1,3-bis(trimethylsilyl)urea

Endpoint summary

Description of key information

Experimental studies on toxicokinetics are not available. Based on molecular structure, molecular weight, water solubility and octanol-water partition coefficient it can be expected that the parent substance and it’s hydrolysis products are likely to be absorbed via the oral and dermal routes. Based on the low vapour pressure of the substance, systemic bioavailability is further considered likely after inhalation of aerosols. 1,3-bis(trimethylsilyl)urea is rapidly hydrolysed to urea and trimethylsilanol. Trimethylsilanol is expected to be widely distributed in the organism, and, due to it’s log Pow, is expected to be lipophilic enough to distribute into cells. Accumulation in the body is not favourable for the substance. A number of hepatic metabolites and metabolites after microbial metabolism in the GI tract were predicted. Due the low molecular weight and good water solubility of the parent and hydrolysis product both substances are likely to be excreted via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no experimental studies available in which the toxicokinetic behaviour of 1,3-bis(trimethylsilyl)urea (CAS 18297-63-7) has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of REACH (Regulation (EC) No. 1907/2006) and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), an assessment of the toxicokinetic behaviour of 1,3-bis(trimethylsilyl)urea was conducted to the extent that can be derived from relevant available information on physico-chemical and toxicological properties of the test substance itself as well as of its hydrolysis products.

 

Physico-chemical properties

1,3-bis(trimethylsilyl)urea is a white solid powder with a molecular weight of 204.4175 g/mol. The log Pow was estimated to be 2.72. The particle size distribution of 1,3-bis(trimethylsilyl)urea revealed 98.3% particles with a size of < 100 µm, < 3.3% particles with a size < 10 µm and < 0.73% particles with a respirable size of < 5.5 µm.

1,3-bis(trimethylsilyl)urea is highly unstable in water with an estimated half-life of less than 10 min at pH 4, pH 7 and pH 9 (Covance, 2020). The water solubility of pure 1,3-bis(trimethylsilyl)urea could not be quantified. Based on the chemical structure of the test item, the primary hydrolysis products would be N-(trimethylsilyl)urea and trimethylsilanol. An additional hydrolysis step would lead to urea and another molecule of trimethylsilanol. This suggests systemic exposure rather to the hydrolysis products (trimethylsilanol and urea) than to the parent compound. However, no experimental animal data on the hydrolysis and quantification of hydrolysis products is available and exposure to the parent compound cannot be excluded. Hence, this toxicokinetic behaviour assessment will rather focus on the behaviour of the hydrolysis products and consider the parent compound 1,3-bis(trimethylsilyl)urea to a minor degree.

The hydrolysis product urea is also found as an endogeneous product of protein and amino acid catabolism. It is formed during normal physiological processes that occur preliminary in the liver for detoxification of ammonia via the urea cycle. The urea produced by the urea cycle is eliminated from the body primarily through the urinary system by glomerular filtration. The toxicokinetics of urea is discussed in literature and not included in this summary. Therefore, the present summary focusses mainly on the toxicokinetic properties of the hydrolysis product trimethylsilanol.

The molecular weight of the hydrolysis product trimethylsilanol is 90.2 g/mol and the predicted water solubility is about 1000 mg/mL (EPI Suite WSKOWWIN v1.42 and WATERNT v1.01). This shows that the hydrolysis product is smaller in size and, due to its high water solubility, suggested to have a greater potential to be absorbed through biological membranes than the parent compound. Additionally, the predicted moderate log Pow value of 2.72 for the parent substance 1,3-bis(trimethylsilyl)urea and the estimated log Pow value of 1.14 for the hydrolysis product trimethylsilanol (QSAR: EPI Suite KOWWIN v1.68) indicates that both are lipophilic enough to pass through biological membranes by passive diffusion efficiently.

 

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 Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

 

Oral:

The smaller the molecule, the more easily it will be taken up. In general, substances with a molecular weight < 500 g/mol and with a log Pow between -1 and 4 are favourable for oral absorption. Lipophilic compounds can be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (ECHA, 2017).

If ingestion occurs, the hydrolysis of the parent substance 1,3-bis(trimethylsilyl)urea in the presence of the low pH environment of the stomach will be rapid, so any absorption of the parent substance is expected to be minimal and it is more likely to be the silicon-containing hydrolysis product trimethylsilanol that is absorbed.

The low molecular weight of the parent compound (204.4175 g/mol) and of the hydrolysis product (90.2 g/mol) and the predicted water solubility of the hydrolysis product (1000 mg/L) suggest that both substances are favourable for absorption via the gastrointestinal (GI) tract. Due to the low size, both compounds have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The log Pow of the substances (2.72 for the parent compound and 1.14 for the hydrolysis product trimethylsilanol) suggest that the absorption occurs by passive diffusion. In addition, absorption of 1,3-bis(trimethylsilyl)urea and trimethylsilanol after oral administration is predicted according to the “Lipinski Rule of Five” (Lipinski et al., 2001).

