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Toxicological information

Dermal absorption

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Administrative data

Endpoint:
dermal absorption
Type of information:
other: assessment of dermal absorption based on physico-chemical properties
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An assessment of the toxicokinetic behaviour of calcium sulfonate target substance was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicological data.
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
basic toxicokinetics
Type of information:
other: assessement of toxicokinetic behaviour based on physico-chemical properties and toxicological data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An assessment of the toxicokinetic behaviour of the calcium sulfonate target substance was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicological data.
Reason / purpose for cross-reference:
reference to same study
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
according to guideline
Guideline:
other: Technical guidance document, Part I, 2003; ECHA guidance R7C., 2014
Deviations:
no
GLP compliance:
no
Type:
absorption
Results:
The absorption of the calcium sulfonate target substance is rather limited, based on the absorption-hindering properties (high molecular weight, slight water solubility and high LogPow) and the observed effects in toxicological experiments.
Type:
distribution
Results:
Even though the high LogPow would indicate the possibility to reach the intracellular compartment, this seems to be unlikely as the molecular weight of the un-metabolised substance is fairly high. Therefore, the distribution is expected to be limited.
Type:
excretion
Results:
The metabolites formed of the calcium sulfonate target substance should be eliminated mainly via the urine and to a smaller extent via the bile.
Details on 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. According to ECHA’s guidance R.7c [ECHA 2014], it is stated that the smaller the molecule the more easily it may be taken up (substances with molecular weights below 500 are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes.
The calcium sulfonate target substance is not favourable for absorption, due to its molecular weight (MW >= 859.4 and <= 1026.7 g/mol), very limited water solubility (0.0735 mg/L) and a high logPow (5.38 – 7.44). Following oral ingestion such lipophilic low water soluble substances are hindered to be absorbed because the dissolving in the gastrointestinal fluids is impaired. On the other hand, any lipophilic compound may be taken up by micellular solubilisation and this mechanism may be of particular importance for the calcium sulfonate target substance since it is poorly soluble in water. The substance does not bear surface activity; therefore an enhancement of absorption is not applicable, and it is not irritating to skin or eyes confirming that no further enhancement of absorption seems to be applicable.
The above mentioned properties determine the absorption of the calcium sulfonate target substance to be rather limited based on the absorption-hindering properties (molecular weight, slight water solubility and high LogPow) and the observed effects in toxicological experiments.
The available data suggest that orally administered reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts may be absorbed to a limited extent, while micellular solubilisation, pinocytosis and persorption cannot be ruled out. This thesis is supported by the LD50 value of 10000 mg/kg bw available for the calcium sulfonate read across substance CAS 70024-69-0, which shows that absorption of the substance did occur to a certain extent, and that the substance is not acutely toxic after oral exposure (no systemic effects, but only GI-Tract associated effects; Swan, 1972). Moreover, the following supporting LD50 data of the read-across substances Analogue of CAS 70024-69-0, CAS 115733-09-0, CAS 68783-96-0 and CAS 61789-86-4 support this thesis by LD50 values of more than 5000 mg/kg (Sanitised, F, 1989, Sanitised, A. 1981, Sanitised C., 1984, Sanitised E., 1985, Regel, 1970, Gabriel 1981a, Ohees, 1968a, b) and the non-occurrence of significant systemic effects.
Due to the lack of further data, an absorption rate of 50% should be taken into account when performing the subsequent risk assessment.
Concerning absorption in the respiratory tract, any gas or vapour or other substances inhaled as respirable dust (i.e. particle size ≤ 15 μm) has to be sufficiently lipophilic to cross the alveolar and capillary membranes (moderate LogPow values between 0-4 are 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 pass across the respiratory epithelium via aqueous membrane pores. Lipophilic substances (LogPow >0) have the potential to be absorbed directly across the respiratory tract epithelium. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed [ECHA, 2008]. Very hydrophilic substances can be absorbed through aqueous pores (for substances with molecular weights below and around 200) or be retained in the mucus.
Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts is a brown paste at room temperature, so dust inhalation does not need to be regarded. It has a low vapour pressure (0.184 Pa at 25°C). According to the BG Bau [BG Bau 2017], a vapour pressure of p < 0.01 hPa is very low, p = 1-10 hPa low and p > 10 hPa is high. The 31. BImSchV describes an organic substance as volatile if it has a vapour pressure of 0.01 kPa or more at 293.15 K. Also, according to ECHA’s guidance, substances are not available for inhalation as a gas in a relevant manner with a vapour pressure less than 0.5 kPa (or a boiling point above 150°C) [ECHA, 2008]. This applies for the calcium sulfonate target substance and all together indicates only low availability for inhalation. The high molecular weight and the high LogPow also indicate no possibility for absorption through aqueous pores. Based on this data - even though the LogPow value above 0 indicates the potential for absorption directly across the respiratory tract epithelium (which is unlikely as the substance is ionisable) - it can be expected that reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts is marginally available in the air for inhalation and any inhaled substance which is not be subjected to ciliary clearance is not expected to be absorbed.
However, due to the lack of toxicokinetic test data, the inhalative absorption used in subsequent risk assessments is 100% as a worst case assumption.
In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration of the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal; TGD, Part I, Appendix IV). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Vapours of substances with vapour pressures below 100 Pa are likely to have enough contact time to be absorbed and the amount absorbed dermally is most likely more than 10% and less than 100 % of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.
