1,3,5-triazine-2,4,6(1H,3H,5H)-trithione, trisodium salt

Endpoint summary

Description of key information

No studies are available. The molecular structure, molecular weight, water solubility and octanol-water partition coefficient of anhydrous TMT favours oral absorption. From the toxicological studies, a distribution throughout the body – at least to some extent – can be presumed. It is suggested, that TMT will not be metabolised. Since it is very water soluble, it is expected to be excreted predominantly via the urine.
 

Additional information

There are no studies available in which the toxicokinetic properties of 1,3,5-triazine-2,4,6(1H,3H,5H)-trithione, trisodium salt (TMT) were investigated.

According to REACh, the human health hazard assessment shall consider the toxicokinetic profile (Annex I). However, generation of new data is not required as the assessment of the toxicokinetic behaviour of the substance should be performed to the extent that can be derived from the relevant available information (REACh Annex VIII, 8.8.1). Qualitative information on toxicokinetic behaviour can be derived taking into account the information on the chemical properties of the compound as well as on toxicological properties obtained in a basic data set.

 

TMT (Na3S3C3N3) is a very hygroscopic solid. Thus, hydrates of TMT are formed by association with water. Two different hydrate forms are possible, which occurs as crystalline agglomerates. TMT nonahydrate (Na3S3C3N3 x 9 H2O) consists of 60% TMT by weight and 40% water by weight (TMT 60) and TMT undecahydrate (Na3S3C3N3 x 11 H2O) of 55% TMT by weight and 45% water by weight (TMT 55) provided an analytical purity of 100%.

 

Anhydrous TMT, TMT nonahydrate and TMT undecahydrate have a molecular weight of 243.2 g/mol, 405.3 g/mol and 441.3 g/mol, respectively. TMT is highly soluble in water based on measured water solubility of 346 g anhydrous TMT/L solution at 22 °C (2011-0376-DKP). The major part of the molecule is existent in the keto form and only a minor, probably negligible part in the enolic form. In aqueous solution, TMT dissociates to form sodium cations and the anions of the acid 1,3,5-triazine-2,4,6(1H,3H,5H) trithione(TMT-H3) (CAS No. 638-16-4)depending on the pH values. The acidic form1,3,5-triazine-2,4,6(1H,3H,5H)-trithione dominates at pH values <7.The log Pow values at 25 °C for the keto form are as follows: -1.55 at pH9, 0.01 at pH 7, 0.68 at pH 5.5 and 0.73 at pH 2 (2011-0008-DKB). Based on this log Pow values TMT would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace.

 

 

Absorption

To be absorbed, the substance has to cross biological membranes, either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility. In general, low molecular weight (MW ≤ 500) and moderate lipophilicity (log Pow values of -1 to +4) are favourable for membrane penetration and thus absorption. The molecular weight of the different TMT forms can be considered low, favouring oral absorption of the compound. In addition, the high water solubility leading to a ready dissolving of the compound in the gastrointestinal fluids favours oral absorption. Also for dermal uptake, sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. In the respiratory tract, the compound would readily diffuse into in the mucous lining. However, very hydrophilic substances might be retained in the mucous in the upper respiratory tract and transported out by mucociliary activity.

 

The observation of systemic toxicity following exposure by any route is also an indication for substance absorption; however, this will not provide any quantitative information.

In an acute oral toxicity study, rats were administered three different volumes of an aqueous solution with 15% wt. TMT (TMT 15) by gavage. A LD50 value of 1122 mg anhydrous TMT/kg bw was determined for males and a LD50 >1596 mg anhydrous TMT/kg bw for females based on the observed mortality. The animals of the mid and high dose groups showed piloerection, labored respiraton, increased pain perception, stilled gait and clonic convulsions (82-0043-DKT). Since acute oral toxicity was observed, absorption of TMT via the gastrointestinal tract (at least to some extent) has evidently occurred.

 

In an acute dermal toxicity study a dose level of 2000 mg TMT 55/kg bw (corresponding to 1100 mg anhydrous TMT/kg bw) was administered to rats (93-0163-FGT). The LD50 level was not attained. Neither mortality, nor effects on body weight or clinical sings except of skin irritation were observed. The lack of systemic toxic effects following dermal exposure compared to oral exposure may be traced to a limited dermal absorption of the test item TMT 55 via the dermal route.

 

TMT has a very low vapour pressure of 5.45E-14 Pa at 25°C (QSAR calculation for TMT anhydrous 2002-0396-DKB) and thus exposure of TMT via the inhalation route as vapour can be considered negligible.

 

Rarely, exogenous compounds (e. g. similar to a nutrient) may be taken up via a carrier mediated or active transport mechanism. However, prediction in this direction is not generally possible. Active transport (efflux) mechanisms also exist to remove exogenous substances from gastrointestinal epithelial cells thereby limiting entry into the systemic circulation. From physicochemical data, identification of substances ready for efflux is not possible.

 

 

Distribution

Some information or indication on the distribution of the compound in the body might be derived from the available physico-chemical and toxicological data. Once a substance has entered the systemic circulation, its distribution pattern is likely to be similar for all administration routes. However, first pass effects after oral exposure influence the distribution pattern and distribution of metabolites is presumably different to that of the parent compound.

The smaller a molecule, the wider is its distribution throughout the body. Membrane-crossing substances with a moderate log P and molecular weight will be able to cross the blood-brain and blood-testes barrier and reach the central nervous system (CNS) or testes, respectively. However, due to the high water solubility, penetration of TMT through these barriers is presumably limited.

From the toxicological studies, the predominant target organs after repeated exposure to TMT were identified to be spleen (female animals) and the kidney (93-0162-FGT, 2015 -0078 -DGT). Thus, distribution throughout the body – a least to some extent – can be presumed. There is no indication of CNS effects or effects on spermatogenesis, thus no conclusion regarding blood-brain or – testes barrier penetration can be drawn.

 

 

Metabolism

Prediction of compound metabolism based on physico-chemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. It is even more difficult to predict the extent of metabolism along different pathways and species differences possibly existing.

Evidence for differences in toxic potencies due to metabolic changes can be derived for instance from in vitro genotoxicity tests conducted with or without metabolic activation.

Studies on genotoxicity (Ames-Test, gene mutation in mammalian cells in vitro, micronucleus assay in vivo) were negative, i.e. there is no indication of a reactivity of TMT or its metabolites under the test conditions.

In addition, no metabolites were calculated by OECD toolbox 2.3.

 

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physico-chemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product.

Since TMT is very water soluble, it is expected to be excreted predominantly via the urine.