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Toxicological information

Basic toxicokinetics

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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

Referenceopen allclose all

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 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

Constituent 1
Chemical structure
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.