In the case of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, the molecular weight is above 500, which indicates already a marginal potential to penetrate the skin. This is accompanied by a low hydrophilicity of the substance and even though the stratum corneum is open for lipophilic substances, the epidermis is very resistant against penetration by highly lipophilic substances. However, the amount of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts which is absorbed following dermal exposure into the stratum corneum is unlikely to be transferred into the epidermis. The substance does not show characteristics of a surfactant and, furthermore, the calcium sulfonate target substance is not irritating to skin and eyes, and therefore enhancement of dermal absorption can not be expected.
In support of this hypothesis (the low dermal absorption), the systemic toxicity of the calcium sulfonate read across substance CAS 70024-69-0 and of 115733-09-0 via the skin is low (acute dermal toxicity, LD50 value of > 2000 and > 5000 mg/kg bw for rats, respectively).
However, as the substance is classified as a skin sensitizer, it is clear that at least a limited amount is absorbed via the dermal route of exposure.
In conclusion, the evaluation of all the available indicators and the results of toxicity studies allow the allocation of the chemical in question into the group of chemicals with a low dermal absorption. In detail, due to it’s molecular weight and the results for acute toxicity, the use of a factor of 10 % for the estimation of dermal uptake for reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts is justified (Schuhmacher –Wolz et al.,2003; TGD, Part I, 2003).
Details on distribution in tissues:
In general, the following principle applies: the smaller the molecule, the wider the distribution. A lipophilic molecule (LogPow >0) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. It’s not possible to foresee protein binding, which can limit the amount of a substance available for distribution. Furthermore, if a substance undergoes extensive first-pass metabolism, predictions made on the basis of the physico-chemical characteristics of the parent substance may not be applicable.
In case of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, no quantitative data is available for distribution patterns. Even though the high LogPow would indicate the possibility to reach the intracellular compartment, this seems to be unlikely as the molecular weight of the un-metabolised substance is high. Therefore, the distribution is expected to be limited.
After oral exposure, the first target will be the gastrointestinal tract, where the substance may not be absorbed in significant amounts; however, possible bacterial metabolites might be absorbed in higher quantities and transferred via the blood stream to the liver.
After reaching the liver via the portal vein, any absorbed calcium sulfonate target substance will be further distributed via the bloodstream. Here, especially the kidneys due to their filter function and the heart due to its enormous need for nutrients and consequently large blood flow through coronary arteries will be exposed.
Possible metabolites (See 3.4 Metabolism) and degradation products are expected to be of the same or smaller size and at least same or higher hydrophilicity as the parent compound. Hence, similar distribution patterns can be expected and no differentiation between the parent compound and metabolites has to be made regarding distribution.
Details on excretion:
In general, the major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). For orally administered substances which are not absorbed to a significant extent, it is clear that large amounts remain in the GI tract and will subsequently be excreted again via the faeces. For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and 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 or without metabolism with skin cells.
For reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts no data is available concerning its elimination. However, due to limited absorption after oral ingestion, a large amount of un-absorbed subtstance will be excreted unchanged via the faeces. Concerning the above mentioned behaviour predicted for its metabolic fate, it is unlikely that absorbed parent substance will be excreted unchanged. The metabolites and degradation products formed of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts are expected to be smaller, more hydrophilic and higher soluble in water. So excretion of the compounds via the kidneys and so urine is expected to be efficient. Furthermore, excretion via the GI tract (unabsorbed material) and via the bile and consequent subjection to enterohepatic recycling applies only to a smaller extent.
Metabolites identified:
yes
Details on metabolites:
Route specific toxicity results 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.
As specified above, hydrolysis does not apply reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts (very low water solubility of 0.735 mg/L). However, its metabolism is very likely to occur via the Cytochrome P450 group of metabolising enzymes, as it has been predicted with the TOXTREE modelling tool (Chemservice, S.A., 2017e). According to the modelling results, reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, containing the structural alerts: sulfonic acid derivative and aromatic 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, next to aromatic ring, which are predicted to be subject to aliphatic hydroxylation (Phase-I-metabolism). The tertiary sites of metabolism are the terminal carbon-atoms of the chain, which is predicted to be also subject to aliphatic hydroxylation (Phase-I-metabolism).
Moreover, it is possible that further Phase-I-metabolism steps occur - the long carbon chains are subject to initial omega- and then successive beta-oxidation, possibly followed by oxidative scission of the aromatic ring and desulfonation. The above mentioned functional groups can react in phase 2 of the biotransformation with different molecules, leading to the formation of conjugations. This might be necessary for the parent compound, as its water solubility is fairly low and it cannot be eliminated via the urine without further metabolism. Further metabolism is most likely the conjugation of the hydroxyl-groups with glucuronic acid, activated sulphate or activated methionine. A facilitated distribution may be given for the direct metabolites due to an enhanced water solubility arising from the hydroxyl group and / or smaller size.
In conclusion, it is likely that the substance of interest will be subject to metabolism by cytochrome P450 enzymes, followed by omega- and beta-oxidation and cleavage of the aromatic ring and desulfonation.

