Registration Dossier

Administrative data

Link to relevant study record(s)

Referenceopen allclose all

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Nov - Dec 2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
excretion
metabolism
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
one dose group
GLP compliance:
not specified
Specific details on test material used for the study:
Phosphoricacidethylhexylester; Reaction mass of bis(2-ethylhexyl) hydrogen phosphate and 2- ethylhexyl dihydrogen phosphate and este... / 12645-31-7 / 235-741-0
Radiolabelling:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system 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
daysIN-LIFE DATES: From: 24.11. To: 01.12.2000
Route of administration:
oral: gavage
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
Single dose
Dose / conc.:
200 mg/kg bw/day (nominal)
No. of animals per sex per dose / concentration:
5
Control animals:
no
Positive control reference chemical:
no
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 s
ample to reach a pH of 9. Thereafter, the samples were mixed with 200 μL D2O and measured.
Preliminary studies:
no data
Type:
metabolism
Results:
complete hydrolysis of the phosphoric acid, 2-ethylhexyl ester
Type:
excretion
Results:
via urine within 24 h
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 (or Bioavailability) testing results:
Since a quantitative hydrolsis takes place good bioaccessibility can be assumed.
Conclusions:
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:

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..

Endpoint:
basic toxicokinetics, other
Type of information:
other: In accordance with REACH Annex VIII (8.8.1) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Relevant studies were reviewed by a qualified toxicologist with a view to fulfilling the requ irements of Annex VIII (8.8.1).
Objective of study:
toxicokinetics
Qualifier:
no guideline required
Principles of method if other than guideline:
In accordance with REACH Annex VIII (8.8.1) an assessment of toxicokinetic behaviour has been
conducted to the extent that can be derived from the relevant available information. The assessment
is based on the Guidance on information requirements and chemical safety assessment R.7c: Endpo
int specific guidance (ECHA, May 2008)
GLP compliance:
no
Specific details on test material used for the study:

REACTION MASS OF BIS(2-ETHYLHEXYL) HYDROGEN PHOSPHATE AND 2-ETHYLHEXYL DIHYDROGEN PHOSPHATE

TOXICOKINETIC BEHAVIOUR

The substance is composed, as listed in the Section 1.2 of IUCLID. It is an amber coloured liquid and the molecular weight is 210.21 – 322.42 g/mol. The low vapour pressure value (8.5 x 10-2Pa at 25°C) and predicted negative explosive and oxidising properties shows that the substance is non volatile therefore inhalation is not a significant route of exposure. The substance is considered as flammable.

The substance has a low log octanol/water partition coefficient value (Log10 Pow <0.3- 2.18) and low water solubility (5.95 x 10-3– 13.2 g/l at 20°C).

The available acute dermal irritation/corrosion (OECD 404) and repeated dose reproductive screening studies showed evidence of absorption however the repeated dose reproductive screening study did not show evidence of metabolism or excretion.

The test item was non-mutagenic in bacteria , non-clastogenic in mammalian cells in vitro and non-mutagenic in mammalian (CHO) cells in vitro in either the absence or presence of an auxiliary metabolising system.

Absorption

Although the test item is lipophobic in nature the small molecular size of the substance should allow absorption through passive diffusion. This would suggest that the gastrointestinal tract provides a route of absorption, following oral administration, before entering the circulatory system via the blood.

Limited absorption may also take place via the skin due to small molecular size. The substance is corrosive therefore damage to the skin surface may allow for increased penetration of the substance through the skin.

The low vapour pressure value (8.5 x 10-2Pa at 25°C) shows that the substance is not available as a vapour therefore inhalation is not a significant route of exposure.

Distribution

Once absorbed, the substance may be distributed in plasma due to the water solubility and may therefore be distributed systemically. The lipophobic nature of the test item suggests that bioaccumulation in body fat is unlikely.

Metabolism

The results of the repeated dose/reproductive screening study did not show evidence to indicate any test item influenced hepatic metabolism. The results of the genotoxicity assays have shown that genotoxicity is neither enhanced or diminished in the presence

of the S9 metabolising system.

