Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:

Description of key information

There are no specific studies available on the ADME of RD 14156. However, data is available from the physico-chemical parameters, in vitro and in vivo toxicology studies.

Absorption

Oral route

The physico-chemical characteristics of RD 14156 suggest that the UVCB may be well absorbed via the gastro-intestinal tract. The MW covers a broad range since RD 14156 is a UVCB (approximately MW 144.17 – 625.02), but the reported Log P value is 1.0 and its solubility in water is moderate at 260 mg/L (average) at 20°C. These values could be indicative of significant oral absorption. A pKa (dissociation constant) in water has not been determined.

The low toxicity in the acute oral toxicity study and the oral 14-day repeat-dose dose toxicity study might indicate low bioavailability; however it might also be a function of innate low toxicity associated with the structural and functional characteristics of the molecules in the UVCB.

Dermal route

RD 14156 is a solid with a broad MW range and a Log P value of 1.0. Its solubility in water is moderate at 260 mg/L (average) at 20°C. These parameters suggest that the substance may be capable of significant systemic absorption through the dermal route. A solid substance with moderate water solubility and a Log P value of under 6.0 could be considered capable of significant systemic absorption through the dermal route. This is because the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Absorption is expected to be moderate in those compounds that have a water solubility of over 100 mg/L.

Therefore, given that the water solubility of RD 14156 is 260 mg/L the dermal absorption is anticipated to be appreciable. RD 14156 is not classified as a skin sensitiser nor is it a dermal irritant based on in vivo data. The low irritancy potential of RD 14156 might be attributed to low skin penetration. Irritation usually occurs as a result of skin penetration giving rise to an inflammatory response (irritation). The lack of sensitisation potential of RD 14156 may indicate poor absorption by the skin, therefore unlikely to enter the systemic circulation. It is worth noting that these data do not provide conclusive evidence for the absorption potential via the dermal route of exposure and the lack of sensitisation and irritation could be the result of low toxicological activity rather than poor skin absorption/penetration.

Inhalation route

RD 14156 is not expected to be highly volatile given that vapour pressure is <0.1mm Hg at 25°C and boiling temperature has not been determined. Therefore, significant exposure as a vapour is unlikely. There are

no studies available to investigate the toxicity of particles via the inhalation route of exposure. RD 14156 has a medium particle size of 5.94 μm which suggests that a significant proportion of the RD 14156 particles will be respirable into the lung. Once particles are in the lung, absorption can be assumed to be 100% given that RD 14156 is water soluble.

Ocular route

Irritation was observed following ocular exposure of New Zealand White rabbits to RD 14156 but there was no accompanying toxicological effects. The level of effect was not sufficient for classification in the EU. The irritation effects may be indicative of some ocular absorption, but equally may also be indicative of the low toxicological activity of RD 14156 via this route of exposure.

Distribution

There are no studies available to evaluate the systemic distribution of RD 14156. The low toxicity findings from the oral/dermal acute and oral repeated dose studies provide no evidence regarding the systemic distribution of RD 14156. In the absence of other information it is not possible to make conclusions on the distribution of RD 14156 in the body.

Metabolism

There are no studies available to evaluate the metabolism of RD 14156. However, RD 14156 did not induce mutagenicity or genotoxicity in in vitro studies both in the presence and absence of a metabolic activation system. This could be indicative of a lack of metabolism of the parent compounds, however this could also be taken to mean that both the parent compounds and any metabolites that are formed are not mutagenic or genotoxic.

Excretion

There are no studies available to evaluate the excretion of RD 14156. The MW of RD 14156 is a range because it is a UCVB. Small organic compounds are more likely to be excreted in the urine, particularly those that are water soluble. Biliary excretion is more likely for high MW compounds either because of biotransformation by phase 2 conjugation or because the parent is innately large (>500 MW). Therefore it is possible that the smaller molecules in RD 14156 may be excreted via the urine and the larger molecules may be excreted via biliary excretion. However, there is no conclusive evidence for this and it will depend on the extent of metabolism.

Summary and conclusions

The MW range and physico-chemical properties of RD 14156 indicate that it is likely to be absorbed via the oral and dermal routes of exposure. The MW ranges from approximately 144.17 – 625.02, it has a moderate water solubility and a Log P of 1.0. The available toxicology studies via the oral route show that there are no adverse effects associated with acute and subacute exposure to RD 14156. This is suggestive of either a lack of appreciable absorption via this route and/or a function of innate low toxicity. Similarly the absence of irritation or sensitization effects could be the result of a lack of skin penetration/absorption and/or the low toxicological activity. Exposure via the inhalation route to particulate RD 14156 is likely to result in significant absorption due to the small particle size and the water solubility. In the absence of further information, absorption via this route should be assumed to be 100%. However, the vapour pressure of RD 14156 is relatively low and inhalation exposure to RD 14156 vapour is not expected to be significant. There is no evidence regarding the distribution, metabolism, metabolite fate or excretion of RD 14156. Excretion via the kidneys is considered a possibility based on the Log P and low MW for some constituents of the UVCB. The larger MW constituents of the UVCB may be excreted via the biliary route. There was no information on bioaccumulation but, based on the Log P of 1.0, significant bioaccumulation is unlikely.

Key value for chemical safety assessment

Additional information