Background:

There is data available on the physico-chemical properties of the calcium sulfonate target substance. The calcium sulfonate target substance is a dark brown coloured paste with a relatively high molecular weight (MW 859.4 and 1026.7 g/mol, Fox, 2017a). It has a melting point of 69 ± 3 °C (342 ± 3 K) determined by a modified pour point method (Fox., 2017a). Partial boiling was observed from approximately 223 °C (496 K) at 101 kPa by a differential scanning calorimetry (fox, 2017a). Its density was determined using a gas comparison pycnometer and was found to be 954 kg/m3 at 20.0 ± 1.0 °C, relative density of 0.954 (Fox, 2017a). In addition, the target substance has been tested for its vapour pressure and it was found to have a low vapour pressure of 0.184 Pa at 25°C (Tremain, 2017b). Furthermore, the partition Coefficient (n-octanol/water) was estimated using the HPLC method and was found to be 2.42 x 10E5 to 2.75 x 10E7, which corresponds to a log10 Pow of 5.38 to 7.44. The water solubility was determined using the flask method and was found to be 0.0735 mg/L at 20.0 ± 0.5 °C from a nominal loading rate of 0.1 g/L (Fox, 2017a). The calcium sulfonate target substance was found to be not surface active (with a measured surface tension of 72.5 to 73.0 ± 0.5 mN/m at 20.2 ± 0.5 °C (90 % saturated solution from a loading rate of 1.1 g/L, determined using the ring method, Fox, 2017a).

Last but not least, the physico-chemical hazardous properties of the calcium sulfonate target substance have been determined (Tremain, 2017a). The substance has a flash point of 105 ± 2 °C (closed cup equilibrium method), an auto-ignition temperature (Liquids and Gases) of 370 ± 5 °C and it is predicted not to bear explosive or oxidising properties (predicted based on the chemical structure of the test item).

The calcium sulfonate read across substances (CAS 70024-69-0 and CAS 61789-86-4; please refer to the separate read across statement by Chemservice S.A., 2017f) are slightly soluble in water (1.69 mg/L at 20°C (Fox and White, 2011a) and 0.113 mg/L at 20°C, (Fox and White, 2011b)). The partition coefficient Log10Pow of the calcium read across substances has been estimated to be > 5.47 (CAS 70024-69-0; Fox and White, 2011a) or 6.65 (Fox and White, 2011b).

The calcium sulfonate read across substances were shown not to be skin or eye irritating (Kern, T.G., 1999b, c, e; Swan, 1972, Hoff 2002a/b, Buehler, 1990a/b, 1991 a/b, Costello, 1986, Ohees, 1968 c/d, Gabriel, 1981b/c).