There is one acute oral toxicity study (ICCR-Roßdorf GmbH, 2020) and an oral repeated dose toxicity study with an reproductive and developmental toxicity screening test available for the parent compound 1,3-bis(trimethylsilyl)urea (Covance Laboratories Ltd., 2021), both of them indicating that oral absorption must have occurred. In the acute oral toxicity study (ICCR-Roßdorf GmbH, 2020), decreased activity, hunched posture, piloerection, lethargy and laboured respiration was noted in all 4 females at 300 mg/kg bw within 24 hours post-dosing. The effects were fully reversible within 2 Days after administration. There were no treatment-related effects on the body weight development and no macroscopical findings at scheduled necropsy. The LD₅₀was > 300 – < 2000 mg/kg bw. In the oral repeated dose toxicity study with an reproductive and developmental toxicity screening test (Covance Laboratories Ltd., 2021), clinical signs of toxicity comprised decreased activity (2/10 males and 6/10 females) and unsteady gait (5/10 males and 4/10 females) in both sexes up to Day 7 of treatment at the top dose of 375 mg/kg bw/day and unsteady gait in a single male at 125 mg/kg bw/day on study Day 2. In addition, there was a reduction in body weight development in males (-27.5% during weeks 1 – 5 and -55.5% during Week 1) and in females (-35.3% during weeks 1 – 2), which was consistent with a reduced food intake in both sexes (-17.7% in males and -8.8% females) during the first week of administration. Small changes in haematology and clinical chemistry parameters were attributed to treatment, but considered as non-adverse. At scheduled necropsy, there was a statistically significant increase in relative liver and kidney weights in males at 375 mg/kg bw/day, which was consistent with centrilobular hepatocyte hypertrophy in the liver of male animals and with incidences of alpha 2u-globulin nephropathy in the kidneys of the male animals. There were no adverse effects on reproduction and on the development of the offspring. The NOAEL for systemic effects was 125 mg/kg bw/day in males, based on the observed alpha 2u-globulin nephropathy. The NOAEL for systemic effects in females as well as for reproduction and for development was 375 mg/kg bw/day.

Overall, systemic bioavailability of 1,3-bis(trimethylsilyl)urea and its hydrolysis product trimethylsilanol is considered likely after oral uptake of the substance.

 

 

Inhalation:

1,3-bis(trimethylsilyl)urea is a solid of low volatility (8.35E-03 Pa at 25 °C).In humans, particles with aerodynamic diameters below 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 µm may reach the thoracic region and those below 15 µm the alveolar region of the respiratory tract (ECHA, 2017).

The registered substance has a particle size distribution of 98.3% particles with a size of < 100 µm, ≤ 3.3% particles with a particle size < 10 µm and ≤ 0.73% particles with a size of < 5.5 µm. Upon inhalation, a small portion of the substance may therefore reach the thoracic and the alveolar region. Substances may be absorbed directly from the respiratory tract or, through the action of clearance mechanisms, may be transported out of the respiratory tract and swallowed. This means that absorption from the GI tract will contribute to the total systemic burden of substances that are inhaled (ECHA, 2017). In case of oral uptake after swallowing of inhaled particles, the substance is expected to be hydrolysed as described above. As for oral absorption, the molecular weight, log Pow and water solubility suggest that the absorption occurs by passive diffusion. Hence, as systemic effects were observed after oral absorption, it is likely that the parent substance and its hydrolysis product trimethylsilanolhave the potential to be absorbed via the inhalation route if inhaled as anaerosol.

However, in an acute inhalation toxicity study (Covance Laboratories Ltd., 2020a), no systemic toxicity and no respiratory irritation were observed. Unspecific symptoms included powder in the nose and unsteady gait one hour after exposure, decreased activity with a flattened posture, piloerection and hunched posture in the animals up to two days after exposure. In addition, one animals showed salivation, closed bilateral eyes and slow breathing up to 2 hours after exposure. All signs had resolved by study Day 2.

In summary, systemic bioavailability of 1,3-bis(trimethylsilyl)urea or its hydrolysis products in humans is considered likely after inhalation of aerosols but is not expected to be higher than following oral exposure.

 

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 (ECHA, 2017). As the registered substance 1,3-bis(trimethylsilyl)urea is a solid, the substance needs to be dissolved before it can penetrate through the skin.

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 Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow 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 Pow 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 Pow 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).

As the parent substance 1,3-bis(trimethylsilyl)urea is rapidly hydrolysed in water, it can be assumed that predominantly the hydrolysis product trimethylsilanol needs to be considered for dermal absorption.

The predicted values for water solubility (1000 mg/L) and log Pow (1.14), as well as the low molecular weight of the hydrolysis product (90.2 g/mol) suggest that absorption via the dermal route is possible. The dermal permeability coefficient (Kp) for the hydrolysis product trimethylsilanol can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

Using the QSAR DERMWIN tool for calculations, the Kp is thus 2.80E-03 cm/h, predicting a medium high dermal absorption potential medium high (DERMWIN V2.00.2009).

