Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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)

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Remarks:

Toxtree (version 2.6.0.) modelling tool was developed by IDEA Consult Ltd (Sofia, Bulgaria) and is approved and recommended by the EU Joint Research Center in Ispra (Italy) (LINK: http://ecb.jrc.ec.europa.eu/qsar/qsar-tools/index.php?c=TOXTREE).

Justification for type of information:

1. SOFTWARE
Toxtree, v2.6.0 (Ideaconsult, Sofia, Bulgaria, 2013)

2. MODEL (incl. version number)
Structural Alerts for Functional Group Identification (ISSFUNC)
SMARTCyp - Cytochrome P450-Mediated Drug Metabolism and metabolites prediction

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See section 'Test Material'.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF.

5. APPLICABILITY DOMAIN
See attached QPRF.

6. ADEQUACY OF THE RESULT
- The model is scientifically valid (see attached QMRF).
- The model identifies the functional groups and the probable Cytochrme P450-mediated Drug metabolism sites (inkl. metabolites prediction) as required information point under Regulation (EC) No 1907/2006 [REACH], Annex VIII, 8.8 Toxicokinetic (see also attached QMRF).
- See attached QPRF for reliability assessment.

Objective of study:

metabolism

Qualifier:

no guideline required

Principles of method if other than guideline:

Prediction using TOXTREE (v.2.6.0)

GLP compliance:

no

Specific details on test material used for the study:

not relevant for QSAR

Radiolabelling:

other: not applicable

Species:

other: not applicable

Strain:

other: not applicable

Details on species / strain selection:

not relevant for QSAR

Details on test animals or test system and environmental conditions:

not relevant for QSAR

Route of administration:

other: not applicable

Details on exposure:

not relevant for QSAR

Duration and frequency of treatment / exposure:

not applicable

Remarks:

not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not relevant for QSAR

Details on study design:

not relevant for QSAR

Details on dosing and sampling:

not relevant for QSAR

Statistics:

not relevant for QSAR

Type:

other: Prediction of metabolism by modelling

Results:

The target chemical, 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 metabolising enzymes.

Details on metabolites:

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.
The tertiary sites of metabolism are the terminal carbon-atoms of the chain, which is predicted to be subject to aliphatic hydroxylation.

Results of identification of organic functional groups:

