1-(3-sulphonatopropyl)pyridinium

Endpoint summary

Description of key information

The substance is expected to be well absorbed after oral exposure, based on its low molecular weight, its high water solubility and its logPow of < -2.78. Concerning the absorption after exposure via inhalation, as the chemical has a low vapour pressure, it is clear, that the substance has a low availability for inhalation. Given its hydrophilicity (logPow of < -2.78), if any of the substance is available for inhalation, it is expected to be absorbed directly through aqueous pores. Moreover, the average particle size is 32.1 µm (< 100 µm), indicating the potential to be inspired. 3-(1-Pyridinio)-1-propanesulfonate is expected to be absorbed to a limited extent following dermal exposure into the stratum corneum and into the epidermis, due to its high water solubility and its logPow. The substance is expected to be extensively and wide distributed throughout the body into the intravasal compartment. The substance does not bear accumulative potential after repeated exposures. 3-(1-Pyridinio)-1-propanesulfonate is expected to be metabolised via the Cytochrome P450 group of metabolizing enzymes. However, elimination of unchanged or metabolised substance will occur mainly via the urine, either without or after conjugation to glucuronic acid, activated sulphate or activated methionine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Background

There is little data available on physico-chemical properties of3-(1-Pyridinio)-1-propanesulfonate. With the aid of the EPIWIN software some physical-chemical properties were calculated.

The substance is a white solid odourless powder at room temperature (Raschig, 2011). The substance is very soluble in water (240.5 g/L at 20 °C as calculated by EPIWIN (Chemservice, 2011a) and has a logP_owof < -2.78 (Cuthbert and Mullee, 2001). Furthermore, it has a very low vapour pressure (calculated by Modified Grain Method: 4.24 E-05 Pa at 25 °C, Chemservice, 2011b). The melting point amounts to 266 °C (BAM, 2005) and it decomposes above 284 °C (BAM, 2005).

Hydrolysis as a function of pH has not been determined. However, hydrolysis is not expected, due to the lack of functional groups. The substance is not toxic in rats by oral and dermal routes of exposure (oral LD₅₀> 5000 mg/kg bw, Ullmann and Sacher, 1983; dermal LD₅₀> 2000 mg/kg bw, Driscoll, 2001). It is neither an eye (Ullmann and Suter, 1982), nor a skin irritant (Clauss and Ullmann, 1982). The substance was not sensitising to skin in Guinea Pig Maximisation Test (Driscoll, 2001). The substance was not mutagenic in bacterial strains (OECD 471, Guenard, 1983; Deparade, 2004) and in in vitro mammalian Micronucleus Test conducted with human lymphocytes (OECD 487, Bohnenberger, 2012). Additionally, the results of the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD 422, Dunster, 2013, Report No. 41300260) show that the substance in not toxic by prolonged exposures in rats. No mortality and clinical signs were detected in treated animals. Body weight, food consumption, haematology and blood chemistry parameters were comparable to controls. Behavioural parameters, functional performance and sensor reactivity were not affected. There were no treatment-related effects on mating, fertility and gestation lengths for treated animals. No clinically observable signs of toxicity were detected for offspring from all treatment groups. Litters size, sex ratio, body weight development and surface righting reflex were not affected. No findings at necropsy were detected in adults and offspring. NOAEL of 1000 mg/kg bw, the highest dose level tested, was established for systemic toxicity and for reproductive performance.

Toxicokinetic statement for 3-(1-Pyridinio)-1-propanesulfonate

The available physico-chemical data of the substance of interest are analysed and used to assess the toxicological behaviour of 3-(1-Pyridinio)-1-propanesulfonate.The results of this analysis will answer the question, how the chemical will react in the body.

The EU Technical Guidance Document on Risk Assessment (TGD, Part I, Appendix VI) gives a number of physico-chemical properties that normally determine oral, inhalatory and dermal absorption, distribution, metabolism and elimination of substances (LINK to Guidance Document: http://ecb.jrc.ec.europa.eu/tgd/).

Absorption

In general, absorption of a chemical is possible, if the substance crosses biological membranes. This process requires a substance to be soluble both in lipid and in water and is also dependent on its molecular weight (substances with molecular weights below 500 g/mol are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes.

3-(1-Pyridinio)-1-propanesulfonateis favourable for absorption, when taking its molecular weight (201.24 g/mol) into account. In addition, the substance is very soluble in water (240.5 g/L), so it is apparent, that its absorption is also favoured. The value of the logP_ow(< -2,78) shows the substance to be better soluble in water than in octanol (positive logP_owfor lipophilic substances, negative logP_owfor hydrophilic substances). Considering its water solubility and the value for logP_owbelow 0, the absorption into the body will still be favoured (logP_owbetween 0 and 4 are most favourable for absorption).3-(1-Pyridinio)-1-propanesulfonateis not irritating to the skin, or to the eyes. Therefore, the above mentioned enhancement of absorption for irritants, applies to a limited extent.

