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Assessment of the Toxicokinetic behaviour of (2-(((2-(3-((4-((3-(ethenylsulfonyl)phenyl)(ethyl)amino)-6-fluoro-1,3,5-triazin-2-yl)amino)-2-(hydroxy-κO)-phenyl)(phenyl)-benzoato(6-)-κO), heterocyclo, polysulfonato, sodium salt

 

The test substance represents an organic dye based on a sulfobenzoato-cuprate sodium salt with a purity of 40 – 85% (main constituent: 54.3 – 57.8%). Impurities are inorganic (calcium sulfate (approx. 0.8%), sodium chloride (0.59 – 0.63%), sodium fluoride (0.47 – 1.07%), sodium sulfate (10.12 – 12.48%) and disodium hydrogenphosphate (2.93 – 4.15%)) and organic compounds (unknown uncoloured organic by-product (0.6 – 0.8%), unknown coloured organic by-product (2.39 – 3.31%) and known coloured by-products (16.26 – 17.29%)). Unsulfonated aromatic amines including diverse anilin derivates were not detected in concentrations > 1ppm. All known organic by-products possess chemical structures pretty similar to the main component and are therefore considered to exhibit similar toxicokinetic properties. For further details, please refer to chapter 1.2 in the CSR (Composition of the substance) and IUCLID chapter 1.2 and 1.4 respectively.

 

Basic toxicokinetics

In accordance with Regulation (EC) 1907/2006, Annex VIII, Column 1, Item 8.8 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behavior of (2-(((2-(3-((4-((3-(ethenylsulfonyl)phenyl)(ethyl)amino)-6-fluoro-1,3,5-triazin-2-yl)amino)-2-(hydroxy-κO)-phenyl)(phenyl)-benzoato(6-)-κO), heterocyclo, polysulfonato, sodium salt was conducted to the extent that can be derived from the relevant available information including physicochemical and toxicological characteristics.

 

The test substance is a dark blue powder consisting of several constituents with molecular weights ranging from 42 to 1064.84 g/mol (Müller and Bollinger, 2011a, b), high water solubility (> 10 000 mg/L at 20°C, Mollandin, 2011b) and a log Pow < 0.3 at 25°C (Mollandin, 2011a). No signs of melting were detected up to a temperature of 400 °C (Fieseler, 2011a). The vapour pressure was estimated to be < 1E-10 Pa at 20 °C (Meinerling, 2012) and the dissociation constant (pKa) was determined as 7.783 (titration with 0.01 M NaOH at 20°C) and 6.716 (titration with 0.01 M HCL at 20 °C) (Fieseler, 2011b) resulting in the “free acid” at physiologic pH.

 

Absorption

Absorption of a substance depends on the potential to diffuse across biological membranes, a process determined by the molecular weight, the log Pow and water solubility (ECHA, 2012).

 

Oral:

The smaller the molecule, the more easily it will be taken up. In general, substances with molecular weights below 500 and log Pow values between -1 and 4 are favorable for oral absorption via passive diffusion in the gastro-intestinal tract (ECHA, 2012). Highly hydrophilic substances dissolve easily in the gastrointestinal fluid and passive diffusion through biological membranes is limited by the rate at which the substance partitions out of the gastrointestinal fluids (ECHA, 2012). Thus, in regard to the physicochemical properties, oral absorption of the main constituent and organic impurities of the test substance in the gastrointestinal tract is expected to be low due to its molecular weight of 1064.84 (saturated sodium salt) and the high water solubility. In contrast, the moderate log Pow indicates that passive diffusion across biological membranes might be possible. Subacute and reproductive toxicity studies provide evidence that the test substance has been absorbed after oral ingestion which is indicated by colored organs including tissues and organs like kidney, testes, epididymides, liver and the skin (Allingham 2014; Schleh, 2012). Considering the physiocochemical properties, absorption via active transport mechanisms seems most likely. Absorption of the inorganic impurities cannot be excluded as passage of small, water-soluble molecules like ions or carriage of ionic species with the passage of water is possible through aqueous pores (ECHA, 2012). Moreover, transport via ion channels and/or active transport mechanisms is possible for the inorganic impurities like sodium, calcium, sulfate, chloride and phosphate ionic species.

