Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
Nov - Dec 2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well performed non guideline study with sufficient reporting and scientitifc sound test design.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Objective of study:
excretion
metabolism
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
one dose group
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 12 weeks
- Weight at study initiation: 250-300 g
- Fasting period before study: no data
- Individual metabolism cages: yes (transparent Macrolan)
- Diet (e.g. ad libitum): Altromin, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 5 days


IN-LIFE DATES: From: 24.11. To: 01.12.2000

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Phosphoric acid, 2-ethylhexyl ester was administered to rats by stomach tube at a dose of 200 mg/kg bw .
Total volume: 1 mL
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
200 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Positive control:
none
Details on study design:
After application urine and feces was collected every 12 h for a total of 72 h.
Details on dosing and sampling:
Samples were analysed via P31-NMR spectroscopy.Sodium hydroxide was added to 700 µL urine sample to reach a pH of 9. Thereafter, the samples were mixed with 200 µL D2O and measured.
Statistics:
none

Results and discussion

Preliminary studies:
No data
Main ADME resultsopen allclose all
Type:
metabolism
Results:
complete hydrolysis of the phosphoric acid, 2-ethylhexyl ester
Type:
excretion
Results:
via urine within 24 h

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Only Phosphate peak was found in the urine samples. Therefore, it was concluded, that Phosphoric acid, 2-ethylhexyl ester is quantitatively hydrolysed to Phosphate and the alcoholic compound, 2-Ethylhexanol.

Bioaccessibility

Bioaccessibility testing results:
Since a quantitative hydrolsis takes place good bioaccessibility can be assumed.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
From this study it appears that Phosphoric acid, 2-ethylhexyl ester is efficiently absorbed, metabolised and excreted quantitatively by the body. Hydrolysis of the ester linkage provides an adequate degradation mechanism. There was no sign of accumulation.
Executive summary:

Phosphoric acid, 2 -ethylhexyl ester (the test item used in this metabolism/excretion study) and the Phosphoric acid ester components of the reaction mass of Methyl dihydrogen phosphate and Orthophosphoric acid and Dimethyl hydrogen phosphate (the substance to be registered) are member of the Phosphoric acid, alcyl ester family.The characteristic and functional active center of both substances is the ester binding between the alcoholic compound and Phosphate. With reference to the occurrence of endogenous esterases which take part in the mammalian phase I metabolism it can be assumed that both Phosphoric acid esters are hydrolysed independent from the constitution of the alcoholic part. Since the ester binding is the specific target of endogenous esterases it is justified to perform a read across between the both ester type substances Phosphoric acid, 2 -ethylhexyl ester and Phosphoric acid ester components of the reaction mass of Methyl dihydrogen phosphate and orthophosphoric acid and Dimethyl hydrogen phosphate in order to estimate its potential metabolism.

5 male and 5 female rats received 200 mg/kg bw Phosphoric acid, 2 -ethylhexyl ester via gavage. Urine and feces were collected in 12 h intervals for 72 h. The samples were analysed by NMR spectroscopy.

Besides the Phosphate peak no other peaks were detected indicating a complete hydrolysis of the Phosphoric acid ester into Phosphate and 2 -Ethylhexanol.