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Description of key information

Short description of key information on bioaccumulation potential result: 
1) Toxicokinetik Statement, Chemservice S.A., 2013;
2) Prediction using TOXTREE (v.2.5.0), Chemservice S.A. 2011;
3) Shaw and Graham, 1987 - Read-across toxicokinetic data on structural analogue mesna (animals and human).
4) Brock, 1981 - Read-across toxicokinetic data on structural analogue mesna (animals and human).
5) Ormstad, 1983 - Read-across toxicokinetic data on structural analogue mesna (animals and human).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
Absorption rate - dermal (%):
Absorption rate - inhalation (%):

Additional information

Pharmacokinetics and metabolism of the read-across substance Mesna (CAS 19767-45-4)

Mesna was tested for its uroprotective efficacy in 10 (per dose level) Sprague Dawley rats treated with 68 mg/kg ifosfamide that is known to induce haemorrhagic cystitis (Brock et al., 1981). Mesna was administered by i. v. administration 15 min before the injection of ifosfamide at dose levels of 6.81, 10.0, 14.7 and 21.5 mg/kg bw. The uroprotective efficacy of Mesna was evaluated 24 hours after the administration of ifosfamide. The rats were killed and the urinary bladder were evaluated (inflammation, bleeding and weight). The pharmakokinetic behaviour of mesna was also studied.

The severity of the inflammation of the bladder after i.v. administration of ifosfamide was dose-dependent. An ifosfamide dose of 68 mg/kg always induced an approximately 2- fold increase in the wet weight of the bladder and a damage score of about 2. Some of the rats also showed bladder haemorrhages. The scoring system used takes into account two parameters: firstly, increased capillary permeability (which is demonstrable objectively by the extravasal occurrence of intravenously injected trypan blue) and secondly, the increase in the weight of the bladder, which can also be assessed macroscopically as a swelling of the bladder. In some selected groups the bladder damage and the extent of bladder protection were also investigated histologically. The uroprotective effect of mesna was dose-dependent. It was reflected in a reduced increase in the bladder weight and reduced extravasation of trypan blue, and it was also demonstrable histologically. In the case of mesna, the lowest dose ensuring reliable uroprotection was determined (10 mg/kg bw). The longer chain homologue of mesna, Asta 7100 (= MPS, the target substance), was also effective in protection of urinary bladder against ifosfamide induced urotoxicity. Regarding excretion of mesna, after i.v. administration of 21.5 mg/kg to the rat, about 40% of the administered dose is excreted with the urine as the sulfhydryl compound within the first hour. Within the first 3 hour about 50% of the dose is excreted as the sulfhydryl compound and a further 30% of the dose as the disulphide. Rapid renal excretion of sulfhydryl groups is also observed after oral administration of mesna to rats. Similar findings have also been made on the dog. The behaviour of dimesna after intravenous and after oral administration to rats and dogs is very similar to that of mesna. After i.v. administration of 42.4 mg/kg to rats, 28% of the dose was excreted with the urine as the free sulfhydryl compound within 3 hours.

The pharmacokinetics and metabolism of mesna and dimesna have been investigated in the intact rat and in several in vitro systems including isolated perfused organs, freshly isolated cells, subcellular fractions (Ormstad et al., 1983). The mechanism of reduction of dimesna to form the pharmacologically active thiol mesna has been further studied with purified enzyme preparations.

After p.o. administration, mesna and dimesna are both absorbed from the intestine, and dimesna undergoes reduction to mesna during intestinal absorption. When present in plasma, mesna is rapidly oxidized to dimesna by a metal-dependent reaction. Mesna and dimesna pass unchanged through the hepatic vasculature, are not taken up into liver cells, and are not excreted in bile. In the kidney, dimesna is filtered through the glomeruli and subsequently reabsorbed, whereupon reduction to the pharmacologically active thiol form occurs in the renal tubular epithelium, and the thiol is then reexcreted into the tubular lumen. Reduction of dimesna to mesna occurs in intestinal and renal epithelial cells by a mechanism involving the cytosolic enzymes thiol transferase and glutathione reductase. Thus, the formation of the pharmacologically active thiol form from dimesna is associated with the consumption of equimolar concentrations of reduced glutathione.

