Sulfonium compounds, C11-14-alkylbis(hydroxyethyl), 2-hydroxyethyl sulfates (salts)

Endpoint summary

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 administration and become systemically available.
Although unlikely, it cannot be completely ruled out that substance’s intrinsic skin corrosion properties may facilitate a certain uptake of the chemical if the skin barrier is compromised.
Considering the estimated low vapour pressure, it is unlikely that relevant amounts of the substance will become systemically available via inhalation. 
Absorbed components will be distributed within the body with the blood stream and potentially reach internal organs (e.g. liver). Depending on the molecular structure, absorbed amounts of the UVCB substance may be metabolised via Phase I and/or Phase II enzymes before being excreted in the urine. Moreover, absorbed sulphate ions may be incorporated into macromolecules during biotransformation processes, before being mainly excreted via the kidney in the urine. Fractions of the substance which are not absorbed within the GI tract are readily excreted 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 on the reaction product of dodecene-1 with mercaptoethanol, ethyleneoxide and sulfuric acid

 

The UVCB substance “reaction product of dodecene-1 with mercaptoethanol, ethyleneoxide and sulfuric acid” is an organic salt in solution which appears as a yellowish, viscous and turbid liquid at standard ambient temperature and pressure.

Due to the ionic bonding of compounds with varying aliphatic chain lengths the molecular weight (Mw) will be found in the range of approximately 370 to 460 g/mol. However, in solution the substance will be present in its dissociated, ionised form. Depending on the varying chain length, the Mw of the cation and the anion are expected to be in the range of approximately 275 to 320 g/mol and 90 to 150 g/mol, respectively.

At standard ambient pressure, the substance’s melting point was determined to fall in the range of minus 45 to minus 20°C. The boiling point could not be determined due to the limited stability of the substance above 70°C. Also the vapour pressure could not be determined experimentally but was estimated to be a 0.087 hPa (based on a read-across to similar substances). The substance is very well water soluble with a determined water solubility value of 1000 g/L at 20°C. Because of the chemical’s intrinsic surface activity it was not possible to determine the logPow.

2         Toxicokinetic analysis of the reaction product of dodecene-1 with mercaptoethanol, ethyleneoxide and sulfuric acid

 

Absorption

 

Oral route:

Within the fluids of the gastrointestinal (GI) tract, the chemical will be present in its ionised form. It is generally accepted that ionic and surface active substances do not readily diffuse across the walls of theGI tract.However, absorption properties may be enhanced following micellular solubilisation by bile salts. Also potentialhydrolysis reactions may enhance the overall absorption properties of the chemicals.Furthermore, the reduced molecular weight (< 200 g/mol) and the high water solubility of the anions will probably lead to systemic absorption by passing through aqueous pores or membranes with bulk transport of water.

Also, hHydrogen sulphate ions are readily absorbed into the systemic circulation within the GI tract. (Florinet al., 1991).

With regards to toxicological data, the acute oral systemic toxicity of the UVCB substance was evaluated in rats via three independent studies (OECD 401). The LD50 was determined to be in range of 950 to 1600 mg/kg bw. For animals that died during the studies local effects within the GI tract and severe diarrhea were noted which were most likely caused by the corrosive properties of the surface active substance to mucous membranes. No gross pathological findings were noted in animals surviving the treatment.

The findings observed in a combined repeated dose toxicity study with the reproduction and developmental toxicity screening test (OECD 422) in rats support the assumption that at least fractions of the UVCB substance become bioavailable following oral exposure. Here the UVCB substance was orally administered at dose levels of 0, 30, 100 and 300 mg/kg bw/day. Besides local effects on the GI tract and resultant weight loss, systemic effects on the adrenal glands (hypertrophy) and on the thymus (lymphoid atrophy) were noted at dose levels of 100 and 300 mg/kg bw/day. The reproductive ability of males and females remained undisturbed at any dose level. An increase in intrauterine and postnatal mortality and lower number of pups born, noted at dose levels of 100 and 300 mg/kg bw/day, was considered as secondary effects linked to the observed maternal toxicity. Conclusively, the NOAELs for systemic and developmental toxicity were determined to be 30 mg/kg bw/day, and the NOAEL for reproductive performance was determined to be 300 mg/kg bw/day.

Overall, the physicochemical properties and findings of toxicological investigation indicate that at least fractions of the UVCB substance are absorbed into the systemic circulationfollowing oral administration.

 

Dermal route:

The ionic nature and the surface active properties of the organic salt will drastically hinder dermal uptake as it its general thought that such substances do not readily diffuse across biological membranes. Furthermore, due to the high water solubility the substance may be too hydrophilic in order to cross the lipid rich environment of the stratum corneum. However, twoin vivotests on rabbit skin confirmed that the surface active UVCB substance has skin corrosive properties. These results need to be taken into consideration as due to local skin damage, direct absorption into the systemic circulation may be facilitated for a certain amount.

 

Inhalation route:

Considering the estimated 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 higher temperatures, inhalation exposure is unlikely due to the limited thermal stability of the substance.

 

 

Distribution

 

Based on the physicochemical properties and on data available in scientific literature, fractions ofthe UVCB substance will reach the systemic circulationvia the oral route and potentially via the 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). At least fractions of the absorbed chemicals will also be transported to the liver where further biotransformation processes will take place.

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.

Absorbed sulphate ions may be used for further biotransformation reactions (Morriset al.,1984) and can be biosynthetically incorporated into other macromolecules such as glycoproteins, glycosaminoglycans, and glycolipids (Morris and Sagawa, 2000).

 

 

Excretion

 

Depending on the physicochemical properties and molecular structure, absorbed components of the UVCB substance or the potential metabolism products may be mainly excreted with the urine.Unboundsulphate ions are regulated by the kidney through re-absorption mechanism (Morris and Levy, 1983; Cole and Scriver, 1980). Ultimately, sulphates, in unbound form or as conjugates of various substances, are eliminated from the blood via the kidneys and are excreted with the urine.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 oraladministration and become systemically available.

Although unlikely, it cannot be completely ruled out that substance’s intrinsic skin corrosion properties may facilitate a certain uptake of the chemical if the skin barrier is compromised.

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

Absorbed components will be distributed within the body with the blood stream and potentially reach internal organs (e.g. liver). Depending on the molecular structure, absorbed amounts of the UVCB substance may be metabolised via Phase I and/or Phase II enzymes before being excreted in the urine. Moreover, absorbed sulphate ions may be incorporated into macromolecules during biotransformation processes, beforebeing mainly excretedvia the kidney in the urine.Fractions of the substance which are not absorbed within the GI tract are readily excreted 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.

 

Cole D.E.C., Scriver C.R. (1980) Age-dependent serum sulfate levels in children and adolescents. Clinica Chimica Acta 107:135-139.

 

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,,, 2nd Edition 688-689.

 

Morris M.E, Levy G. (1983) Serum concentration and renal excretion by normal adults of

inorganic sulfate after acetaminophen, ascorbic acid, or sodium sulfate. Clinical Pharmacolgy and Therapeutics 33:529-536.

 

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

mammalian central nervous system by acetaminophen. Journal of Pharmaceutical Sciences 73:853.

 

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.

 

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.