Potassium 3-sulphonatopropyl acrylate

Endpoint summary

Additional information

There are no experimental studies available in which the toxicokinetic properties of Acrylic acid, 3-sulfopropyl ester, potassium salt (SPA) were investigated. Therefore, whenever possible, toxicokinetic behaviour was assessed taking into account the available information on physicochemical and toxicological characteristics of SPA according to “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014)”.

In its pure state, SPA is a white odourless powder which is highly soluble in water (≥ 3000 g/L). The molecular weight of SPA is 232.3g/mol and the octanol/water partition coefficient (log Pow) was determined to be -3.63.

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful physico-chemical parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2014).

Absorption after oral exposure

In general, the smaller the molecule, the more easily it will be absorbed. Molecular weights below 500 g/mol are favorable for oral absorption (ECHA, 2014). As the molecular weight of SPA is 232.3g/mol, oral absorption of SPA in the gastrointestinal (GI) tract is considered possible.

As a general rule, moderate log P values (between -1 and 4) are favourable for absorption by passive diffusion. The negative log Pow of -3.63 indicates that SPA is more soluble in water than in octanol, i.e. hydrophilic. Water-soluble substances will readily dissolve into the GI fluids. However, absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the GI fluid. The high water solubility of SPA (≥ 3000 g/L) and the log Pow value of -3.63 indicates that absorption from the GI tract may be limited.

It should be noted that prior to absorption, hydrolysis of SPA in the GI tract may occur. For SPA it seems to be likely that it will be hydrolysed and that the cleavage products could be absorbed. Potential metabolites predicted by OECD QSAR toolbox v. 3.3 indicate that SPA will be hydrolysed to potassium 3-hydroxypropane-sulfonate and acrylic acid.

The available data on acute oral toxicity of the test item were also considered for the assessment of the oral absorption. An acute oral toxicity study performed with SPA showed that a single dose of 2000 mg/kg bw did not cause deaths or signs of systemic toxicity in male and female rats (Driscoll, 2001). The results indicate that SPA or its potential metabolites possess either a low toxic potency or a low absorption.

 

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening testaccording to OECD guideline 422, no treatment-related effects were observed with 100, 300 and 1000 mg SPA/kg bw/day (Przybyła, 2015).

In general, it can be assumed that SPA may undergo chemical changes in the GI tract due tohydrolysis. As a result of the hydrolysis, potassium 3-hydroxypropane-sulfonate and acrylic acid will be formed as the metabolites.

The physico-chemical properties of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance may no longer apply (ECHA, 2014). For the cleavage products potassium 3-hydroxypropane-sulfonate and acrylic acid, it is anticipated that they will be absorbed from the GI tract.

The cleavage product acrylic acid is a colorless liquid and highly soluble in water (~ 1000 g/L). It is totally miscible with water and most organic solvents (log Pow 0.35 - 0.46). Kutzman et al. (1982) showed that 26 µg/kg bw (1-¹¹C)-acrylic acid orally administered to female rats was rapidly absorbed and expired mainly as ¹¹CO₂ within 1 h post-administration.

Physico-chemical data estimated using Epi suite v.4.10 predict that potassium 3-hydroxypropane-sulfonate is highly water-soluble (~ 1000 g/L) with a log Pow value of -5.01. Based on the physico-chemical properties, it can be assumed that absorption of potassium 3-hydroxypropane-sulfonatefrom the GI tract may be limited. However, as the molecular weight is less 200 (MW 178.24), potassium 3-hydroxypropane-sulfonatemay pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water (Renwick, 1994).

In summary, the physico-chemical properties of SPA discussed above and relevant data on the potential metabolites predicted using OECD QSAR toolbox, indicate the hydrolysis of SPA to potassium 3-hydroxypropane-sulfonate and acrylic acid and absorption of the cleavage products in the GI tract.

 

Absorption after inhalation exposure

No data on acute inhalation toxicity are available. As the physical state of SPA is solid and the mass median diameter is 60.69 µm, SPA has the potential to be inhaled. Thus,exposure to humans via the inhalation route cannot be excluded. For absorption of deposited material similar criteria as for GI absorption can be applied.

 

Absorption after dermal contact

In general, dry particles will have to dissolve into the surface moisture of the skin before uptake can begin. The smaller the molecule, the more easily it may be taken up. A molecular weight below 100 g/mol favors dermal absorption and above 500 g/mol the molecule may be too large (ECHA, 2014). As the molecular weight of SPA is 232.3 g/mol, dermal absorption of the molecule is likely.

Moreover, if a substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2014). However, as SPA is not considered as irritating to the skin, an enhanced penetration of the substance due to local skin damage can be excluded.

