Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An extended assessment of the toxicokinetic behaviour of the UVCB substance was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicity data.

Data source

Referenceopen allclose all

Reference Type:
other: Expert Statement
Title:
Unnamed
Year:
2013
Report date:
2013
Reference Type:
other: Prediction by the OECD QSAR Toolbox
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
according to guideline
Guideline:
other: TGD, Part I, Annex IV, 2003); ECHA guidance R7c., 2008
Deviations:
no
Principles of method if other than guideline:
An assessment of toxicological behaviour of the UVCB target substance is based on its physico-chemical properties and on the results of available toxicity data data.
GLP compliance:
no

Test material

Radiolabelling:
no

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Oral absorption is significant due the average MW of 400 g/mol and logPow range favourable for absorption via GI tract. Dermal absorption is moderate and low absorption potential via inhalation is due to the low vapour pressure (0.0004 Pa at 25 °C).
Type:
distribution
Results:
Distribution of products of dissociation and/or hydrolysis products absorbed from the gastrointestinal tract is expected to be extensive throughout the body. However, no wide distribution is expected in case of dermal or inhalation exposure.
Type:
excretion
Results:
The metabolism products (C8 alcohols and their corresponding carboxylic acids, hydroxylated and/or oxidised derivatives of 2-ethylhexyl amine) are sufficiently soluble in water; they can be filtered by the kidneys and undergo primarily urinary excretion.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In case of oral exposure, the substance will dissociate releasing mono-, and di-alkyl phosphates and 2-ethylhexylamine, which are expected be readily absorbed in the gastrointestinal tract.
Details on distribution in tissues:
In case of exposure by oral route, the distribution of dissociation products mono-, and di-alkylphosphates (subsequently hydrolysed to C8 alcohols and phosphoric acid) and 2-ethylhexyl amine will be wide and extensive throughout the body.
Details on excretion:
All predicted metabolites (C7-9, C8 rich iso and linear aliphatic alcohols and alkylamines) are polar and are expected to be excreted via the urine.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Metabolism of the target substance applies in case of oral and partly in case of dermal route of exposure. The substance is expected to dissociate under acidic conditions. The dissociation products will be mono-, and dialkyl phosphates and 2-ethylhexyl amine. Further expected metabolites are phosphoric acid, C7-9,C8 rich, iso and linear aliphatic alcohols and their corresponding carboxylic acids as well as hydroxylated derivatives of 2-ethylhexylamine and its aldehydes and/or carboxylic acids.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The substance will be limted absorbed following inhalation exposure due to its low vapour pressure (0.0004 Pa at 25 °C). In case of oral and dermal exposure the substance will dissociate under acidic conditions (pH of the skin is acidic) releasing mono-, and di-alkyl phosphates and 2-ethylhexylamine, which are expected be readily absorbed, wide distributed and extensively metabolised in the body. Excretion will be primarily via the urine.
Executive summary:

The toxicokinetics of the substance (Reaction products of diphosphorus pentaoxide and alcohol C7-9-iso, C8 rich, salted with 2-ethylhexylamine) was assessed based on its physical chemical properties and toxicity data, QSAR modelling, and published data on structurally similar substances. Because the substance is a salt which dissociates and subsequently its alkyl phosphate moieties undergo hydrolysis under acid conditions in the gut and even the skin (pH 4 to 7), the toxicokinetics of the alkylamine and alkylphosphate hydrolysis products as well as the parent amine-salted alkylated phosphate were assessed.

The substance is expected to be readily absorbed via oral and inhalation (mists) routes of exposure. Because the substance is a liquid with a low vapour pressure (0.0004 Pa at 25 °C), inhalation of vapours is not expected. Dermal absorption is expected to be limited because it has a molecular weight > 100 and <500 g/mol and because the logPow values for the analytes are below or above the optimal logPow value range (between 2 and 3) for dermal absorption. 

The results of the reproductive/developmental toxicity study in rats shows that it is distributed to the kidneys. The substance of relatively small molecular size (MW < 500) and lipophilicity also indicates that it is likely to be distributed to other tissues, but it does not allow predictions of specific targets or concentrations.

In contrast, once dissociated both alkylamine and alkyl phosphate species are expected to be subject to first pass metabolism. Alkyl phosphates will undergo hydrolysis to phosphoric acid and C8 alcohols which are expected to be further metabolised to their corresponding carboxylic acids and excreted predominantly via the urine. The other dissociation product 2-ethylhexylamine will not undergo hydrolysis due to the absence of hydrolysable groups. In analogy to other primary alkyl amines, it is expected to be readily absorbed and metabolised by oxidative deamination or N-oxidation. The expected metabolites are hydroxylated derivatives, aldehydes and carboxylic acids. All the metabolites are supposed to be excreted mainly via the urine.

Based on the logPow values of <4.5 (0.84, 0.28, and 4.28, respectively) for the amine, monoalkyl phosphate, and dialkyl phosphate analytes of the substance and evidence that alkylamines and alkyl phoshphates/C8 alcohols are readily metabolised and eliminated, the substance is not expected to bioaccumulate.