QFG1.cationNo

QFG2.anionNo

QFG3_LS.carbonyl compound: aldehyde or ketoneNo

QFG3_1.aldehydeNo

QFG3_2.ketoneNo

QFG4_LS.thiocarbonyl compound: aldehyde or ketoneNo

QFG4_1.thioaldehydeNo

QFG4_2.thioketoneNo

QFG5.imineNo

QFG6.hydrazoneNo

QFG7.semicarbazoneNo 

QFG8.thiosemicarbazoneNo

QFG9.oximeNo

QFG10.oxime etherNo

QFG11.keteneNo

QFG12.ketene acetal derivativeNo

QFG13.carbonyl hydrateNo

QFG14.hemiacetalNo

QFG15.acetalNo

QFG16.hemiaminalNo

QFG17.aminalNo

QFG18.thiohemiaminalNo

QFG19.thioacetalNo

QFG20.enamineNo

QFG21.enolNo

QFG22.enoletherNo

QFG23_LS.alcoholNo

QFG23_1.primary alcoholNo

QFG23_2.secondary alcoholNo

QFG23_3.tertiary alcoholNo

QFG23_4.1,2-diolNo

QFG23_5.1,2-aminoalcoholNo

QFG23_6.phenolNo

QFG23_7.1,2-diphenolNo

QFG23_8.enediolNo

QFG24_LS.etherNo

QFG24_1.dialkyletherNo

QFG24_2.alkylaryletherNo

QFG24_3.diaryletherNo

QFG25.thioetherNo

QFG26.disulfideNo

QFG27.peroxideNo

QFG28.hydroperoxideN

QFG29.hydrazine derivativeNo

QFG30.hydroxylamineNo

QFG31_LS.amine No

QFG31_1.primary aliphatic amineNo

QFG31_2.primary aromatic amineNo

QFG31_3.secondary aliphatic amineNo

QFG31_4.secondary mixed amine (aryl alkyl)No

QFG31_5.secondary aromatic amineNo

QFG31_6.tertiary aliphatic amineNo

QFG31_7.tertiary mixed amineNo

QFG31_8.tertiary arom_amineNo

QFG31_9.quaternary ammonium saltNo

QFG32.N-oxideNo

QFG33_LS.halogen derivative (alkyl or aryl)No

QFG33_1.alkyl fluorideNo

QFG33_2.alkyl chlorideNo

QFG33_3.alkyl bromideNo

QFG33_4.alkyl iodideNo

QFG33_5.aryl fluorideNo

QFG33_6.aryl chlorideNo

QFG33_7.aryl bromideNo

QFG33_8.aryl iodideNo

QFG34_LS.organometallic compoundNo

QFG34_1.organolithium compoundNo

QFG34_2.organomagnesium compoundNo

QFG35_LS.carboxylic acid derivativeNo

QFG35_1.carboxylic acidNo

QFG35_2.carboxylic acid saltNo

QFG35_3.carboxylic acid esterNo

QFG35_4.lactoneNo

QFG35_5.carboxylic acid prim. AmideNo

QFG35_6.carboxylic acid sec. AmideNo

QFG35_7.carboxylic acid tert. AmideNo

QFG35_8.lactamNo

QFG35_9.carboxylic acid hydrazideNo

QFG35_10.carboxylic acid azideNo

QFG35_11.hydroxamic acidNo

QFG35_12.carboxylic acid amidineNo

QFG35_13.carboxylic acid amidrazoneNo

QFG36.nitrileNo

QFG37_LS.acyl halideNo

QFG37_1.acyl fluorideNo

QFG37_2.acyl chlorideNo

QFG37_3.acyl bromideNo

QFG37_4.acyl iodideNo

QFG38.acyl cyanideNo

QFG39.imido esterNo

QFG40.imidoyl halideNo

QFG41_LS. thiocarboxylic acid derivativeNo 

QFG41_1.thiocarboxylic acidNo

QFG41_2. thiocarboxylic acid esterNo

QFG41_3.thiolactoneNo

QFG41_4.thiocarboxylic acid amideNo

QFG41_5.thiolactamNo

QFG42.imidothioesterNo

QFG43.oxohetareneNo

QFG44.thioxohetareneNo

QFG45.iminohetareneNo

QFG46_LS. orthocarboxylic acid derivativeNo

QFG46_1.carboxylic acid orthoesterNo

QFG46_2.carboxylic acid amide acetalNo

QFG47.carboxylic acid anhydrideNo

QFG48_LS.carboxylic acid imideNo

QFG48_1.carboxylic acid unsubstituted imideNo

QFG48_2.carboxylic acid substituted imideNo

QFG49.CO2 derivative (general)No

QFG50_LS.carbonic acid derivativeNo

QFG50_1.carbonic acid monoesterNo

QFG50_2.carbonic acid diesterNo

QFG50_3.carbonic acid ester halideNo

QFG51_LS.thiocarbonic acid derivativeNo

QFG51_1.thiocarbonic acid monoesterNo

QFG51_2.thiocarbonic acid diesterNo

QFG51_3.thiocarbonic acid ester halideNo

QFG52_LS.carbamic acid derivativeNo

QFG52_1.carbamic acidNo

QFG52_2.carbamic acid ester (urethane)No

QFG52_3.carbamic acid halideNo

QFG53_LS.thiocarbamic acid derivativeNo

QFG53_1.thiocarbamic acidNo

QFG53_2.thiocarbamic acid esterNo

QFG53_3.thiocarbamic acid halideNo

QFG54.ureaNo

QFG55.isoureaNo

QFG56.thioureaNo

QFG57.isothioureaNo

QFG58.guanidineNo

QFG59.semicarbazideNo

QFG60.thiosemicarbazideNo

QFG61.azideNo

QFG62.azo compoundNo

QFG63.diazonium saltNo

QFG64.isonitrileNo

QFG65.cyanateNo

QFG66.isocyanateNo

QFG67.thiocyanateNo

QFG68.isothiocyanateNo

QFG69.carbodiimideNo

QFG70.nitroso compoundNo

QFG71.nitro compoundNo

QFG72.nitriteNo

QFG73.nitrateNo

QFG74_LS.sulfuric acid derivativeNo

QFG74_2.sulfuric acid monoester No

QFG74_3.sulfuric acid diesterNo

QFG74_4.sulfuric acid amide ester No

QFG74_5.sulfuric acid amideNo

QFG74_6.sulfuric acid diamideNo

QFG74_7.sulfuryl halideNo

QFG75_LS.sulfonic acid derivativeYes

QFG75_1.sulfonic acidNo

QFG75_2.sulfonic acid esterNo

QFG75_3.sulfonamideNo