For SPA a QSAR-based model published by DERMWIN, taking into account molecular mass and log Kow, estimated a dermal permeability constant Kp of 3.19E-07 cm/h. Similar to the approach taken by Kroes et al. (2007), the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated, resulting in dermal absorption of 0.95596 µg/cm²/h SPA. Generally, this value is considered to indicate a dermal absorption of approximately 20% (Mostert and Goergens, 2011). Therefore, the calculated dermal uptake indicates that SPA has a medium to low potential for dermal absorption.

However, as SPA is highly water-soluble and the log Pow value is below 0, poor lipophilicity will limit penetration of SPA into the stratum corneum (ECHA, 2014). Furthermore, SPA is not sufficiently lipophilic to cross the lipid rich environment of the stratum corneum and thus dermal uptake will be low (ECHA, 2014). This is in accordance with the result of the acute dermal toxicity study, in which no systemic toxicity was found up to 2000 mg/kg bw in male and female rats (Driscoll, 2001).

Overall, the physico-chemical parameters as well as the fact that SPA is not irritating to skin imply that dermal uptake of SPA will be low.However, it should be noted that the skin sensitisation study showed a positive result, indicating that some dermal absorption takes place (Driscoll, 2001).

 

Distribution

Distribution within the body through the circulatory system will depend on the molecular weight, the lipophilic character and water solubility of a substance. In general, the smaller the molecule, the wider is the distribution. Small water-soluble molecule and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution. If the molecule is lipophilic (log Pow > 0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rates of absorption (ECHA, 2014).

As discussed above, the oral absorption of SPA is considered to be low based on the physico-chemical properties (highly water-soluble, log Pow of -3.63, MW of 232.3 g/mol). But nevertheless, SPA will undergo hydrolysis in the GI tract, leading to the cleavage products acrylic acid and potassium 3-hydroxypropane-sulfonate. 

Acrylic acid is a highly water-soluble substance (~1000 g/L) with a log Pow of 0.35-0.46 and a molecular weight of 72.06 g/mol. As the molecular weight is low (less than 200), the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water (ECHA, 2014). Regardless of the route of exposure, acrylic acid is rapidly absorbed and metabolized. It is extensively metabolized, mainly to 3-hydroxy propionic acid, CO₂ and mercapturic acid, which are eliminated via the expired air and urine (WHO, 1997).

Based on the physico-chemical data of potassium 3-hydroxypropane-sulfonate (highly water-soluble, log Pow of -5.01, MW of 178.24), absorption from the GI tract may be limited. However, as the molecular weight is less 200,the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water and thus distributed in the organism (ECHA, 2014). It can be assumed that potassium 3-hydroxypropane-sulfonate is distributed in the organism, but it is unlikely that the substance distributes into cells due to its hydrophilic characteristic (log Pow of -5.01).

Overall, the available information indicate that the cleavage products acrylic acid and potassium 3-hydroxypropane-sulfonate can be distributed in the organism.

 

Accumulation

In general, lipophilic substances tend to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. Substances with log Pow values of 3 or less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous (ECHA, 2014). The log Pow of -3.63 implies that SPA may have a low potential to accumulate in adipose tissue. As mentioned, the absorption of SPA is considered to be low and therefore the potential of bioaccumulation is low as well. Furthermore, SPA will undergo hydrolysis in the GI tract, leading to the cleavage products acrylic acid and potassium 3-hydroxypropane-sulfonate.

The physico-chemical data on acrylic acid (highly soluble in water, log Pow of 0.35-0.46, MW of 72.06 g/mol) indicate that the potential for bioaccumulation in adipose tissue is low. With respect to the rapid metabolism and elimination of acrylic acid, its half-life is short (minutes) and therefore it has no potential for bioaccumulation (WHO, 1997).

The log Pow ofpotassium 3-hydroxypropane-sulfonateis -5.01 and it is highly soluble in water (WHO, 1997). Consequently, there is no potential to accumulate in adipose tissue.

Overall, the available information indicate that no significant bioaccumulation of SPA and its cleavage products in adipose tissue is anticipated.

 

Metabolism

Based on the physico-chemical properties of SPA, low oral absorption is predicted. However, SPA undergoeshydrolysis in the GI tract, leading to the cleavage products acrylic acid and potassium 3-hydroxypropane-sulfonate. It is assumed that the cleavage products acrylic acid and potassium 3-hydroxypropane-sulfonate will be absorbed from the GI tract.

Kutzman et al. (1982) reported that26 µg/kg bw (1-¹¹C)-acrylic acid orally administered to female rats was rapidly absorbed and expired, mainly as ¹¹CO₂ within 1 h post-administration.Regardless of the route of exposure, acrylic acid is rapidly absorbed and metabolized. It is extensively metabolized, mainly to 3-hydroxy propionic acid, CO₂ and mercapturic acid (WHO, 1997).

