Reaction mass of disodium 2-[[2-hydroxy-3-[[methyl-(2-oxido-2-oxoethyl)amino]methyl]-5-nonylphenyl]methyl-methylamino and sodium 2-[(2-hydroxy-5-nonylphenyl)methyl-methylamino]acetate

Endpoint summary

Description of key information

There is no requirement to generate experimental toxicokinetic data under REACH. No toxicokinetic data are identified; however a theoretical assessment of the toxicokinetic properties of the substance is made, based on existing toxicity data, and taking into account the physico-chemical properties of the substance.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Assessment of the toxicokinetic properties of the substance

The substance has a molecular weight of 343.4 – 466.5 g/mol (< 500 g/mol) and a LogP value of 2.013 (<5) indicating that absorption via the oral route is possible, taking into account Lipinski’s rules for oral bioavailability.

The substance is amphiphilic, having both hydrophobic (water-insoluble) and hydrophilic (water soluble) components and will form micelles when dissolved in aqueous solutions. Hence, the water solubility of the substance cannot be readily determined. In surface tension studies, the substance has been determined to be surface active; and the critical aqueous micelle concentration value was determined to be 154 mg/L at 20^oC. The behaviour of the substance in physiological systems is expected to be determined by its amphiphilic characteristics. In mammalian toxicity studies in which the substance was administered using a water as a vehicle, test-item related signs of systemic toxicity were observed indicating that oral uptake and systemic exposure takes place.

 

Absorption

Oral absorption

Oral bioavailability is predicted for the substance based on a molecular weight < 500 g/mol and a LogP value < 5 according to Lipinski’s rules.In an acute oral toxicity study, the substance had an LD₅₀>2000 mg/kg bw, suggesting limited potential for acute systemic toxicity. However, in a combined repeated dose oral toxicity and screening reproductive/developmental toxicity study in the rat, evidence of systemic effects; most notably in the kidneys and the liver were observed, indicating that extensive absorption and systemic distribution can occur following oral exposure.The data therefore indicate extensive and rapid oral absorption of the substance.

There are no experimental data which provide an oral absorption value, hence for risk assessment purposes, a default oral absorption value of 50% has been used.

Dermal absorption

Taking into account that the substance has a molecular weight <500 g/mol, absorption across the dermis may be possible and due to the amphiphilic nature of the substance, a certain degree of solubility in aqueous systems is expected. However, the substance will tend towards the formation of micelles; aggregates of molecules dispersed in aqueous systems. The behaviour of the substance in the aggregeted form in physiological systems (e.g. on the surface of the skin) and the extent to which it may be bioavailable via the dermal route is unknown, but expected to be low.

Dermal absorption values for the main components of the substance: CAS Nos. 62568-43-8 and 56968-08-2 have been predicted to be 2.7 4 x 10^-6mg/cm²/event and 1.1 x 10^-5mg/cm²/event using the EPI DERWIN model (Danish QSAR database). 

Absorption of the substance via the dermal route is not expected to be more significant than via the oral route, hence for risk assessment purposes, dermal absorption is expected to be the same as oral exposure i.e. 50%.

Inhalation absorption

The physicochemical properties of the test material do not preclude absorption via the inhalation route, in theory, as passage across biological membranes cannot be excluded.

The substance (tested as a solid powder) has a low vapour pressure (8.6 x 10^-3Pa at 25^oC) suggesting that the inhalation of volatised particles would be unlikely. Studies on the particle size distribution of the substance (tested as a solid power), indicate that the proportion of respirable particles is negligible. Inhalation exposure to the substance in the solid form would not arise during the use of the substance: the manufactured substance is formulated with a solvent at a concentration of 50% w/w to produce a liquid product in a closed production process. Due to the amphiphilic nature of the substance, the molecules of respective components will aggregate in aqueous solutions to form micelles. While the behaviour of these micelles in physiological systems such the mucus membranes of the respiratory system is unknown, extensive absorption would be unlikely.

There are no experimental data which provide an inhalation absorption value, hence for risk assessment purposes, a default value of 100% has been used.

Distribution

The combined repeated oral dose and screening reproductive/developmental toxicity conducted in rats provides evidence for the distribution of the substance to the organs, including the liver and the kidneys.

Metabolism

In a repeated oral dose toxicity study, hepatic changes including centrilobular hypertrophy and altered glycogen storage were observed in histopathological assessments of the liver of rats treated at high doses suggesting that hepatic processes may be affected by exposure to the substance. Metabolism simulators (OECD QSAR Toolbox; Danish QSAR Database) predict the metabolism of the two components of the substance (CS Nos. 62568-43-8 and 56968-08-2). In respect of both components, negative results have been reported for the induction of key cytochrome P450 enzymes from liver microsomes involved in the metabolism of xenobiotic and endogenous compounds, suggesting that the metabolism of the substance may not be mediated via the cytochrome P450 systems. The pathway for the hepatic metabolism of the substance is therefore unclear.

Excretion

There is no direct evidence from the available toxicity studies for the excretion of the substance by a specific route. However, taking into account that the substance is orally absorbed, may undergo hepatic metabolism and has been shown in a repeated oral dose toxicity study to cause histopathological changes in the kidneys, the renal route is potentially the primary route of excretion, resulting in the elimination of the substance or its metabolites via the urine.

Bioaccumulation

Bioaccumulation is considered to be unlikely for the substance, based on its physicochemical properties and the likelihood of hepatic metabolism and excretion via the renal-urinary system.

Conclusion

Based on its physico-chemical properties, the substance is likely to be bioavailable via the oral route and data indicates oral uptake following repeated dose exposures leads to systemic distribution to the organs including the liver and the kidneys. For risk assessment purposes, a default oral absorption value of 50% has been used. The route of metabolism is not known but may be mediated in the liver, possibly by non-microsomal processes. Treatment-related effects in the kidneys observed in repeated dose studies suggest the substance may be eliminated via the renal route and excreted via the urine. Based on its properties and observations from toxicity studies, bioaccumulation is considered to be unlikely.

The substance is amphiphilic and forms micelles (e.g. aggregates of molecules) in aqueous systems. Extensive absorption of the substance via the dermal or the inhalation route from aqueous formulated products is unlikely. For risk assessment purposes, default dermal and inhalation absorption values of 50% and 100%, respectively, have been used.