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Description of key information

Trihexyl phosphate (CAS 2528-39-4) is expected to be enzymatically degraded within the gastrointestinal tract. The metabolites are predicted to be readily absorbed via the oral route. Potential for absorption via inhalation and dermal route is predicted to be low. The metabolites are expected to be utilized within physiologic energy metabolism pathways. The excretion of absorbed metabolites will be mainly as carbon dioxide in expired air. No bioaccumulation will take place.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Basic toxicokinetics

 

There are no studies available in which the toxicokinetic behaviour of trihexyl phosphate (CAS 2528-39-4) has been investigated.

 

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of trihexyl phosphate (CAS 2528-39-4) is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017).

Trihexyl phosphate (CAS 2528-39-4) is a liquid at 20°C with a molecular weight of 350.48 g/mol, a water solubility of 0.25 mg/L at 20°C, a vapour pressure of 0.00054 Pa at 20°C and a log Pow of 7.04.

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

Oral: Regarding oral/gastro-intestinal (GI) absorption, molecular weights below 500 are favourable for absorption, whereas molecular weights above 1000 do not favour absorption. Generally the smaller the molecule the more easily it may be taken up. Water-soluble substances will readily dissolve into the gastrointestinal fluids. Moderate log P values (between -1 and 4) are favourable for absorption by passive diffusion. Any lipophilic compound may be taken up by micellar solubilisation but this mechanism is of relevance for highly lipophilic compounds (log P >4), and particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed (ECHA, 2017).

 

The predicted water solubility of trihexyl phosphate is 0.25 mg/L at 20 °C, suggesting that the substance will not readily dissolve into the gastrointestinal fluids. Furthermore, the log Pow of 7.04 suggests that it is not favourable for the substance to be absorbed by passive diffusion. Also, the molecular weight of the substance suggests that it does not have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Absorption of the parental substance is expected to be limited; however metabolites are expected to be absorbed.

 

Inhalation: The vapour pressure indicates if a substance may be available for inhalation as a vapour. As a general guide, highly volatile substances are those with a vapour pressure greater than 25 kPa. Substances with low volatility have a vapour pressure of less than 0.5 kPa (or a boiling point above 150 °C) (ECHA, 2017).

The predicted vapour pressure of the liquid substance (0.00054 Pa at 20 °C) indicates that inhalation as a vapour is unlikely to occur. The predicted water solubility (0.25 mg/L) and log Pow (7.04) of the substance are not favourable for absorption from the respiratory tract epithelium by passive diffusion.

Dermal: To partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. Moreover, a log Pow between 1 and 4 and low molecular weights are favourable for dermal absorption (ECHA, 2017). If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). While there were no acute dermal toxicity studies for trihexyl phosphate (CAS 2528-39-4), in vitro skin irritation studies showed no irritation or corrosion.

The water solubility (0.25 mg/L) and log Pow (7.04) of the substance suggest that dermal absorption is likely to be low. QSAR based dermal permeability prediction (DERMWIN V2.00.2009) using molecular weight, log Pow and water solubility, calculated a dermal penetration rate of 0.0002 mg/cm²/h for trihexyl phosphate. This indicates that dermal penetration of the substance and its hydrolysis products will be medium/low (for further information regarding metabolism / hydrolysis see below).

 

Distribution

Distribution of a compound within the body depends on the rates of the absorption and the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

The molecular weight (350.48 g/mol) and low water solubility (0.25 mg/L at 20 °C), suggest the substance will not diffuse through aqueous channels and pores. Additionally, the high log Pow of 7.04 indicates that distribution into cells will be unlikely and therefore the extracellular concentration will be higher than the intracellular concentration. Metabolites of the parental substance are expected to be widely distributed in the body.

Metabolism

The potential metabolites following enzymatic metabolism of the substance were assessed using the QSAR OECD toolbox (OECD, 2018). The toolbox did not provide any data on observed metabolism of trihexyl phosphate. Thus, metabolites were predicted using metabolism simulators of the QSAR toolbox. Two metabolites were predicted for skin; both skin metabolites differed from the parent substance only by the addition of a hydroxyl (-OH) group to one of the three hexyl moieties. Fourteen metabolites were predicted for in vivo rat metabolism and also 14 metabolites for rat liver S9 metabolism. These included the hydroxylated trihexyl phosphate, hydroxylated hexyl phosphate, hexyl dihydrogen phosphate, dihexyl hydrogen phosphate, acetic acid, butyric acid, hexanoic acid, hexanal, and hexanol. Metabolites predicted for microbial metabolism were trihexyl phosphate, acetoacetic acid, acetic acid, β-hydroxybutyric acid, (2E)-2-butenoic acid, 3-oxohexanoic acid, butyric acid, 3-hydroxyhexanoic acid, (2E)-2-hexenoic acid, hexanoic acid, hexanal, hexanol, dihexyl hydrogen phosphate, hexyl dihydrogen phosphate.

Metabolites predicted to occur by hydrolysis or skin metabolism are not expected to be absorbed to a significant amount via the dermal route of absorption. Oral absorption of metabolites resulting from enzymatic activity in the gastrointestinal tract is expected. These metabolites are expected to be distributed within different compartments of the body. The predicted metabolites are expected to feed into endogenous metabolic pathways and to be utilized for energy metabolism. Fatty acids (like hexanoic acid) can be re-esterified into triacylglycerols and stored in adipose tissue. As energy need rises, they can be enzymatically degraded for energy primarily via β-oxidation. Therefore, no bioaccumulation potential is expected.

Excretion

Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine. In contrast, molecules that are excreted in the bile have a high molecular weight (ECHA, 2017). Based on the physico-chemical properties of trihexyl phosphate, absorption is not likely through any route of exposure. If absorbed, trihexyl phosphate is likely to be excreted via bile based on its molecular weight and poor water solubility (0.25 mg/L at 20 °C). Metabolites of the parental substance are expected to be utilized for energy metabolism; their excretion will mainly be as carbon dioxide in expired air.

 

References

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0, June 2017.

OECD (2018). (Q)SAR Toolbox v4.2 Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Calculation performed 25 Apr 2018. http://toolbox.oasis-lmc.org/?section=overview.