O,O,O-tris(2(or 4)-C9-10-isoalkylphenyl) phosphorothioate

Endpoint summary

Additional information

Information on toxicokinetic properties is derived from experimental data on the actual substance and on an analogue substance. Details on the analogue substance including a data matrix is attached in IUCLID Chapter 13.

The test substance is a clear to yellow, viscous liquid at room temperature with a molecular weight range of 486.0 to 846.0 g/mol and a relative density of 1.0133. The test substance has a melting point below -50 °C and a boiling point of 533 °C at 1013 hPa (extrapolated). The substance is highly insoluble in water, as water solubility is smaller than detection limit of the analytical method (0.21 mg/L at 20 °C). Partition coefficient (logPow) of the substance was estimated by QSAR calculation to be within the range of 19.0 – 19.9 and is thus too high for determination by experimental study. The substance was found to be fully miscible in fat at 37 °C. Vapor pressure of the substance was determined to be 2.8E-8 Pa at 25 °C. 

1.1 Absorption

Oral route

Bioavailability via oral route is strongly linked to physico-chemical properties of the substance (ECHA Guidance, 2008). Generally, oral absorption is favored for molecular weights below 500 g/mol and with a logPow in the range of -1 to 4. Thus, with a logPow greater than 19 and a molecular weight range at the edge of and greater than 500 (486.0 - 846.0 g/mol), the substance is expected to highly unlikely pass biological membranes. Furthermore, the substance is highly insoluble in water. In addition, the substance is expected to unlikely undergo hydrolysis. However, if hydrolysis takes place it is expected to be very slowly in acidic media such as the intestinal environment (please refer to IUCLID Section 5.1.2.). Taken together, the physico-chemical properties of the substance indicate that intestinal absorption is highly unlikely. Therefore, the test substance is expected to be not or only very poorly absorbed.

The above considerations are confirmed by findings of toxicity studies with the test substance. In an acute oral as well as a 28 days repeated dose toxicity study no signs of toxicity were observed up to the highest doses tested of 2000 and 1000 mg/kg bodyweight per day, respectively, indicating that the substance was not absorbed even at very high dose levels. In the repeated dose study, possibly treatment related findings were observed for hematology and clinical biochemistry. However, these findings were all within the historical control values and may be incidental. They do not reflect adverse findings and are no proof of systemic availability.

The analogue substance is of lower molecular weight which favors better absorption. Relevant physico-chemical properties are given in the read across justification document. Lipid solubility and logPow increase with alkyl chain length. Whereas for the target substance, the log Pow is above the range for the experimental methods (calculated value > 19), it can be measured for the components of the butylated analogue substance: The log Pow values of its components are in the range of 4 to 9 which is generally considered to be favorable for absorption. Therefore, and in contrast to the target substance, the analogue substance is considered to be more likely absorbed and bioavailable via the oral route. Clear indication of absorption is observed for the read-across substance as indicated by histopathology findings (for details see read across justification document attached to chapter 13).

Since the effects reported for the analogue were not observed upon subacute exposure at 1000 mg/kg bw, and as outlined above, the physico-chemical properties indicate absent or poor absorption. Therefore, the target substance is considered to be not or very poorly absorbed upon ingestion.

Dermal route

Also for dermal application, the substance is considered to be not permeating. According to ECHA guidance on toxicokinetics, there are no exclusion criteria for skin permeability, but a molecular weight of > 500 Da and a log Pow of > 4 are given as indicators for low absorption (10% or less). Considering the molecular weight of 721 Da and a calculated log Pow >19, these criteria are by far fulfilled. Furthermore, in an acute dermal toxicity study only nonspecific signs of treatment, i. e. dermal absorption were observed up to the highest dose of 2000 mg/kg bw.

Inhalation route

Due to a very low vapor pressure of 2.8E-8 Pa it is very unlikely that the substance is available as a vapor. Boiling point of the substance is extrapolated to be 533°C at 1013 hPa. Therefore, regarding inhalation, exposure is not relevant since the substance is a non-volatile liquid. However, if the case of inhalation should occur the substance is expected to not pass biological membranes, for the same reasons as outlined above.

 

1.2 Distribution

As mentioned before, no or very poor bioavailability is expected from the target substance. However, any distribution, if relevant, is expected to occur via plasma protein binding based on very low water solubility of the substance. Furthermore, the substance is not expected to bioaccumulate as indicated by QSAR calculation and an OECD 301 compliant study in carp (1994).

Regarding the analogue substance, histopathological findings in the subacute oral toxicity studies indicate that circulation and distribution at least to the liver can be assumed. For the target substance, no adverse finding was observed in the subacute gavage study at 1000 mg/kg bw.

 

1.3 Metabolism

Considering the functional groups, both enzymatic and non-enzymatic reactions would be theoretically plausible. The non-enzymatic oxidation originates from the technical function of the substance, which is to neutralize reactive oxygen or oxides in oil-based hydraulic fluids. This mode of action is shown in the figure in the read across document:  eg Fe(O)OH  -> Fe₂S₃

The target substance is considered unlikely undergo significant phosphate ester hydrolysis, especially at acidic conditions i.e. in the gastro-intestinal tract. QSAR calculations estimated Half-lives of 15 to 18 days at pH 5 and 2 to 4 days at pH 10. Thus, if at all, hydrolysis would rather occur under basic conditions and would be very slow.

Indeed, there is no indication that the target substance might undergo hydrolysis while passaging the organism, because possible corresponding alcohols are known to cause liver and kidney effects upon repeated gavage dosing and no such effects were observed upon subacute gavage dosing at the highest tested dose of 1000 mg/kg bw. Details are summarized in the OECD SIDS document for CAS 84852-15-3 and 25154-52-3, 12, 27-29 June 2001. In contrast to the read-across substance, the target substance is also considered to unlikely be a substrate of enzymatic cleavage by esterases, because enzymatic binding would be sterically hindered by the bulky branched alkyl side chains.

Further targets for metabolism could be a methyl group at the branched alkylated side chain. Oxidation of both a tert-butyl phenol and an isononyl phenol function has been published (Daniel et al, Biochem. J. (1968) 106, pp 783-790, Zalko et al, Drug Metabol. Disp. (1991)31, pp 168-176). Oxidative metabolism occurs most prominently in the liver which is consistent with the adaptive liver enlargement of the tert-butyl analogue. Absence of adaptive liver enlargement in the subacute gavage study with the target substance is again indicative of absence of absorption.

 

1.4 Elimination

The analogue substance is in the molecular weight range where elimination would occur predominantly via the kidney. The target substance is of larger molecular weight and – if absorbed – would be eliminated via the bile.

 

2. Summary

Based on the physicochemical properties, particularly water solubility, log Pow and high molecular weight, absorption via the gastrointestinal tract is highly unlikely for the test substance. The same applies for uptake of relevant amounts following dermal exposure. Based on its very low vapor pressure it is highly unlikely that the test substance will become systemically available after inhalation. It is highly unlikely that the substance undergoes abiotic transformation i.e. hydrolysis or is metabolized by esterase activity within the organism. If hypothetically absorbed, the target substance would bind to plasma protein, because of its low water solubility and be eliminated via bile based on its high molecular weight. Bioaccumulation is not to be expected.