A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Literature review as directed in the Guidance on Information Requirements and the Chemical Safety Assessment, European Chemical Agency, May 2008.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Literature review as directed in the "Guidance on Information Requirements and the Chemical Safety Assessment", European Chemical Agency, May 2008.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate

EC Number:

415-430-8

EC Name:

A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate

Cas Number:

86403-32-9

Molecular formula:

C25H49NO2 and C27H53NO2

IUPAC Name:

Reaction mass of 2,2,6,6-tetramethylpiperidin-4-yl hexadecanoate and 2,2,6,6-tetramethylpiperidin-4-yl octadecanoate

Radiolabelling:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

This substance is likely digested to individual fatty acid esters which are readily absorbed in the digestive tract, whereas low water solubility and polymeric structure result in lower absorption of parent compound.

Main ADME results 2

Type:

distribution

Results:

Fatty acid esters are likely distributed in the body fat and in breast milk.

Main ADME results 3

Type:

metabolism

Results:

This substance is likely digested to individual fatty acid esters, which will undergo acylation, desaturation and β-oxidation.

Main ADME results 4

Type:

excretion

Results:

Fecal excretion is likely a major route of elimination of the unabsorbed and unchanged material, as well as the likely pathway of elimination of any fatty acid esters.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

EC 415-430-8 has low water solubility, relatively high log octanol water partition coefficient and high molecular weight polymeric structure which suggest somewhat lower potential for absorption across the skin and gastrointestinal tract. The low vapor pressure exerted is an indication of low potential exposure by the inhalation route as well. EC 415-430-8 is not acutely toxic by the oral route (LD50 values of >15,000 and >10,000 mg/kg in the rat and mouse, respectively), the dermal route (LD50 in rats >5000 mg/kg) or by inhalation (LC50 in rat is > 5mg/m3). The lack of systemic toxicity in 28-day repeat dose toxicity studies in rats by both the oral and dermal routes is a further indication of a lack of absorption and/or toxicity through the gastrointestinal tract and skin (NICNAS, 2001).
The products of digestion and metabolism of EC 415-430-8 are not known however it is known that esters of stearic and palmitic fatty acids are the two primary components by weight. Stearic and palmitic acid esters are long chain fatty acid esters that occur naturally in animal fats and oils and in some vegetable oils and are also essential components of the average human diet (Emken, 1994). Both stearic acid and palmitic acid are readily absorbed in the gastrointestinal tract (Emken, 1994). Neither are considered toxic and both are listed by the FDA as generally recognized as safe (GRAS). Longer chain fatty acids are less readily absorbed in the gastrointestinal tract than shorter chain fatty acids (HSDB, 2008)

Details on distribution in tissues:

No evidence of systemic target organ toxicity was seen in repeat dose studies in the rat given EC 415-430-8 by either the oral or dermal route (NICNAS, 2001). The low water solubility and relatively high estimated partitioning into octanol of EC 415-430-8 indicates that it may accumulate in body fats and/or breast milk. Stearic acid content of milk fat from cows range from 7.8% to 20 % therefore individual fatty acid esters if formed are likely to be expressed in breast milk. Fatty acid esters are distributed to plasma and therefore will be distributed to highly perfused tissues such as the liver.

Details on excretion:

Genotoxicity testing with EC 415-430-8 indicates that the compound is non-mutagenic and non-clastogenic in both in vitro and in vivo tests. In the two in vitro microbial mutagenicity assays in E.coli and in S. typhimurium the assays were conducted both with and without the presence of an S9 metabolic activation system isolated from rat liver. In each assay metabolism by S9 rat livers enzymes did not result in increased mutation frequency (NICNAS, 2001).

Individual fatty acids are found in the plasma lipid fraction and therefore circulated throughout the body. Fatty acids undergo acylation by acyl transferases to triglycerides, phosphatidylcholine and cholesteryl ester (Emken, 1994) which are found in the plasma lipid fraction. Fatty acids are also oxidized via the β-oxidation cycle. Once in the β-oxidation cycle most fatty acids are completely oxidized to carbon dioxide. Β-oxidation is higher in rodents than in humans and is slower with increasing fatty acid saturation (Dupont and Mathias, 1969). Stearic acid may also be desaturated to oleic and palmitic acids.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Fecal excretion is likely a major route of elimination of unabsorbed and unchanged EC 415-430-8. Fecal excretion is also a likely major pathway of elimination of any fatty acid esters.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
The literature on the toxicokinetics of EC 415-430-8 was reviewed. Its low water solubility and high molecular weight polymeric structure suggests a lower potential for absorption across the skin, gastrointestinal tract and respiratory tract compared to the fatty acid esters, the digestion products. These are readily absorbed in the digestive tract. Fatty acid esters are taken up in the plasma and distributed to highly perfused tissues. Fatty acid esters are also likely distributed in the body fat and in breast milk. Any fatty acid esters formed will undergo acylation, desaturation and β-oxidation. EC 415-430-8 (the fatty acid esters) and the products of metabolism are not likely to be toxic.