QFG75_4.sulfonyl halideNo

QFG76.sulfoneNo

QFG77.sulfoxideNo

QFG78_LS.sulfinic acid derivativeNo

QFG78_1.sulfinic acidNo

QFG78_2.sulfinic acid esterNo

QFG78_3.sulfinic acid halideNo

QFG78_4.sulfinic acid amideNo

QFG79_LS.sulfenic acid derivativeNo

QFG79_1.sulfenic acidNo

QFG79_2.sulfenic acid esterNo

QFG79_3.sulfenic acid halideNo

QFG79_4.sulfenic acid amideNo

QFG80_LS.thiolNo

QFG80_1.alkylthiolNo

QFG80_2.arylthiolNo

QFG81_LS.phosphoric acid derivativeNo

QFG81_1.phosphoric acidNo

QFG81_2.phosphoric acid esterNo

QFG81_3.phosphoric acid halideNo

QFG81_4.phosphoric acid amideNoQFG82_LS.thiophosphoric acid derivativeNo

QFG82_1.thiophosphoric acidNo]

QFG82_2.thiophosphoric acid esterNo

QFG82_3. thiophosphoric acid halideNo

QFG82_4.thiophosphoric acid amideNoQFG83_LS.phosphonic acid derivativeNo

QFG83_1.phosphonic acidNo

QFG83_2.phosphonic acid esterNo
QFG83_3.phosphineNo
QFG83_4.phosphinoxideNo
QFG84_LS.boronic acid derivativeNo
QFG84_1.boronic acidNo
QFG84_2.boronic acid esterNo

QFG85.alkeneNo

QFG86.alkyneNo

QFG87.aromatic compoundYes

QFG88.heterocyclic compoundNo
QFG89.alpha-aminoacidNo

QFG90.alpha-hydroxyacidNo
QAny alert?.At least one alert fired?YesClassAt least one functional group found (Class I)

Results of identification of sites in the molecule which are labile for enzymes from group of drug metabolizing Cytochrome P450 family:

Q1.SMARTCyp primary sites of metabolismYesClassSMARTCyp.Rank1.sites
Q2.SMARTCyp secondary sites of metabolismYesClassSMARTCyp.Rank2.sites
Q3.SMARTCyp tertiary sites of metabolismYesClassSMARTCyp.Rank3.sites
Q4.SMARTCyp sites of metabolism with Rank>=4YesClassSMARTCyp.Rank>=4.sites

Conclusions:

Interpretation of results (migrated information): other: well metabolized substance
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, 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 the aromatic ring, which are predicted to be subject to aliphatic hydroxylation. The tertiary sites of metabolism are the terminal carbon-atoms of the chain, which are predicted to be also subject to aliphatic hydroxylation.

Executive summary:

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 the aromatic ring, which are predicted to be subject to aliphatic hydroxylation. The tertiary sites of metabolism are the terminal carbon-atoms of the chain, which are predicted to be subject to aliphatic hydroxylation.

Reference 3

Endpoint:

basic toxicokinetics

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
In this justification, the read-across (bridging) concept is applied, based on the chemical structure of the potential analogues, their toxicokinetic behaviour and other available (eco-)toxicological data.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
C20-24 calcium sulfonate and sodium salt of linear alkylbenzene sulfonates (LAS) are members of a category of chemicals described as alkaryl sulfonates, which was established as part of the U.S. Environmental Protection Agency High Production Volume (HPV) Challenge Program. The substances of this category have a common functional group - the salt of aryl sulfonic acid. Furthermore, they all have a mono- or divalent alkaline earth metal, one or more linear and/or branched alkyl groups of variable chain length and branching characteristics or extended heterocyclic carbon system from the sulfonated benzene ring. Finally, they have common precursors and/or the likelihood of common breakdown products via physical and biological processes, resulting in structurally similar chemicals, and similar physicochemical properties, environmental fate, ecotoxicity and mammalian toxicity.
Concerning their basic toxicokinetics, it is believed that both substance will behave and be metabolised by the same mechanisms by mammalian organisms. Therefore they are expected to follow the same pattern. For the detailed procedure of the read-across principle and justifications, please refer to the analogue approach justification depicted below and the separate Read-Across Statement (Chemservice S.A., 2017).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source chemical: sodium salt of linear alkylbenzene sulfonates (LAS)
Target chemical: Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts (C20-24 calcium sulfonate, CAS No none, EC No none)

