Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

no bioaccumulation potential

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
5
Absorption rate - dermal (%):
1

Additional information

The substance under registration (CAS 13863 -31 -5) belongs to the category of Stilbene Fluorescent Whitening Agents. All members of this category are organic salts with high molecular weight, solids with high thermal stability, low Kow and high to very high water solubility.

They do not show acute toxic effects after oral, inhalation, and dermal administration. They are neither irritant to skin nor eyes, nor genotoxic in-vitro and in-vivo, nor sensitizing. Six over fourteen registered substances were tested for subchronic toxicity and four of them were tested for chronic toxicity up to two years with no relevant toxic effects.

They are mainly excreted in the faeces in a few hours by oral administration and practically not absorbed by skin, therefore no systemic effects are expected.

Results were reported by Black et al. (1977) about the intestinal absorption and skin penetration of CAS 16090-02 -1. Two groups of 9 rats each were treated by oral gavage with 0.5 ml of a solution containing 0.007 % tritiated substance in 1 % (w/v) detergent (alkyl benzene sulphonate and sodium tripolyphosphate) or in an aqueous solution. All animals were placed in separate metabolic cages and urine and faeces samples were collected every 24 hours for up to 4 days. At scheduled necropsies after 24, 48 and 96 hours blood samples were taken by heart puncture and selected organs were sampled for radioanalysis. The bulk of radioactivity from both treatment groups was excreted in the faeces, mostly during the first 24 hours. Small amounts were present in the urine. Recovery of radioactivity was essentially complete after 48 hours (total recovery > 92 % with 48 hours). No significant amount of radioactivity was found in urine, blood and faeces samples from 16 rats treated topically with 0.2 ml of a solution containing 0.007 % tritiated substance in 1 % aqueous detergent. In two rats, treated topically with 0.5 ml of a solution containing 0.43 mg/ml tritiated test material in ethanol, however small amounts of radioactivity were detected in faeces, large and small intestines and their contents as well as in the content of the stomach. Only minor amounts of radioactivity were found in the liver, bladder, kidneys, and heart of one of the treated animals. Approximately 0.1 % of the applied dose (i.e. approximately 0.01 μg/cm²) had been absorbed through the skin during two days.

In the Unilever (1976) study was found that after application in methanol 14C-activity was lost from the skin of hairless mice at a constant rapid rate for the first 2 hours; thereafter loss continued at a lesser rate.

These findings are confirmed by absorption, distribution and excretion experiments in rats published by Mücke et al. (1975) (Ciba-Geigy, 1972). Following an oral dose of 14C-labeled CAS 13863-31-5 in water at 5.9 mg/kg bw to rats of both sexes, rapid and complete excretion of radioactive material was observed, with an excretion half-life ranging from 7 to 13 hours. Faeces were practically the only route of excretion (more than 95 % of the administered radioactive material was excreted within 48 hours), indicating, in combination with the short half life times that no significant amounts were absorbed from the gastro-intestinal tract. No radioactivity was found in blood, liver kidney, brain, muscle, or fat 96 hours after dosing (limit of quantification 0.005 - 0.01 ppm equivalents). The total recovery of radioactivity was 97.5 % and 95.2 % of the orally applied dose for males and females, respectively.

Which metabolite is excreted is demonstrated comparing the two main available oral studies, based on the specific position of the radiolabelling. Black (Black J.G., 1977), studied the oral toxicokinetic with radiolabelling of the aniline moiety and they found the radioactivity completely in the faeces. Muecke (Muecke W., 1975) instead, labelled the triazine ring and found in the faeces both the isomers cis and trans.

As a consequence the whole molecule, included the aniline or suphonated aniline moieties are not metabolised.

Based on OECD Toolbox estimations (see Category Justification Report attached to the section 13 of the dossier), the metabolism is just related to the organic variable functionality (morpholino, dihydroxyethyl, diethyl etc.), a potential final common metabolite seems to be formed and completely excreted (the simple primary amino derivative).