Systemic toxicity is expected to be low; as the calcium sulfonate read across substances were non-toxic by ingestion (Swan, 1972 - LD50 > 10,000 - < 20,000 mg/kg bw; Sanitised, F., 1989 - LD50 < 5,000 mg/kg bw; Sanitised, A., 1981 - LD50 < 5,000 mg/kg bw, Sanitised, C., 1984 - LD50 >5.000 mg/kg bw; Sanitised, E., 1985 - LD50 >5.000 mg/kg bw; Ohees, P. 1968a - LD50 > 20,000 mg/kg bw; Regel, L., 1970 - LD50 > 10,000 mg/kg bw; Ohees, P., 1968b - LD50 > 20,000 mg/kg bw, Gabriel, K. L:, 1981a - LD50 > 16,000 mg/kg bw). In addition no toxicity was found after percutaneous absorption (Sanitised, G., 1989, LD50 < 2,000 mg/kg bw; Sanitised, B., 1981 - LD50 > 5,000 mg/kg bw, Sanitised, J., 1993 - LD50 > 2000 mg/kg bw, Costello, B. A:, 1986a - LD50 > 4000 mg/kg bw). The calcium sulfonate read across substances (EC 939-141-6) and CAS 75975-85-8; please refer to the separate read across statement by Chemservice S.A., 2017f) were shown in a Local Lymph Node Assay and several Buehler tests to bear a potential to cause allergic reactions (Lees, 1996, Shults, 1993, Bonnette, 1993a, b). However, the other high TBN (please refer to Classification and labelling Proposal for Skin sensitisation) calcium sulfonate read across substance (CAS 61789-86-4) was shown not to be skin sensitising (Kiplinger, 1992a/b, Blaszcak, 1992, Reagan, 1988). The calcium sulfonate with TBN =300 was found to be sensitising (Category 1B, Kiplinger, 1992c). The skin sensitisation potential was analysed in a weight-of-evidence approach (in conjunction with various human patch test data) and the conclusion was drawn, that low TBN calcium sulfonate target substance (mono-C20-24 (even)) (TBN < 300) is a skin sensitizer (Cat. 1B, H317) with a specific concentration limit (SCL) of 10%, in accordance with CLP Regulation 1272/2008. In contrast, the high TBN calcium sulfonate target substance (mono-C20-24 (even)) (TBN ≥ 300) is not a skin sensitizer. Repeated oral exposures to the calcium sulfonate read across substance analogue of CAS 70024-69-0 (28-day study, according to OECD 407) revealed a NOAEL of 500 mg/kg bw (based on a decrease in serum cholesterol and a LOAEL of 1000 mg/kg bw, the highest dose tested (Wong, Z., 1989). Additionally, the calcium sulfonate read across substance CAS 115733-09-0 showed a systemic NOAEL of 1000 mg/kg bw for rats (Rush, R.E:, 2003). The calcium sulfonate read across substance CAS 61789-86-4 was shown to have a dermal NOAEL of 1000 mg/kg bw (Laveglia, 1988, limit test, no test article related effects). Furthermore, a repeated inhalation exposure of the calcium sulfonate read across substance (CAS 61789-86-4) according to OECD 412 by aerosol atmospheres for a period of twenty-eight consecutive days at target concentrations of 50, 150 and 250 mg/m3produced treatment-related changes at all dose levels. Clinical signs consisted of red nasal discharge, matted coat and decreased activity. On this basis a ‘No Observed Effect Level’ (NOEL) could not be established (Hoffman, 1987). The change observed at a target dose of 50 mg/m3was considered not to be indicative of an adverse effect of treatment and on this basis may be regarded as a “No Observed Adverse Effect Level” (NOAEL). The calcium read across substance (CAS 68783-86-4) was found to have a NOAEL of 1000 mg/kg after dermal exposure (Sanitised, K., 1995).

Concerning gene mutation, the calcium sulfonate read across substance CAS 70024-69-0 was shown in tests according to OECD 471 not to bear a genotoxic potential (Sanitised, H., 1989, and Sanitised, L., 1995) and the calcium sulfonate read across substance CAS 68783-96-0 was not mutagenic in tests according to OECD 476 and OECD 473 (Sanitised, D. 1984, Sanitised, M., 1995). The calcium sulfonate read across substance, (CAS 61789-86-4) was also shown in a test s according to OECD 471 to be non-mutagenic (Loveday, 1988a). Moreover, the calcium sulfonate read across substance (Analogue of 70024-69-0) was shown not to induce micronuclei (Sanitised,I., 1989, OECD 474). In addition, the calcium sulfonate read across substances (CAS 68783-96-0 and CAS 61789-86-4) were also shown not induce micronuclei (Sanitised, N., 1995, OECD 474; and Loveday, 1988b).

The calcium sulfonate read across substance (CAS 115733-09-0) was reported not to induce adverse effects in a 1-generation reproduction toxicity study according to OECD 415 (Bjorn, 2004).

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. According to ECHA’s guidance R.7c [ECHA 2014], it is stated that the smaller the molecule the more easily it may be taken up (substances with molecular weights below 500 are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes.

The calcium sulfonate target substanceis not favourable for absorption, due to its molecular weight (MW >= 859.4 and <= 1026.7 g/mol), very limited water solubility (0.0735 mg/L) and a high logPow (5.38 – 7.44). Following oral ingestion such lipophilic low water soluble substances are hindered to be absorbed because the dissolving in the gastrointestinal fluids is impaired. On the other hand, any lipophilic compound may be taken up by micellular solubilisation and this mechanism may be of particular importance for the calcium sulfonate target substance since it is poorly soluble in water. The substance does not bear surface activity; therefore an enhancement of absorption is not applicable, and it is not irritating to skin or eyes confirming that no further enhancement of absorption seems to be applicable.

