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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

Toxicokinetic Assessment

 

No specific study was performed on the absorption/distribution/metabolism/excretion (ADME) of RD 14153 but data are currently available from the physico-chemical andin vivotoxicology studies.

 

Absorption

Oral route

The physico-chemical characteristics of RD 14153 suggest that the UVCB may be well absorbed via the gastro-intestinal tract. The molecular weight is a broad range since RD 14153 is a UVCB  (MW 172.23 – 625.04), but the reported Log P value is low (Log P = 1.02) and its solubility in water is medium to low at 0.321 g/L (average) at 20°C. These values do not suggest low 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 does not necessarily support low bioavailability; rather it may be a function of innate low toxicity associated with the structural and functional characteristics of the molecules in the UVCB.   

 

Dermal route

RD 14153 is a solid with a broad MW range and a Log P value of 1.02. Its solubility in water is medium to low at 0.321 g/L(average) at 20°C. A solid substance with medium to low water solubility and a Log P value of below 6.0 must be considered capable of significant systemic absorption though the dermal route. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Water solubility above 100 mg/L, absorption is anticipated to be moderate to high and therefore RD 14153 would be anticipated to be significant.RD 14153 is not classified as askin sensitiser based onin vivodata, but this does not suggest poor absorption since it may lack toxicological activity.

Inhalation route

With a vapour pressure at 13 Pa at 25°C and boiling temperature not determined because the freezing temperature is so high, RD 14153 is not a highly volatile substance and therefore significant exposure as a vapour is not likely, however no inhalation study is available to investigate toxicity of particles via the inhalation route. RD 14153 has a mean particle size of5.9 ± 1.4 µmwhich suggests that a significant proportion of the RD 14153 particles will be respirable into the lung. Once particles are in the lung, absorption can be assumed to be 100%.

 

Distribution

 

The low toxicity findings from the oral acute and repeated dose studies provide no evidence for or against systemic distribution. In the absence of other information it is not possible to make conclusions on the distribution of RD 14153 in the body.

 

Metabolism

 

No data are available on metabolism in the existing toxicity studies. There was no evidence of any effect on tissues with high metabolism capability which could have provided evidence for metabolism.

 

Excretion

 

No data are available on metabolism or excretion in the existing toxicity studies. There are no otherin vivodata on the way in which RD 14153 is excreted. 

Molecular weight of RD14153 is a range. 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 molecular weight 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 14153 may be excreted via the urine and the larger molecules may be excreted via biliary excretion. However, there is no evidence for or against this and it will depend on the extent of metabolism.   

 

Conclusion

 

There is no strong experimental evidence from toxicity studies for the oral absorption of RD 14153 because the toxicity is so low. However, the physicochemical properties of RD14153 including relatively low water solubility, low LogP and a relatively large molecular weight range suggest that absorption via the oral and dermal routes cannot be ruled out and may be significant. Exposure via the lung to particulate RD 14153 is likely to result in significant absorption because of the small particle size and in the absence of further information should be assumed to be 100%. However, the vapour pressure of RD 14153 is relatively low and inhalation exposure to RD 14153 vapour is not considered to be high.  There is no evidence of distribution metabolism, metabolic fate or excretion. Excretion via the kidney is considered a possibility based on the low LogP and low molecular weight for some constituents of the UVCB. Excretion via the biliary route particularly for larger molecular weight constituents of RD 14153 may be possible too. There was no information on bioaccumulation but based on the low LogP significant bioaccumulation is not anticipated.

 

Key value for chemical safety assessment

Additional information