In a review, the role of mesna as uroprotective drug in anticancer therapy is presented (Shaw and Graham, 1987). Mesna acts as a scavenger of acrolein and chloroacetaldehyde, reactive metabolites of oxazaphosphorines (cyclophosphamide, ifosfamide), preventing bladder toxicity during chemotherapy. The free thiol group of mesna can react with an electrophilic centre of the reactive compounds (epoxides, chlorinated hydrocarbons, free radicals etc.) forming a thioether, facilitating its excretion. The toxicokinetic behaviour of mesna is evaluated with regard to its absorption, distribution, uptake by cells, metabolism and excretion (Shaw et al., 1986). Mesna is very well absorbed from GI tract following oral dosing. Mesna does not enter most cells due to its hydrophilicity and therewith does not reduce cytotoxicity of anticancer drugs in tumour cells. It is predominantly present in plasma and extracellular fluids but is taken up by kidney cells. On entering the blood stream, mesna is almost immediately oxidized to its dimeric form dimesna by forming a disulphide bridge. Dimesna is chemically less reactive than mesna and so is less likely to react with oxazaphosphorine metabolites. A small proportion (9.7%) of circulating mesna/dimesna is bound to plasma proteins, including albumin and immunoglobulins. The half-life of 17 min and 4 hours were calculated using [14C]-mesna and [35S]-mesna in radioactivity measurements in experimental animals, respectively. Mesna can be sequestered by erythrocytes, increasing its half-life. Mesna is rapidly eliminated in the urine.

Assessment of toxicokinetic behaviour of MPS

In order to assess the toxicological behaviour of 1-Propanesulfonic acid, 3-mercapto-, monosodium salt, the available and predicted physico-chemical and toxicological data have been evaluated. According to its physico-chemical characteristics, the substance is expected to be poorly absorbed after oral exposure, based on its high water solubility (LogPow of -2.94) and its molecular weight. However, as its structural analogue mesnahas been shown to be surprisingly well absorbed, it is likely that MPS will be also well absorbed after oral exposure.Concerning the absorption after exposure via inhalation, as the chemical has low vapour pressure and a high water solubility, it is clear, that it is poorly available for inhalation. Given its hydrophilic properties - if absorbed - it is expected to be absorbed through aqueous pores.1-Propanesulfonic acid, 3-mercapto-, monosodium saltis also expected to be poorly absorbed following dermal exposure into the stratum corneum, due to its LogPow of -2.94. Moreover, systemic toxicity after dermal exposure to the skin is low and this has been proven with the results of the acute dermal toxicity study, which showed no mortality after dermal application of 7500 mg/kg bw in rats. Concerning its distribution in the body,the chemicalis expected to be distributed mostly in the intravasal/extracellular system, since it is a very hydrophilic substance. Moreover, it does not indicate a potential for accumulation.1-Propanesulfonic acid, 3-mercapto-, monosodium salt is expected to be either excreted unchanged via the urine or metabolised via Cytochrome P450s. It will be eliminated via urine, in cases as glucuronic acid conjugates. The possibility of protein binding can not be ruled out without adequate experimental data,because it is theoretically possible for the thiol-group to react with amino acids. However, for the structural analogue mesna there are data available which prove it to bind in rats to plasma albumin and to different immunoglobulins. This increases the probability of protein binding of MPS significantly.

Prediction using TOXTREE

The chemical structure of 1-Propanesulfonic acid, 3-mercapto-, monosodium salt was assessed by Toxtree (v.2.5.0) modelling tool for possible metabolism. SMART Cyp is a prediction model, included in the tool, which identifies sites in a molecule that are labile for the metabolism by Cytochromes P450.

1-Propanesulfonic acid, 3-mercapto-, monosodium salt, containing the structural alerts: cation, anion, sulfonic acid derivative, sulfenic acid derivative, thiol and alkyl thiol (Class 1: At least one functional group), is expected to be well metabolized by the Cytochrome P450 group of drugs metabolizing enzymes. The primary site of metabolism is the terminal sulphur atom. The secondary and tertiary sites of metabolism are the carbon-atoms of the chain.