The above mentioned properties determine the absorption of the calcium sulfonate target substance to be rather limited based on the absorption-hindering properties (molecular weight, slight water solubility and high LogPow) and the observed effects in toxicological experiments.

Absorption from the gastrointestinal tract

Regarding oral absorption, in the stomach, a substance may be hydrolysed, because this is a favoured reaction in the acidic environment of the stomach.The calcium sulfonate target substance (reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts)is not expected to hydrolyse in the stomach (due to its low water solubility).

In the small intestine absorption occurs mainly via passive diffusion or lipophilic compounds may form micelles and be taken into the lymphatic system. Additionally, metabolism can occur by gut microflora or by enzymes in the gastrointestinal mucosa. Water-soluble substances will readily dissolve into the gastrointestinal fluids [ECHA 2014] and the guidance value of > 1 mg/L indicates when absorption is significantly hindered. The absorption of highly lipophilic substances (LogPow of 4 or above) may be limited by the inability of such substances to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. The absorption of such substances will be enhanced if they undergo micellular solubilisation by bile salts. Substances absorbed as micelles enter the circulation via the lymphatic system, bypassing the liver.

The available data suggest that orally administeredreaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium saltsmay be absorbed to a limited extent, while micellular solubilisation, pinocytosis and persorption cannot be ruled out. This thesis is supported by the LD50 value of 10000 mg/kg bw available for the calcium sulfonate read across substance CAS 70024-69-0, which shows that absorption of the substance did occur to a certain extent, and that the substance is not acutely toxic after oral exposure (no systemic effects, but only GI-Tract associated effects; Swan, 1972). Moreover, the following supporting LD50 data of the read-across substances Analogue of CAS 70024-69-0, CAS 115733-09-0, CAS 68783-96-0 and CAS 61789-86-4 support this thesis by LD50 values of more than 5000 mg/kg (Sanitised, F, 1989, Sanitised, A. 1981, Sanitised C., 1984, Sanitised E., 1985, Regel, 1970, Gabriel 1981a, Ohees, 1968a, b) and the non-occurrence of significant systemic effects.

Due to the lack of further data, an absorption rate of 50% should be taken into account when performing the subsequent risk assessment.

Absorption from the respiratory tract

Concerning absorption in the respiratory tract, any gas or vapour or other substances inhaled as respirable dust (i.e. particle size ≤ 15 μm) has to be sufficiently lipophilic to cross the alveolar and capillary membranes (moderate LogPow values between 0-4 are 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 pass across the respiratory epithelium via aqueous membrane pores. Lipophilic substances (LogPow >0) have the potential to be absorbed directly across the respiratory tract epithelium. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed [ECHA, 2008]. Very hydrophilic substances can be absorbed through aqueous pores (for substances with molecular weights below and around 200) or be retained in the mucus.

Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts is a brown paste at room temperature, so dust inhalation does not need to be regarded. It hasa low vapour pressure (0.184 Pa at 25°C). According to the BG Bau [BG Bau 2017], a vapour pressure of p < 0.01 hPa is very low, p = 1-10 hPa low and p > 10 hPa is high. The 31. BImSchV describes an organic substance as volatile if it has a vapour pressure of 0.01 kPa or more at 293.15 K. Also, according to ECHA’s guidance, substances are not available for inhalation as a gas in a relevant manner with a vapour pressure less than 0.5 kPa (or a boiling point above 150°C) [ECHA, 2008]. This applies for the calcium sulfonate target substance and all together indicates only low availability for inhalation. The high molecular weight and the high LogPow also indicate no possibility for absorption through aqueous pores. Based on this data - even though the LogPow value above 0 indicates the potential for absorption directly across the respiratory tract epithelium (which is unlikely as the substance is ionisable) - it can be expected thatreaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium saltsis marginally available in the air for inhalation and any inhaled substancewhich is not be subjected to ciliary clearanceis not expected to be absorbed.

However, due to the lack of toxicokinetic test data, the inhalative absorption used in subsequent risk assessments is 100% as a worst case assumption.

Absorption following dermal exposure

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration of the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal; TGD, Part I, Appendix IV). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Vapours of substances with vapour pressures below 100 Pa are likely to have enough contact time to be absorbed and the amount absorbed dermally is most likely more than 10% and less than 100 % of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.