3. ANALOGUE APPROACH JUSTIFICATION
C20-24 calcium sulfonate and sodium salt of linear alkylbenzene sulfonates (LAS) are UVCB substances that are produced using similar manufacturing process and raw materials and are manufactured in mineral oil. They are members of a category of chemicals described as alkaryl sulfonates, which was established as part of the U.S. Environmental Protection Agency High Production Volume (HPV) Challenge Program. These substances are similar in that they have a common functional group, the salt of aryl sulfonic acid. They have similar physicochemical properties, similar environmental fate characteristics, and similar ecotoxicity and mammalian toxicity profiles. For example, these substances can dissociate only in the presence of strong acids such as in the stomach but are not expected to dissociate under environmental conditions. The similar toxicity profiles indicate that they have a similar MOA. C20-24 calcium sulfonate is classified as Skin Sens Cat. 1B and sodium salt of linear alkylbenzene sulfonates (LAS) is classified as irritating to the skin at concentrations above 20%.
The similar findings for both substances support the conclusion that similar molecules are expected to be formed from both substances, and in consequence, similar effects can be reasonably expected. Hence, the analogue may serve as a read-across substance for the C20-24 calcium sulfonate. So, based on the WoE of these data, the available data on sodium salt of linear alkylbenzene sulfonates (LAS) can be used to support the data on the systemic endpoints currently lacking for C20-24 calcium sulfonate and read across is scientifically justified, making further testing obsolete.

4. DATA MATRIX
There is mainly data available on the toxicological properties of the analogues CAS 61789-86-4 / its overbased version CAS 68783-96-0 and for CAS 70024-69-0 / its overbased version CAS 70024-71-4. Data on Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts covers merely the physico chemical properties. Hence, the identification and discussion of common properties of the analogues and the C20-24 calcium sulfonate will be mainly based on this physicochemical data.
The available data for the following physico-chemical properties, which are relevant for absorption into living organisms, are very similar. The substances are rather huge molecules and have a similar molecular weight range, which triggers already similarities in their absorption behaviour. Furthermore, the physico-chemical properties like their partition coefficient, water solubility and vapour pressure are similar. Regarding the application of these substances, the substances are usually solved in an inert mineral oil to enable handling. The C20-24 calcium sulfonate and all analogous substances are hydrolytically stable and at least CAS 70024-69-0 and CAS 61789-86-4 are not readily biodegradable, and the available data suggests this to apply also for C20-24 calcium sulfonate. Taking into account the vast amount of data available for partition coefficient data on various calcium sulfonates it can be concluded that they do not have a significant potential for bioaccumulation in aquatic and terrestrial organisms. However, they are expected to be adsorbed to a significant extent to the sediment and soil and to be thereby not bioavailable, which was confirmed by the results of short-term toxicity tests to fish, daphnia and algae for CAS 70024-71-4; CAS 115733-09-0 and CAS 61789-64-4, in which the lowest LL50 was already > 100 mg/L WAF.
For the following toxicological endpoints there is data available derived from CAS 70024-69-0/ CAS 70024-71-4, Analogue of CAS 70024-69-0, CAS 115733-09-0, CAS 61789-86-4/ CAS 68783-96-0 and CAS 75975-85-8: Acute toxicity, Skin irritation / corrosion, Eye irritation /corrosion, Skin sensitization, Repeated dose toxicity, Genetic toxicity in vitro and in vivo and Toxicity to reproduction (fertility / developmental toxicity). Furthermore a rather extensive data package is available concerning the human sensitization potential of numerous analogous substances. For the acute oral toxicity, the values for all read across substances are very high, all LD50 values being above 2000 mg/kg (reaching in older tests up to greater than 20,000 mg/kg) and the values for the substances can be considered as similar within normal biological variations. The substances are also not toxic via the inhalation or the dermal route of exposure. Regarding Skin/Eye Irritation, the available data on CAS 70024-69-0 and CAS 61789-86-4 shows both substances to be not irritating to the skin or the eyes. The skin sensitization data in animals and humans (for CAS 75975-85-8; CAS 61789-86-4 and EC 939-141-6) evaluated in a weight-of-evidence approach indicates that low TBN calcium sulfonates (TBN < 300) are skin sensitizers with a specific concentration limit (SCL) of 10% and that high TBN calcium sulfonates (TBN ≥ 300) are not skin sensitizers. Last but not least, the available genetic toxicity data for Analogue of CAS 70024-69-0, CAS 61789-86-4 and its overbased version CAS 68783-96-0 prove all of these substances to be not mutagenic. The NOAELs derived for the endpoints Repeated dose toxicity (Analogue of CAS 70024-69-0 and CAS 61789-86-4) and Toxicity to reproduction (fertility / developmental toxicity for CAS 115733-09-0)) have been also found to be in a similar range.
For further details please refer to the separate Read-Across Statement (Chemservice S.A., 2017) and/or the robust study summaries of the respective studies in this IUCLID file.

Reason / purpose for cross-reference:

read-across source

Type:

absorption

Results:

Linear alkylbenzene sulfonates (LAS), alpha-olefin sulfonates (AOS), and alkyl sulfonates(AS) are readily absorbed by the gastrointestinal tract. Only minimal amounts of LAS and AS are absorbed through intact skin.

