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Description of key information

Based on the high elimination rates via feces and urine within a very short time frame of 24 hours, it can be concluded that the test substance has no bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Key study

In a toxicokinetic study according to OECD guideline 417 four female and four male Sprague-Dawley rats received a dose of about 100 mg/kg body weight of a mixture of N-Tris-(2-hydroxyethyl)-[14C]-methylammonium-iodide and non labelled test substance (Henkel KGaA, 1991). Both substances are salts with differing anions but identical cations. The organic cation is considered as the toxicologically relevant part for both substances (therefore no readacross was performed). A similar metabolism and excretion is therefore assumed and the ADME characteristics of the cation can be derived appropriately for both test substances by testing a mixture of radiolabeled of N-Tris-(2 -hydroxyethyl)-methylammonium-iodide and the unlabeled test substance.

Before the intestinal absorption of the test substance was studied, the bioavailability of the radiolabelled N-Tris-(2hydroxyethyl)-14C-methylammonium-iodide was determined after a single intravenous administration to two female rats (mean weight: 247.5 g) and one male rat (343 g). The excretion of the radioactivity in urine, feces and expired air was measured over a period of 3 days. In addition, the radioactivity in some organs (heart, lung, liver, kidneys, urinary bladder, gastro-intestinal tract) was determined at the end of the study. After a single intravenous administration of [14C]-N-Tris(2-hydroxyethyl)-methylammoium-iodide to female and male Sprague Dawley rats most of the radioactive material (96.1 %) was excreted in the urine within three days. The elimination rate was very fast. Of the administered dose, 90 % was eliminated via urine within the first 24 hours. Only 1.3 % of the administered radioactivity was recovered in the feces, 0.6 % were eliminated in the expired air. The radioactivity found in the organs at the end of the study was low. As expected, the highest level was found in the liver (about 0.1 %), followed by the gastro-intestinal tract (about 0.07 %) and in the blood (0.05 %). This preliminary study supports the hypothesis that the biliary excretion of the test substance is of no importance.

In the main investigation N-Tris-(2-hydroxyethyl)-14C-methylammonium-iodide together with the unlabeled test substance was administered orally using a single dose of 100 mg/kg body weight to a group of 4 female (mean weight: 288 g) and 4 male rats (mean weight: 412 g). Most of the radioactive material (about 61 %) was excreted with the feces within the first three days. 28 % of the administered radioactivity was excreted via the urine within three days. Here too, the elimination was rapid, most being eliminated within the first 24h. The radioactivity found in the organs at the end of the study was low. The highest amounts were found in the gastro-intestinal tract (about 0.15 %) and the liver (about 0.12 %).

Expert statement

Tris(2-hydroxyethyl)methylammonium methyl sulphate is a yellowish liquid at room temperature with a molecular weight of 275.32 g/mol. The substance is highly soluble in water. A log Pow of the free base of -4.31 and a BCF value of 3.162 L/kg were calculated. A very low vapour pressure was estimated to 6.92E-15 Pa at 25 °C.

Absorption

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties such as molecular weight, water solubility and the log Pow. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of tris(2-hydroxyethyl)methylammonium methyl sulphate is 275.32 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is likely (ECHA, 2014). The test substance will readily dissolve in the gastrointestinal fluid due to the high water solubility. But the very high hydrophilicity may limit the absorption by passive diffusion due to the limited partition rate of the test substance out of the gastrointestinal fluid. In a study on toxicokinetics, the intestinal absorption of the test substance was examined showing that it became only partly systemically available. Administered to rats via gavage in an acute oral toxicity study, the test substance led to a LD50 of above 6400 mg/kg bw without any clinical signs or mortality. Furthermore, long-term administration of the test substance in a 90-day repeated dose toxicity study in rats indicates only some bioavailability of the compound. The pH of the urine in the highest dosing group was significantly lower in both male and female animals.

Considering the low vapour pressure of the test substance and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. If the test substance would reach the lungs in its vapour or gaseous state, absorption directly across the respiratory tract epithelium by passive diffusion may be limited due to its high hydrophilicity. An inhalation risk test was performed and proved this assumption. No mortality or any clinical signs was observed after exposure to an atmosphere saturated with the test substance for 8 hours.

Based on the physico-chemical properties of the test substance the penetration of skin is not likely to happen. Based on the high water solubility the test substance is to hydrophilic to cross from the stratum corneum into the epidermis. Furthermore the ionic structure of the substance minimizes the dermal uptake due to the barrier function of the stratum corneum against ions or polar substances. The assumption of low or no dermal absorption is strengthened by the results achieved from the dermal toxicity testing. In an acute dermal toxicity study, the test substance did not cause any toxic effects. The LD50 was determined to be greater than the limit dose (2000 mg/kg bw). Topical application of the test substance onto the skin of rabbits also caused no sign of irritation as observed in a skin irritation study. No evidence of tissue damage was observed which in turn could have favoured direct absorption into the systemic circulation. A negative LLNA additionally supports the assumption of low dermal absorption.

 

 

Distribution

Based on the physico-chemical properties and the results from the comprehensive toxicity testing the test substance can become systemically available to some extent. Once absorbed, the substance will most likely be transported within the body via the blood stream. Due to its high hydrophilicity a distribution into cells or fatty tissues is neglible. This is further supported by the study on toxicokinetics with radiolabelled test substance showing a very low distribution in the organs. In all organs examined (heart, lung, liver kidneys, urinary bladder, gastro-intestinal tract) the amount of radioactivity detected was very low, in total about 0.39 % of the administered dose. Only the liver (female: 0.07 %, male: 0.17 %), the gastro-intestinal tract (female: 0.13 %, male: 0.18 %) and the blood (female: 0.07 %, male: 0.07 %) contained relevant amounts of radioactivity.

Metabolism

Based on the chemical structure, a metabolisation of the test substance by Phase I enzymes is not likely to occur. The chemical structure already includes several hydroxyl groups. The compound may directly be conjugated in a phase II reaction with an endogenous substrate to further increase its hydrophilicity. The substance is most likely not enzymatically activated (toxified) during metabolism. The assumption is supported by the cytotoxicity results of three genotoxicity tests. The cytotoxicity of the test substance was not higher as compared to the metabolically activated test substance.

Excretion

Based on the substance characteristics, excretion via urine and feces is both possible. In the toxicokinetics study in rats around 61 % were excreted via feces within the first three days after administration. The high hydrophilicity limited the absorption of the substance in the intestines to a high extent. Excretion was rapid, most being eliminated within the first 24 hours. 28 % were excreted via urine within the first three days, a big share 24 hours after administration due to the high water solubility.

Summary

Based on the physico chemical properties, particularly water solubility and octanol-water partition coefficient absorption via oral route is to some extent likely. Absorption via dermal may not occur because the high water solubility and the ionic structure of the test substance impede partitioning of the test substance from the strateum corneum into the epidermis. Due to the low vapour pressure absorption via inhalation is unlikely to happen. A conjugation reaction may increase the high hydrophilicity and possible metabolites are not considered to be more toxic than the parent compound. Excretion is possible via urine and feces but most likely occurs via feces. Bioaccumulation is unlikely due to rapid excretion of the test substance.

References

ECHA (2014) 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.