Excretion

There is no evidence to indicate the route of excretion but water-soluble products are not favourable for biliary excretion and therefore urinary excretion may well be a significant route for this material. Any test item that is not absorbed will be excreted in the faeces.

Conclusions:
The available information suggests that absorption of the test substance from the gastrointestinal tract can take place. Some absorption may also take place via the skin. Once absorbed, the substance would be distributed in the serum and urine is the significant route of excretion. There is no evidence to suggest that the test substance may be metabolised, however no studies have been conducted to identify metabolites.
Executive summary:

The available information suggests that the substance is readily available via the oral route; however, absorption via the skin is also possible. This is supported by the physicochemical properties of the substance. Once absorbed, the substance would result in distribution in the serum. There is no evidence to indicate the route of excretion..

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reason / purpose for cross-reference:
read-across source
Type:
metabolism
Results:
complete hydrolysis of the phosphoric acid, 2-ethylhexyl ester
Type:
excretion
Results:
via urine within 24 h
Endpoint:
basic toxicokinetics, other
Type of information:
other: In accordance with REACH Annex VIII (8.8.1) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.
Adequacy of study:
key study
Reason / purpose for cross-reference:
read-across source

TOXICOKINETIC BEHAVIOUR

The substance is composed, as listed in the Section 1.2 of IUCLID. It is an amber coloured liquid and the

molecular weight is 210.21 – 322.42 g/mol. The low vapour pressure value (8.5 x 10-2 Pa at 25°C) and

predicted negative explosive and oxidising properties shows that the substance is non volatile therefore

inhalation is not a significant route of exposure. The substance is considered as flammable.

The substance has a low log octanol/water partition coefficient value (Log10 Pow <0.3- 2.18) and low

water solubility (5.95 x 10-3 – 13.2 g/l at 20°C).

The available acute dermal irritation/corrosion (OECD 404) and repeated dose reproductive screening

studies showed evidence of absorption however the repeated dose reproductive screening study did

not show evidence of metabolism or excretion.

The test item was non-mutagenic in bacteria , non-clastogenic in mammalian cells in vitro and nonmutagenic

in mammalian (CHO) cells in vitro in either the absence or presence of an auxiliary

metabolising system.

Absorption

Although the test item is lipophobic in nature the small molecular size of the substance should allow

absorption through passive diffusion. This would suggest that the gastrointestinal tract provides a route

of absorption, following oral administration, before entering the circulatory system via the blood.

Limited absorption may also take place via the skin due to small molecular size. The substance is

corrosive therefore damage to the skin surface may allow for increased penetration of the substance

through the skin.

Basic toxicokinetics.Assessment of toxicokinetic behaviour

The low vapour pressure value (8.5 x 10-2 Pa at 25°C) shows that the substance is not available as a

vapour therefore inhalation is not a significant route of exposure.

Distribution

Once absorbed, the substance may be distributed in plasma due to the water solubility and may therefore

be distributed systemically. The lipophobic nature of the test item suggests that bioaccumulation in body

fat is unlikely.

Metabolism

The results of the repeated dose/reproductive screening study did not show evidence to indicate any test

item influenced hepatic metabolism. The results of the genotoxicity assays have shown that genotoxicity

is neither enhanced or diminished in the presence

of the S9 metabolising system.

Excretion

There is no evidence to indicate the route of excretion but water-soluble products are not favourable for

biliary excretion and therefore urinary excretion may well be a significant route for this material. Any test

item that is not absorbed will be excreted in the faeces.

Description of key information

The available information suggests that the substance is readily available via the oral route; however

absorption via the skin is also possible. This is supported by the physicochemical properties of the

substance. Once absorbed, the substance would result in distribution in the serum.There is no evidence

to indicate the route of excretion.

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.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
90

Additional information

Based on the results from the toxicokinetic studies, the orally dosed toxicity studies, the small molecular size of the test substance and it's physico-chemical characteristics, it can be assumed that the test substance would be readily absorbed through the gastrointestinal tract. It is likely that the majority of the test substance would be absorbed via the oral route and therefore it may be assumed that in the region of 90% oral absorption would likely occur.