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Endpoint:
basic toxicokinetics
Type of information:
other: Publication
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Executive summary:

The toxicological profile of this substance, based upon experimental data available for this registration, is of a substance that is not highly toxic to mammalian species with no apparent long term threat. Furthermore, the substance is only ever used neat for the production of formulated products and this is mostly conducted in a closed system. In use, the substance is contained in formulated products at low levels and is therefore considered to be of low exposure. It is therefore considered that any distinct study can be neglected on the basis of animal welfare considerations and it is instead acceptable to provide a summary of effects based upon the available mammalian toxicity data. The study is therefore considered not scientifically justified.

The WHO document states for linear alkylbenzene sulfonates, that, according to Michael (1968), the main metabolites from an orally administered radiolabelled mixture of C10-14 ABS in rats were sulfophenyl butanoic acid and sulfophenyl pentanoic acid, formed via ω-oxidation and ß-oxidation of the parent ABS molecules. Furthermore, arat study of ABS isomers of similar chain length (C12) given orally or intravenously showed differential excretion in urine and faeces depending on the position of sulfonate moieties on the benzene ring (position 2 or 6). For either route of administration, after 48 hours around 75% of position 2 isomer was found in the urine, whereas 78% of the position 6 isomer was found in the faeces. In bile duct cannulated rats following intravenous administration, 89% of the 2 isomer was recovered in the urine whilst 83% of the 6 isomer was found in the bile (Rennison et al, 1987, as cited in WHO, 1996).

 

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:
other: Toxtree (version 2.5.0.) 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).
Objective of study:
metabolism
Qualifier:
no guideline required
Principles of method if other than guideline:
Prediction using TOXTREE (v.2.5.0)
GLP compliance:
no
Radiolabelling:
other: not applicable
Species:
other: not applicable
Route of administration:
other: not applicable
Duration and frequency of treatment / exposure:
not applicable
Remarks:
Doses / Concentrations:
not applicable
No. of animals per sex per dose:
not applicable
Type:
other: Prediction of metabolism by modelling
Results:
benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, containing the structural alerts: cation, anion, sulfonic acid derivative and aromatic compound, is expected to be well metabolized by the Cytochrome P450 group of metabolizing enzymes.
Details on metabolites:
The primary and secondary sites of metabolism are the carbon atoms of the chain, where it branches, which are predicted to be subject to aliphatic hydroxylation. The tertiary site 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.cationYes

QFG2.anionYes

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.phosphine
No
QFG83_4.phosphinoxide
No
QFG84_LS.boronic acid derivative
No
QFG84_1.boronic acid
No
QFG84_2.boronic acid ester
No

QFG85.alkeneNo

QFG86.alkyneNo

QFG87.aromatic compoundYes

QFG88.heterocyclic compoundNo
QFG89.alpha-aminoacid
No

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 metabolism
YesClassSMARTCyp.Rank2.sites
Q3.SMARTCyp tertiary sites of metabolism
YesClassSMARTCyp.Rank3.sites
Q4.SMARTCyp sites of metabolism with Rank>=4
YesClassSMARTCyp.Rank>=4.sites

Conclusions:
Interpretation of results (migrated information): other: well metabolized substance
Benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, containing the structural alerts: primary aromatic amine 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, where it branches, which are predicted to be subject to aliphatic hydroxylation. The tertiary site of metabolism are the terminal carbon-atoms of the chain, which is predicted to be subject to aliphatic hydroxylation.
Executive summary:

Benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, containing the structural alerts: cation, anion, 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, where it branches, which are predicted to be subject to aliphatic hydroxylation. The tertiary site of metabolism are the terminal carbon-atoms of the chain, which is predicted to be subject to aliphatic hydroxylation.

