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Description of key information

Based on the physicochemical properties, results obtained in the toxicity tests, and from data published in scientific literature, fractions of the UVCB substance will be absorbed following oral and dermal administration and become systemically available.
Considering the low vapour pressure, it is unlikely that relevant amounts of the substance will become systemically available via inhalation.
Absorbed fractions of the UVCB substance will be distributed within the body via the blood stream. Depending on the molecular structure, absorbed amounts of the UVCB substance may be metabolised via Phase I and/or Phase II enzymes. Ultimately, absorbed chemicals and their metabolism products will mainly excreted with the urine and to a lesser extend with the faeces. Based on the physicochemical properties, the UVCB substance is not considered to be bioaccumulative.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

1 Physicochemical data of the reaction product of Maleic anhydride, 2-Ethylhexylamine and Triethanolamine

 

The UVCB substance “reaction product of Maleic anhydride, 2-Ethylhexylamine and Triethanolamine” appears as a liquid at ambient pressure and temperature.The molecular weight (Mw) of the UVCB substance is expected to be in the range of approximately 227 to 454 g/mol.Furthermore, the reaction product contains triethanolamine which has a Mw of 149.19 g/mol.

The substance has a low vapour pressure which was determined to be 0.4 hPa at 20°C. At standard ambient pressure, the substance’s melting point falls in the range of minus 100 to minus 50°C. The boiling point could not be determined due to limited stability of the substance above 110°C.The substance is very well water soluble with a determined water solubility value of 1000 g/Lat 20 °C.Depending on the different structures the respective logPow values of the reaction products, estimated by Epiwin, are expected to be in the range of -0.53 to 3.22. The logPow value for triethanolamine was empirically determined to be -2.3. Hydrolysis of the UVCB substance is not considered to play an important role with regard to this assessment, also such reactions are assumed to take place at a minor extend.

 

2 Toxicokinetic analysis ofthe reaction product of Maleic anhydride, 2-Ethylhexylamine and Triethanolamine

 

Absorption

 

Oral route:

The physicochemical properties of the UVCB substance favour absorption into the systemic circulation following oral intake. Due to the high water solubility the UVCB substance will readily dissolve into the gastro intestinal (GI) fluids, which in turn enhances the contact with the intestinal mucosa. Subsequently, the moderate logPow values may facilitate uptake into the systemic circulation by passive diffusion. Considering the good water solubility and the low Mw of triethanolamine, it is also possible that this chemical reaches the systemic circulation by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water. This assumption is supported by in vivo studies conducted by Kohriet al.(1982) which showed that triethanolamine is rapidly absorbed within the GI tract of rats following oral administration.

With regard to available toxicological data on the reaction product of maleic anhydride, 2-ethylhexylamine and triethanolamine, an acute oral systemic toxicity study in rats (OECD 401) determined the LD50 value to be 4752 mg/kg bw (above limit dose of 2000 mg/kg bw). For animals that died following the administration of such high doses, local effects within the GI tract were noted which were caused by the irritation properties of the substance to mucous membranes. Furthermore, acute atrial dilatation combined with acute congestive hyperemia was observed, which was linked to the very high doses (by far exceeding the limit dose) administered. No adverse effects were noted in animals surviving the treatment.

No signs of adverse systemic effects were observed in a subacute combined repeated dose toxicity study with the reproduction and developmental toxicity screening test (OECD 422). The respective NOAELsfor systemic toxicity, reproductive performance and developmental toxicity were determined to be 1000 mg/kg bw/day (limit dose).

Overall, although fractions of the UVCB substance are likely to be absorbed into the systemic circulation, the results of respective toxicological investigation indicate that those havea limited potential to cause systemic toxicity following a single and repeated oral administration.

 

Dermal route:

The physicochemical properties of the UVCB substance, such as logPow and molecular weight, favour dermal absorption.However, the high water solubility may somewhat reduce the amount available for uptake into the systemic circulation through the skin as parts of the UVCB substance may be too hydrophilic in order to cross the lipid rich environment of the stratum corneum.

In an acute dermal toxicity study performed on rats (OECD 402)the LD50 for the UVCB substance was determined to be > 2000 mg/kg bw (limit dose). No systemic effects were observed, but the substance caused skin erythema which was confined to the application site. A furtherin vivotest on rabbit skin confirmed the expected 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. Nevertheless, even with a partially compromised skin, no systemic effects were noted which in turnindicates that the UVCB substance hasa limited potential to cause systemic toxicity following dermal application. Furthermore, the immunological response observed in a guinea pig maximisation test (OECD 406) provides evidence that at least fractions of the UVCB substance become systemic available following dermal administration.

