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Endpoint summary

Description of key information

The physico-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 suggest the liver as a target organ as demonstrated by enhanced metabolism and a change in blood cholesterol level. 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 at the time of this review. However, physico-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 substance 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 test item was very poorly soluble in water (≤ 7.8 x 10E-04 gCa/L, ≤ 3.2 x 10E-04 gB/L and < 1 x 10E-03 gTOC/L at 20.0 ± 0.5 °C); no partition coefficient was determined because the method was demonstrated to be not applicable (Method 117 of the OECD Guidelines for Testing of Chemicals, 13 April 2004). The test substance is an inorganic active and was suspended in an organic medium (oil) and the partition coefficient of inorganic substances is not usually required. The flash point (211 ± 2 °C), boiling point (partial boiling from approximately 190 °C to 400 °C at 100 kPa), vapour pressure (9.53 x 10E-03 Pa at 25 °C) and melting/freezing point (< -20 °C) do not suggest that this substance would present a risk of inhalation exposure under ambient environmental conditions. The surface tension (72.0 mN/m at 19.5 ± 0.5 °C. meant that the substance was not considered to be surface active.

 

Available studies

The acute toxicity studies with the test item (used as supplied), by either the oral or dermal route, revealed no toxicity, each presenting the same LD50 of greater than 2000 mg/kg bw. The substance was also not a skin or eye irritant. Furthermore, the substance was not mutagenic or clastogenic in any of the genotoxicity assays conducted. However, data from a LLNA revealed that the test item was a skin sensitiser - there was no sign of systemic toxicity in this assay.

 

In an oral gavage (formulated in arachis oil and mineral oil mixture), combined 28-day toxicity and reproductive/developmental toxicity screening study (OECD 422), where the dosages of the substance tested were 0, 5, 150, 375, and 1000 mg/kg bw/day, the parental systemic and neonatal toxicity NOAEL was considered to be 1000 mg/kg bw/day. This was based on a lack of significant adverse parental systemic toxicity and lack of effects on the developing neonates. In this study, some changes in mean reticulocyte values were noted in the 1000 mg/kg bw/day group and at 375 and 1000 mg/kg bw/day higher alanine aminotransferase (ALT) activity and lower cholesterol levels were observed. However, there were no histologic correlates in these groups.

 

The data from these studies, except for the LLNA, clearly indicate a substance with no acute or adverse sub-chronic systemic or adverse reproductive/developmental toxicity and no genotoxicity.

 

Adsorption and distribution

The poor water solubility of the test material and its apparent solubility in oils, indicates that the substance should be absorbed across the lipid bilayers of cell membranes after oral exposure, and this may have been aided by using the vehicle arachis oil (plus oil used in the test substance preparation) for oral gavage dosing.

 

The lack of toxicity seen in either the acute oral or dermal studies does not preclude acute oral or dermal absorption. Indeed, the nature of the test material would suggest that oral as well as dermal absorption was highly likely. When considering the LLNA result, this too suggests that dermal absorption occurred.

 

Similarly, in the OECD 422 study, after repeat dosing, ready oral absorption and systemic exposure would have been expected. This was confirmed by the effects seen on a small number of haematological of clinical pathology parameters at 375 or 1000 mg/kg bw/day.

 

The physical nature of the substance and physical chemistry data suggest that it is unlikely that acute inhalation exposure (not expected to present an exposure risk) would result in adverse toxicity considering the 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 mostly 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). For example, in the OECD 422 study higher mean alanine aminotransferase (ALT) activity was seen at 375 or 1000 mg/kg bw/day group. This was coupled with lower mean cholesterol levels. This is suggestive of enhanced liver metabolism (and excretion). No adverse histopathological findings in the liver were evident, suggesting an adaptive rather than adverse change in the liver.

 

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 (enhanced hepatic metabolism) and probable limited bioaccumulation, it is predicted that excretion, (of parent and metabolites) would mostly be via the urine and faeces.

 

Conclusion

The physico-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 suggest the liver as a target organ as demonstrated by enhanced metabolism and a change in blood cholesterol level. 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.