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well documented publication which meets basic scientific principles
Reason / purpose:
reference to same study
Objective of study:
excretion
Qualifier:
no guideline followed
GLP compliance:
no
Radiolabelling:
yes
Species:
rat
Strain:
other: Colworth-Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 100-120g
- Individual metabolism cages: yes

ENVIRONMENTAL CONDITIONS
- Air changes: 1.5 L/min
Route of administration:
other: intraperitoneal and subcutaneous
Vehicle:
other: solutions in 25% polyethylene glycol in water or in water only
Details on exposure:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 or 0.5 mL.
- concentration (if 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)

VEHICLE
- Justification for use and choice of vehicle (if other than water): test material is poor soluble in water
Duration and frequency of treatment / exposure:
single applications
Remarks:
Doses / Concentrations:
8.69 µCi (1.02 mg/kg bw )
No. of animals per sex per dose:
3 (intraperitoneal)
3 (subcutaneous)
Control animals:
no
Positive control:
None
Details on study design:
Not applicable
Details on dosing and sampling:
PHARMACOKINETIC STUDY (excretion)
- Tissues and body fluids sampled: urine, faeces, cage washes, expired air;
- Time and frequency of sampling: after 6 or 24 hours after test material administration.
Statistics:
Not reported
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 (migrated information): no bioaccumulation potential based on study results
DOBC is excreted predominantly via urine.
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% radiactivity 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.

Endpoint:
basic toxicokinetics
Type of information:
other: assessement of toxicokinetic behaviour based on phisico-chemical properties
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An assessment of the toxicokinetic behaviour of target substance magnesium sulfonate salt was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicological data.
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
according to
Guideline:
other: Technical guidance document, Part I, 2003
Deviations:
no
GLP compliance:
no
Type:
absorption
Results:
The target substance magnesium sulfonate is not favourable for absorption via all routes of exposure, due to its molecular weight (MW = 955.8), water solubility (0.198 mg/L), vapour pressure (1.0 * 10E-2 Pa at 25°C) and logPow (>4).
Type:
distribution
Results:
The distribution in tissues is expected to be limited due to the molecular weight of 955.8. The substance is not expected to cross biological membranes.
Type:
excretion
Results:
The metabolites 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 (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.
Benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts is not favourable for absorption, due to its molecular weight (MW = 955.8 g/mol), water solubility (0.198 mg/L) and logPow (>4). 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 but this mechanism may be of particular importance for the target substance magnesium sulfonate since it is again poorly soluble in water. The substance does bear however surface activity; therefore an enhancement of absorption is theoretically possible but 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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts 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.
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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, no 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 so high. Therefore, the distribution is expected to be limited.
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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts might indicate a potential for accumulation in the body. This, however, is limited as the absorption is expected to be low via all route of exposure and because metabolism of the magnesium sulfonate target substance is expected to influence this initial prediction.
Details on excretion:
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 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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts no data is available concerning its elimination. Concerning the fate of the metabolites formed of benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, the metaboiltes should be eliminated mainly via the urine and to a smaller extent via the bile.
Metabolites identified:
yes
Details on metabolites:
Hydrolysis in GI tract does not apply for the target substance magnesium sulfonate. Its metabolism is very likely to occur via the Cytochrome P450 group of metabolising enzymes. The primary and secondary sites of metabolism are the carbon atoms of the chain, where it branches, which can be subject to aliphatic hydroxylation. The tertiary sites of metabolism are the terminal carbon-atoms of the chain, which can also be hydroxylated. On the other hand, the long carbon chains are subject to initial omega- and then successive beta-oxidation, probably followed by oxidative scission of the aromatic ring and desulfonation. Hydroxylated intermediates can react in phase 2 of the biotransformation with different molecules, leading to the formation of conjugates with glucuronic acid, activated sulphate or activated methionine.

Absorption from the gastrointestinal tract

Regarding oral absorption, in the stomach, a substance will most likely be hydrolysed, because this is a favoured reaction in the acidic environment of the stomach.Benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium saltsis not expected to hydrolyse (due to its low water solubility). Accordingly, it is very unlikely forbenzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium saltsto be hydrolysed in the stomach.

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. However, 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 administeredbenzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium saltswill be absorbed to a limited extent, even though micellular solubilisation, pinocytosis and persorption can not be ruled out. This thesis is supported by the LD50 value of 16000 mg/kg bw available for magnesium sulfonate read across substance CAS 71786-47-5, which shows that the substance is not acutely toxic after oral exposure.

Absorption from the respiratory tract

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

Benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts hasa low vapour pressure (1.0 * 10E-2 Pa at 25°C), which 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 and 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 thatbenzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium saltsis marginally available in the air for inhalation and any inhaled substance is expected not to be absorbed.

