N,N”-hexane-1,6-diylbis(N’-alkylaryl)urea

Endpoint summary

Description of key information

No studies are available. The molecular weight, physicochemical properties incl. water solubility and octanol-water partition coefficient of the substance suggest that some oral and inhalative absorption may occur. Dermal absorption is supposed to be very low (approximately 1%). Widely distribution within the water compartment of the body after systemic absorption is because of lipophilicity of the test substance not expected. However, the distribution into cells particularly in fatty tissues is likely. Based on its log Pow the test substance is not considered to accumulate. The test substance might be metabolized in case of absorption. Excretion predominantly via the faeces is expected.

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of the test substance was conducted to the extent that can be derived from the relevant available information on physico-chemical and toxicological characteristics. There are no studies available evaluating the toxicokinetic properties of the substance.

The test substance is a white crystalline powder with a molecular weight of 410.55 g/mol and a water solubility of 0.24 mg/L at 20 °C. The substance has a very lowvapourpressure of 6.33E-11 Pa at 25 °C and the log Pow is 2.4 at 23 °C. The sample has a multimodal particle size distribution between 0.04 and 60 µm with a maxima at about 0.3, 4 and 15 µm. The mean size is 6.3 µm and the median 3.0 µm.

Absorption

Absorption is a function of the potential of 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, 2014).

Oral

Generally the smaller the molecule the more easily it may be taken up. Molecular weights below 500 arefavourablefor absorption. The molecular weight of 410.55 g/mol is lower than 500 g/mol, indicating that the substance is available for absorption. In addition, moderate lipophilicity (log P values between -1 and +4) favours membrane penetration by passive diffusion. Nevertheless, a substance with such a log Pow value can be poorly soluble in lipids and hence not readily absorbed when its water solubility is very low. The slight water solubility indicates that absorption may be limited by the inability to dissolve into GI fluids. However, micellular solubilisation by bile salts may enhance absorption.

Since the test substance has been dosed using a vehicle in the available oral toxicity studies, the water solubility of the vehicle and the vehicle/water partition coefficient of the test substance may have affected the rate of uptake. Data from acute and repeated oral toxicity studies (Latour, 2014; Zmarowski, 2015) revealed no adverse effects up to the limit doses. Clinical observation from the repeated oral toxicity study revealed higher incidences of clinical signs including uncoordinated movements and erythema of the ears in all groups, but particularly at 300 and 1000 mg/kg bw/day. Based on the results from the acute and repeated oral toxicity studies the LD50 was > 2000 mg/kg bw and the NOAEL was ≥ 1000 mg/kg bw/day. No conclusion can be drawn from these studies regarding toxicokinetic behaviour. Nevertheless, the physicochemical properties and molecular weight of the test substance suggest that some oral absorption may occur.

 

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. Log P values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal). However, the dermal uptake is anticipated to be low if the water solubility is < 1 mg/L. Moreover, the slight water solubility of the substance will inhibit partitioning from the stratum corneum into the epidermis. The dermal permeability constant Kp of the substance was estimated to be 3.06E-04 cm/h using Dermwin^TM(v.2.01) and taking into account the log Pow and molecular weight. Further on the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated similar to the approach taken by Kroes et al. (2007) and yielded in a value of 0.00007 µg/cm²/h. This flux value can be assigned to a very low dermal absorption of 1% (Kroes at al., 2007). Furthermore, data from an acute dermal toxicity study revealed no effects of the test substance up to the limit dose of 2000 mg/kg bw (Latour, 2014). Thus the test substance is not expected to be absorbed via skin.

 

Inhalation

The test substance has a low vapour pressure of 6.33E-11 Pa at 25 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapour can be excluded.

The mean particle size of the test substance is 6.3 µm and the median 3.0 µm. 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 the alveolar region of the respiratory tract (ECHA, 2014). Based on the particle size the test substance may reach the respiratory tract up to the alveolar region. Moreover, slight water solubility and small particle size enhance penetration to lower respiratory tract. The moderate log P value (between -1 and 4) mayfavourabsorption directly across the respiratory tract epithelium by passive diffusion. However, for poorly water-soluble dusts, the rate at which the particles dissolve into the mucus will limit the amount that can be absorbed directly. It can be assumed that clearance of poorly water-soluble deposits in the alveolar region will mainly be done by alveolar macrophages. The macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues (ECHA, 2014). Data from the acute inhalation toxicity study (van Huygevoort, 2015) revealed no test substance related effects up to technically maximum achievable concentration of 2.1 mg/L air. This indicates that the test substance has a low potential for inhalation toxicity, although no assumptions can be made regarding the absorption potential based on the experimental data. Absorption via inhalation is in general assumed to be possible, but is considered to be not higher than through the intestinal epithelium.

 

Distribution

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, 2014). Since the test substance is lipophilic (log Pow 2.4) the distribution into cells is likely and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues, if the substance is absorbed systemically.

Substances with log P values of 3 or less would be unlikely to accumulate in adipose tissues 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, 2014).

 

Metabolism

No metabolism studies are available with the test substance itself. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo.

The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v3.3, OECD, 2014). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. 4 hepatic and 2 dermal metabolites were predicted for the test substance, respectively. Primarily, hydroxylation of the substance occurs in the liver and skin. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. Up to 66 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Most of the metabolites were found to be a consequence of the degradation of the molecule. There was no evidence for differences in genotoxic potencies due to metabolic changes in in vitro genotoxicity tests. The studies performed on genotoxicity (Ames test, chromosome aberration assay in mammalian cells in vitro) were negative, with and without metabolic activation (Andres, 2014; Verbaan, 2015).

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. The molecular weight (> 300 g/mol) and a slight water solubility of the molecule are propertiesfavouringexcretion via faeces. Thus the test substance is expected to be excreted predominantly via the faeces. This assumption is supported by the clinical observation from the repeated oral toxicity study (Zmarowski, 2015) which revealed palefaecesfor all animals in the mid and high dose group with much lower incidence in the low dose group. The result was likely related to the color of the cloudy, white formulation and indicates an excretion via faeces.

 

References

ECHA (2014): Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance. European Chemicals Agency, Helsinki

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