2-(1-(2-hydroxy-3,5-di-tert-pentyl-phenyl)ethyl)-4,6-di-tert-pentylphenyl acrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Toxicokinetic assessment

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable expert judgement meeting basic scientific principles.

Data source

Reference

Reference Type:

other: Expert judgement

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Objective of study:

absorption

Principles of method if other than guideline:

Expert judgement and calculation of the absorption of Sumilizer GS based on physico-chemical properties.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-(1-(2-hydroxy-3,5-di-tert-pentyl-phenyl)ethyl)-4,6-di-tert-pentylphenyl acrylate

EC Number:

413-850-6

EC Name:

2-(1-(2-hydroxy-3,5-di-tert-pentyl-phenyl)ethyl)-4,6-di-tert-pentylphenyl acrylate

Cas Number:

123968-25-2

Molecular formula:

C37H56O3

IUPAC Name:

2-{1-[2-hydroxy-3,5-bis(2-methylbutan-2-yl)phenyl]ethyl}-4,6-bis(2-methylbutan-2-yl)phenyl prop-2-enoate

Constituent 2

Reference substance name:

2-(1-(2-hydroxy-3,5-di-tert-pentylphenyl)ethyl)-4,6-di-tert- pentylphenylacrylate

IUPAC Name:

2-(1-(2-hydroxy-3,5-di-tert-pentylphenyl)ethyl)-4,6-di-tert- pentylphenylacrylate

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral absorption was set at 1 %.
Inhalation absorption was considered negligible.
Dermal absorption of 1 % (equivalent to oral absorption) was considered to be more appropriate, although 10% was derived from physical/chemical properties according to TGD.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Sumilizer GS is a solid with a very low water solubility (< 5x10^-6g/L). Since in general a substance needs to be dissolved before it can be taken up from the gastro-intestinal tract (1), it is unlikely that Sumilizer GS will show a high exposure after oral administration. The absorption will furthermore be lowered by the relatively large molecular size (molecular weight of 548 g/mol, estimated Dmax_average(average maximum diameter) of 1.5 to 2.5 nm) of this substance limiting the passage through biological membranes. In addition, Sumilizer GS is a lipophilic substance (log P_OW> 6.2, and calculated as > 10) and in general, highly lipophilic substances (log P_OW> 4) are not easily absorbed via passive diffusion. Uptake via micellular solubilisation might be restricted due to its relatively large particle size (only 0.3 % < 106 μm). Overall, it is expected that Sumilizer GS will be absorbed to a limited extent in the gastrointestinal tract. For risk assessment purposed the oral absorption of Sumilizer GS is set at 1 %. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption.

After absorption of Sumilizer GS from the gastrointestinal tract, metabolism may occur in the liver (3).

The relatively low vapour pressure / high boiling point indicate that the substance is not available for inhalation as a vapour. The particle size (0.3% < 106 μm) indicates that there are no inhalable/respirable particles present. Based on these properties, no respiratory exposure and hence no inhalation absorption is to be expected. If however during use of the product particles between 100 and 10 μm are generated, these will deposit in the nasopharyngeal region and subsequently be coughed or sneezed out of the body or swallowed. Particles below 10 μm might reach the tracheobronchial or pulmonary regions. Based on its low water solubility (<5x10^-6g/L) Sumilizer GS will not dissolve into the mucus lining the respiratory tract. Following its lipophilic character (log P_OW> 6.2) Sumilizer GS has the potential to be absorbed directly across the respiratory tract epithelium, however, the absorption will be lowered for the same reason explained in the above paragraph. It is thus concluded that for risk assessment purposes, the potential for inhalation absorption of Sumilizer GS might be considered negligible.

Sumilizer GS being a solid with a relative high molecular weight has no real potential for dermal absorption. Furthermore, its low water solubility and lipophilic character do not facilitate dermal absorption. As the criteria for 10 % dermal absorption as given in the TGD (2) (MW > 500 and log P_OW>4) are met, 10 % dermal absorption is proposed for risk assessment purposes. It is, however, generally accepted that dermal absorption is lower compared to oral absorption. The 10 % dermal absorption derive from physical/chemical properties of the substance should therefore be considered as an extreme worst case assumption and for risk assessment purposes a lower dermal absorption of e.g. 1 % might be considered more appropriate. Based on the present available data, no additional conclusion can be drawn on the distribution, metabolism and excretion of Sumilizer GS after dermal absorption.

 

References

1., Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002 Jun;42:620-43.

2. ECB EU Technical Guidance Document on Risk Assessment, 2003

3. A. Parkinson. In: Casarett and Doull's Toxicology. The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics.,, 2001.