Type:

distribution

Results:

Linear alkylbenzene sulfonates, alpha-olefin sulfonates and alkyl sulfonates are widely distributed throughout the body.

Type:

metabolism

Results:

Linear alkylbenzene sulfonates, alpha-olefin sulfonates and alkyl sulfonates are extensively metabolised. They can undergo omega- and beta-oxidation, which is followed by oxidative scission of the aromatic ring and desulfonation.

Type:

excretion

Results:

Linear alkylbenzene sulfonates, the parent compounds, and their metabolites are excreted mainly through the kidneys and via the bile.

Conclusions:

linear alkylbenzene sulfonates, alpha-olefin sulfonates and alkyl sulfonates are readily absorbed by the gastrointestinal tract, widely distributed throughout the body and extensively metabolised. They can undergo omega- and beta-oxidation, which is followed by oxidative scission of the aromatic ring and desulfonation. For LAS, the parent compounds and the metabolites are excreted mainly through the kidneys and via the bile. AOS and AS are mainly excreted via the urine. Only minimal amounts of LAS and AS are absorbed through intact skin. These results can be used to fulfill the information requirements for the chemical substance Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, due to the high structural similarity of these substances. For the detailed procedure of the read-across principle and justifications, please refer to the separate Read-Across Statement (Chemservice S.A., 2017).

Executive summary:

Linear alkylbenzene sulfonates (LAS), alpha-olefin sulfonates (AOS) and alkyl sulfates (AS)

The World Health Organization (WHO assessment of alkyl/aryl sulfates and sulfonates (ISBN 92 4 157169 1, 1996)), shows that linear alkylbenzene sulfonates, alpha-olefin sulfonates and alkyl sulfonates are readily absorbed by the gastrointestinal tract, widely distributed throughout the body and extensively metabolised. They can undergo omega- and beta-oxidation, which is followed by oxidative scission of the aromatic ring and desulfonation. For LAS, the parent compounds and the metabolites are excreted mainly through the kidneys and via the bile. AOS and AS are mainly excreted via the urine. Only minimal amounts of LAS and AS are absorbed through intact skin.

These results can be used to fulfill the information requirements for the chemical substance Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, due to the high structural similarity of these substances. For the detailed procedure of the read-across principle and justifications, please refer to the separate Read-Across Statement (Chemservice S.A., 2017).

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
In this justification, the read-across (bridging) concept is applied, based on the chemical structure of the potential analogues, their toxicokinetic behaviour and other available (eco-)toxicological data.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
C20-24 calcium sulfonate and Sodium dodecylbenzenesulfonate (CAS 25155-30-0) are members of a category of chemicals described as alkaryl sulfonates, which was established as part of the U.S. Environmental Protection Agency High Production Volume (HPV) Challenge Program. The substances of this category have a common functional group - the salt of aryl sulfonic acid. Furthermore, they all have a mono- or divalent alkaline earth metal, one or more linear and/or branched alkyl groups of variable chain length and branching characteristics or extended heterocyclic carbon system from the sulfonated benzene ring. Finally, they have common precursors and/or the likelihood of common breakdown products via physical and biological processes, resulting in structurally similar chemicals, and similar physicochemical properties, environmental fate, ecotoxicity and mammalian toxicity.
Concerning their basic toxicokinetics, it is believed that both substance will behave and be metabolised by the same mechanisms by mammalian organisms. Therefore they are expected to follow the same pattern. For the detailed procedure of the read-across principle and justifications, please refer to the analogue approach justification depicted below and the separate Read-Across Statement (Chemservice S.A., 2017).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source chemical: Sodium dodecylbenzenesulfonate (CAS 25155-30-0; EC 246-680-4)
Target chemical: Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts (C20-24 calcium sulfonate, CAS No none, EC No none)

3. ANALOGUE APPROACH JUSTIFICATION
C20-24 calcium sulfonate and Sodium dodecylbenzenesulfonate (CAS 25155-30-0) are UVCB substances that are produced using similar manufacturing process and raw materials and are manufactured in mineral oil. They are members of a category of chemicals described as alkaryl sulfonates, which was established as part of the U.S. Environmental Protection Agency High Production Volume (HPV) Challenge Program. These substances are similar in that they have a common functional group, the salt of aryl sulfonic acid. They have similar physicochemical properties, similar environmental fate characteristics, and similar ecotoxicity and mammalian toxicity profiles. For example, these substances can dissociate only in the presence of strong acids such as in the stomach but are not expected to dissociate under environmental conditions. The similar toxicity profiles indicate that they have a similar MOA. C20-24 calcium sulfonate is classified as Skin Sens Cat. 1B and Sodium dodecylbenzenesulfonate (CAS 25155-30-0) is classified as Acute Tox. 4, Skin Irrit. 2 and Eye Damage 1.
The similar findings for both substances support the conclusion that similar molecules are expected to be formed from both substances, and in consequence, similar effects can be reasonably expected. Hence, the analogue may serve as a read-across substance for the C20-24 calcium sulfonate. So, based on the WoE of these data, the available data on Sodium dodecylsulfonate (CAS 25155-30-0) can be used to support the data on the systemic endpoints currently lacking for C20-24 calcium sulfonate and read across is scientifically justified, making further testing obsolete.