The assumptions based on the physicochemical properties of the UVCB substance also correlate withfindings published in scientific literature where the component triethanolamine was readily absorbed via the skin following topical administration to rats and mice (Knaaket al.,1997; Stottet al.,2000).

Overall, the physicochemical properties, the results from the toxicological evaluation and findings available in current literature suggest that fractions of the UVCB substance reach the systemic circulation following dermal application. However, as no adverse systemic effects were noted it is assumed that the UVCB substance has a limited potential to cause systemic toxicity.

 

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. When handled at higher temperatures, inhalation exposure is unlikely due to the limited thermal stability of the substance.

 

Distribution

 

Based on the physicochemical properties and furthermore on data available in scientific literature, fractions ofUVCB substance will reach the systemic circulationvia the oral and dermal route. Once absorbed, the water soluble chemicals will be distributed within the body with the blood stream. The transport efficiency to the body tissues is limited by the rate at which the substances cross cell membranes. More specifically, access of the well water soluble chemicals to the central nervous system or the testes is likely to be restricted by the blood-brain and blood-testes barriers (Rozman and Klaassen, 1996).

Due to the limited adverse effects observed in the oral and dermal toxicity studies, there are no hints with regard to any potential target organ.

Based on the physicochemical properties, the UVCB substance has a negligible potential to bioaccumulate in the human body.

 

Metabolism

 

Absorbed fractions of the UVCB substance may be biotransformed within the body by Phase I enzymes while undergoing functionalisation reactions aiming to further increase the hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the absorbed chemicals or the respective Phase I metabolites in order to ultimately facilitate excretion.

According to scientific literature the majority of systemically available triethanloamine does not participate in any biotransformation reactions (Melnick and Thomaszewski, 1990). Only a small fraction will be directly conjugated via the phase II enzyme UDP-glucuronosyltransferase (Kohriet al.,1982).

 

Excretion

 

Depending on the physicochemical properties and molecular structure, absorbed components of the UVCB substance may be excreted as such via faeces or urine. In addition, following biotransformation, metabolites are likely to be excreted via the urine. Absorbed triethanolamine is mainly excreted in its unchanged form with the urine and to a lesser part with the faeces (Kohriet al.,1982; Melnick and Thomaszewski, 1990; Scottet al.,2000).

Fractions of the UVCB substance which are not absorbed within the GI tract are readily excreted with the faeces.

 

3 Summary

 

Based on the physicochemical properties, results obtained in the toxicity tests, and from data published in scientific literature, fractions of the UVCB substance will be absorbed following oral and dermal administration and become systemically available.

Considering the low vapour pressure, it is unlikely that relevant amounts of the substance will become systemically available via inhalation.

Absorbed fractions of the UVCB substance will be distributed within the body via the blood stream. Depending on the molecular structure, absorbed amounts of the UVCB substance may be metabolised via Phase I and/or Phase II enzymes. Ultimately, absorbed chemicals and their metabolism products will mainly excreted with the urine and to a lesser extend with the faeces. Based on the physicochemical properties, the UVCB substance is not considered to be bioaccumulative.

 


4 References

 

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

 

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

 

Stott W.T., Waechter J.M., Rick D.L. Mendrala, A.L. (2000) Absorption, distribution, metabolism and excretion of intravenously and dermally administered triethanolamine in mice. Food and Chemical Toxicology 38(11):1043-1051.

 

Knaak J.B., Leung H.W., Stott W.T., Busch J., Bilsky J. (1997) Toxicology of mono-, di-,

and triethanolamine. Reviews of Environmetal Contamination and Toxicology 149:1–86.

 

Kohri N., Matsuda T., Umeniwa K., Miyazaki K., Arita T. (1982) Development of assay method in biological fluids and biological fate of triethanolamine. Yakuzai Gaku 42:

342–348.

 

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

 

Melnick R.L., Tomaszewski K.E. (1990) Triethanolamine. In: Buhler D.R., Reed, D.J.,

(eds) Ethel Browning’s Toxicity and Metabolism of Industrial Solvents, Vol. II, Nitrogen and

Phosphorus Solvents, Amsterdam, Elsevier: 441–450.

 

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: 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.