Absorption from the gastrointestinal tract

Regarding oral absorption, hydrolysis, as a favoured reaction in the acidic environment of the stomach, is not expected for 3-(1-pyridinio)-1-propanesulfonate due to the lack of hydrolysable functional groups.

The physico-chemical data suggest that orally administered 3-(1-pyridinio)-1-propanesulfonate will be absorbed to a higher extent due to its molecular weight (201.24 g/mol) and high water solubility (240.5 g/L). Regarding molecular weight, 3-(1-pyridinio)-1-propanesulfonate is a small molecule and therefore it may be taken up easily. The substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Regarding water solubility, the substance will readily dissolve into the gastrointestinal fluids. However, its absorption by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid because of its negative logP_owvalue (-2.78) which is out of the range (between -1 and 4) favourable for absorption.Additionally, metabolism may occur by gut microflora or by enzymes in the gastrointestinal mucosa. The available acute toxicity data show that the substance was absorbed systemically if administered orally to rats. This was confirmed by the fact that three male rats of the 5000 mg/kg group showed mottled lungs (Ullmann and Sacher, 1983). The substance is, however, not toxic per se since no mortality, neither signs of toxicity nor other findings at necropsy were observed at the highest dose level of 5000 mg/kg bw.
Based on this data, 100 % absorption is assumed for oral route (in case of hazard assessment: DNEL calculation) and considered to be equal in rats and in humans since no substance specific information is available.

Absorption from the respiratory tract

Regarding absorption in the respiratory tract, any gas or vapour has to be sufficiently lipophilic to cross the alveolar and capillary membranes (moderate logP_owvalues between 0-4 favourable for absorption). The rate of systemic uptake of very hydrophilic gases or vapours may be limited by the rate at which they partition out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. Such substances may be transported out of the lungs with the mucus and swallowed or may pass across the respiratory epithelium via aqueous membrane pores. Very hydrophilic substances might be absorbed through aqueous pores (for substances with molecular weights below and around 200 g/mol) or be retained in the mucus.

3-(1-Pyridinio)-1-propanesulfonate has a very low calculated vapour pressure (4.24 E-05 Pa at 25 °C), which indicates a low availability for inhalation. However, the low logP_owindicates a potential for absorption through aqueous pores. Furthermore, a certain amount of the substance can be available for inhalation due to its appearance form as powder. The average particle size is 32.1 µm (< 100 µm), indicating the potential to be inspired. According to the Endpoint specific guidance R.7.C., particles with aerodynamic diameters below 50 µm may reach thoracic region of lungs. Moreover, water soluble dusts could readily diffuse/dissolve into the mucus lining the respiratory tract and thereafter be absorbed through aqueous pores due to its high solubility in water. Based on this data, 100 % absorption is assumed for inhalation route (in case of the route-to-route extrapolation for DNEL calculation) and considered to be equal in rats and in humans since no substance specific information is available.

Absorption following dermal exposure

In order to cross the skin, a compound must first penetrate into the dead stratum corneum and may subsequently reach the viable epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the viable epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 g/mol are favourable for penetration of the skin and substances above 500 g/mol are normally not able to penetrate. The molecular weight of 3-(1-pyridinio)-1-propanesulfonate (201.24 g/mol) is in the range favourable for absorption. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. However, 3-(1-Pyridinio)-1-propanesulfonate may be too hydrophilic to cross the lipid rich environment of the stratum corneum due to its very high water solubility (240.5 g/L) and logP_owof -2.78. Absorption of 3-(1-pyridinio)-1-propanesulfonate into the stratum corneum via its partition from the air can be ruled out due to the low vapour pressure of the substance (4.24 E-05 Pa at 25 °C). The substance is neither a skin irritant nor corrosive, therefore no enhancement of dermal absorption is expected due to the damage of the skin surface. The systemic toxicity of 3-(1-pyridinio)-1-propanesulfonate via the skin is low. This has been proved by the results of the acute dermal toxicity study, which showed no mortality after dermal application of 2000 mg/kg bw in rats (Driscoll, 2001). During the whole absorption process into the skin, the compound may be subject to biotransformation.

Based on this knowledge, 3-(1-pyridinio)-1-propanesulfonate is expected to be absorbed following dermal exposure to a limited extent into the stratum corneum and from there into the epidermis, due to its negative logP_ow(-2.78) and high water solubility (240.5 g/L). The molecular weight of 201.24 g/mol (< 500 g/mol) points to a moderate absorption through the skin. Therefore, 50 % dermal absorption is considered appropriate for the hazard assessment (DNEL derivation).

Distribution

In general, the following principle applies: the smaller the molecule, the wider the distribution. The rate at which highly water-soluble molecules distribute may be limited by the rate at which they cross cell membranes. In case of 3-(1-pyridinio)-1-propanesulfonate, no data is available for distribution patterns. The distribution of 3-(1-Pyridinio)-1-propanesulfonate is expected to be limited to the intravasal compartment, due to its better solubility in water than in octanol (logP_ow< -2.78).