In the case of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, the molecular weight is above 500, which indicates already a marginal potential to penetrate the skin. This is accompanied by a low hydrophilicity of the substance and even though the stratum corneum is open for lipophilic substances, the epidermis is very resistant against penetration by highly lipophilic substances. However, the amount of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts which is absorbed following dermal exposure into the stratum corneum is unlikely to be transferred into the epidermis. The substance does not show characteristics of a surfactant and, furthermore, the calcium sulfonate target substance is not irritating to skin and eyes, and therefore enhancement of dermal absorption can not be expected.

In support of this hypothesis (the low dermal absorption), the systemic toxicity ofthe calcium sulfonate read across substance CAS 70024-69-0 and of 115733-09-0via the skin is low (acute dermal toxicity, LD50 value of > 2000 and > 5000 mg/kg bw for rats, respectively).

However, as the substance is classified as a skin sensitizer, it is clear that at least a limited amount is absorbed via the dermal route of exposure.

In conclusion, the evaluation of all the available indicators and the results of toxicity studies allow the allocation of the chemical in question into the group of chemicals with a low dermal absorption. In detail, due to it’s molecular weight and the results for acute toxicity, the use of a factor of 10 % for the estimation of dermal uptake for reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts is justified(Schuhmacher –Wolz et al.,2003; TGD, Part I, 2003).

Distribution

In general, the following principle applies: the smaller the molecule, the wider the distribution. A lipophilic molecule (LogPow >0) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. It’s not possible to foresee protein binding, which can limit the amount of a substance available for distribution. Furthermore, if a substance undergoes extensive first-pass metabolism, predictions made on the basis of the physico-chemical characteristics of the parent substance may not be applicable.

In case ofreaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, no quantitative data is available for distribution patterns. Even though the high LogPow would indicate the possibility to reach the intracellular compartment, this seems to be unlikely as the molecular weight of the un-metabolised substance is high. Therefore, the distribution is expected to be limited.

After oral exposure, the first target will be the gastrointestinal tract, where the substance may not be absorbed in significant amounts; however, possible bacterial metabolites might be absorbed in higher quantities and transferred via the blood stream to the liver.

After reaching the liver via the portal vein, any absorbed calcium sulfonate target substance will be further distributed via the bloodstream. Here, especially the kidneys due to their filter function and the heart due to its enormous need for nutrients and consequently large blood flow through coronary arteries will be exposed.

Possible metabolites (See 3.4 Metabolism) and degradation products are expected to be of the same or smaller size and at least same or higher hydrophilicity as the parent compound. Hence, similar distribution patterns can be expected and no differentiation between the parent compoundand metabolites has to be made regarding distribution.

Accumulation

It is also important to consider the potential for a substance to accumulate or to be retained within the body. Lipophilic substances have the potential to accumulate within the body (mainly in the adipose tissue), if the dosing interval is shorter than 4 times the whole body half-life. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, substances with high LogPow values tend to have longer half-lives. On this basis, there is the potential for highly lipophilic substances (LogPow >4) to accumulate in biota which are frequently exposed. Highly lipophilic substances (LogPow between 4 and 6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systemically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off. A turnover time of 12 days has been quoted for skin epithelial cells.

Accordingly, the high LogPow and the predicted behaviour concerning absorption and metabolism ofreaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium saltsmight indicate a potential for accumulation in the body. This, however, is limited as the absorption is expected to be low via all routes of exposure and because metabolism of the calcium sulfonate target substance is expected to influence this initial prediction.

Metabolism:

Route specific toxicity results 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.

As specified above,hydrolysis does not applyreaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts (very low water solubility of 0.735 mg/L). However, its metabolism is very likely to occur via the Cytochrome P450 group of metabolising enzymes, as it has been predicted with the TOXTREE modelling tool (Chemservice, S.A., 2017e). According to the modelling results,reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, containing the structural alerts: sulfonic acid derivative and aromatic 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, next to aromatic ring, which are predicted to be subject to aliphatic hydroxylation (Phase-I-metabolism). The tertiary sites of metabolism are the terminal carbon-atoms of the chain, which is predicted to be also subject to aliphatic hydroxylation (Phase-I-metabolism).

However, as the calcium target substance may be absorbed as micelles after micellular solubilisation by bile salts, subsequently they may enter the circulation via the lymphatic system, bypassing the liver. Consequently, immediate Cytochrome P450 metabolism is less important here as for substances which directly enter the hepatic system via the portal vein.

