Triphenyl phosphate

Endpoint summary

Description of key information

Metabolism study of triphenyl phosphate (TPP) incubated with rat liver homogenate with and without NADPH and other enzyme systems showed that TPP is decomposed to diphenyl phosphate (DPHP, major metabolite) by mixed function oxidase system and arylesterase in microsomes. In a study on human liver microsomes TPP is metabolized into its diester metabolite DPHP and mono- and dihydroxylated metabolites by cytochromes P450 (CYP) in human liver microsomes, while CYP1A2 and CYP2E1 isoforms are mainly involved in such processes.

In human liver preparations other Phase-I metabolites of TPP were found, namely a mono hydroxylated metabolite (TPHP-M6), a di-hydroxylated metabolite (TPHP-M7, two isomers), and a metabolite resulting from hydroxylation and O-dealkylation of TPP (TPHP-M1). In primary human hepatocytes diphenyl phosphate corresponded to less than half of the depletion of TPP. Other metabolite structures were produced at 4- to 10-fold lower rates.

In FVB mice after intraveneous exposure to TPhP via vein-tail injection, this molecule could not be detected in blood (Limit Of Detection LOD TPhP = 0.7 ng/mL), or only after high doses and only in few of the treated animals. After quantification of DPhP in the same experiments, DPhP could not be detected in the blood of animals treated. Therefore, the large majority of injected or force-fed TPhP seemed not to have been metabolized into DPhP in the animals.

Additional information

In a study on the metabolism of triphenyl phosphate (TPP) was incubated with rat liver homogenate with and without NADPH and other enzyme systems (Sasaki et al, 1984). Gas chromatography identified diphenyl phosphate as the major metabolite following decomposition of TPP. Arylesterase in the microsomes contributes to TPP metabolism. The metabolic reactions were inhibited almost completely by SKF-525A and carbon monoxide in the absence of NADPH whereas KCN, NAN3, dipyridyl and EDTA showed little effect. Therefore, mixed function oxidase system in the microsomes play a central role in the metabolism of TPP. Authors concluded TPP is degraded by hydrolysis in rat liver homogenate to diphenyl phosphate as the major metabolite.

In a study on human liver microsomes TPP is metabolized into its diester metabolite DPHP and mono- and dihydroxylated metabolites by cytochromes P450 (CYP) in human liver microsomes, while CYP1A2 and CYP2E1 isoforms are mainly involved in such processes (Zhang et al., 2018).

In human liver preparations other Phase-I metabolites of TPP were found, namely a mono hydroxylated metabolite (TPHP-M6), a di-hydroxylated metabolite (TPHP-M7, two isomers), and a metabolite resulting from hydroxylation and O-dealkylation of TPP (TPHP-M1). In primary human hepatocytes diphenyl phosphate corresponded to less than half of the depletion of TPP. Other metabolite structures were produced at 4- to 10-fold lower rates. (Van den Eede et al., 2015)

 

Para (p) and meta (m)- OH-TPHP glucuronides were detected in the urine of 4 human volunteers from Ottawa (Su et al., 2016).

 

Frederiksen M et al. (2018) investigated dermal uptake and percutaneous penetration of organophosphate esters (OPEs) in a human skin ex vivo model (Franz diffusion cell system). Large variation in penetration profiles was observed between the OPEs. Triphenyl phosphate (TPHP) tended to build up in the skin tissue and only smaller amounts permeated through the skin. The rates at which OPEs permeated through the skin decreased in the order TCEP > TCIPP _ TBOEP > TIBP _ TNBP > TDCIPP > TPHP > TMPP. Generally, the permeation coefficient, kp, decreased with increasing log Kow, whereas lag time and skin deposition increased with log Kow.

In FVB mice exposed to a single 0.1 or 1 µg concentrations of TPhP via vein-tail injection, this molecule could not be detected in blood (Limit Of Detection LOD TPhP = 0.7 ng/mL). After administration of 10 µg or 100 µg TPhP, TPhP was only quantified above the LOD in the blood of two animals at 2.33 ng/mL and 10.20 ng/mL, exposed to 100 µg following intravenous injection and oral gavage, respectively. In all other animals (18 out of 20 animals), TPhP remained undetected. To determine whether TPhP transformation into DPhP was the reason for the lack of detection of TPhP in the blood stream, DPhP was quantified in the same experiments. DPhP could not be detected in the blood of animals treated with 0.1 or 1 µg of TPhP (LOD DPhP = 0.3 ng/mL, LOQ DPhP = 0.5 ng/mL). At the highest doses of TPhP (10 and 100 µg), DPhP was detected in the blood of animals, but in a level comparable to that obtained after exposure to DPhP a hundred times lower. Therefore, the large majority of injected or force-fed TPhP seemed not to have been metabolized into DPhP in the animals.