Phosphorous ester

Endpoint summary

Additional information

GARDO TP10451 is a highly viscous liquid at room temperature with a molecular weight of 1173.4 g/mol (ideally). The melting point/boiling point of the substance could not be determined analytically, as the substance shows a glass transition at -53 °C and decomposes on heating starting at 168 °C. Melting point/boiling point calculation with the EPIWEB 4.0 programme (US EPA 2008) revealed a boiling point of 480.00 °C and a melting point of 90.27 °C. Estimation of the vapour pressure on the base of the calculated MP/BP yielded a vapour pressure of 2.75E-09 Pa at 25 °C (Modified Grain method). The partition coefficient (log Pow = 18.43) was estimated using the EPIWEB 4.0 programme (US EPA 2008). The substance’s water solubility was estimated to be 3.825E-018 mg/l at 25 °C, also with the EPIWEB 4.0 programme (US EPA 2008). As the substance is a liquid with a high molecular weight, vapour pressure was estimated to be extremely low and the substance decomposes upon heating, very little exposure via inhalation (as gas) is expected. Even though the log Pow suggests that some absorption directly across the respiratory tract epithelium can occur, the high molecular weight indicates that the substance will hardly become bioavailable via the inhalation route. Further, the substance showed low toxicity after oral and dermal administration. Together this indicates low systemic availability after inhalation and, if bioavailable, low toxicity via this route of administration. Based on physical-chemical properties GARDO TP10451 absorption across the skin is likely to be low. Due to the substance’s high log POW (higher 6), the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Further, uptake into the stratum corneum may itself be low, not only due to the high log POW, but also because the molecular weight is high and water solubility is low. No toxicity, neither local nor systemic, was observed following dermal application of 2000 mg/kg bw (limit dose). Administered orally, GARDO TP10451 is not likely to dissolve in the stomach easily, due to its low water solubility (much lower than 1 mg/L). As only dissolved substance is available for adsorption, the quantity of GARDO TP10451 to become bioavailable via the oral route is low. Further, high molecular weight does not favour passive diffusion across the gastrointestinal tract. Therefore, most likely very low amounts of GARDO TP10451 or breakdown products will become bioavailable. Most of GARDO TP10451 ingested will be eliminated through faeces. Respectively, toxicity to orally administered GARDO TP10451 is low, as shown in acute and subacute toxicity tests (NOAEL = 1000 mg/kg bw/day; limit dose). If bioavailable, GARDO TP10451 is not likely to bioaccumulate. A BCF estimation using the estimated log Pow of 18.43 shows an estimated log BCF of 0.500 with a resulting BCF of 3.162 (EPIWEB 4.0 programme; US EPA 2008).Therefore, bioaccumulation/concentration is not very likely. Low amounts of GARDO TP10451 available systemically are likely to be metabolised and parent compound and degradation products are expected to distribute via systemic circulation. Metabolism may transform GARDO TP10451 into more polar degradation products. Likely pathways are reactions such as cleavage at the ester side-chains by esterases and ß-oxidation, which mediates the chain degradation of the fatty acids. Parent compound and metabolites formed in metabolic reactions may be rendered more polar by further metabolic activity in subsequent reactions. The parent compound or possible metabolites may undergo conjugation (e.g. with glutathione), before being excreted in urine or bile. In the absence of any clinical pathology alterations in the long-term studies, no adverse effects are assumed. It is unlikely that GARDO TP10451 is metabolised to more reactive (toxic) products. This assumption is supported by results obtained in oral and dermal toxicity studies and three in vitro tests (Reverse Mutation Assay using Bacteria (Ames-Test),In vitroMammalian Chromosome Aberration Test in Chinese Hamster V79 cells,In vitroMammalian Cell Gene Mutation Test – Mouse Lymphoma Assay). In acute and subacute in vivo studies toxicity was low. In an Ames test and a chromosome aberration assay no significant increase in toxicity was noted in the presence of a rodent microsomal S9-fraction, when compared to incubation without S9-fraction. Together, this data indicates that formation of reactive metabolites is rather unlikely. Based on the substance’s structure and associated physical-chemical characteristics, very low to low amounts of GARDO TP10451 will become bioavailable through inhalation, upon contact to skin or following oral ingestion. When bioavailable, the substance or its metabolites are expected to distribute, with excretion via urine or bile (polar conjugated forms, breakdown products) and via faces (high molecular weight forms, unchanged substance). Bioaccumulation is unlikely.