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2017). The available data on skin irritation (Envigo CRS GmbH, 2019 and ICCR-Roßdorf GmbH, 2019) and skin sensitisation (Covance CRS Ltd., 2020 and ICCR-Roßdorf GmbH, 2020) did not show any irritating or sensitising effects on human non-transformed keratinocytes and in rabbits, therefore no enhanced penetration of the substance 1,3-bis(trimethylsilyl)urea or its hydrolysis product trimethylsilanol due to skin damage is expected.

Overall, taking all available information into account, the dermal absorption potential is considered to be medium to high.

 

Distribution and accumulation

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).

For blood : tissue partitioning, a QSPR algorithm has been developed by De Jongh et al. (1997) in which the distribution of compounds between blood and human body tissues as a function of water and lipid content of tissues and the log Pow is described. Using this value for the hydrolysis product trimethylsilanol predicts that it will distribute approximately equally to liver, muscle, brain and kidney and about 13-fold higher to fat. For the parent substance 1,3-bis(trimethylsilyl)urea an even higher fat : blood partition coefficient was predicted, however, due to the rapid hydrolysis it can be assumed that predominantly the hydrolysis product trimethylsilanol is distributed in the organism.

 

	Log Pow^1	Pow	Liver	Fat	Muscle	Kidney	Brain
Trimethylsilanol	1.14	13.80	0.93	12.92	0.98	1.00	1.25
1,3-bis(trimethylsilyl)urea	2.72	524.80	4.60	115.43	3.11	2.40	3.46

¹: The log Pow value for the hydrolysis product trimethylsilanol was modelled (QSAR: EPI Suite KOWWIN v1.68), the log Pow value for the parent substance 1,3-bis(trimethylsilyl)urea was determined experimentally by HPLC (please refer to IUCLID section 4.7 (Partition coefficient)).

 

As discussed under oral absorption, 1,3-bis(trimethylsilyl)urea is expected to be rapidly hydrolysed in the GI tract to its hydrolysis product trimethylsilanol prior to absorption. After being absorbed, trimethylsilanol is expected to be widely distributed, due to the size and the functional groups that increase its water solubility. The low molecular weight (90.2 g/mol) and high water solubility (1000 mg/L) of the silicon-containing hydrolysis product suggest that it will readily diffuse through aqueous channels and pores and will be widely distributed. The substances absorbed from the GI tract will be transported via the portal vein to the liver, where further metabolism can take place. Substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before they are transported to the liver where metabolism will take place.

Furthermore, the log Pow of 1.14 of trimethylsilanol indicates that it is lipophilic enough to distribute into cells and the intracellular concentration may be higher than the extracellular concentration, particularly in fatty tissues.

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. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance (ECHA, 2017).As the half-life time of the parent substance 1,3-bis(trimethylsilyl)urea is < 10 minutes, and as the hydrolysis producttrimethylsilanolis expected to be metabolised, accumulation in the body is considered unlikely.

Based on the acute oral toxicity data (ICCR-Roßdorf GmbH, 2020) and an oral repeated dose toxicity study with an reproductive and developmental toxicity screening test available for the parent compound 1,3-bis(trimethylsilyl)urea (Covance Laboratories Ltd., 2021) it was shown that the substance is systemically available. After repeated exposure, the kidneys were identified as predominant target organ.

 

Metabolism

Biotransformation is one of the main factors, which influence the fate of a substance in the body, its toxicity, and its rate and route of elimination.

1,3-bis(trimethylsilyl)urea hydrolyses quickly in contact with water, generating trimethylsilanol and N-(trimethylsilyl)urea, which is subsequently hydrolysed into trimethylsilanol and the naturally occurring product urea. There are no data regarding the enzymatic metabolism of trimethylsilanol.

The potential metabolites following enzymatic metabolism of the main isomers of the test substance were predicted using the QSAR OECD toolbox v4.4 (OECD, 2014). This QSAR tool predicts which metabolites of the test substance may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the GI tract. Simplified, 11 and 7 hepatic metabolites and 18 and 4 metabolites resulting from the microbial metabolism in the GI tract were predicted for the parent substance 1,3-bis(trimethylsilyl)urea and for the hydrolysis producttrimethylsilanol.

 

Excretion

The low molecular weight and good water solubility of the parent and hydrolysis product suggest that they are likely to be excreted by the kidneys into the urine. This assumption is supported by the findings obtained in an oral repeated dose toxicity study, in which the kidneys were identified as predominant target organ.

 

 

References

DeJongh, J., H.J. Verhaar, and J.L. Hermens (1997). A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Arch Toxicol,72(1): 17-25

 

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0.

 

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (March 2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.Adv. Drug Deliv. Rev.46(1–3): 3–26

 

OECD (2014). (Q)SAR Toolbox v3.3. Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Prediction performed 21 June 2016.http://toolbox.oasis-lmc.org/?section=overview