Phosphoric acid, P,P'-[(1-methylethylidene)di-4,1-phenylene] P,P,P',P'-tetraphenyl ester

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Fyrolflex BDP is not expected to be absorbed by any of the three major exposure routes into the body.

Additional information

An actual toxicokinetics (TK) study was not performed on Fyrolflex BDP. The following

qualitative assessment of the toxicokinetic behaviour of Fyrolflex BDP is provided based upon relevant available information in the absence of a specific study (REACH Annex VIII, Section 8.8.1) undertaken according to EC Method, B.36 (or OECD Test Guideline 417).

 

(a)Physical chemical properties

The physical chemical characteristics of Fyrolflex BDP shown in Table 1 were utilised when assembling scientifically robust arguments to evaluate the potential uptake of the substance into the body, its lifecycle within the body and its ultimate loss i.e.Absorption,Distribution,Metabolism &Excretion.

 

Table1: Physical chemical properties of Fyrolflex BDP

Parameter	Value
Structure	An organic phosphorus based chemical with bulky side groups
Physical	Viscous liquid
Molecular weight	692 gr/mole
Water solubility	Low; 0.415 mg/L
Log P	4.5
Vapour pressure	1.2 x 10^-3Pa

 

(b)Absorption

The major routes of absorption are via:

·      the gastro-intestinal tract

·      the skin

·      the lungs

 

To be absorbed substances must have the ability to cross cell membranes, which may occur as a result of either passive diffusion, if the substance is both water and lipid soluble, or, by active mechanisms if these physical chemical properties are not present.

Fyrolflex BDP, has a Log P of 4.5 i.e. it is lipophilic and thus is more soluble in lipid than water. However, the Log P is > 4 which takes it outside of the most favourable criteria for absorption (range -1 to 3.5). A value of > 4 would hinder the ability of the substance to dissolve in gastric fluids and hence preclude contact with the mucosal cell surface. This fact coupled with a molecular weight which exceeds 500 (actual value 692) and low water solubility would militate against any significant absorption.Any potential concern with respect to possible micellular solubilisation of the Fyrolflex BDP by reaction with bile salts in the small intestine may be insignificant since there were no systemic toxic effects observed in relevant in vivo studies at extremely high dose levels (up to 1000mg/L in a 28-day repeat dose oral study).The above qualitative assessment of potential absorption via the gastro-intestinal route is borne out by the available toxicological data provided in two in vivo studies, described in Table 2.

 

Table 2: Fyrolflex BDP - Oral toxicity studies in the rat

Study	Information gained
Acute oral toxicity Limit test in the rat	Fyrolflex BDP was dosed in arachis oil at a dose level of 2000mg/Kg. No signs of systemic toxicity were observed despite the fact that the dosing vehicle used was liable to emulsification and then digestion in the gastro-intestinal tract. The use of this dosing vehicle giving rise to significantly increased potential for absorption of test material than if a mineral oil had been employed as the vehicle.
28-day repeat dose oral (gavage) study in the rat	Fyrolflex BDP was dosed in PEG 400 for 28 consecutive days at dose levels of 15, 150 and 1000mg/Kg. There were no clinical signs of toxicity, no adverse effects on bodyweight or food consumption, no treatment-related effects on haematology, blood chemistry, urinalysis or organ weights and no macroscopic or microscopic abnormalities detected. The NOEL was 1000mg/Kg

Insofar as the dermal route is concerned the available and relevant toxicological study data can be found in Table 3.

 

Table 3: Dermal toxicity data for Fyrolflex BDP

Study	Information gained
Acute dermal toxicity study	Fyrolflex BDP when dosed at 2000mg/Kg did not induce any signs of systemic toxicity.
Skin irritation study	Not a skin irritant
Eye irritation study	Not an eye irritant
Skin sensitisation study	Did not cause an allergic skin reaction

 

The available dermal toxicological data coupled with the high molecular weight of Fyrolflex BDP militate against any significant dermal absorption potential.

Inhalation of Fyrolflex BDP is not expected. The substance is a viscous liquid at room temperature and has a low vapour pressure. The Log P value is > 4 and this also does not favour absorption via passive diffusion directly across the respiratory tract epithelium.

The oral toxicity studies described in Table 2 indicate no systemic toxicity after repeated dosing at levels of up to 1000mg/Kg and this supports the premise that Fyrolflex BDP is unlikely to be absorbed if it was inhaled.

(c)   Distribution/ accumulation potential

 Fyrolflex BDP is a high molecular weight substance (> 500) and as such is generally considered to be unable to readily cross cell membranes and therefore will not be widely distributed in the body. In addition the substance has a low water solubility which limits its ability to diffuse through aqueous channels and pores. Although Fyrolflex BDP has a Log P value of > 0 this physical chemical value alone is a poor surrogate for prediction of its distribution into cells.

The available and relevant in vivo toxicological information (28-day repeat dose oral study at dose levels up to 1000mg/Kg) clearly indicates that no specific target organ or tissue toxicity was observed and there were no changes in haematology or blood chemistry or any signs of CNS effects. 

The repeated dosing of the test substance at 1000mg/Kg on 28 consecutive days without any overt signs of toxicity supports the hypothesis that Fyrolflex BDP is unlikely to be bioaccumulative. Although the Log P of Fyrolflex BDP is between 4 and 6 and there may be skin penetration into the stratum corneum there is adequate toxicological data to show that there is little, or no, systemic absorption. Fyrolflex BDP may persist in the stratum corneum until such time as it is cleared when this outer keratinised layer is sloughed off.

(d) Metabolism

Based upon the available and relevant in vivo toxicological study data and the lack of systemic toxicity seen following oral dosing at levels of 1000 and 2000mg/Kg Fyrolflex BDP and despite the predominance of the liver as the centre for metabolic activity following the oral exposure route it is likely that this substance is not significantly metabolised.

(e)  Excretion

The major routes of excretion of substances from the systemic circulation are via urine and/or faeces.Based upon the molecular weight (> 300) and low water solubility of Fyrolflex BDP it is unlikely that urine will be a major excretion route. Excretion in the faeces as a consequence of direct transfer from the gastro-intestinal tract is potentially the major route for excretion of mainly unchanged parent Fyrolflex BDP.

 

CONCLUSIONS

Based upon the Guidance provided in REACH document Chapter R.7.c; specifically R.7.12 Guidance on Toxicokinetics, Fyrolflex BDP is not expected to be significantly absorbed by any of the three major exposure routes into the body. The available and relevant physical chemical and toxicological data support the contention that Fyrolflex BDP is unlikely to be widely distributed in the body and may not undergo any significant metabolism before being excreted unchanged in the faeces.