4,4'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)imino[6-[bis(2-hydroxyethyl)amino]-1,3,5-triazine-4,2-diyl]imino]]bisarenoate sodium salt

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

1

Additional information

The following remarks on the toxicokinetics of the registered substance Benzoic acid, 4,4'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)imino[6-[bis(2-hydroxyethyl)amino]-1,3,5-triazine-4,2-diyl]amino]]bis-, tetrasodium salt (CAS 32257-57-1) are based on physico-chemical properties as well as on data obtained from a basic toxicological dataset of a close structural analogue, Benzenesulfonic acid, 2,2'-(1,2-ethenediyl)bis[5-[[4-[bis(2- hydroxyethyl)amino]-6-[(4-sulfophenyl)amino]-1,3,5-triazin-2-yl]amino]-, tetrasodium salt (CAS 16470-24-9).

No experimental toxicokinetic studies are available and generation of new data is not required as the assessment of the toxicokinetic behaviour of the substance should be performed to the extent that can be derived from the relevant available information (REACh Annex VIII, 8.8.1).

 

The target substance (CAS 32257-57-1) has a molecular weight of 1092.929 g/mol. It is a solid powder at room temperature. As it is marketed and used as liquid, its dustiness is not of relevance. The estimated partition coefficient Log P is -5.31(Szymoszek, 2012) and its water solubility is approx. 280 g/L (Haferman, 2012). Because of its two carboxyl and two sulphonate groups, the substance is a weak acid (calculated pKa = 2.46) and can be ionized. The source substance used for read-across of the toxicological endpoints (CAS 16470-24-9) has a molecular weight of 1165.0355 g/mol, a LogP value of -11.8, and a water solubility of > 400 g/L. Thus, the physico-chemical parameters are similar in magnitude and the structures of source and target substance are closely related because they have the same basis structure (trans-stilbene derivate) and therefore, read-across is considered appropriate.

 

Absorption

Oral

In an acute oral study conducted with CAS 16470-24-9 a LD50 of > 5000 mg/kg bw was estimated. No mortality was observed at the limit dose and only slight clinical signs occurred that were fully reversible within 3 hours (diarrhoea), 3 days (exophthalmos), or 6-8 days (dyspnoea, ruffled fur, and curved body position). The minor effects of this high dose indicate low oral absorption and/or low toxicity of the substance. Based on the physical chemical parameters absorption in the gastrointestinal (GI) tract is not likely because of its high molecular weight (> 1000 g/mol). The high water solubility and its hydrophilic property favour dissolution in the GI fluid; cellular uptake, however, will hardly appear because the substance can poorly cross the lipid cell membranes.

Inhalative

No experimental data is available concerning inhalative toxicity; however, based on the high molecular weight, the high particle size (MMD of CAS 16470-24-9 is approx. 100 µm), the high water solubility and low LogP value, absorption via the respiratory tract is not likely. If inhaled, particles will remain in the mucus of the upper respiratory tract and swallowed or directly excreted.

Dermal

An acute dermal toxicity study performed with CAS 16470-24-9 is available. No mortality and no systemic signs of toxicity were observed in the animals indicating a low dermal absorption potential of the substance.

In fact, a very low dermal absorption potential was calculated for the test substance and can be assigned to a dermal absorption of 1% (QSAR published by Potts and Guy, 1992; Kroes et al., 2007; Mostert and Goergens, 2011). The calculated permeability constant is 9.30E-14 cm/h and the calculated Flux 0.00000 mg/cm²/h. Therefore, the dermal bioavailability is negligible (bioavailability after oral administration is reported to be 100%; Danish (Q)SAR Database Report, 2005).

 

Distribution

Some information or indication on the distribution of the compound in the body might be derived from the available physico-chemical and toxicological data. Once a substance has entered the systemic circulation, its distribution pattern is likely to be similar for all administration routes. However, first pass effects after oral exposure influence the distribution pattern and distribution of metabolites is presumably different to that of the parent compound.

The smaller a molecule, the wider is its distribution throughout the body. Membrane-crossing substances with a moderate LogP and molecular weight will be able to cross the blood-brain and blood-testes barrier and reach the central nervous system (CNS) or testes, respectively. Since the test substance has a high molecular weight and a low LogP value, it is not likely to pass these barriers. From repeated dose studies performed with CAS 16470-24-9, no target organ could be identified and no indications of CNS effects or effects on spermatogenesis were observed.

Bioaccumulation

The potential to accumulate within the body in adipose tissue is very low, because the substance is highly water soluble. Excretion is thus favoured over accumulation.

Metabolism

Prediction of compound metabolism based on physico-chemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. An important role plays the liver where many metabolites may arise. No data on metabolism is available; however, no elevated toxicity was observed after oral treatment, nor were there evidence in in vitro genotoxicity tests because no difference could be seen with respect to the addition of metabolic activation in Ames tests or in a chromosome aberration test with CAS 16470-24-9 (i.e. no increased mutagenicity or cytotoxicity in treatments with metabolic activation). Hence, there is no indication for reactive metabolites.

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physico-chemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product.

Water soluble substances with rather high molecular weight, as is the case for the registered substance, tend to be rapidly excreted via biliary excretion.

 

References:

Potts, R.O. and Guy, R.H., Predicting skin permeability. Pharm. Res. 9: 663-669 (1992)