 

Overall, despite the physicochemical characteristics which in general impede absorption via passive diffusion, the available toxicity data indicate systemic bioavailability of the main constituent and/or coloured organic by-products of the test substance after oral ingestion. Furthermore, absorption of inorganic impurities is considered likely. In general, absorption of the test substance after repeated oral administration is considered to be associated with low systemic toxicity and the absence of adverse effects in the target organs of absorption.

 

Dermal:

Dermal absorption correlates with molecular size: small molecules may be taken up more easily than bigger molecules. In general, a molecular weight < 100 favors dermal absorption, whereas molecules of molecular weights > 500 may be too large (ECHA, 2012). Moreover, dermal absorption is favorable for substances with a log Pow value between 1 and 4, whereas lower log Pow values (<0) suggest a lipophilicity which is not sufficient for transfer between the stratum corneum and the epidermis (ECHA, 2012). Furthermore, a substance must be sufficiently soluble in water to diffuse from the stratum corneum into the epidermis. However, if the water solubilty is above 10 000 mg/L and the log Pow below 0, the substance may be too hydrophilic to cross the stratum corneum (ECHA, 2012). With a molecular weight of 1064.84 (saturated sodium salt), a high water solubility (> 10 000 mg/L at 20°C) and a log Pow value < 0.3, dermal absorption of the main constituent is expected to be rather negligible. However, (2-(((2-(3-((4-((3-(ethenylsulfonyl)phenyl)(ethyl)amino)-6-fluoro-1,3,5-triazin- 2-yl)amino)-2-(hydroxy-κO)-phenyl)(phenyl)-benzoato(6-)-κO), heterocyclo, polysulfonato, sodium salt exhibits skin sensitizing properties which indicate that at least a small fraction of the applied dose is able to penetrate the skin.

Using the OECD toolbox (Vs 2.3), the main constituent and one potential skin metabolite were identified as potential skin sensitizers due to protein binding most probably based on Michael Addition reactions. However, it has to be considered that dermal absorption of the main constituent, the respective skin metabolite and organic by-products is impeded by their chemical state as dry particulates first have to dissolve into the surface moisture of the skin before dermal uptake can occur (ECHA, 2012). In regard to the low molecular weight (<40 – 150 g/mol) and the water solubility (2.1 – 359 g/L) of the inorganic compounds, moderate dermal absorption is expected in general for the inorganic impurities. However, the ionic character of the inorganic constituents may hinder dermal absorption.   

 

Overall, in regard to the physicochemical properties (high water solubility, high molecular weight (>100) and moderate log Pow value), dermal absorption of the main constituent and organic impurities of the test substance is considered unlikely. However, due to skin sensitising properties, penetration of the main constituent and skin metabolites cannot be excluded. Furthermore, dermal absorption of the inorganic constituents is expected to a low extent.

 

Inhalation:

In dependence to the physical state, respiratory absorption of the test substance after inhalation of dust cannot be excluded. In general, particles with aerodynamic diameters < 100μm have the potential to be inhaled by humans. Particles with aerodynamic diameters < 50μm may reach the thoracic region and those < 15μm the alveolar region of the respiratory tract (ECHA, 2012). A particle size distribution of 58.3 (D10) – 271.9 µm (D90) leading to a mass median aerodynamic diameter (MMAD) of 137.2 ± 1.81 indicates that a minor proportion of particles is of inhalable size which may reach the thoracic and/or alveolar region (< 100µm: < 34%, < 50µm: < 8% and < 15 µm: < 1%) (Smeykal, 2012). However, depositions on the surface of the respiratory tract at the thoracic and/or alveolar region and absorption of the test substance have to be differentiated (ECHA, 2012). In general, substances may be absorbed directly from the respiratory tract via transfer through the epithelial membranes or through clearance mechanisms via mucociliary transport and subsequent swallowing which may result in gastrointestinal absorption (ECHA, 2012).

Transfer from the respiratory tract into the blood leading to systemic bioavailability is considered as likely for the main component, the organic by-products and the inorganic impurities due to their particle sizes, ionic character and high water solubility. Moreover, systemic absorption may be possible for the main component, the organic by-product and the inorganic impurities after mucociliary transport followed by swallowing and subsequent absorption in the gastrointestinal tract. Furthermore, deposition of inhaled particles on the respiratory surface has to be considered when endogenous clearance mechanisms are overloaded.