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 for benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts. 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., 2013). According to the modelling results, benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, containing the structural alerts: cation, anion, 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, where it branches, 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.

Moreover, it is possible that the long carbon chains are subject to initial omega- and then successive beta-oxidation, probably 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.

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.
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The target substance magnesium sulfonate is not expected to be absorbed into the body extensively; distribution and accumulation in tissues will be limited. It is expected to undergo omega- and/or beta-oxidation of the carbon chains, with following oxidative scission of the aromatic ring and desulfonation; the metabolism via the Cytochrome P450 group of metabolising enzymes with subsequent hydroxylation and forming of conjugates can also apply. The substance is expected to be excreted mainly via urine or to a minor extent via faeces.
Executive summary:

In order to assess the toxicological behaviour of benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts,the available physico-chemical and toxicological data for it and its near magnesium and calcium read across substances have been evaluated. The magnesium sulfonate target substance is expected to be absorbed to a limited extent after oral exposure, based on its high molecular weight, its low water solubility and its high LogPow. Concerning the absorption after exposure via inhalation, as the chemical is considered to have a low vapour pressure, 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 magnesium sulfonate target substanceis also not expected to be absorbed following dermal exposure into the epidermis, due to its low water solubility and its fairly high molecular weight and its. Concerning its distribution in the body the magnesium sulfonate target substanceis expected to be distributed into the intravasal compartment and possibly also into the intracellular compartment. The substance does not indicate a significant potential for accumulation, when taking into account the predicted behaviour concerning absorption and metabolism.The magnesium sulfonate target substanceis expected to be significantly extensively metabolised (metabolism by cytochrome P450 enzymes, followed by omega- and beta-oxidation and cleavage of the aromatic ring and desulfonation) andto be eliminated mainly via the urine and also via the bile.

Endpoint:
dermal absorption
Type of information:
other: assessment of dermal absorption based on physico-chemical properties
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An assessment of the toxicokinetic behaviour of target substance magnesium sulfonate salt was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicological data.
Qualifier:
according to
Guideline:
other: Technical guidance document, Part I, 2003
Deviations:
no
GLP compliance:
no
Parameter:
percentage
Absorption:
10 %
Remarks on result:
other: The target substance magnesium sulfonate is expected to be poorly absorbed following dermal exposure into the stratum corneum, due to its LogPow of 21.8 and low water solubility (0.198 mg/L)

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 case of benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium 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 ofbenzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts,which is absorbed following dermal exposure into the stratum corneum is unlikely to be transferred into the epidermis. Although the substance does show characteristics of a surfactant, the magnesium sulfonate target substance is not irritating to skin and eyes, and therefore this does not enhance dermal absorption.

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).

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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts is justified(Schuhmacher –Wolz et al.,2003; TGD, Part I, 2003).
Conclusions:
No significant dermal absorption is expected for the target substance magnesium sulfonate.
Executive summary:

In order to assess the toxicological behaviour of benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts,the available physico-chemical and toxicological data for it and its near magnesium and calcium read across substances have been evaluated. The magnesium sulfonate target substance is expected to be absorbed to a limited extent after oral exposure, based on its high molecular weight, its low water solubility and its high LogPow. Concerning the absorption after exposure via inhalation, as the chemical is considered to have a low vapour pressure, 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 magnesium sulfonate target substanceis also not expected to be absorbed following dermal exposure into the epidermis, due to its low water solubility and its fairly high molecular weight and its. Concerning its distribution in the body the magnesium sulfonate target substanceis expected to be distributed into the intravasal compartment and possibly also into the intracellular compartment. The substance does not indicate a significant potential for accumulation, when taking into account the predicted behaviour concerning absorption and metabolism.The magnesium sulfonate target substanceis expected to be significantly extensively metabolised (metabolism by cytochrome P450 enzymes, followed by omega- and beta-oxidation and cleavage of the aromatic ring and desulfonation) andto be eliminated mainly via the urine and also via the bile.

