Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
review of the literature
Type of information:
other: study report
Adequacy of study:
key study
Study period:
April-May 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:
2017
Report date:
2017

Materials and methods

Objective of study:
toxicokinetics
Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: Annex VIII Section 8.8 of Regulation (EC) No. 1907/2006
Qualifier:
according to guideline
Guideline:
other: Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014)
Principles of method if other than guideline:
Paper-based review of the published scientific literature
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Addition product of maleic anhydride, tall oil fatty acids, linseed oil and methanol
Molecular formula:
not available for this UVCB substance
IUPAC Name:
Addition product of maleic anhydride, tall oil fatty acids, linseed oil and methanol
Test material form:
liquid
Details on test material:
UVCB Purity 100% Batch Number 210150084 Expiry Date 29 April 2017
Specific details on test material used for the study:
no test material used
Radiolabelling:
no

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Relatively low by the oral, dermal and inhalation routes
Type:
distribution
Results:
No systemic toxicity suggests no significant distribution. Theoretically, lipophilic substances can accumulate in body fats and/or breast milk. Fatty acids are distributed into plasma and may appear in the liver
Type:
metabolism
Results:
The test substance was negative in genotoxicity studies in the presence of rat liver metabolic activation. Fatty acids in the plasma lipid fraction can undergo acylation to triglycerides and are oxidised by the β-oxidation cycle to CO2.
Type:
excretion
Results:
Primarily by fecal extraction

Toxicokinetic / pharmacokinetic studies

Details on absorption:
ZWA 5496/100 is slightly water soluble, has a relatively high log octanol water partition coefficient with a high molecular weight polymeric structure which suggests somewhat lower potential for absorption across the skin and gastrointestinal tract. Lipophilic substances have limited solubility in gastrointestinal fluids. It is likely that ZWA 5496/100 may be digested to individual fatty acids and esters which are more readily absorbed in the digestive tract. 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 repeat dose studies in the rat given ZWA 5496/100 by the oral route. The low water solubility and relatively high estimated partitioning into octanol of ZWA 5496/100 indicates that it may accumulate in body fats and/or breast milk. Fatty acids are distributed into plasma and therefore 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 ZWA 5496/100. Fecal excretion is also a likely major pathway of elimination of any fatty acids.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
ZWA 5496/100 was negative for the ability to induce gene mutations in tester strains of Salmonella typhimurium and Escherichia coli, as measured by reversion of auxotrophic strains to prototrophy. The following five tester strains were used: TA1535, TA1537, TA98, TA100 and WP2 uvrA. Experiments were performed both in the absence and presence of metabolic activation, using liver S9 fraction from rats pre-treated with Phenobarbital and 5-6 Benzoflavone (Allnex, 2015g). ZWA 5496/100 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 (Allnex, 2016d). ZWA 5496/100 did not 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, 2017a). 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 and will be circulated throughout the body, especially in perfused tissues. Fatty acids can undergo acylation by acyl transferases to triglycerides, phosphatidylcholine and cholesteryl ester (Emken, 1994) 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 (Dupont and Mathias, 1969).

Any other information on results incl. tables

ZWA 5496/100 is a UVCB of multiple individual components, many of a high molecular weight polymeric structure > 1000 d. Estimated behaviour of a model representative compound shows a low water solubility (estimated at 2.03 x 10-6mg/L) and a relatively high log octanol water partition coefficient (estimated at 9.96). This indicates a relatively lower potential for absorption via oral, dermal and inhalation routes of exposure.

Applicant's summary and conclusion

Conclusions:
The substance ZWA 5496/100 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 through the β-oxidation cycle. Metabolites are not expected to be systemically toxic. The substance is expected to show fecal elimination.