For potassium 3-hydroxypropane-sulfonate it can be assumed that it is metabolised to potassium 3-sulfopropanal and further to potassium 3-sulfopropanoic acid. The major metabolic pathway of propionic acid begins with its conversion to propionyl coenzyme A (propionyl-CoA). As propionic acid has three carbons, propionyl-CoA cannot directly enter either beta oxidation or the citric acid cycles (Nelson and Cox, 2001). In most vertebrates, propionyl-CoA is carboxylated to D-methylmalonyl-CoA, which is isomerized to L-methylmalonyl-CoA. A vitamin B12-dependent enzyme catalyzes rearrangement of L-methylmalonyl-CoA to succinyl-CoA, which is an intermediate of the citric acid cycle and can be readily incorporated into this well-established pathway (Nelson and Cox, 2001). The minor metabolic pathway is the endogenous catabolism of propionic acid via acrylyl coenzyme A and 3-hydroxy propionic acid (Nelson and Cox, 2001). This pathway is analogous with fatty acid beta oxidation, which is common to all mammalian species.

The potential metabolites were predicted using the OECD QSAR toolbox 3.3. The metabolites predicted by the hydrolysis metabolism simulator indicatethat SPA will be hydrolysed to potassium 3-hydroxypropane-sulfonate and acrylic acid. The microbial and the liver metabolism simulator similarly indicate hydrolysis of SPA.The metabolism simulators predicted 4 liver, 1 skin, and 18 microbial metabolites.

 

Excretion

Based on the assumption that the oral absorption of SPA is low, the main route of excretion is expected to be via faeces. However, as described above, SPA mayundergo hydrolysis in the GI tract. As a result of hydrolysis,acrylic acid and potassium 3-hydroxypropane-sulfonatewill be formed.

If absorbed, acrylic acid is rapidly metabolized mainly to 3-hydroxy propionic acid, CO₂and mercapturic acid, which are eliminated via the expired air and urine (WHO, 1997).

3-hydroxypropane-sulfonate is metabolized by endogenous pathways to propionic acids (Nelson and Cox, 2001). The respective metabolites may be excreted in the urine, exhaled as CO₂or incorporated into normal processes of the fat metabolism (Nelson and Cox, 2001). Thus, propionic acid is unlikely to be excreted to a significant degree in its unchanged form via the urine or faeces. It is highly likely that the same reasoning can be applied to the cleavage product 3-hydropropane-sulfonate.

In conclusion, taking into account all available data, the absorption rate of SPA will be limited following oral ingestion or dermal contact due to its physico-chemical properties. The inhalation exposure route cannot be excluded, asthe physical state of SPA is solid and the mass median diameter is 60.69 µm. For absorption of deposited material similar criteria as for GI absorption can be applied.

 

In general, it can be assumed that SPA will undergo hydrolysis in the GI tract, leading to the cleavage products acrylic acid and potassium 3-hydroxypropane-sulfonate. Both cleavage products will be absorbed in the GI tract and distributed in the organism. The available data indicate that no significant bioaccumulation of acrylic acid and potassium 3-hydroxypropane-sulfonate in adipose tissue is anticipated. Acrylic acid is extensively metabolized, mainly to 3-hydroxy propionic acid, CO₂ and mercapturic acid, which are then eliminated via the expired air and urine (WHO, 1997). It is likely that potassium 3-hydroxypropane-sulfonate will be metabolized by endogenous pathways and to a lesser extent by direct beta-oxidation. The respective metabolites may be excreted in the urine, exhaled as CO₂ or incorporated into normal processes of the fat metabolism.

References not cited in the IUCLID:

ECHA (2014) Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, Version 2, November, 2014

Kroes et al. (2007) Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food Chem. Toxicol. 45, 2533–2562

Nelson D. and Cox M., 2001, Lehninger Biochemie, 3^rdedition, ISBN 3-540-41813-X Springer Verlag Berlin, Heidelberg, New York

Lipinski et al. (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 46: 3-26

Mostert and Georgens (2011) Dermal DNEL setting: using QSAR predictions for dermal absorption for a refined route-to-route extrapolation. Society of Toxicology, Annual Meeting, ISSN 1096-6080 (http://www.toxicology.org/AI/PUB/Toxicologist11.pdf), 120(2): 107

Potts and Guy (1992) Predicting skin permeability.Pharm. Res. 9(5): 663-669

Rehner and Daniel (2002) Biochemie der Ernährung, 2nd edition, Spektrum Akademischer Verlag

Renwick, A.G. (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes,A.W. (ed.) Principles and Methods of Toxicology. Raven Press, New York, p 103.

Kutzman R.S., et al. (1982) The biodistribution and metabolic fate of (11C) acrylic acid in the rat after acute inhalation exposure or stomach intubation. J Toxicol Environ Health, 10(6): 969-980.