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: acceptable well-documented publication which meets basic scientific principles
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
GLP compliance:
no
Radiolabelling:
yes
Species:
other: dorsal skin (rat) and female abdominal epidermis (human)
Strain:
other: Colworth-Wistar rats; human
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 100-120 g
Type of coverage:
other: in vitro penetration through the skin
Vehicle:
other: 25% polyethylene glycol in water or water only
Duration of exposure:
2, 6, 24 hours (rat, human) and 48 hours (human)
Doses:
- Nominal doses: DOBS concentration in solutions was 1.2 mg/mL (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);
- Dose volume: 0.25 mL of each test solution was applied to the rat skin (4.9 cm²) and 0.1 mL to the human epidermal samples (0.78 cm²).
No. of animals per group:
Not relevant
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: suspensions were prepared by homogenizing and equilibration in an all glass homogenizer.


APPLICATION OF DOSE

VEHICLE
- Concentration (if solution): 25% v/v Polyethylene Glycol 400 in water

ANALYSIS
- Method type(s) for identification: liquid scintillation counting
Details on in vitro test system (if applicable):
Not reported
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Absorption in different matrices:
The results show no measurable penetration (<0.1 µg/cm²) of DOBS through the rat skin up to 24 h after application. DOBC did not penetrate through the human epidermis until 48 hours after application (<0.1 µg/cm²). Permeability constant of 0.1 µcm/min (= 1.0E-7cm/min) was calculated for the isolated human epidermis 6 and 24 hours after skin contact.
Total recovery:
- Total recovery (rat skin): 30% [14C] DOBS was recovered in the rinsings and 70% remained associated with the skin of rats;
-Total recovery (human epidermis): 30-50% of [14C] DOBC retained in the human epidermis after rinsing;
- Limit of detection (LOD): 0.1 µg/cm².
Dose:
0.1 µg/cm²
Parameter:
percentage
Absorption:
0.16 %
Remarks on result:
other: 2, 6, 24 hours (rat)
Remarks:
based on the applied amount of 0.25 mL DOBC (concentration in vehicle 1.2 mg/mL) to the rat skin of 4.9 cm² and penetration of 0.1 µg/cm² (lower limit of detection was taken as worst-case).
Dose:
0.1 µg/cm²
Parameter:
percentage
Absorption:
0.07 %
Remarks on result:
other: 2, 6, 24 and 48 hours (human)
Remarks:
based on the applied amount of 0.1 mL DOBC (concentration in vehicle 1.2 mg/mL) to the human epidermis of 4.9 cm² and penetration of 0.1 µg/cm² (lower limit of detection was taken as worst-case).
Conclusions:
No significant penetration through the skin can be expected for dodecyl benzene sulphonate.
Executive summary:

Dodecylbenzene sulphonate (DOBC) was studied in in vitro penetration study through rat skin and human epidermis. 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. 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 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 accociated 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 taken into account concentration of DOBC in vehicle of 1.2 mg/mL, 0.16% and 0.065% absorption through the skin was calculated for the rat skin and human epidermis, respectively.

Endpoint:
dermal absorption in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented publication which meets basic scientific principles.
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
GLP compliance:
no
Radiolabelling:
yes
Species:
rat
Strain:
other: Colworth-Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 100-120 g
- Individual metabolism cages: yes

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): 1.5 L/min


Type of coverage:
open
Vehicle:
water
Duration of exposure:
15 min
Doses:
- Dose volume: 0.2 mL of the 3 mM aqueous suspension
No. of animals per group:
3
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: suspensions were prepared by homogenizing and equilibration in an all glass homogenizer.

APPLICATION OF DOSE:
The hair from animals' backs was removed with fine bladed clippers 24 h before topical application. Only animals with visibly undamaged skin were
usedi n the topical studies and all animals w ere lightly anaesthetized w ith a cyclopropane: carbon dioxide: oxygen gas mixture during treatment. The solution was lathered over the treatment area with a rounded glass rod for 1 min during application.

TEST SITE
- Preparation of test site: the hair was clipped
- Area of exposure: back
- % coverage: 7.5 cm²
- Type of cover / wrap if used: no
- Time intervals for shavings or clipplings: 24 h before topical application

REMOVAL OF TEST SUBSTANCE
- Washing procedures and type of cleansing agent: yes.
- Time after start of exposure: 15 min.
After 15 min contact with the skin the animal was inverted over a 6-inch diameter funnel and the excess of test solution was rinsed off with distilled water at 37°C from a wash bottle. After about 50 mL of water had been used the treated area of skin was lightly drawn over the top of the funnel to squeeze excess of rinse water from the skin. This process was then repeated and the skin dried with paper tissue.

