Oleic acid, compound with N-(2-aminoethyl)ethane-1,2-diamine

Endpoint summary

Description of key information

Based on the physicochemical properties, systemic availability of the UVCB substance via passive absorption processes is unlikely but potential micellular solubilisation processes may increase the possibility for uptake into the systemic circulation. Although unlikely, the substance’s intrinsic skin irritation potential may facilitate a certain uptake of the chemical through damaged skin parts. However, the absence of any systemic effects in the comprehensive toxicological investigation indicates that no toxicologically relevant concentrations may reach the systemic circulation even if the skin barrier is compromised. Considering the low vapour pressure, it is unlikely that relevant amounts of the reaction product will become systemically bioavailable via inhalation. 
For amounts potentially becoming bioavailable, it is assumed that circulation within the blood stream and subsequent degradation via common physiological fatty acid pathways and/or biotransformation by Phase I and II enzymes may occur. Depending on the metabolism pathway, the substances may be either degraded within the body or excreted with the urine. Fractions which are not absorbed within the GI tract are readily excreted with the faeces. Due its lipophilic character, enrichment in the body fat depots cannot be excluded, especially if no metabolic transformation has taken place.

Additional information

1 Physico-chemical data of the reaction product of oleic acid and N-(2-aminoethyl)ethane-1,2-diamine

 

The UVCB substance “reaction product of oleic acid and N-(2-aminoethyl)ethane-1,2-diamine” appears as a liquid.The molecular weight (Mw) of the lead structure of the UVCB substance is 385.6275 g/mol and the molecular formula is C₂₂H₄₇N₃O₂.

The substance has a low vapour pressure which was determined to be 0.5 hPa at 20°C. At standard ambient pressure, the substance has a melting point of approximately minus 38 to minus 40°C. The boiling point could not be determined due to limited stability of the substance above 120°C.The substance has a low water solubility with the determined water solubility value being in the range of 2 to 4 mg/Lat 20 °C.The logPow value was determined to be > 4.8.Hydrolysis of the UCVB substance is not expected based on the chemical structure.

2 Toxicokinetic analysis ofthe reaction product of oleic acid and N-(2-aminoethyl)ethane-1,2-diamine

 

Absorption

 

Oral route:

In order to be absorbed into the systemic circulation, chemicals have to dissolve into the gastro-intestinal (GI) fluids and make contact with the mucosal surface. Hence, the poor water solubility of the UVCB substance may drastically reduce the amount available for uptake into the systemic circulation. On the other hand, depending on the molecular structure and the arrangement of the oleic acid part, absorption of the highly lipophilic compound may be facilitated by micellular solubilisation via bile salts, which is also the predominant absorption mechanism for physiological fatty acid compounds in the GI tract (Aungst and Shen, 1986). If absorbed as micelles, the substance may enter the lymphatic system while by-passing the liver.With regards to toxicological data, an acute oral systemic toxicity study in rats (OECD 423), conducted with the UVCB substance, determined the respective LD50 value to be greater than 2000 mg/kg (limit dose) with no local or systemic effects noted. Furthermore, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats (OECD 422) was conducted on the UVCB substance with dose levels of up to 800 mg/kg bw/day. No systemic effects were observed in the parental animals and the offspring. Conclusively, the NOAEL for general, reproductive and developmental toxicity was determined to be 800 mg/kgbw/day. Overall, while passive absorption following oral administration is unlikely, uptake of the highly lipophilic substance via micellular solubilisation cannot be ruled out. However, considering the absence of systemic effects in the toxicological investigation, it is unlikely that toxicological relevant amounts of the substance will reach the systemic circulation.

Dermal route:

The physicochemical properties of the UVCB substance such as the high LogPow and low water solubility, do not favour dermal absorption. More specifically, the low water solubility will hinder the transfer from the stratum corneum to the underlying epidermis and this, in turn, will drastically limit the amount available for percutaneous absorption.

These assumptions based on the physicochemical properties are further supported by the results achieved from an acute dermal toxicity study with the UVCB substance performed on rats (OECD 402). During this study, no systemic effects were observed and the LD50 was determined to be > 2000 mg/kg bw (limit dose). However, in this study indications of a certain skin irritation potential of the chemical were observed. Nevertheless, even with a partially compromised skin, no systemic effects were noted. A furtherin vivotest on rabbit skin (OECD 404) confirmed the irritation potential of the chemical. These results need to be taken into consideration as due to local skin damage, direct absorption into the systemic circulation may be facilitated.