The chemical has no structural alerts linked to high reactivity with biomolecules (proteins and DNA). It was confirmed by the profiling methods of the OECD QSAR Toolbox (v3.2, please refer to the attached pdf “The profiling results of the target chemical”). Thus, the amount of substance available for distribution cannot be limited due to protein binding. The substance can undergo extensive first-pass metabolism. In this case, the predictions made on the basis of the physico-chemical characteristics of the parent substance may not be applicable.

Based on these data, distribution of 3-(1-pyridinio)-1-propanesulfonate is expected to be extensive and wide throughout the body.

Accumulation

The experimentally determined logP_owof < -2.78 and the predicted water solubility of 240.5 g/L of 3-(1-pyridinio)-1-propanesulfonate do not indicate potential for accumulation in the body.

Metabolism

Route specific toxicity may result from several phenomena, such as hydrolysis within the gastrointestinal or respiratory tracts, also metabolism by gastrointestinal flora or within the gastrointestinal tract epithelia (mainly in the small intestine), respiratory tract epithelia (sites include the nasal cavity, tracheo-bronchial mucosa [Clara cells] and alveoli [type 2 cells]) and skin.

Hydrolysis is judged not to apply for 3-(1-pyridinio)-1-propanesulfonate, as it lacks the necessary functional groups. However, its metabolism is very likely to occur via the Cytochrome P450 group of metabolising enzymes, as it has been predicted by the TOXTREE modelling tool (Chemservice, 2011c) and the OECD QSAR Toolbox (v3.2, please see attached to this file below). According to the modelling results, 3-(1-pyridinio)-1-propanesulfonate contains the structural alerts: “cation”, “anion”, “sulfonic acid derivative”, “aromatic compound” and “heterocyclic compound” (Class 1: At least one functional group). The primary and secondary sites of metabolism are the carbon atoms of the chain, which are predicted to be subject to aliphatic hydroxylation. The tertiary site of metabolism is the nitrogen-atom of the aromatic ring, which is predicted to be subject toN-oxidation.

The above mentioned functional groups can react in phase 2 of the biotransformation with different molecules, leading to the formation of conjugations. This is not necessary for 3-(1-pyridino)-1-propanesulfonate as its water solubility is already very high and it can be eliminated via the urine without further metabolism. If metabolism of the substance takes place, it is most likely that the hydroxyl-groups will be conjugated to glucuronic acid, activated sulphate or activated methionine.

The oxidised or hydroxylated nitrogen can be further metabolised by the monoaminooxigenase to an imine via dehydration, which can be hydrolysed to ammonia and an aldehyde. Furthermore, this amino-group could be subject either to conjugation with glucuronic acid, activated sulphate or subject toN-acetylation mediated byN-acetyltransferases. In conclusion, it is possible that the substance of interest will be subject to metabolism by cytochrome P450 enzymes.

Excretion

The major routes of excretion for substances from the systemic circulation are via the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). Substances that are excreted favourable in the urine tend to be water soluble and of low molecular weight (below 300 g/mol in the rat). Furthermore, they might be ionized at the pH of urine. Most will have been filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for reabsorption into the systemic circulation across the tubular epithelium. Substances that are excreted in the bile tend to be amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have higher molecular weights and pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling which will prolong their biological half-life. This is particularly a problem for conjugated molecules that are hydrolysed by gastrointestinal bacteria to form smaller more lipid soluble molecules that can then be reabsorbed from the GI tract. Those substances less likely to recirculate are substances having strong polarity and high molecular weight of their own accord. Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the GI tract directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed. Non-ionized and lipid soluble molecules may be excreted in the saliva, where they may be swallowed again, or in the sweat. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.

For 3-(1-Pyridinio)-1-propanesulfonate no data is available concerning its elimination. Concerning the above mentioned behaviour predicted for its metabolic fate, it is likely that the parent substance will be excreted unchanged. However, if unchanged excretion is assumed, it is likely to be excreted via the urine. This is based on the chemical structure of 3-(1-pyridinio)-1-propanesulfonate, its molecular weight and its high water solubility.

Concerning the fate of the metabolites formed of 3-(1-pyridinio)-1-propanesulfonate, the hydroxylated carbon-atoms and the nitrogen, in cases linked to glucuronic acid,activated sulphate or activated methionine or acetylated byN-acetyltransferasesshould be eliminated via the urine.

 

Prediction using TOXTREE

The chemical structure of 3-(1-Pyridinio)-1-propanesulfonate 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.

3-(1-Pyridinio)-1-propanesulfonate, containing the structural alerts: cation, anion, sulfonic acid derivative, aromatic compound and heterocyclic compound (Class 1: At least one functional group), is expected to be well metabolized by the Cytochrome P450 group of metabolizing enzymes. The primary and secondary sites of metabolism are the carbon atoms of the chain, which are predicted to be subject to aliphatic hydroxylation. The tertiary site of metabolism is the nitrogen-atom of the aromatic ring, which is predicted to be subject to N-oxidation.