4. DATA MATRIX
There is mainly data available on the toxicological properties of the analogues CAS 61789-86-4 / its overbased version CAS 68783-96-0 and for CAS 70024-69-0 / its overbased version CAS 70024-71-4. Data on Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts covers merely the physico chemical properties. Hence, the identification and discussion of common properties of the analogues and the C20-24 calcium sulfonate will be mainly based on this physicochemical data.
The available data for the following physico-chemical properties, which are relevant for absorption into living organisms, are very similar. The substances are rather huge molecules and have a similar molecular weight range, which triggers already similarities in their absorption/adsorption and desorption behaviour. Furthermore, the physico-chemical properties like their partition coefficient, water solubility and vapour pressure are similar. Regarding the application of these substances, the substances are usually solved in an inert mineral oil to enable handling. The C20-24 calcium sulfonate and all analogous substances are hydrolytically stable in the natural environment and at least CAS 70024-69-0 and CAS 61789-86-4 are not readily biodegradable, and the available data suggests this to apply also for C20-24 calcium sulfonate. Taking into account the vast amount of data available for partition coefficient data on various calcium sulfonates it can be concluded that they do not have a significant potential for bioaccumulation in aquatic and terrestrial organisms. However, they are expected to be adsorbed to a significant extent to the sediment and soil and to be thereby not bioavailable, which was confirmed by the results of short-term toxicity tests to fish, daphnia and algae for CAS 70024-71-4; CAS 115733-09-0 and CAS 61789-64-4, in which the lowest LL50 was already > 100 mg/L WAF.
For the following toxicological endpoints there is data available derived from CAS 70024-69-0/ CAS 70024-71-4, Analogue of CAS 70024-69-0, CAS 115733-09-0, CAS 61789-86-4/ CAS 68783-96-0 and CAS 75975-85-8: Acute toxicity, Skin irritation / corrosion, Eye irritation /corrosion, Skin sensitization, Repeated dose toxicity, Genetic toxicity in vitro and in vivo and Toxicity to reproduction (fertility / developmental toxicity). Furthermore a rather extensive data package is available concerning the human sensitization potential of numerous analogous substances. For the acute oral toxicity, the values for all read across substances are very high, all LD50 values being above 2000 mg/kg (reaching in older tests up to greater than 20,000 mg/kg) and the values for the substances can be considered as similar within normal biological variations. The substances are also not toxic via the inhalation or the dermal route of exposure. Regarding Skin/Eye Irritation, the available data on CAS 70024-69-0 and CAS 61789-86-4 shows both substances to be not irritating to the skin or the eyes. The skin sensitization data in animals and humans (for CAS 75975-85-8; CAS 61789-86-4 and EC 939-141-6) evaluated in a weight-of-evidence approach indicates that low TBN calcium sulfonates (TBN < 300) are skin sensitizers with a specific concentration limit (SCL) of 10% and that high TBN calcium sulfonates (TBN ≥ 300) are not skin sensitizers. Last but not least, the available genetic toxicity data for Analogue of CAS 70024-69-0, CAS 61789-86-4 and its overbased version CAS 68783-96-0 prove all of these substances to be not mutagenic. The NOAELs derived for the endpoints Repeated dose toxicity (Analogue of CAS 70024-69-0 and CAS 61789-86-4) and Toxicity to reproduction (fertility / developmental toxicity for CAS 115733-09-0)) have been also found to be in a similar range.
For further details please refer to the separate Read-Across Statement (Chemservice S.A., 2017) and/or the robust study summaries of the respective studies in this IUCLID file.

Reason / purpose for cross-reference:

read-across source

Type:

excretion

Results:

Most of the administered [14C] was recovered in the urine at 24 h after dosing (78%). 22% and 1.5% of applied dose were recovered in carcasses and in faeces, respectively. <0.1% was measured in the expired air.

