3-methyl-1-vinyl-1H-imidazolium methyl sulphate

Endpoint summary

Description of key information

Based on the physicochemical properties, the ions of 3-methyl-1-vinyl-1H-imidazolium methyl sulphate may be absorbed via the GI tract with the bulk passage of water and become systemically available.
Uptake into the systemic circulation following dermal exposure is expected to be negligible due to the solid and ionic nature of the substance. Based on the low vapour pressure and granular appearance, it is unlikely that relevant amounts of the substance will become systemically bioavailable via inhalation.
For the amounts potentially being bioavailable, it is assumed that the ions will circulate within the blood stream and metabolism may occur. Ultimately the metabolism products will be excreted via the kidney in the urine. 
Based on the physicochemical properties neither the ions of -methyl-1-vinyl-1H-imidazolium methyl sulphate nor its potential metabolism products are considered to be bioaccumulative.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

1 Physico-Chemical Data on 3-methyl-1-vinyl-1H-imidazolium methyl sulphate

 

The salt 3-methyl-1-vinyl-1H-imidazolium methyl sulphate appearsas a solid in granular form at standard ambient temperature and pressure.The molecular weight (Mw) of the substance is 222.26 g/mol and the molecular formula is C₆H₁₁N₂^.CH₃O₄S. At standard ambient pressure, the melting point is 31°C while the boiling point could not be determined due to limited stability of the substance above 300°C.The substance has a very low vapour pressure which can be regarded as negligible for the present assessment.

The substance is very well water soluble (1000 g/L) as expected for salts like this. When placed in an aqueous solution, the substance immediately dissociates into the 3-methyl-1-vinyl-1 H-imidazolium cation (Mw: 111.16g/mol) and a methyl sulphate anion (Mw: 111.10g/mol).The logPow value for theH-imidazolium and the methyl sulphate ion was determined to be -3.6 and < -3.3, respectively. Hydrolysis of the ions itself is not expected.

2 Toxicokinetic analysis of 3-methyl-1-vinyl-1H-imidazolium methyl sulphate

 

Absorption

 

Oral route:

Within the gastrointestinal (Gl) tract, the ionic nature, the high water solubility and low LogPow of the H-imidazolium and the methyl sulphate ion will drastically limit an uptake into the systemic circulation via passive diffusion. However, absorption with the physiological transport of water cannot be excluded. More specifically, due to the high water solubility and the low Mw (i.e., < 200 g/mol), the ions may pass through aqueous pores or be carried through the epithelial barrier with the bulk passage of water (Renwick, 1994).

With regards to toxicological data, in an acute oral systemic toxicity study in rats (OECD 423), the LD50 value for 3-methyl-1-vinyl-1H-imidazolium methyl sulphate was determined to be higher than 2000 mg/kg bw (limit dose). In this study no local or systemic effects were noted.

Furthermore, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats (OECD 422) was conducted on the substance. No adverse effects were observed in the parental animals and the offspring. Thus, the NOAEL for general, reproductive and developmental toxicity was determined to be 1000 mg/kgbw/day (limit dose).

Overall, while passive absorption following oral administration is highly unlikely, uptake of the ions with bulk transfer of water cannot be ruled out. 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.

Inhalation route:

Based on the very low vapour pressure and the fact that the substance appears in granular form, inhalation exposure, either to vapour or to dust particles, is highly unlikely.

 

Dermal route:

The physicochemical properties of3-methyl-1-vinyl-1H-imidazolium methyl sulphatedo not favour dermal absorption. As the substance is a solid at room temperature, it has to dissolve into the surface moisture of the skin before any potential uptake can take place. Once dissolved, the ionic nature of the constituents will drastically hinder dermal uptake.

The assumption that no dermal absorption occurs is further strengthened by the results achieved from the dermal toxicity testing. In an acute dermal toxicity study (OECD 402), the substance did no cause any local or systemic effects and the LD50 was determined to be greater than the limit dose (2000 mg/kg bw).

Overall, the physicochemical properties and the findings from the dermal toxicity studysupport that no absorption into the systemic circulation is expected after dermal application.

 

Distribution

 

If absorbed following oral administration, it is expected that due to the high water solubility the ions are distributed within the blood stream. Here the transport efficiency to the body tissues is drastically limited by the rate at which the water soluble ions cross cell membranes. More specifically, access to the central nervous system or the testes is most likely to be restricted by the blood-brain and blood-testes barriers (Rozman and Klaassen, 1996).

Due to the lacking systemic toxicity of the substance as observed in the oral toxicity studies, no relevant target organ was identified which could provide further hints towards the distribution profile. Based on the physicochemical properties value, the ions or their potential metabolism products are not expected to bioaccumulate in the human body

 

Metabolism

 

Based on the structure of the 3-methyl-1-vinyl-1 H-imidazolium cation, it cannot be ruled out that the ion may be metabolised by Phase I enzymes while undergoing functionalisation reactions aiming to further increase the ion’s hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the cation or its Phase I metabolite in order to ultimately facilitate excretion.

With regard to the methyl sulphate ion, Phase I enzymes may remove the methyl group to yield the intermediate metabolite sulphuric acid which will be further metabolised to sulphate(World Health Organization, 1985).Sulphate represents a physiological molecule that is used during the biotransformation of several compounds (Morriset al.,1984) and can be biosynthetically incorporated into other macromolecules such as glycoproteins, glycosaminoglycans, and glycolipids (Morris and Sagawa, 2000).

 

Excretion

 

Based on the expected biotransformation reactions, molecular size and water solubility, it is most likely that 3-methyl-1-vinyl-1 H-imidazolium or its final metabolites are excreted via the urine. Fractions of the chemical which are not absorbed within the GI tract may be readily excreted via the faeces.

Also sulphates, in unbound form or as conjugates of various substances, are ultimately eliminated from the blood via the kidneys and will be excreted with the urine.

 

 

3 Summary

 

Based on the physicochemical properties, the ions of 3-methyl-1-vinyl-1H-imidazolium methyl sulphate may be absorbed via the GI tract with the bulk passage of water and become systemically available.

Uptake into the systemic circulation following dermal exposure is expected to be negligible due to the solid and ionic nature of the substance. Based on the low vapour pressure and granular appearance, it is unlikely that relevant amounts of the substance will become systemically bioavailable via inhalation.

For the amounts potentially being bioavailable, it is assumed that the ions will circulate within the bloodstream and metabolism may occur. Ultimately the metabolism products will be excreted via the kidney in the urine.

Based on the physicochemical properties neither the ions of -methyl-1-vinyl-1H-imidazolium methyl sulphate nor its potential metabolism products are considered to be bioaccumulative.

4 References

 

 

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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

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Ghiringhell L., Colombo U., Monteverde, A. (1957) Observations on the toxicity of dimethylsulphate in animal experiments. La Medicina del Lavoro 48:634–641.

 

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

 

Morris M.E, Galinsky RE, Levy G. 1984. Depletion of endogenous inorganic sulfate in the

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Morris M.E., Sagawa K. (2000) Molecular mechanisms of renal sulfate regulation. CRC Critical Reviews in Clinical Laboratory Medicine. 37(4):345-388.

 

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.

 

WHO (1985) World Health Organization - Environmental Health Criteria 48. Dimethyl sulfate. Geneva.