mixture rules, the NOAEL for hydrolysis products of 3-(triethoxysilyl)propan-1-amine (15%) is 667 mg/kg bw/day.

In summary, the above discussed physico-chemical properties of the test substance and relevant data with the read-across substance 3-(triethoxysilyl)propan-1-amine indicate that the test substance possesses either a low toxic potency or a low absorption in combination with a low systemic toxicity. In contrast to the read-across substance 3-(triethoxysilyl)propan-1-amine, lower systemic toxicity can be assumed for the hydrolysis product due to the lower initial concentrations of 3-(triethoxysilyl)propan-1-amine (> 0.1 - < 16%) in aqueous solutions.

 

Absorption after inhalation exposure

The test substance is a liquid and is expected to have a very low vapour pressure based on QSAR calculations of its main constituents. However, as test substance contains ethanol in the concentration range of 0.06 - 15% and only exists under aqueous conditions, the vapour pressure of ethanol and water should also be taken into consideration. Since ethanol has the highest vapour pressure within the constituents, the vapour pressure of the test substance should be lower than the value of ethanol (< 7906 Pa at 25 °C).

As the use of the test substance will not result in spray applications and the vapour pressure represents a worst case assumption based on a weight of evidence approach, exposure to humans via the inhalation route can be expected to be rather limited. With respect to the read-across substance 3-(triethoxysilyl)propan-1-amine, the 4-hour inhalation LC50 for exposure to aerosolized 3-(triethoxysilyl)propan-1-amine was determined to be greater than 7.35 mg/L in rats (OECD SIDS, 2003).

 

Absorption after dermal contact

In general, the smaller the molecule, the more easily it may be taken up. A molecular weight below 100 g/mol favors dermal absorption and above 500 g/mol the molecule may be too large (ECHA, 2014). As the molecular weight of the monomer, dimer and polymer ranges from 137.2 g/mol to ≥ 375.6 g/mol, dermal absorption cannot be ruled out. However, as test substance exists only in aqueous solution and the log Pow is estimated to be -2.83 for the monomer and -3.15 for the dimer, it can be assumed that the monomer and the dimer are too hydrophilic to cross the stratum corneum, therefore dermal absorption is likely to be low.

If a substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2014). As test substance is not considered as irritating to the skin, enhanced penetration can be excluded.In addition, the skin sensitisation study showed a negative result (Schmid, 2012).

For the monomer and the dimer a QSAR based modelling published by Potts and Guy (1992), taking into account molecular mass and log Pow, estimated a dermal permeability constant Kp of 2.29E-06 cm/h for the monomer and of 2.86E-07 cm/h for the dimers. Similar to the approach taken by Kroes et al. (2007), the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated, resulting in dermal absorption of 2.29 µg/cm²/h for the monomer and of 0.29 µg/cm²/h for the dimer. Usually, this value is considered as indicator for a dermal absorption of 40% for the monomer, indicating a moderate potential for dermal absorption (Mostert and Goergens, 2011). For the dimer, the calculated dermal uptake confirmed that the monomer has a moderate to low potential for dermal absorption (ca. 20%).

Overall, the calculated moderate to low dermal absorption potential, the very high water solubility (10 ⁶ mg/L) and the log Pow of <-2.83 which limits the transfer to cross the stratum corneum imply that dermal uptake of test substance will be low.

 

Distribution

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. In general, the smaller the molecule, the wider is the distribution. Small water-soluble molecule and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution. If the molecule is lipophilic (log Pow > 0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rates of absorption (ECHA, 2014).

As discussed above, the test substanceexists only in aqueous solutions and the log Pow is estimated to be -2.85 for the monomer and -3.15 for the dimer, indicating that absorption from the GI tract may be limited. However, based on its molecular weight, the monomer could pass through aqueous pores. The available data on oral toxicity with the read-across substance 3-(triethoxysilyl)propan-1-amine indicates that the hydrolysis product is systemically bioavailableafter single and repeated oral administration and distribution within the body is likely.

Overall, the available information indicates that test substance can be distributed in the organism.

 

Accumulation

In general, lipophilic substances tend to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. Substances with log Pow values of 3 or less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous (ECHA, 2014). The log Pow of-2.85 for the monomer and -3.15 for the dimer imply that the tests substance may have a low potential to accumulate in adipose tissue. As already mentioned, the absorption of the test substance is considered to be low and therefore the potential of bioaccumulation is low as well.

 

Metabolism

By calculating potential metabolites of the monomer via OECD QSAR toolbox 2.3.0, metabolites generated by the microbial, liver and skin metabolism simulator indicate that the amino group will be cleaved, but the Si-C bond is stable. The metabolism simulators predict 3 liver, 5 skin, and 8 microbial metabolites. Furthermore, it is known that the hydrolysed monomer will be rapidly dimerized and condensation polymers will be formed.

Based on the physico-chemical properties of the test substance, low absorption is predicted. Thus, it can be assumed that the test substance will be absorbed to some extent from the GI tract and distributed within the body, hence, biotransformation cannot be ruled out.

 

Excretion

Based on the assumption that absorption of the test substance is low, the main route of excretion is expected to be via faeces. If absorbed from the GI tract, metabolism cannot be ruled out and potential metabolites may be excreted in the urine.

 

In conclusion, taking into account all available data, absorption of the test substance after oral ingestion or dermal contact is considered to be limited due to its physico-chemical properties. The inhalation exposure route plays no important role, as the physical state is liquid, the vapour pressure is presumably low and spray applications are not relevant.

It can be assumed that the test substance will be absorbed to some extent in the GI tract and distributed in the organism. The available data indicate that no significant bioaccumulation of the test substance in adipose tissue is anticipated.

 

 

References not cited in the IUCLID:

ECHA guidance document, endpoint specific guidance, Chapter R.7c, Version 2, November, 2014

OECD SIDS (2003) 3-AMINOPROPYLTRIETHOXYSILANE (APTES), CAS 919-30-2

Kroes et al. (2007) Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food Chem. Toxicol. 45, 2533–2562

Mostert and Georgens (2011) Dermal DNEL setting: using QSAR predictions for dermal absorption for a refined route-to-route extrapolation. Society of Toxicology, Annual Meeting, ISSN 1096-6080 (http://www.toxicology.org/AI/PUB/Toxicologist11.pdf), 120(2): 107

Potts and Guy (1992) Predicting skin permeability.Pharm. Res. 9(5): 663-669

Renwick, A.G. (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes,A.W. (ed.) Principles and Methods of Toxicology. Raven Press, New York, p 103.