Bis(2-ethylhexyl) hydrogen phosphate

Basic toxicokinetics

Administrative data

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: special investigation

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Induction of xenobiotic-metabolizing enzymes and peroxisome proliferation in rat liver caused by dietary exposure to di(2-ethylhexyl)phosphate

Author:

Lundgren B, DePierre JW

Year:

1987

Bibliographic source:

Xenobiotica 17, 585-593

Reference 2

Reference Type:

publication

Title:

JACC report no. 20 Tris-/bis-/mono-(2-ethylhexyl)phosphate

Author:

ECETOC

Year:

1992

Bibliographic source:

European Chemical Industry Ecology & Toxicology Centre, B-1160 Brussels, Belgium

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

Rats were exposed for 5 days to bis(2-ethylhexyl) hydrogen phosphate in diet and the induction of liver enzymes was evaluated.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Bis(2-ethylhexyl) hydrogen phosphate

EC Number:

206-056-4

EC Name:

Bis(2-ethylhexyl) hydrogen phosphate

Cas Number:

298-07-7

Molecular formula:

C16H35O4P

IUPAC Name:

bis(2-ethylhexyl) hydrogen phosphate

Details on test material:

Bis(2-ethylhexyl) hydrogen phosphate was obtained from Sigma Chemical Co., St Louis, MO, USA.

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: Bis(2-ethylhexyl) hydrogen phosphate was disolved in 20 ml acetone and mixed with 100 g powdered rat chow.

Duration and frequency of treatment / exposure:

5 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0.25%, 0.1%, or 3% w/w in diet (2.500, 10.000 or 30.000 ppm)

No. of animals per sex per dose / concentration:

3 animals

Control animals:

yes, concurrent vehicle

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

not examined

Details on distribution in tissues:

not examined

Details on excretion:

not examined

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The authors of the study postulated that the metabolite 2-ethylhexanol is responsible for the induction of xenobiotic-metabolising enzymes and/or the proliferation of peroxisomes and/or mitochondria.

Any other information on results incl. tables

Male Sprague-Dawley rats exposed to a diet of 0.25%, 1%, or 3% bis(2-ethylhexyl) hydrogen phosphate for 5 days had a twofold increase of liver cytosolic epoxide hydrolase activity together with an increase of microsomal cytochrome p-450 activity with the 1% and 3% diets. No increase was observed in cytochrome P-450 c, but cytochrome P-450 b and e were induced 20 to 35 fold.

Considerably smaller effects were observed on NADPH-cytochrome c reductase, microsomal expoxide hydrolase and microsomal cytochrome b5 and there was no effect on cytosolic glutathione transferase activity under the same conditions.

A 28 fold increase in cyanide-intensitive palmitolyl-CoA oxidation and a 4 fold increase of the total mitochondrial protein, with smaller increases in total catalase and cytochrome oxidase activities, were observed after treatment with bis(2-ethylhexyl) hydrogen phosphate.

Applicant's summary and conclusion

Executive summary:

Dietary exposure to bis(2-ethylhexyl) hydrogen phosphate results in a relatively large increases in the microsomal content of cytochrome P-450 and cytosolic epoxide hydrolase activity in rat liver. The authors of the study postulated that the metabolite 2-ethylhexan-1-ol (CAS No. 104-76-7) is responsible for the induction of xenobiotic-metabolising enzymes and/or the proliferation of peroxisomes and/or mitochondria.