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Administrative data

basic toxicokinetics
Data waiving:
other justification
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Data source

Materials and methods

Test material


Results and discussion

Applicant's summary and conclusion

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:

Vinyl laurate is hydrolytically unstable and it reacts with humidity and with water under formation of vinyl alcohol and lauric acid. As the resulting vinyl alcohol as an enol is not stable under normal conditions it will tautomerize to form the respective acetaldehyde. It can be assumed that in aqueous environment of biological systems similar reactions occur probably supported in parts by hydrolytic enzymes. The presence of carboxylesterases assumed to be capable of hydrolysing vinyl laurate has been demonstrated in the nose, oral cavity, respiratory tissue, skin, blood, and liver of several species including man (Bogdanffy, M.S., Taylor, M.L. (1993), Kinetics of nasal carboxylesterase-mediated metabolism of vinyl acetate, Drug Metab. Dispos., 21, 1107-1111; Bogdanffy, M.S., Sarangapani, R., Kimbell, J.S., Frame, S.R., Plowchalk, D.R. (1998), Analysis of vinyl acetate metabolism in rat and human nasal tissues by an in vitro gas uptake technique, Toxicol. Sci., 46, 235-246.; Morris, J.B. (1997), Uptake of acetaldehyde vapour and aldehyde dehydrogenase levels in the upper respiratory tracts of the mouse, rat, hamster, and guinea pig, Fundam. Appl. Toxicol, 35, 91-100.; Simon, P., Filser, J.G., Bolt, H.M. (1985), Metabolism and pharmacokinetics of vinyl acetate, Arch. Toxicol., 57, 191-195.; Strong, H.A., Cresswell, D.G., Hopkins, R. (1980), Investigations into the metabolic fate of vinyl acetate in the rat and mouse, Report No. 2511-51/11-14, Part 2, Hazleton Laboratories Europe). These tissues include the sites of entry following inhalation, oral and dermal exposure; pre-systemic hydrolysis of vinyl laurate at these sites will reduce systemic exposure to intact vinyl laurate to a degree in proportion with enzyme activity i.e. where enzyme activity is highest, systemic exposure will be lowest and visa-versa. The hydrolysis will also be catalyzed at lower pHs like in the stomach. Thus it can be assumed that after oral uptake resorption of at least the resulting metabolites will occur. Both metabolites are well known.

Fatty acids like lauric acid are an important part of the normal daily diet of mammals, birds and invertebrates. Lauric Acid is one of the three most widely distributed naturally occurring saturated fatty acids. The fatty acid content of the seeds of Lauraceae is greater than 90% Lauric Acid. Sources of Lauric Acid include coconut and palm kernel oils, babassu butter (approximately 40%) and other vegetable oils, and milk fats (2-8%). Camphor seed oil has a high Lauric Acid content. (Final Report on the Safety Assessment of Oleic Acid, Lauric Acid, Palmitic Acid, Myristic Acid, and Stearic Acid, Int J Toxicol 1987; 6; 321).

After hydrolysis of fat, beta oxidation is the process by which free fatty acids, in the form of Acyl-CoA molecules, are broken down in mitochondria and/or in peroxisomes to generate Acetyl-CoA, the entry molecule for the Krebs cycle. The ultimate metabolite is Acetyl-Coenzyme A (Acetyl-CoA) which it is present in different metabolic pathways and enters the citric acid cyle (krebs cycle) of organisms where it is degraded to form water and carbon dioxide.

Offering humans a lauric acid rich diet the subjects’ serum total cholesterol concentration in-creased as well as the high-density-lipoprotein (HDL)-cholesterol concentrations. No effects were seen in serum triacylglycerol and lipoprotein(a) concentrations (E.H.M. Temme, R.P. Men-sink, G. Hornst, Am J Clin Nutr 1996;63: 897-903, M.B. Katan, P.L. Zock, R.P. Mensink Am J Clin Nutr 1994;60(suppl): 1017S-22S, R.P. Mensink, P.L. Zock, A.D.M. Kester, M.B. Ka-tan, Am J Clin Nutr 2003;77:1146–55.). Other authors state that lauric acid raises total and LDL cholesterol concentrations compared with oleic acid, but no differences were noted in plasma triglycerides or HDL cholesterol (MA Denke and SM Grundy , Am J Clin Nutr 1992;56: 895-8).