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes:
The animals were then fitted with either restraining collars or non-occlusive protection patches and placed in the metabolism cages for collection of excreta.
The restraining collar was a thin (0.25 mm) card disc, 10 cm diameter, in which was cut a central hole to fit around the animal's neck. The disc was opened by a single radial cut and placed around the animal's neck. The cut disc w as then stapled up slightly overlapping the cut edges to form a shallow cone similar to a large ruff. This type of collar was successful in preventing small rats (up to 150 g) from grooming the treated area for up to 12 h after treatment.
The non-occlusive protective patch used in this study was similar to that described by Noakes and Sanderson (10). The treated area of skin was covered with a triple layer of surgical gauze approximately 1 cm larger in each direction to the treated area of skin. Over the surgical gauze a stainless steel gauze( 100 mesh) ,approximately 0 .5 cm smaller in each direction to the surgical gauze, was placed and 'Sleek' surgical strapping (Smith & Nephew Ltd., Welwyn Garden City, Herts), which had been punctured to give some 10 X 1 mm holes/cm² a over the treated area, was wrapped around the animal. This has been found to be effective in preventing grooming of the treated area of skin for 2 days and for some animals up to 4 days after treatment.

SAMPLE COLLECTION

- Collection of urine and faeces: yes
- Collection of expired air: yes
- Analysis of organs: carcasses and excised treated skin

SAMPLE PREPARATION
- Storage procedure: freezing
- Preparation details: the metabolism cages consisted of airtight perspex cages mounted on polythene collection funnels which directed the excreta into 'Metabowl' urine/faeces separators (Jencons Ltd, Hemel Hempstead, Herts). Air was drawn through the cages at 1.5 L/min 4 and bubbled through towers 30 cm deep and containing 240 mL of 50% aqueous ethanolamine. 1.0 mL aliquots of this solution were monitored for 14C at regular time intervals. Each urinary sample was made up to 25 mL with cage rinsings and faecals samples were freeze-dried. After 24 h the animals were killed by cervicald islocation.The carcasses of the animals were homogenized in an 'Atomix' blender (M.S.E. Ltd, Crawley, Sussex) and aliquots of the homogenate were freeze dried.

ANALYSIS
- Method type(s) for identification (Liquid scintillation counting)
- Limits of detection and quantification: 2.0, 5.0 and 10.0x 10³ dpm for urine, faeces and expired CO2, respectively. For analysis of whole carcass a limit of accurate measurement of 1 x 10E4 dpm is possible.
Signs and symptoms of toxicity:
not specified
Dermal irritation:
not specified
Absorption in different matrices:
- Rinsing: 135 ± 27 µg
- Skin test site: 11 ± 4µg
- Protective patch: < 2 µg
- Penetration: < 0.1 µg/cm²
The 14C levels in the skin and protective patch were determined 24 h after application and the penetration result is based on levels of 14C excreted in urine, faeces and expired CO2 during the 24 h after application plus levels of 14C in the carcass of the animals at 24 h.
Total recovery:
- Total recovery: 100%
- Limit of detection (LOD): 2.0, 5.0 and 10.0x 10E3 dpm for urine, faeces and expired CO2, respectively. For analysis of whole carcass a limit of accurate measurement of 1 x 10E4 dpm is possible.
Dose:
250 µg
Parameter:
percentage
Absorption:
0.3 %
Remarks on result:
other: 24 hours
Remarks:
based on the applied amount of 250 mg per test site (7.5 cm²) and the penetration of 0.1 µg/cm².
Conclusions:
The results show that only small amounts of DOBC penetrate the skin although considerable amounts are deposited on the skin. No 14C was detected in any of the excreta from the [14C] DOBS treated animals.
Executive summary:

Dodecylbenzene sulphonate (DOBC) was studied in in vivo absorption study in Colworth-Wistar rats (Howes, 1975). The [14C] 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 limit of detection (<0.1 µg/cm²). Based on the ammount applied (250 µg) and the penetration of 0.1 µg/cm², skin absorption would result in 0.3%.