Moreover, it is possible that further Phase-I-metabolism steps occur - the long carbon chains are subject to initial omega- and then successive beta-oxidation, possibly followed by oxidative scission of the aromatic ring and desulfonation. The above mentioned functional groups can react in phase 2 of the biotransformation with different molecules, leading to the formation of conjugations. This might be necessary for the parent compound, as its water solubility is fairly low and it cannot be eliminated via the urine without further metabolism. Further metabolism is most likely the conjugation of the hydroxyl-groups with glucuronic acid, activated sulphate or activated methionine. A facilitated distribution may be given for the direct metabolites due to an enhanced water solubility arising from the hydroxyl group and / or smaller size.

In conclusion, it is likely that the substance of interest will be subject to metabolism by cytochrome P450 enzymes, followed by omega- and beta-oxidation and cleavage of the aromatic ring and desulfonation.

Excretion:

In general, the major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). For orally administered substances which are not absorbed to a significant extent, it is clear that large amounts remain in the GI tract and will subsequently be excreted again via the faeces. For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and 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 or without metabolism with skin cells.

Forreaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium saltsno data is available concerning its elimination. However, due to limited absorption after oral ingestion, a large amount of un-absorbed subtstance will be excreted unchanged via the faeces. Concerning the above mentioned behaviour predicted for its metabolic fate, it is unlikely that absorbed parent substance will be excreted unchanged. The metabolites and degradation products formed ofreaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts are expected to be smaller, more hydrophilic and higher soluble in water. So excretion of the compounds via the kidneys and so urine is expected to be efficient. Furthermore, excretion via the GI tract (unabsorbed material) and via the bile and consequent subjection to enterohepatic recycling applies only to a smaller extent.

Conclusions:
The calcium sulfonate target substance was evaluated regarding its toxicokinetic behaviour. Due to its physico-chemical properties it is reasonable to assume, that the calcium sulfonate target substance is absorbed to a limited extent after oral and poorly after dermal exposure. In addition, it is assumed to be poorly absorbed after exposure via inhalation. The calcium sulfonate target substance is expected to be distributed throughout the body, possibly reaching also the intracellular compartment, due to its low hydrophilicity / high lipophilicity. However, it does not indicate a significant potential for accumulation, due to extensive metabolism. Concerning excretion, unabsorbed test material will be excreted unchanged via the faeces. Absorbed calcium target substance is expected to be extensively metabolised (omega- and beta-oxidation, probably followed by oxidative scission of the aromatic ring and desulfonation) and to be eliminated via urine or to a minor extent via the faeces.
Executive summary:

In order to assess the toxicokinetic behaviour of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts,the available physico-chemical and toxicological data for it and its near calcium read across substances have been evaluated. Due to the lack of experimental absorption data, physico-chemical data and data gained within acute and repeated application studies of calcium sulfonate read across substances via the oral route needed to be taken into account when evaluating its absorption into the body.The calcium sulfonate target substance is expected to be absorbed to a limited extent only after oral exposure, based on its high molecular weight (≥ 859.4 and ≤ 1026.7 g/mol), its low water solubility (0.0735 mg/L) and its high LogPow (5.38 – 7.44). Micellular solubilisation, pinocytosis and persorption cannot be completely ruled out. Concerning the absorption after exposure via inhalation, tests revealed for the chemical a low vapour pressure (0.184 Pa at 25 °C), and as it is highly lipophilic, has a high LogPow, and has a rather high molecular weight, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly. The calcium sulfonate target substance is also not expected to be absorbed following dermal exposure into the epidermis, due to its low water solubility and its fairly high molecular weight. Evaporation after skin contact is not considered possible. Concerning its distribution in the body any limited amount of absorbed calcium sulfonate target substance is expected to be distributed into the intravasal compartment and possibly also into the intracellular compartment (due to its lipophilicity). The substance is not considered to be to a significant extent bioavailable and, does not indicate a significant potential for accumulation, when taking into account the high LogPow, the predicted behaviour concerning absorption and metabolism. More specifically, any accumulation is therefore limited as the absorption is expected to be low via all routes of exposure and because metabolism of the calcium sulfonate target substance is expected to influence the theoretically possible bioaccumulation. The calcium sulfonate target substance is expected to be extensively metabolised (metabolism by cytochrome P450 enzymes, followed by omega- and beta-oxidation and cleavage of the aromatic ring and desulfonation) and to be – only if taken up - eliminated mainly via the urine and also via the bile. Any non absorbed test material will be excreted unchanged via the faeces.

