Reaction mass of 3-[(diphenoxyphosphoryl)oxy]phenyl triphenyl 1,3-phenylene bis(phosphate) and tetraphenyl 1,3-phenylene bis(phosphate)

Endpoint summary

Additional information

Studies on kinetics in the dossier

An in vivo toxicokinetic study (Klimisch 2; no guideline study) with¹⁴C-labeled resorcinol bis-diphenyl phosphate (RDP) has been performed in several species and via various routes: rat (IV, inhalation, dermal, oral), mouse (Intravenous), and monkey (IV, dermal). (McCormick, 1997). The level of radioactivity was measured in plasma, faeces, urine, expired air, and in several tissues.

 

Systemic delivery of RDP was highest when the compound was administered intravenously, followed by the inhalation, oral, and dermal route (in order). The absorption rates are based on the AUC compared with IV.

The rat study shows an inhalatory absorption of ca 60%. As the estimated retention in the lungs is 25% (of applied dose), this should be considered as a worst case value.

The oral absorption in the rat was ca 58% (based on the AUC compared with IV) (McCormick, 1997).

After dermal exposure in the rat the dermal absorption was estimated to be 15% (based on the AUC compared with IV) (McCormick, 1997). Thjs is in line with the dermal absorption which was reported in an earlier study, in which an absorption of 17% was observed in rats (Little, 1994). The Monkey study reported a lower or no dermal absorption (<9%) (McCormick, 1997). However this is disputable because of a low recovery (67%), probably due to the study design. Therefore, the value found in rats will be used for risk assessment.

 

Distribution of RDP was studied after intravenous injection in the rat (IV dose of 100mg/kg). RDP was mainly distributed to the lungs (ca 5-10%). Tissues other than lungs demonstrated comparable levels of radioactivity, with liver and fat showing slightly more radioactivity than other tissues and carcass, and the brain showing less radioactivity.

All IV studies (mouse, rat, monkey) show that the primary route of elimination is the faeces (ca 50%) and secondary the urine. A minimum is excreted via expired air. In the rat after IV-, oral- and inhalatory exposure a half-life of ca 2,5 days was reported. After dermal exposure half-life was slightly higher (3,7 days).

 

Physicochemical properties

The available physicochemical properties can provide useful information regarding the behaviour of RDP in the body (based on the REACH Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c Endpoint Specific Guidance).

The molecular weight of RDP is indicative for readily absorption after oral administration. This might occur by micellular solubilisation, due to the moderate till high log Kow and despite of the poor water solubility. This is in line with the observed oral absorption in rats.

Although respiratory exposure is unlikely to occur on a large scale due to the low vapour pressure of RDP, some respiratory exposure and absorption (aerosols, comparable to oral absorption) may be expected, which is in line with the observed respiratory absorption in rats.

The physical state of RDP (liquid), the low vapour pressure and to a lesser extent the molecular weight indicates that dermal absorption is possible. The poor water solubility and rather high log Kow are an indication for a high uptake into the stratum corneum, but a limited rate of penetration from the stratum to the epidermis. This is confirmed by the available dermal absorption studies in rats.

 

Conclusions

Based on an extensive toxicokinetics study, RDP is expected to be absorbed after oral and inhalatory exposure (58 and 60%, respectively). Dermal absorption is limited (17%). Studies indicate that RDP is slowly metabolized. The main excretion route is the faeces (ca 50%) and the urine.