Fatty acids, C16-18 and C18-unsatd., reaction products with glycidyl neodecanoate and 7-oxabicyclo[4.1.0]hept-3-ylmethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

review of existing data

Type of information:

other: review of existing data

Adequacy of study:

key study

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

A paper-based toxicokinetic assessment (TKA) was conducted in accordance with Annex VIII Section 8.8 of Regulation (EC) No. 1907/2006 and based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2107

Report date:

2017

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: Regulation (EC) No. 1907/2006, Annex VIII Section 8.8

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: ECHA, 2014, Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance

Principles of method if other than guideline:

Paper-based review of the available literature

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Esterification reaction of fatty acids, C16-18 and C18-unsatd.; 3,4-epoxycyclohexyl methyl-3,4-epoxycyclohexan carboxylate and neodecanoic acid, oxiranylmethyl ester

Molecular formula:

not available for UVCB substances

IUPAC Name:

Esterification reaction of fatty acids, C16-18 and C18-unsatd.; 3,4-epoxycyclohexyl methyl-3,4-epoxycyclohexan carboxylate and neodecanoic acid, oxiranylmethyl ester

Test material form:

liquid

Details on test material:

UVCB Purity 100% Batch Number: 210164480 Expiration Date: 16 December 2017

Radiolabelling:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Low absorption via oral, dermal and inhalation routes

Main ADME results 2

Type:

distribution

Results:

Low observed toxicity suggests minimal distribution or absorption into the systemic compartment. Theoretically, absorbed material may be broken down into fatty acid derivatives, which are distributed through the systemic circulation and metabolised.

Main ADME results 3

Type:

metabolism

Results:

In in vitro mutagenicity studies, metabolism by rat hepatic S9 fraction did not result in formation of mutagenic products.

Main ADME results 4

Type:

excretion

Results:

Elimination of unabsorbed and unchanged ZEF 6099/100, as well as fatty acid esters, is likely via fecal excretion.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

ZEF 6099/100 is very slightly water soluble, has a relatively high log Kow with a high molecular weight polymeric structure which suggests low potential for absorption across the skin and gastrointestinal tract. Lipophilic substances have limited solubility in gastrointestinal fluids. While dermal absorption data for ZEF 6099/100 are not available, topically applied fatty acid methyl esters are theoretically able to penetrate to the living cells of normal epidermis, enter into metabolism and significantly modify endogenous epidermal lipids. Due to its molecular weight, ZEF 6099/100 will not readily penetrate the epidermis and due to the low water solubility, ZEF 6099/100 will not readily pass from epidermis to dermis. The low vapor pressure exerted is an indication of low potential exposure by the inhalation route as well.

Details on distribution in tissues:

No evidence of systemic target organ toxicity was seen in a repeated dose study in the rat with ZEF 6099/100 by oral administration. The low water solubility and relatively high partitioning into octanol of ZEF 6099/100 indicates that it may accumulate in body fats and/or breast milk. Fatty acid esters are distributed into plasma and will be distributed to highly perfused tissues such as the liver.

Details on excretion:

Fecal excretion is likely a major route of elimination of unabsorbed and unchanged ZEF 6099/100. Fecal excretion is also a likely major pathway of elimination of any fatty acid esters.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

ZEF 6099/100 is not active in mutagenicity assays in the absence and presence of metabolic activation by rat liver S9-mix induced by Aroclor 1254. ZEF 6099/100 also did not induce gene mutations at the HPRT locus in V79 cells in the absence and presence of metabolic activation by rat liver S9-mix induced by Aroclor 1254, nor did it induce the formation of micronuclei in human lymphocytes in vitro in the absence and presence of metabolic activation by rat liver S9-mix induced by Aroclor 1254 (Allnex, 2016, 2017). In each of these assays, metabolism by S9 rat liver enzymes did not result in increased mutation frequency.
Individual fatty acids found in the plasma lipid fraction will be circulated throughout the body, especially in perfused tissues. Fatty acids can undergo acylation by acyl transferases to triglycerides, phosphatidylcholine and cholesteryl ester which are found in the plasma lipid fraction. Fatty acids can also be 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.

Any other information on results incl. tables

ZEF 6099/100 is a UVCB of complex reaction products, many of which are polymers/oligomers which have a high molecular weight over 1000 d. Results from computer models ((QSAR, EPI-Suite and OECD QSAR Toolbox) of the individual components of the UVCB show high log Kow values ranging from 10.46 -16.95.

Applicant's summary and conclusion

Conclusions:

The substance ZEF 6099/100 is expected to show low absorption by the oral, dermal and inhalation routes. If absorbed, it may be distributed to highly perfused organs, and the fatty acid components metabolised as triglycerides through the β-oxidation cycle. Metabolites are not expected to be systemically toxic. The substance is expected to show significant fecal elimination.