 

So in summary, taking into account the above mentioned facts, the following absorption rates may be estimated and applied in subsequent risk assessment while performing route-to-route extrapolations:

- Absorption via oral route: 50% (worst case value due to very limited absorption (sign. less than 100 %))

- Absorption via inhalative route: 100% (worst case)

- Absorption via dermal route: 10% (for substances with molecular masses above 500 and LogPow values outside the range of 1-4; refer to R.7c)

Data source

Reference
Reference Type:
other: Expert statement
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: Technical guidance document, Part I, 2003
Deviations:
no
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts
EC Number:
947-519-7
Molecular formula:
Too complex
IUPAC Name:
Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts
Test material form:
liquid

Results and discussion

Percutaneous absorption
Parameter:
percentage
Absorption:
10 %
Remarks on result:
other: The calcium sulfonate target substance is expected to be poorly absorbed following dermal exposure into the stratum corneum, due to its LogPow of 5.38-7.44 and low water solubility (0.735 mg/L)

Any other information on results incl. tables

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration of the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal; TGD, Part I, Appendix IV). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Vapours of substances with vapour pressures below 100 Pa are likely to have enough contact time to be absorbed and the amount absorbed dermally is most likely more than 10% and less than 100 % of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.

In the case of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, the molecular weight is above 500, which indicates already a marginal potential to penetrate the skin. This is accompanied by a low hydrophilicity of the substance and even though the stratum corneum is open for lipophilic substances, the epidermis is very resistant against penetration by highly lipophilic substances. However, the amount of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts which is absorbed following dermal exposure into the stratum corneum is unlikely to be transferred into the epidermis. The substance does not show characteristics of a surfactant and, furthermore, the calcium sulfonate target substance is not irritating to skin and eyes, and therefore enhancement of dermal absorption can not be expected.

In support of this hypothesis (the low dermal absorption), the systemic toxicity ofthe calcium sulfonate read across substance CAS 70024-69-0 and of 115733-09-0via the skin is low (acute dermal toxicity, LD50 value of > 2000 and > 5000 mg/kg bw for rats, respectively).

However, as the substance is classified as a skin sensitizer, it is clear that at least a limited amount is absorbed via the dermal route of exposure.

In conclusion, the evaluation of all the available indicators and the results of toxicity studies allow the allocation of the chemical in question into the group of chemicals with a low dermal absorption. In detail, due to it’s molecular weight and the results for acute toxicity, the use of a factor of 10 % for the estimation of dermal uptake for reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts is justified(Schuhmacher –Wolz et al.,2003; TGD, Part I, 2003).

Applicant's summary and conclusion

Conclusions:
No significant dermal absorption is expected for the calcium sulfonate target substance.
Executive summary:

In order to assess the toxicokinetic behaviour of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts,the available physico-chemical and toxicological data for it and its near calcium read across substances have been evaluated.Due to the lack of experimental absorption data, physico-chemical data and data gained within acute and repeated application studies of calcium sulfonate read across substances via the oral route needed to be taken into account when evaluating its absorption into the body.The calcium sulfonate target substance is expected to be absorbed to a limited extent only after oral exposure, based on its high molecular weight (≥ 859.4 and ≤ 1026.7 g/mol), its low water solubility (0.0735 mg/L) and its high LogPow (5.38 – 7.44). Micellular solubilisation, pinocytosis and persorption cannot be completely ruled out. Concerning the absorption after exposure via inhalation, tests revealed for the chemical a low vapour pressure (0.184 Pa at 25 °C), and as it is highly lipophilic, has a high LogPow, and has a rather high molecular weight, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly.The calcium sulfonate target substanceis also not expected to be absorbed following dermal exposure into the epidermis, due to its low water solubility and its fairly high molecular weight. Evaporation after skin contact is not considered possible. Concerning its distribution in the body any limited amount of absorbedcalcium sulfonate target substanceis expected to be distributed into the intravasal compartment and possibly also into the intracellular compartment (due to its lipophilicity). The substance is not considered to be to a significant extent bioavailable and, does not indicate a significant potential for accumulation, when taking into account the high LogPow, the predicted behaviour concerning absorption and metabolism. More specifically, any accumulation is therefore limited as the absorption is expected to be low via all routes of exposure and because metabolism of the calcium sulfonate target substance is expected to influence the theoretically possible bioaccumulation.The calcium sulfonate target substanceis expected to be extensively metabolised (metabolism by cytochrome P450 enzymes, followed by omega- and beta-oxidation and cleavage of the aromatic ring and desulfonation) andto be – only if taken up - eliminated mainly via the urine and also via the bile. Any non absorbed test material will be excreted unchanged via the faeces.

 

So in summary, taking into account the above mentioned facts, the following absorption rates may be estimated and applied in subsequent risk assessment while performing route-to-route extrapolations:

- Absorption via oral route: 50% (worst case value due to very limited absorption (sign. less than 100 %))

- Absorption via inhalative route: 100% (worst case)

- Absorption via dermal route: 10% (for substances with molecular masses above 500 and LogPow values outside the range of 1-4; refer to R.7c)