Trisodium 5-[[4-chloro-6-(ethylphenylamino)-1,3,5-triazin-2-yl]amino]-4-hydroxy-3-[(4-methyl-2-sulphonatophenyl)azo]naphthalene-2,7-disulphonate

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolism and excretion of the substance. Trisodium 5-[[4-chloro-6-(ethylphenylamino) -1,3,5-triazin-2-yl]amino]-4-hydroxy-3- [(4-methyl-2-sulphonatophenyl)azo]naphthalene-2,7-disulphonate (Ractive Red 45:1) is expected to be readily absorbed via the oral route.Using the precautionary principle the final absorption percentage derived is 100% for oral and inhalatory absorption. Based on the physico-chemical properties of the substance a 10% absorption via dermal route is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Toxico-kinetic information on Reactive Red 45:1

Introduction

Reactive Red 45:1 (CAS 73816-74-7), is a mono-constituent substance with amolecular weight of 816.12455 g/mol, and is an odourless, solid powder undergoing degradation above 200 °C (boiling point could not be determined because of thermal degradation of the test substance started at 200°C), a water solubility of 129.22g/L, a very low vapour pressure of 2.76E-25 Pa (estimated by using QSAR) and a log Kow below -2. The determination of the vapour pressure was not possible due to decomposition of the test substance. The log Kow was estimated based on the water and n-octanol solubility. The test substance is insoluble in n-octanol (solubility was found to be below the limit of detection – LOQ = 0.5 mg/L). Based on this information and an Expert Statement Partition coefficient (log Kow) of the test substance is expected to be below -2.0.

 

Absorption

Oral route: In an oral (gavage) repeated dose and reproduction/ developmental toxicity screening tests, systemic effects were observed in exposed animals. The effects on kidneys (macro- and microscopic) indicate that Reactive Red 45:1 is absorbed via the oral route. Based on high water solubility (129.22 g/L) absorption through in the small intestine is expected. All this information indicates that Reactive Red 45:1 is likely to be absorbed orally and using the precautionary principle (based on systemic effects) the oral absorption is assumed to be 100%.

 

Inhalation route: The vapour pressure of the substance is very low, however, based on the granularity (D50 48.5 µm) of the substance and the high water solubility the rate of respiratory absorption is considered likely. Based on physico-chemical properties and using the precautionary principle the final absorption percentage derived is 100% for the inhalation route.

 

Dermal route: Absorption via dermal route is anticipated for the test substance based on its physico-chemical properties. High molecular weight (> 500 g/mol) is a limiting factor for dermal absorption as is log Kow below – 1. Poor lipophilicity of Reactive Red 45:1 indicates that it is unlikely that the substance will cross the stratum corneum. However, the lower limit of 10% was chosen, because there is evidence in the literature that substances with molecular weight and/or log P values at these extremes can to a limited extent cross the skin. therefore based on Appendix R.7.12-5 the rate of dermal absorption is assumed to be 10%.

  

Distribution

The log Kow below - 2 would suggest that the substance would not readily pass through the biological cell membranes. However, the systemic effects of oral administration of Reactive Red 45:1, such as red staining of kidneys and microscopic findings characterised by the presence of amorphous material in the tubular cell vacuoles of high dosed animals suggests that the substance is present in these organs after oral exposure.

Very low lipophilicity of the substance (log Kow < -2) suggests no potential for the substance to accumulate in the adipose tissue of exposed individuals.

 

Metabolism

There are no experimental data on the metabolism of Reactive Red 45:1. The following CYP450-mediated reactions are predicted by Xenosite Metabolism v.1: aliphatic and aromatic hydroxylation and N-oxidation (Fig. 1) by the following CYP450 isoforms: 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4. Furthermore, based on the modelling performed by Xenosite UGT v.1, the nitrogens are likely to be the sites for UGT-mediated glucuronidation (Fig. 2). 

Excretion

Reactive Red 45:1 is likely to be excreted via the urine due to its hydrophilicity. This hypothesis is further backed by the presence of the substance in kidneys in the exposed animals. The substance is also likely to be excreted via faeces, as indicated by the red staining of stool in animal experiments. As a glucuronide the substance may be excreted via bile, and may undergo enterohepatic circulation.

 

Discussion

The substance is expected to be readily absorbed orally. Reactive Red 45:1 is absorbed orally and both CYP- and UGT-mediated metabolism is anticipated (see metabolism paragraph). The substance is anticipated to become present in the kidneys upon oral administration based on long-term animal studies available and to have no ability to accumulate in body fat.

  

References

European Chemicals Agency, 2017, Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance

 

Martinez, M.N., and Amidon, G.L., 2002, Mechanistic approach to understanding the factors affecting drug absorption: a review of fundament, J. Clinical Pharmacol., 42, 620-643.

 

Dang, N. L, Hughes, T. B., Krishnamurthy, V., and Swamidass, S. J. (2016). A Simple Model Predicts UGT-Mediated Metabolism. Bioinformatics, DOI: 10.1093/bioinformatics/btw350

Zaretzki, J., Matlock, M., & Swamidass, S. J. (2013). XenoSite: Accurately predicting CYP-mediated sites of metabolism with neural networks. Journal of chemical information and modeling, 53(12), 3373-3383.