Overall, deposition and systemic bioavailability of the test substance after inhalation of dust is likely possible.

 

Distribution and Accumulation:

Distribution within the body depends on physicochemical characteristics of a substance including molecular weight, lipophilicity and water solubility. In general, the smaller the molecule, the wider is the distribution. Log Pow values > 0 indicate distribution into cells and fatty tissues (ECHA, 2012). High hydrophilicity may impede distribution due to the impact on the diffusion rate (ECHA, 2012).

In regard to the physicochemical properties (high molecular weight and high water solubility), a wide distribution of the main constituent and organic by-products throughout the body is expected to be impeded. However, coloring of several organs, the skin and the urine determined in subacute and reproductive toxicity tests after oral administration (Allingham 2014; Schleh, 2012) provides evidence that the main component and at least coloring organic by-products are absorbed in the gastro-intestinal tract followed by transport to the liver and subsequent distribution via the blood system to internal organs to a substantial amount. Moreover, clinical signs of toxicity including reduced salivation, spontaneous activity, constricted abdomen, bradykinesia, catalepsis, recumbency, ophistotonos and eye closure determined after in the in vivo MNT test (Hofman-Hüther, 2012) indicate systemic distribution of FAT 40853. As the inorganic compounds represent small water soluble ions which are most probably able to diffuse through pores and aqueous channels, systemic distribution within the body is expected especially because sodium, calcium, sulfate, chloride and phosphate ions are involved in several physiological processes. Moreover, active transport mechanisms and/or transfer via ion channels may facilitate transport of the inorganic constituents through membranes.

Accumulation of the main constituent, organic and inorganic impurities is not expected due to the high water solubility.

Thus, distribution of the constituents of the test substance throughout the body seems feasible whereas accumulation is considered unlikely.

 

Metabolism

No data are available to evaluate metabolism of the main compound and organic by-products of FAT 40853. Regarding the chemical structure of the main component and organic by-products, the exocyclic fluor atom, the carbonyl and the amino group may represent reactive groups which enable dehalogenation, hydrolysis and cleavage at the amino group. Moreover, oligomeric structures may be formed after hydrolysation due to addition-, substitution- and /or condensation reactions. Using the OECD toolbox (Vs. 2.3), only 2, 3 or 6 potential metabolites were identified for the main constituent with the skin, liver and hydrolysis simulator, respectively. Analysis with the microbial metabolism simulator provided 364 potential metabolites originated from the main constituent. However, the presence of several exocyclic sulfonyl groups and the high water solubility most probably enable gastrointestinal dissolution and absorption and subsequent elimination of the non-metabolised main constituent via the urine and may therefore hinder further chemical reactions. Furthermore, metabolism of inorganic constituents is not expected to occur. 

 

Excretion

In general, characteristics favorable for urinary excretion are low molecular weight, good water solubility and ionization of the molecule at pH of urine. In contrast, molecules with a high molecular weight are excreted in the bile (ECHA, 2012). Moreover, elimination via the feces is generally favored for non-absorbed substances. Taken these aspects into account in combination with the blue colored urine determined after repeated oral administrations and intraperitoneal injection (Allingham, 2014; Hofman-Hüther, 2012), excretion of the main constituent and organic bye-products via the urine is likely after absorption whereas elimination of the non-absorbed fraction may occur via the feces. Due to the high water solubility, the ionic character and the small molecular size, inorganic constituents are most probably eliminated via the urine.

 

References (not included in Iuclid)

ECHA. 2012. Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance.European Chemicals Agency, Helsinki

 

Smeykal, 2012. Particle size distribution (including amendment to report No. 20120128.02), Siemens AG, Frankfurt am Main

 

Müller and Bollinger, 2011a. Report on the Analytical Certificate of FAT 40853/A TE. Huntsman Textile Effects, Basel

 

Müller and Bollinger, 2011b. Report on the Analytical Certificate of FAT 40853/B TE.Huntsman Textile Effects, Basel