(Z)-4-[C11-13 (branched) alkylamino]-4-oxo-2-butenoic acid

Endpoint summary

Description of key information

Based on the physicochemical properties, systemic availability of the main component of substance “(Z)-4-[C11-13 (branched) alkylamino]-4-oxo-2-butenoic acid” via passive absorption processes is unlikely but potential micellular solubilisation processes may increase the possibility for uptake into the systemic circulation. The low water solubility of the main component will limit the amount available for percutaneous absorption. Systemic absorption of the constituents of naphtha cannot be excluded. Also the substance’s intrinsic skin irritation potential may facilitate a certain uptake of the substance through compromised skin parts. However, apart from a certain skin sensitisation potential, the absence of any systemic effects in the comprehensive toxicological investigation, indicates that no toxicologically relevant amounts reach the systemic circulation.
Considering the low vapour pressure, it is unlikely that the substance 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 substance or its metabolites may be excreted with the urine or as Phase II metabolites via faeces. Fractions which are not absorbed within the GI tract are readily excreted with the faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

1 Physico-chemical data of (Z)-4-[C11-13 (branched) alkylamino]-4-oxo-2-butenoic acid

 

The substance “ (Z)-4-[C11-13 (branched) alkylamino]-4-oxo-2-butenoic acid” appears as a yellowish, clear liquid at ambient temperature and pressure. The substance consists of a mixture of components. The molecular weight (Mw) of the main component is 297.43 g/mol and the molecular formula is C₁₇H₃₁NO₃. The substance also contains to a minor amount a mixture of petroleum based hydrocarbons compounds commonly known as naphtha.

The substance has a low vapour pressure which was determined to be 2.7 hPa at 20°C. The substance has no melting point in the temperature range between -100 and 50°C. However, at standard ambient pressure, a broad glass transition at minus 130°C was determined. The substance has a boiling point of 189.8°C.

Every constituent contributes to a different degree to the overall water solubility. The main component of the substance has a very low water solubility which was estimated to be 0.3 mg/L. Due to the fractions of naphtha, the empirically determined water solubility value of the substance as such was determined to be between 31 and 128 mg/l at 20°C depending on the proportions of test substance used in the test (i.e., 1 or 10 g of test substance per one litter of water, respectively). The method used for the experimental logPow value determination was not valid. Hydrolysis of the substance is not expected to play an important part with regard to this assessment.

2 Toxicokinetic analysis of (Z)-4-[C11-13 (branched) alkylamino]-4-oxo-2-butenoic acid

 

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 very limited water solubility of the main component will drastically reduce the amount available for uptake into the systemic circulation via passive diffusion. On the other hand, due to certain structural similarities with physiological fatty acids, absorption may be facilitated by micellular solubilisation via bile salts, which is the predominant absorption mechanism for physiological fatty acid compounds in the GI tract (Aungst and Shen, 1986). If absorbed as micelles, the main component of the substance may enter the lymphatic system while by-passing the liver.

With regard to toxicological data, an acute oral systemic toxicity study in rats (OECD 423), conducted with the substance, determined the respective LD50 value to be greater than 2000 mg/kg (limit dose) with no systemic effects noted. Furthermore, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats (OECD 422) was conducted with the substanceusingdose levels of up to 400 mg/kg bw/day. No treatment related systemic effects were observed in the parental animals and the offspring. Conclusively, the NOAEL for general, reproductive and developmental toxicity was determined to be 400 mg/kgbw/day.                                                                                                                

Overall, 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 low water solubility of the main component 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. For the constituents of naphtha systemic absorption cannot be excluded.

In an acute dermal toxicity study performed on rats with the substance (OECD 402) no systemic effects were observed and the LD50 was determined to be > 2000 mg/kg bw (limit dose). 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 vitroskin irritation/corrosion test (EpiDermTM, OECD 431) confirmed a certain 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 enhanced.

Moreover, the positive immunological response observed in a Murine Local Lymph Node Assay (LLNA) (OECD 429) provides evidence that at least a small amount of the substance becomes systemic available following epicutaneous administration.                                             

Overall, although the results from sensitisation testing show that at least certain fraction of the substance can become bioavailable following dermal application, the results obtained in the acute dermal toxicity test do not suggest that toxicological relevant amounts are absorbed with regard to systemic toxicity.

Inhalation route:

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

 

Distribution

 

Based on the physicochemical properties and the results achieved from the comprehensive toxicity testing, it appears that the bioavailability of certain fractions ofthe substancevia the oral and dermal route cannot be excluded, although expected to be limited. If becoming systemically available, fractions of 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 relating to any potential target organ.

 

Metabolism

 

Following absorption into the systemic circulation, certain components of the substance may be biotransformed within the body by Phase I enzymes while undergoing functionalisation reactions aiming to increase their hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the parent chemicals or their Phase I metabolites in order to ultimately facilitate excretion. Potential metabolic reaction can involve Phase II conjugation of the carbonyl group and/or metabolic cleavage of the C₁₃-alkychain of the main component.

Depending on the molecular structure and on preceding metabolism processes, the main component of the substance may also be metabolised via common physiological fatty acid metabolism pathways.

 

Excretion

 

Depending on the molecular structure and size of the components, the 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, or as Phase II metabolite via the faeces.

 

3 Summary

 

Based on the physicochemical properties, systemic availability of the main component of substance “ (Z)-4-[C11-13 (branched) alkylamino]-4-oxo-2-butenoic acid” via passive absorption processes is unlikely but potential micellular solubilisation processes may increase the possibility for uptake into the systemic circulation.The low water solubility of the main component will limit the amount available for percutaneous absorption. Systemic absorption of the constituents of naphtha cannot be excluded. Also the substance’s intrinsic skin irritation potential may facilitate a certain uptake of the substance through compromised skin parts. However, apart from a certain skin sensitisation potential, the absence of any systemic effects in the comprehensive toxicological investigation, indicates that no toxicologically relevant amounts reach the systemic circulation.

Considering the low vapour pressure, it is unlikely that the substance will become systemically bioavailable via inhalation.

For amounts potentially becoming bioavailable, it is assumed that circulation within the blood stream and subsequent degradationvia common physiological fatty acid pathways and/or biotransformation by Phase I and II enzymesmay occur. Depending on the metabolism pathway, the substance or its metabolites may be excreted with the urine or as Phase II metabolites via faeces. Fractions which are not absorbed within the GI tract are readily excreted with the faeces.

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.

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.