Details on excretion:

The rate and route of excretion of [14C] from intraperitoneally administered [14C] surfactant solutions were the same as that from subcutaneously administered solutions. From the results the route of excretion of [14C] surfactant giving the most sensitive indication of percutaneously absorbed surfactant was indicated.

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
DOBC is excreted predominantly via urine. These results can be used to fulfill the information requirements for the chemical substance Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, due to the high structural similarity of these substances. For the detailed procedure of the read-across principle and justifications, please refer to the separate Read-Across Statement (Chemservice S.A., 2017).

Executive summary:

The excretion of DOBC surfactant was studied in Colworth-Wistar rats (Howes, 1975). The turnover of [14C] labelled DOBC was measured by injecting three animals intraperitoneally and three animals subcutaneously with 0.1 or 0.5 mL of surfactant solution. Two test solutions of the [14C] DOBS were used, the first a 3 mM solution in 25% v/v Polyethylene Glycol 400 in water and a second a 3 mM suspension in water. The administered dose resulted in 1.02 mg/kg bw. The animals were placed in sealed metabolism cages where urine, faeces and expired air were collected and monitored for [14C]. After 6 or 24 h the animals were killed and the radioactivity in their carcasses was measured. The rate and route of excretion of [14C] from intraperitoneally administered [14C] surfactant solutions were the same as that from subcutaneously administered solutions. Most of the administered [14C] was recovered in the urine at 24 h after dosing (78%). 22% and 1.5% of applied dose were recovered in carcasses and in faeces, respectively. Under 0.1% radioactivity was measured in the expired air. From the results the route of excretion of [14C] surfactant giving the most sensitive indication of percutaneously absorbed surfactant was indicated.

These results can be used to fulfill the information requirements for the chemical substance Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, due to the high structural similarity of these substances. For the detailed procedure of the read-across principle and justifications, please refer to the separate Read-Across Statement (Chemservice S.A., 2017).

Description of key information

Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, in the further addressed as 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. Concerning its systemic bioavailability, any absorbed calcium sulfonate target substance is expected to be distributed intravasal throughout the body, possibly reaching also the intracellular compartment, due to its low hydrophilicity / high lipophilicity. Similar distribution patterns can be expected for its metabolites. The high LogPow and the predicted behaviour concerning absorption and metabolism might 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 extensive metabolism of the calcium sulfonate target substance is expected to influence this initial prediction.

Regarding its metabolic fate, the calcium target substance is expected to be extensively metabolised via the following mode of actions during Phase-1-Metabolism: aliphatic hydroxylation, omega- and beta-oxidation, probably followed by oxidative scission of the aromatic ring and desulfonation. These metabolites are expected to be either excreted directly or to react in Phase II of the biotransformation with different molecules, leading to the formation of conjugations. The hydroxyl groups are the most likely functional groups to be conjugated to glucuronic acid, activated sulphate or activated methionine.

It is unlikely that the calcium sulfonate target substance will be excreted unchanged. After oral ingestion, it is expected to be mainly not absorbed and thereby excreted again unchanged via the faeces. Any absorbed calcium sulfonate is expected to be eliminated via urine or to a minor extent via the faeces (as Phase-II-biotransformation conjugates).

 

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 (significantly less than 100 %))

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

- 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)

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic behaviour of Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts

The toxicokinetic profile of the test substance was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physical chemical properties of Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts and acute and repeated-dose toxicity data on the calcium sulfonate read across substances were used to predict toxicokinetic behaviour of Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts.

Toxicological profile of Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts

Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts 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 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 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.

Oral route

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 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.

Inhalation route

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.

Dermal route

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).

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 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.

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 of reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts might 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 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).

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.

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 substance 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.

Prediction using TOXTREE

A representative chemical structure of Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts was assessed by Toxtree (v.2.6.0) 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.

Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salt, 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 the aromatic ring, which are predicted to be subject to aliphatic hydroxylation. The tertiary sites of metabolism are the terminal carbon-atoms of the chain, which are predicted to be subject to aliphatic hydroxylation.

ADME Studies on Related Alkyl/aryl Sulfonates

Linear alkylbenzene sulfonates (LAS), alpha-olefin sulfonates (AOS) and alkyl sulfates (AS)

The World Health Organization (WHO assessment of alkyl/aryl sulfates and sulfonates (ISBN 92 4 157169 1, 1996), shows that linear alkylbenzene sulfonates, alpha-olefin sulfonates and alkyl sulfonates are readily absorbed by the gastrointestinal tract, widely distributed throughout the body and extensively metabolised. They can undergo omega- and beta-oxidation, which is followed by oxidative scission of the aromatic ring and desulfonation. For LAS, the parent compounds and the metabolites are excreted mainly through the kidneys and via the bile. AOS and AS are mainly excreted via the urine. Only minimal amounts of LAS and AS are absorbed through intact skin.

