reaction mass of: 7-amino-3,8-bis-[4-(2-sulfoxyethylsulfonyl)phenylazo]-4- hydroxynaphthalene-2-sulfonic acid, Na/K salt; 7-amino-3-[4-(2-sulfoxyethylsulfonyl)phenylazo]-4-hydroxy-8-[4-(2-sulfoxyethylsulfonyl)-2- sulfophenylazo]naphthalene-2-sulfonic acid, Na/K salt; 7-amino-8-[4-(2-sulfoxyethylsulfonyl)-phenylazo]-4-hydroxy-3-[4-(2-sulfoxyethylsulfonyl)- 2-sulfophenylazo]naphthalene-2-sulfonic acid, Na/K salt; 7-amino-3,8-bis-[4-(2-sulfoxyethylsulfonyl)-2-sulfophenylazo]-4-hydroxynaphthalene-2- sulfonic acid, Na/K salt

Endpoint summary

Description of key information

In accordance with Regulation (EC) No 1907/2006 Annex VIII section 8.8.1, a toxicokinetic study is not required as assessment of the toxicokinetic behaviour of this substance has been derived from the relevant available information.

The results of ADME prediction and basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxicokinetics of Reactive Scarlet F07-0522. The data indicate that there is little or no dermal absorption. No signs of a systemic toxicity associated with absorption through skin have been observed. Based on exposure model from AG Textilien des Bundesinstituts fur Risikobewertung (BfR), the dermal penetration rate for dyes through the skin was found to be less than 2%.

Based on physico-chemical data and the results of oral toxicity studies, Reactive Scarlet F07-0522 has a limited oral bioavailability. The substance is considered to have low volatility as evident from the vapour pressure measurement and the calculated melting point of > 300°C, so the potential for the generation of inhalable forms is low. The molecular weight is higher than 500 g/mol and the chromophore is negative charged. This together with the high water solubility and low partition coefficient value, indicate the substance is not able to cross the mucous layer of the respiratory tract. Due to the high water solubility, vapours if generated/inhaled, will be trapped in the mucus of the respiratory tract, thereby further limiting the absorption. Hence, the main route of exposure of the substance, if inhaled, will be due to swallowing of particles deposited in the nose/mouth. Therefore, the bioavailability for inhalation is considered the same as for oral intake.

Bioaccumulation of Reactive Scarlet F07-0522 can most probably be excluded due to the available data. Based on the results of genotoxicity assays, a metabolisation towards genotoxic metabolites can also be excluded for mammalian species.

On the basis of the results, it is anticipated that the substance does not undergo significant metabolic activity; rather it is metabolised for excretion with little subsequent toxicity.  The substance is therefore not considered to be of concern for ADME related effects.

 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

5

Absorption rate - inhalation (%):

10

Additional information

Evaluation of Toxicokinetics – Absorption, distribution, metabolism and excretion

Absorption

According to ECHA Guidance R.7c (ECHA (2017c)), the smaller the molecule the more easily it may be taken up via oral route. Generally, oral absorption is favoured for molecular weights below 500 g/mol. As the test substance consists of large molecules (> 800 g/mol), they will therefore be taken up at a very low rate following the oral route. This assumption is supported by the results of the acute oral toxicity study in rats, where no deaths and no clinical signs were noted at the limit dose of 2000 mg dye/kg bw. Red discolouration of faeces was noted up to two days after test substance administration. Similarly, discoloured faeces were observed in the repeat-dose study at the intermediate (200 mg/kg bw/day) and high (1000 mg/kg bw/day) dose groups from day 7 and 4, respectively, until day 3 of the recovery phase. In urine, a dose-dependent discoloration from yellow (control and low dose) through deep-yellow (intermediate dose) to red-brown (high dose) was observed, indicating that the test substance is absorbed to some amount and partly excreted via urine. This discolouration was no longer observed at the end of the 2-week recovery phase. No discolouration of internal organs or tissues were reported during necropsy, resulting in the assumption that the substance is not deposited in any organs or tissues and eliminating any concern for bioaccumulation of the test substance.