Based on the metabolic pathway profiled using the OECD Toolbox, it can be also expected that the same conclusions about kinetic and excretion can be drawn and applied to CAS 13863-31-5 and CAS 16090-02-1. The two substances differ in the fact that the substitution on the triazino moiety is a methyl/diyhdroxyethyl for CAS 13863-31-5 and a morpholino for CAS 16090-02-1. Both substances have as a final common metabolite the primary amino derivative.

In the study performed by Muecke (1975) both the substances (also studied by Black) CAS 16090-02-1 and CAS 13863-3-5 were tested in the same conditions, administered in water solution by gavage. In both cases a rapid and complete excretion of radioactive material was observed: after application of the morpholino derivative the radioactive material was completely extractable from faeces with methanol in the form of unchanged parent compounds, while the methyl hydroxyethyl derivative was not extractable. The Author comments that the behaviour is not surprising since the substance is known to bind to cellulose.

This comment suggests that the behaviour of the two substances may be different regarding bioavailability during administration in food and it is not clear if this pathway may regard also the related substances within the category. Nevertheless, the reliability of the comment is doubtful since both derivatives are recommended for cotton (cellulose) treatment with good fastness. The following further consideration needs to be evaluated: based on this hypothesis, it seems that the methylhydroxy derivative would not be bioavailable if administered with food in long-term studies and there would be a difference between morpholino and methylhydroxylamino derivative. This difference is not confirmed by the study of Lyman et al. (F. L. Lyman, 1975), during which both compounds were administered to rats and dogs in food for two years. Tissue samples were taken from representative male and female dogs used in the 90 days and 2 years oral toxicity studies: in each tissue (liver, muscle, fat, kidney, brain, blood) no difference in residues for both compounds were found. The administered doses were given in significant amounts, namely 1000/2000 ppm (from 50 to 300 mg/Kg bw). In most cases residues were below the detection limit (the maximum detected quantity was of 0.09 ppm in the muscle), demonstrating that adsorption is generally very low and accumulation also excluded.

Furthermore, the extraction from faeces in the Muecke (1975) study was performed with methanol at room temperature ; it has to be considered that the stomach environment is a strongly acid environment, with at least 37 °C temperature. In those conditions, even if a physical adsorption on the food may take place, bioavailability would be again granted by the chemical environment.

A study done with CAS 13863-31-5 (Ciba-Geigy Ltd. 1975) was similar to OECD Guideline 427 and examines the skin absorption. 14C-labelled test substance was topically applied to the depilated back of male rabbits at a dose of 20 µg/cm². Within three days approximately 2 % of the applied radioactivity was excreted with urine and faeces; by far the major portion was still on the skin. The subcutaneous tissue underneath the application area contained 0.2 % and the total skeletal muscle certainly less than 1 % of the applied radioactivity assuming the radioactivity found in muscle underneath the subcutaneous tissue of the application area to be representative for the total muscle radioactivity. The radioactivity in the blood, monitored during 72 hours, contained only minute amounts of radioactivity. Even at the peak, reached within two hours, the amount present in the total blood was still below 0.1 %. After six hours the blood radioactivity was below the limit of quantification or even below the limit of detection being 0.016 % and 0.006 % or 2.7 ppb and 0.9 ppb, respectively. From these data it is assumed that the test substance is not absorbed by rabbits after topical application. The small amount of radioactivity excreted with urine and faeces is probably due to impurities present in the 14C-labeled test substance used in this study and to degradation products, which may be formed in trace amounts on the skin during prolonged contact with the compound.

Skin adsorption has been evaluated and calculated for all members of the category (see Category Justification Report attached to the Section 13 of the dossier). As it can be noted, the influence of the variability in functional groups is very low, more related to the variability in the polarity of the substance than on potential reactivity that can arise a concern.

From a metabolic point of view, an estimation with OECD Toolbox of the dermal metabolism was performed in order to verify if breakdown products may be formed: results are negative for all members.

Conclusion: it can be stated that after oral exposure rats excrete the substance almost completely in the faeces within 48 hours. There was no measurable skin penetration when topically applied in a detergent solution to rats. When applied at 0.43 mg/ml in ethanol, approximately 0.01 μg/cm² penetrated rat skin within 2 days