Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

The physical chemical characteristics of the test item and the data from the repeat dose toxicity study clearly suggest and demonstrate that the substance is likely to be rapidly absorbed, distributed, metabolised and excreted with limited bioaccumulation. The data clearly indicate that the liver is a target organ as demonstrated by enhanced metabolism. The toxicity of metabolites is likely to be limited as no overall toxicity was present, in any study, and in the genotoxicity studies metabolic activation was without demonstrable effect. Considering these findings, the most likely route of excretion (parent and metabolites) would be via the urine and the 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. 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. The data were generated specifically on the test item (UVCB substance) inGLP and regulatory compliant studies.An on-line literature search (primarily PubChem, TOXNET, ChemIDplus) did not reveal any further data that might be used to aid in this prediction.

Physico-chemical data

The substance was very poorly soluble in water (< 1.0 x 10E-03 g/L of solution at 20.0 ± 0.5 °C) and had a partition coefficient (Log10 Pow) of greater than 10.0, indicating a highly lipophilic substance.  The flash point (249 ± 2 °C), boiling point (232 °C) vapour pressure (1.75 x 10E-03 Pa at 25 °C) and melting/freezing point (28 to 52 °C) do not suggest that this substance would present a risk of inhalation exposure under ambient environmental conditions. The surface tension (70.5 ± 0.5 mN/m at 21.5 ± 0.5 °C) meant that the substance was not considered to be surface active.

Available studies

The acute toxicity studies with the test item, by either the oral (formulated in corn oil) or dermal route, revealed no toxicity, each presenting the same LD50 of greater than 2000 mg/kg bw. Furthermore, the substance was not a skin sensitizer, was not corrosive or an irritant to the skin or the eyes. In a battery of genotoxicity tests, the test item showed no genotoxic potential (with and without S9 metabolic activation). In an orally dosed reproductive/developmental toxicity screening study (OECD 422), where the dosages tested were 0, 350, 500, 750, and 1000 mg/kg bw/day, the parental systemic and neonatal toxicity NOAEL was 1000 mg/kg bw/day, based on the lack of adverse effects at any dosage level. The dosages, in this study, were formulated in corn oil because of the lipophilic nature of the substance and this may have aided oral absorption of the substance. The data from the acute toxicity studies, the LLNA, genotoxicity studies and the OECD 422 study, clearly indicate a substance with no acute or sub-chronic systemic toxicity, no induced allergenic effects or genotoxicity.

Absorption and distribution

The lipophilicity of the test item clearly indicates that it should be very readily absorbed across the lipid bilayers of cell membranes, after oral exposure, and this may have been aided using the vehicle corn oil for oral gavage dosing. The lack of toxicity seen in the either the acute oral or dermal studies does not preclude acute oral or dermal absorption. It would have been expected that both adequate oral as well as dermal absorption would have been achieved. Similarly, in the OECD 422 study, after repeat dosing, ready oral absorption would have been expected and effects on the liver (organ weight and metabolism) clearly suggest this (see below). The physical nature of the test item and physical chemistry data suggest that it is unlikely that acute inhalation exposure (not expected to present an exposure risk) would result in toxicity considering the very low toxicity evident in the acute or repeat dose studies presented.

Metabolism

It is expected, from the both the physical chemistry and toxicity data, that metabolism would be primarily via the liver (major site) and secondarily the kidneys, although this does not preclude the GI tract. The substance is likely to be extensively metabolised in the liver (Phase 1 and 2 enzymes). Indeed, in the OECD 422 study higher mean alanine aminotransferase (ALT) levels were seen (350, 500, 750, and 1000 mg/kg bw/day group males), in comparison to control group. Concomitant with this were higher liver weights, largely in the 1000 mg/kg bw/day dosage group. This is suggestive of enhanced liver metabolism (and excretion). No adverse histopathological findings in the liver were evident.

In the genotoxicity studies no adverse effects were seen either with or without the addition of metabolic activation (+/- liver S9-mix), this favours the view that potential metabolites were likely to be of no or limited mammalian toxicity. The evidence (lack of toxicity) from the OECD 422 study would support this.

Excretion

Given the physical chemical properties of the substance, the nature of the effects seen in the repeat dose toxicity study (increased liver weight; enhanced hepatic metabolism) and probable limited bioaccumulation, it is predicted that excretion, (of parent and metabolites) would be primarily via the urine and faeces.

Conclusion

The physical chemical characteristics of the test item and the data from the repeat dose toxicity study clearly suggest and demonstrate that the substance is likely to be rapidly absorbed, distributed, metabolised and excreted with limited bioaccumulation. The data clearly indicate that the liver is a target organ as demonstrated by enhanced metabolism. The toxicity of metabolites is likely to be limited as no overall toxicity was present, in any study, and in the genotoxicity studies metabolic activation was without demonstrable effect. Considering these findings, the most likely route of excretion (parent and metabolites) would be via the urine and the faeces.