For dermal absorption, molecular weights below 100 g/mol favours dermal uptake, molecules with a weight above 500 g/mol may be too large to be absorbed (ECHA 2017c). With molecular weights of the test substance above 800 g/mol, the molecules are too large to allow absorption through skin. The high water solubility of the substances, would favour the dermal absorption rates under normal circumstances, as the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. However, the poor lipophilicity (log Kow < -1) will hinder penetration through the lipid rich environment of the stratum corneum and therefore dermal absorption is limited.

As the test substance has a low volatility (melting point above 300°C), they are not available for inhalation as a vapour. Should particles of the solid form of the substances be inhaled, absorption through the respiratory tract epithelium is not expected due to the molecule sizes.

Distribution

In general, the smaller the molecule, the wider the distribution. Based on their molecular weight distribution and the hydrophilicity it is assumed, that if absorbed, the substances were distributed within the aqueous compartment of the organism. Furthermore, an accumulation within adipose tissue can be excluded based on the low log Kow of all constituents of the test substance. No discolouration of inner tissues was noted during necropsy of the acute and repeat-dose toxicity studies.

Metabolism

The substances are not expected to be bioavailable following oral, inhalative or dermal exposure at a relevant level as a result of their properties. Based on the results of in-vitro genotoxicity studies, it can be assumed that the substances are not enzymatically activated (toxified) during metabolism as the metabolic activated test substances showed no higher toxicity compared to the test substances without metabolic activation. Available data indicate that the substances are susceptible to hydrolysis. It is likely that during passage of the GI-tract the azo bond is reduced via azo-reductase. However, as shown in radio-labelled studies with Reactive Black 5, only the parabase ester structure is likely to be absorbed to some extent, and no adverse effects are reported for this structure.

Excretion

According to the physico-chemical properties of the substances, molecular weight and hydrophilic characteristics the main route of excretion is expected to be via faeces, as substances that are excreted in the urine tend to be water-soluble and of low molecular weight (below 300 g/mol in the rat). As seen from the dose-dependent discolouration of urine at the end of the treatment phase in the repeat-dose toxicity study, a very low amount of the substance and/or its metabolites are also excreted via the kidneys.

Conclusion

The results of ADME prediction and basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxicokinetics of Reactive Scarlet F07-0522. The data indicate that there is little or no dermal absorption. No signs of a systemic toxicity associated with absorption through skin have been observed. Based on exposure model from AG Textilien des Bundesinstituts fur Risikobewertung (BfR), the dermal penetration rate for dyes through the skin was found to be less than 2%.

Based on physico-chemical data and the results of oral toxicity studies, Reactive Scarlet F07-0522has a limited oral bioavailability. The substance is considered to have low volatility as evident from the vapour pressure measurement and the calculated melting point of > 300°C, so the potential for the generation of inhalable forms is low. The molecular weight is higher than 500 g/mol and the chromophore is negative charged. This together with the high water solubility and low partition coefficient value, indicate the substance is not able to cross the mucous layer of the respiratory tract. Due to the high water solubility, vapours if generated/inhaled, will be trapped in the mucus of the respiratory tract, thereby further limiting the absorption. Hence, the main route of exposure of the substance, if inhaled, will be due to swallowing of particles deposited in the nose/mouth. Therefore, the bioavailability for inhalation is considered the same as for oral intake.

Bioaccumulation of Reactive Scarlet F07-0522 can most probably be excluded due to the available data. Based on the results of genotoxicity assays, a metabolisation towards genotoxic metabolites can also be excluded for mammalian species.

On the basis of the results, it is anticipated that the substance does not undergo significant metabolic activity; rather it is metabolised for excretion with little subsequent toxicity.  The substance is therefore not considered to be of concern for ADME related effects.