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Administrative data

Link to relevant study record(s)

Description of key information

The physico-chemical characteristics of the target substance and lack of acute oral or repeat dose oral toxicity suggest that, despite predicted oral absorption and distribution, there is likely to be limited bioaccumulation in the animal models studied. Tissue distribution and metabolism are most likely to be predominantly in the liver. Acute exposure via the dermal route also demonstrated no toxicity, although qualitative some absorption through the skin might be assumed. Considering these attributes, the most likely route of excretion would be primarily via the urine and faeces.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Introduction

No specific toxicokinetic or ADME investigations, or studies on potential metabolites, were available at the time of the review. However, physical chemical and mammalian toxicity data were available for evaluation from which a reasoned scientific opinion on the ADME parameters of this substance may be predicted. These data were generated using two closely related structural analogues (see read-across justification attached in Section 13). An on-line literature search did not reveal any further data that might aid in this prediction.

Available data

The target substance was not soluble in water (2.07 x 10E-05 g/L) and had a partition coefficient (Log10 Pow) of 7.37 to >10.0, indicating a highly lipophilic substance. The boiling point (decomposition from 150 °C) and vapour pressure (6.27 x 10E-03 Pa at 25 °C) would not suggest that the target substance presents a risk of inhalation exposure under ambient environmental conditions. Acute toxicity studies, by either the oral (target substance) or dermal (analogue substance) routes, revealed no toxicity each presenting the same LD50 of greater than 2000 mg/kg bw. Furthermore, the analogue substance was not irritating to the skin and was not a skin sensitiser. Mild eye irritation was found with the analogue substance but did not meet EU classification criteria and, in the three genotoxicity studies employed (with and without metabolic activation), there was no evidence for genotoxic potential of the analogue. Using the analogue substance in a 28-day repeat oral toxicity study and a 28-day repeat oral toxicity reproductive/developmental toxicity screening study, where the highest dose tested was 1000 mg/kg bw/day, no parental systemic or reproductive toxicity, no developmental or neonatal toxicity was evident. In both studies the doses were formulated in arachis oil because of the lipophilic nature of the substance and to aid oral exposure. The data from both the acute and repeat dose toxicity studies clearly demonstrated that the substance was not topically or systemically toxic at dose levels that could be considered more than a maximum tolerated dose.

Adsorption

Lipophilicity of the target substance suggests that absorption across cell membranes, after oral exposure, would be predicted to be high and might have been aided by the vehicle (arachis oil) used. The lack of toxicity seen in the acute dermal study does not preclude dermal absorption. The lipophilic nature of the analogue substance would suggest some absorption but the dynamics of absorption into and through the skin cellular architecture are difficult to predict.

Distribution

The target substance would be expected to be widely distributed particularly in the liver and kidneys and available data do not suggest significant bioaccumulation. The physical chemistry data suggest that it is unlikely that acute inhalation exposure would result in toxicity considering the very low toxicity evident in the studies presented.

Metabolism

It is expected, from the both the physical chemistry and toxicity data, that metabolism of the target substance would be primarily via the liver; the nature of the effects seen after repeated oral exposure, and the relatively low toxicity seen, further suggest that potential metabolites may also be of limited toxicity in the animal models used. The data from the genotoxicity studies (with S9-mix, i.e. induced metabolic activation) support this opinion.

Excretion

Given the physical chemical properties of the target substance and assuming limited bioaccumulation, it is predicted that excretion would be mostly via the urine and faeces.

Conclusion

The physico-chemical characteristics of the target substance and lack of acute oral or repeat dose oral toxicity suggest that, despite predicted oral absorption and distribution, there is likely to be limited bioaccumulation in the animal models studied. Tissue distribution and metabolism are most likely to be predominantly in the liver. Acute exposure via the dermal route also demonstrated no toxicity, although qualitative some absorption through the skin might be assumed. Considering these attributes, the most likely route of excretion would be primarily via the urine and faeces.