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Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No OECD guideline or GLP defined.

Objective of study:

toxicokinetics

Principles of method if other than guideline:

effects of i.p. injection on toxicokinetics in rats

GLP compliance:

not specified

Radiolabelling:

not specified

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

intraperitoneal

Vehicle:

olive oil

Duration and frequency of treatment / exposure:

single injection i.p.

Remarks:

Doses / Concentrations:
75, 150 or 300 mg/kg

No. of animals per sex per dose / concentration:

5

Control animals:

not specified

Preliminary studies:

no data

Details on absorption:

no data

Details on distribution in tissues:

4 hours after the intraperitoneal injection of 300 mg test substance the Diphenyl-cresyl-phosphate level in blood was 0.3 +/- 0.2 µg/g. After 24 hours the level was below the detection limit (0.2 µg/g). In the liver the concentrations after 4 hours were 45.8 +/- 28.1 µg/g tissue and after 24 h 1.7 +/- 2.5 µg/g.

Details on excretion:

no data

Toxicokinetic parameters:

other: 4 h after the i.p. injection of 300 mg test subst. the DPK level in blood was 0.3 +/- 0.2 µg/g. After 24 h the level was below the detection limit (0.2 µg/g). In liver the conc. after 4 hours were 45.8 +/- 28.1 µg/g tissue and after 24 h 1.7 +/- 2.5 µg/g.

Metabolites identified:

not specified

Concentrations of Triarylphosphates in rat liver and blood 4 and 24 h after intraperitoneal injektion (300 mg/kg) of commercial cresyl diphenyl phosphate:

The concentrations are in µg/g wet tissue (mean of 5 animals +/- S.D.). The detection limit is 0.2 µg/g).

Time after treatment	TPP	CDPP	DCPP	TCP
Liver
4h	36.6 +/- 23.3	45.8 +/- 28.1	24.0 +/- 15.8	3.5 +/-2.8
24 h	1.8 +/- 1.9	1.7 +/- 2.5	1.4 +/- 1.1	< 0.2
Blood
4h	0.7 +/- 0.3	0.3 +/- 0.2	< 0.2	< 0.2
No detectable amounts were found in blood 24 h after injection.

TCP- tricresyl phosphates.

TPP-triphenyl phosphate

CDPP- cresyl diphenyl phosphates DCPP- dicresyl phenyl phosphates TCP- tricresyl phosphates.

Executive summary:

In a toxicokinetic study male Wistar rats (250 -300g) were injected intraperitoneally with 75, 150 or 300 mg/kg of a commercial triaryl phosphate preparation (Disflamoll DPK/25E, Bayer AG, F.R.G.) which was analysed to contain approximately 35% of triphenyl phosphate, 45% of cresyl diphenyl phosphates, 18% of dicresyl phenyl phosphates and 2% of tricresyl phosphates, in olive oil. The animals were decapitated 4h, 24 h, 1 week or 2 weeks after the injections and their brain, blood, liver, kidneys, glutea muscle and tail nerve samples were taken at autopsy.

4 hours after the intraperitoneal injection of 300 mg test substance the Diphenyl-cresyl-phosphate level in blood was 0.3 +/- 0.2 µg/g. After 24 hours the level was below the detection limit (0.2 µg/g). In the liver the concentrations after 4 hours were 45.8 +/- 28.1 µg/g tissue and after 24 h 1.7 +/- 2.5 µg/g.

Description of key information

Taking into account predicted and experimental data it is assumed that diphenyl cresyl phosphate is moderately absorbed and subsequently distributed in the body (see Justification Document for the Category of CDP (Diphenyl cresyl phosphate), TPP (Triphenyl phosphate) and TCP (Tricresyl phosphate).

For diphenyl cresyl phosphate no valid metabolism studies are available. However, it is assumed that, based on the known biotransformation of substances such as tri-ortho-cresyl phosphate, the ortho-isomer can undergo cyclisation to neurotoxic phenyl saligenin phosphate, whereas this type of metabolism could not occur with the meta- and para-isomers due to steric hindrance involving the alkyl group.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

In order to evaluate the test substance several Reviews were taken into account. The most recent were MAK 2003 and BG Chemie 2000 (see also chapter 7.12 Additional toxicological information / Reviews).

MAK is the national-OEL (occupational exposure limit) commission in Germany, staffed with experts and the BG Chemie is the German accident prevention and insurance association for the chemical industry.

In the review of the BG Chemie it is discussed that the technical test substance containing 45% diphenyl cresyl phosphate-in olive oil at 300 mg/kg bw was administered to 5 rats intraperitoneally in a single dose exposure. Four hours after this administration of the test substance, blood levels of 0.3 + 0.2 µg/g were observed. The levels had fallen below the limit of detection (0.2µg/g) after 24 hours (Vainiotalo et al., 1987). Following concentration levels were found in the liver: after 4 hours: 45.8 + 28.1 µg/g tissue and 1.7 + 2.5 µg/g tissue after 24 hours. On the metabolism of the test substance no studies are available. Nevertheless the diphenyl o-cresyl phosphate isomer can undergo cyclisation to neurotoxic phenyl saligenin phosphate. It has to be mentioned that this type of metabolisation can not take place with the diphenyl m-cresyl and diphenyl p-cresyl phosphate isomers. In these isomers the position of the alkyl group provokes steric hindrance.

The above mentioned metabolisation can be derived from toxicological studies on the neurotoxicity of organophosphates. Additionally the metabolisation was deduced from the biotransformation of tri-o cresyl phosphate. Tri-o cresyl phosphate can be metabolized by rats to cresyl saligenin phosphate (Eto et al., 1962; BG Chemie, 2000; MAK, 2003).