Dodecyl benzenesulfonate (DOBC)

The percutaneous absorption of DOBC surfactant was studied in in vitro studies in rats and humans (Howes, 1975). Two test solutions of the [14C] DOBC were used, the first a 3 mM solution in 25 % v/v Polyethylene Glycol 400 in water and a second 3 mM suspension in water. 0.25 mL of the test solution was applied to the rat skin (4.9 cm²) and 0.1 mL to the human epidermal samples (0.78 cm²). The concentration of the test material in the solutions was 1.2 mg/mL. After 2, 6 and 24 hours (rats) or after 0.5, 1, 2, 3, 4, 6, 7, 8, 24 and 48 hours (human) of exposure, the skin samples were washed with excess of water and the radioactivity was measured in the rinsings and in the tested skin samples to determine the penetration rates. The results show no measurable penetration (<0.1 µg/cm²) of DOBS through the rat skin up to 24 hours. DOBC did not penetrate human epidermis as well (<0.1 µg/cm²). 30% [14C] DOBS was recovered in the rinsings and 70% remained associated with the skin of rats. 30-50% of [14C] DOBC retained in the human epidermis after rinsing.

To calculate percutaneous absorption rates, penetration of 0.1 µg/cm², the lower limit of detection, was taken as worst-case. Based on the applied amount of 0.25 mL to the rat skin (4.9 cm²) and 0.1 mL to the human epidermis (0.78 cm²) and ´the concentration of DOBC in vehicle of 1.2 mg/mL, 0.16% and 0.065% absorption was calculated for the rat skin and human epidermis, respectively. Monitoring at 2, 6, and 24 hours after exposure to rat and human skin showed no measurable percutaneous penetration of 14C (< 0.1 µg/cm²) for DOBS.

Howes (1975) also studied the in vivo dermal absorption of DOBC in rats (Howes, 1975). The [14C]-labelled DOBS was applied (0.2 mL) as a 3 mM aqueous suspension over 7.5 cm² of skin for 15 min. The applied dose resulted in 250 µg per test site. Then the test solution was rinsed off with distilled water and the animals were fitted with either restraining collars or non-occlusive protection patches and placed in the metabolism cages for collection of excreta. The expired CO2, urine, faeces and the carcasses of the animals, after excision of the treated skin, was monitored for [14C] at 24 h after treatment. The excised skin was monitored for [14C] and examined by autoradiography. Autoradiography of the skins showed heavy deposition of the surfactant on the skin surface and in the upper regions of the hair follicles. 11± 4 µg/cm² was recovered in the excised skin of rats, 135 µg in the rinsing and < 2 µg in the protection patches, so the total recovery was complete. All the tissue and excreta samples examined did not contain quantifiable amounts of [14C]. The penetration of the DOBC was below the limit of detection (<0.1 µg/cm²). Based on the amount applied (250 µg) and the penetration of 0.1 µg/cm², rat skin absorption would result in 0.3%.

The turnover (elimination) of [14C]-labelled DOBC was also measured by injecting three animals intraperitoneally and three animals subcutaneously with 0.1 or 0.5 mL of surfactant solution (Howes, 1975). Two test solutions of the [14C] DOBS were used, the first a 3 mM solution in 25% v/v Polyethylene Glycol 400 in water and a second a 3 mM suspension in water. The administered dose resulted in 1.02 mg/kg bw. The animals were placed in sealed metabolism cages where urine, faeces and expired air were collected and monitored for [14C]. After 6 or 24 h the animals were killed and the radioactivity in their carcasses was measured. The rate and route of excretion of [14C] from intraperitoneally administered [14C] surfactant solutions were the same as that from subcutaneously administered solutions. Most of the administered [14C] was recovered in the urine at 24 h after dosing (78%). 22% and 1.5% of applied dose were recovered in carcasses and in faeces, respectively. Less than 0.1% radioactivity was measured in the expired air.

Conclusion:

The toxicology profile for Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts and the calcium sulfonate read across substances indicate that oral and dermal absorption is expected to be absorbed to a limited extent 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, as the chemical was tested and was found to have a low vapour pressure (0.184 Pa at 25 °C), 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. The in vitro and in vivo studies with DOBC and other related alkyl/aryl sulfates and sulfonates provide additional evidence that the skin absorption is expected to be low. No measurable skin penetration could be determined in the in vitro and in vivo studies in rats and/or humans.

Concerning its distribution in the body any 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. 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 any absorbed test material is expected to be eliminated mainly via the urine and also via the bile (unabsorbed test material is excreted unchanged via the faeces).