Even if becoming systematically available, neither animmunological response was triggered in a Local Lymph Node Assay (LLNA, OECD 429), nor signs of systemic toxicity were noted.

Overall, the physicochemical properties and the absence of systemic effects in the toxicological investigation support that absorption into the systemic circulation via passive diffusion is expected to be limited, if taken place at all, after dermal application. Although unlikely, it cannot be completely ruled out that substance’s intrinsic skin irritation properties may facilitate a certain uptake of the chemical if the skin barrier is damaged.

 

Inhalation route:

Considering the low vapour pressure and the resulting low volatility, it is unlikely that the UVCB substance will become bioavailable via inhalation when handled at ambient temperature.

 

Distribution

 

With regards to the physicochemical properties and the results achieved from the comprehensive toxicity testing, it appears that the bioavailability ofthe UVCB substancevia the oral and dermal route cannot be excluded, although expected to be very limited. If becoming systemically available, the substance will most likely be transported within the body via the blood stream and, in turn, gain access to the body tissues. Based on the absence of systemic effects in the oral toxicity studies, there are no hints with regard to any potential target organ. Due to the highly lipophilic properties, the substance might be enriched in body fats if no metabolism and formation of more polar metabolites takes place.

 

Metabolism

 

The substance may be biotransformed within the body by Phase I enzymes while undergoing functionalisation reactions aiming to increase its hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the chemical or its Phase I metabolites in order to ultimately facilitate excretion. Depending on the molecular structure and on preceding metabolism processes, the UVCB substance may also be metabolised via common physiological fatty acid metabolism pathways after the amid moiety is cleaved.

 

Excretion

 

Depending on the molecular structure and size, the components of the UVCB substance may be excreted as such via faeces or urine. In addition, following metabolic cleavage or catabolic conversion processes, metabolites are likely to be excreted via the urine.

 

3 Summary

 

Based on the physicochemical properties, systemic availability of the UVCB substance via passive absorption processes is unlikely but potential micellular solubilisation processes may increase the possibility for uptake into the systemic circulation.Although unlikely, the substance’s intrinsic skin irritation potential may facilitate a certain uptake of the chemical through damaged skin parts. However, the absence of any systemic effects in the comprehensive toxicological investigation indicates that no toxicologically relevant concentrations may reach the systemic circulation even if the skin barrier is compromised.Considering the low vapour pressure, it is unlikely that relevant amounts of the reaction product will become systemically bioavailable via inhalation.

For amounts potentially becoming bioavailable, it is assumed that circulation within the blood stream and subsequent degradation via common physiological fatty acid pathways and/or biotransformation by Phase I and II enzymesmay occur. Depending on the metabolism pathway, the substances may be either degraded within the body or excreted with the urine. Fractions which are not absorbed within the GI tract are readily excreted with the faeces. Due its lipophilic character, enrichment in the body fat depots cannot be excluded, especially if no metabolic transformation has taken place.

4 References

 

Aungst B., Shen D.D. (1986) Gastrointestinal absorption of toxic agents.In Rozman K.K., Hanninen O. (eds.) Gastrointestinal Toxicology. Elsevier, New York.

 

Bonse G., Metzler M. (1978) Biotransformation organischerFremdsubstanzen. Thieme Verlag, Stuttgart.

 

ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

 

Florin T., Neale G., Gibson G.R., Christl S.U., Cummings JH. (1991) Metabolism of dietary

sulphate: Absorption and excretion in humans. Gut 32:766-773.

 

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press, San Diego, USA, 2nd Edition 688-689.

 

Mutschler E., Schäfer-Korting M. (2001) Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft, Stuttgart.

 

Renwick A.G. (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes,A.W. (ed.)

Principles and Methods of Toxicology. Raven Press, New York, p 103.

 

Rozman K.K., Klaassen C.D. (1996) Absorption, Distribution, and Excretion of Toxicants. In Klaassen C.D. (ed.) Cassarett and Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill, New York.