Registration Dossier
Registration Dossier
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EC number: - | CAS number: -
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics, other
- Type of information:
- other:
- Remarks:
- No study on kinetics with the registered substance Dodicor V 5654 is available. Based on all available data an expert statement is provided.
- Adequacy of study:
- other information
Data source
Materials and methods
Results and discussion
Applicant's summary and conclusion
- Conclusions:
- The substance registered is expected to be bioavailable for oral route and undergo rapid elimination. No bioaccumulating property can be derived.
- Executive summary:
Data on toxicokinetic of Reaction products of DL-methionine and C18 unsaturated fatty acid chloride and isopropanol are not available. The major components are N-oleoyl-L-methionine and N-oleoyl-L-methionine isopropylester. The molecular weight of the active content is 413.6 g/mol (calculated for acid; C18:1) and 455.8 g/mol (calculated for isopropylester; C18:1). The calculated vapour pressure is 1.65 Pa (at 20°C), the water solubility 0.7 mg/L (20°C) and the log Pow 3.1 (at 20°C).
Absorption and Distribution
Oral uptake:
Due to the low molecular weight (below 500) and a log Pow less than 4 of the molecule, passive absorption is the favored uptake in the GI tract (please refer to Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c: Endpoint specific guidance, R.7.12.2.1, Version 3.0, June 2017). After absorption the substance registered is considered to be distributed through the whole body.
Dermal uptake:
Dermal uptake is likely to be low as the water solubility is below 1mg/L. No effects in dermal acute toxicity study and in skin sensitization study are supporting the low dermal bioavailability.
Inhalation:
Due to the low vapour pressure, a significant respiratory exposure to gaseous form is not likely to occur. In case of exposure to aerosols, a rapid trapping in the mucus layer in the upper respiratory tract can be assumed, which results ultimately into the oral uptake. A significant exposure of lower respiratory tract is not expected.
Metabolism and Elimination
The substance registered belongs to the N-fatty amino acid amides (NAAA). These molecules are naturally occurring substances in organisms including mammals, for which the biosynthesis and metabolism are well described (Farrel et al, 2008; Tan et al, 2010; Connor et al, 2010).
For the degradation pathways, at least three types of degradation are identified (Connor et al, 2010). The first is the hydrolysis by fatty acid amide hydrolase (FAAH) to produce the free fatty acid and amino acids. The other two types are modification of the acyl moiety or the amino acid moiety.
Based on the above-mentioned information, it is reasonable to consider that the substance registered is degraded to produce the free fatty acid amino acids and isopropanol. Fatty acids and methionine are then to be incorporated into the normal physiological metabolism. Further, Isopropanol is metabolized via acetone to CO2 and water or eliminated directly via lung, kidney or skin (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 1999).
Toxicity profile
No systemic effect was found up to the highest dose of 1000 mg/kg/d in a subacute oral toxicity test in rats (OECD 407) and in a subacute screening test for reproduction and developmental toxicity (OECD 421).
Conclusion:
The substance registered is expected to be bioavailable for oral route and undergo rapid elimination. No bioaccumulating property can be derived.
References
Farrel EK, Merkler DJ: Biosynthesis, degradation and pharmacological importance of the fatty acid amides. Drug Discov Today. 2008 Jul;13(13-14):558-68.
Tan B, O'Dell DK, Yu YW, Monn MF, Hughes HV, Burstein S, Walker JM: Identification of endogenous acyl amino acids based on a targeted lipidomics approach. J Lipid Res. 2010 Jan;51(1):112-9.
Connor M, Vaughan CW, Vandenberg RJ: N-acyl amino acids and N-acyl neurotransmitter conjugates: neuromodulators and probes for new drug targets. Br J Pharmacol. 2010 Aug;160(8):1857-71
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 1999, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 71, hhtps://www.ncbi.nlm.nih.gov/books/nbk499066/
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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