Acetaldehyde is metabolized to acetic acid by nicotinamide adenine dinucleotide (NAD)-dependent aldehyde dehydrogenase (ALDH), which exists in the liver and nasal mucosa, and finally degraded to carbon dioxide and water (J.F.Brien and C.W.Loomis, J. Physiol. Pharmacol. 61, 1983, pp. 1–22 1983). ALDH is present in the tissues of experimental animals including mice, rats, hamsters and guinea pigs. In all species except guinea pig, data supports the presence of two isozymes characterised by high and low affinity forms (Morris, 1997). Similar enzyme activity has been obtained for human nasal and oral cavity tissues; additionally, ALDH activity has been demonstrated in tissue from the human oesophagus and stomach and in saliva (Bogdanffy et al., 1998; Dong, Y., Peng, T., Yin, S, (1996), Expression and activities of class IV alcohol dehydrogenase and class III aldehyde dehydrogenase in human mouth, Alcohol, 13, 257-262.; Yin, S., Liaou, C., Wu, C. et al., (1997), Human stomach alcohol and aldehyde dehydrogenases: comparison of expression pattern and activities in alimentary tract, Gastroenterology, 112, 766-775). 

Regarding ALDH, there are two types of ALDH in mitochondrial and cytosolic forms. Kinetic characteristics of enzymatic reaction of liver mitochondrial ALDH are similar among human, rat and Syrian hamster, while, the Km value of human cytosolic ALDH1 was approximately 180 M but those of rat and Syrian hamster were 15 and 12 M, respectively (. Klyosov et al. BIOCHEMISTRY, 35, 4445-4456, 1996). In human liver, mitochondrial ALDH alone oxidizes acetaldehyde at physiological concentrations, but in rodent liver, both mitochondrial and cytosolic ALDHs have a role in acetaldehyde metabolism (IARC Monographs on the Evaluation of Carcinogenic risks to Humans 71: 319- 335, 1999). Approximately 40% of oriental population is inactive in mitochondrial ALDH2, which is associated with alcohol intolerance (Yo-shida Alcohol Alcohol. 29: 693-696, 1984). In humans, inhaled acetaldehyde is retained in the respiratory tract at a high rate, and, therefore, acetaldehyde metabolism is mainly associated with thiol compounds (cysteine and glutathione) and subsequently hemimercaptal and thia-zolidine intermediates are produced. Thioether and disulfide are excreted in the urine, however, most of them are metabolized to acetic acid by ALDH2, and finally degraded to carbon dioxide and water (Brien and Loomis, 1983; Cederbaum and Rubin, 1976; Hemminki, 1982; Nicholls et al., 1992; Sprince et al., 1974). In an oral administration of acetaldehyde at a dose of 600 mg/kg in dogs, no excretion of unmetabolized acetaldehyde was comfirmed in urine (Booze and Oehme, 1986).

As for carboxylesterases, ALDH activity is present at the major sites of exposure to vinyl laurate. At exposure levels that do not exceed the capacity of the enzyme to oxidise any acetaldehyde to acetic acid, there will be low local exposure to acetaldehyde. Systemically available acetate will be incorporated into the citric acid cycle ultimately either being incorporated into endogenous substances or eliminated as CO2. Input of acetate resulting from vinyl laurate metabolism will be within the capacity of the cycle which in man is approximately 640 mg acetate/kg/day (Simoneau, C., Pouteau, E., Maugeais, P., Marks, L., Ranganathan, S., Champ, M., Krempf, M. (1994), Measurement of whole body acetate turnover in healthy subjects with stable isotopes, Biol. Mass Spectrom., 23, 430-433.).