Description of key information

The magnesium sulfonate target substance is expected to be absorbed to a limited extent after oral exposure, based on its high molecular weight, its low water solubility and its high LogPow. Concerning the absorption after exposure via inhalation, as the chemical is considered to have a low vapour pressure, 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 magnesium 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. Concerning its distribution in the body the magnesium sulfonate target substance is expected to be distributed into the intravasal compartment and possibly also into the intracellular compartment. The substance does not indicate a significant potential for accumulation, when taking into account the predicted behaviour concerning absorption and metabolism. The magnesium 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 eliminated mainly via the urine and also via the bile.

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 the magnesium sulfonate target substance

The toxicokinetic profile of the magnesium sulfonate target substance was not determined by actual absorption, distribution, metabolism or excretion measurements.Rather, the physical chemical properties of the magnesium sulfonate target substance and acute and repeated-dose toxicity data on the magnesium sulfonate target substance and the magnesium and calcium read across substances were used to predict toxicokinetic behaviour of the magnesium sulfonate target substance.

Toxicological profile of the magnesium sulfonate target substance

The magnesium sulfonate target substance is a viscous, dark brown coloured liquid with a relatively high molecular weight (MW = 955.8 g/mol, Tremain. S.P. / Fox, J.M., 2013). It has a melting point at -20 °C (Fox, J.M., 2013). A study shows that it partially boils at approximately 327-400 °C (Fox, J.M., 2013) and has a low vapour pressure, 0.01 Pa at 25°C. Its relative density was reported to be 0.97 (Fox, J.M., 2013). The magnesium sulfonate target substance is slightly soluble in water (0.198 mg/l at 20°C). While the partition coefficient Log10Pow of the undissociated magnesium sulfonate target substance has been estimated to be > 6.40, based on visual assessment and water solubility results, the partition coefficient of the undissociated magnesium sulfonate target substance is expected to be significantly higher in light of the KOWWINv1.68 (Sept 2010), the logPow value is 21.8 (Fox, J.M. 2013).

The magnesium sulfonate target substance was shown not to be skin or eye irritating (Kern, T.G., 1999A; 1999B, Buehler, E.V., 1992). In addition, several magnesium and calcium sulfonate read across substances have been shown not to be acutely toxic when administered to rats orally (LD50 > 16000 mg/kg bw, Sanitised, A., 1980), or dermally (LD50 > 2000 mg/kg bw, Sanitised, D., 1989). Moreover, the calcium sulfonate read across substance (CAS 70024-69-0) was shown neither to be a skin nor an eye irritant (Hoff, 2002a; Hoff, 2002b; Buehler, 1990a; Buehler, 1990b; Swan, 1972; Kern, 1999a and Buehler, 1991a/b; Swan, 1972; Kern, 1999b), and the magnesium sulfonate read across substance (CAS 71768-47-5) was shown not to bear a potential to cause allergic reactions (van Huygevoort, 2012). Repeated oral exposures to the calcium sulfonate read across substance CAS 70024-69-0 (28-day study) 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). Concerning gene mutation, the calcium sulfonate read across substance CAS 70024-69-0 was shown not to bear genotoxic potential (Sanitised, F., 1989) and the magnesium sulfonate read across substance CAS 71786-47-5 not to be mutagenic (Sanitised, I., 1995). Moreover, the calcium sulfonate read across substance (Analogue of 70024-69-0) was shown not to induce micronuclei (Sanitised, G., 1989).

The calcium sulfonate read across substance (CAS 115733-09-0) was reported not to induce adverse effects in a 1-generation reproduction toxicity study (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 (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 magnesium sulfonate target substance, benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts is not favourable for absorption, due to its molecular weight (MG = 955.8 g/mol), water solubility (0.198 mg/L) and logPow (>4). 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 but this mechanism may be of particular importance for the magnesium sulfonate target substance since it is again poorly soluble in water. The substance does bear, however, surface activity; therefore an enhancement of absorption is theoretically possible, but 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 magnesium 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 will most likely be hydrolysed, because this is a favoured reaction in the acidic environment of the stomach. The magnesium sulfonate target substance is not expected to hydrolyse (due to its low water solubility). Accordingly, it is very unlikely that benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts will be hydrolysed in the stomach.

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. However, 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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts will be absorbed to a limited extent, even though micellular solubilisation, pinocytosis and persorption cannot be ruled out. This thesis is supported by the LD50 value of 16000 mg/kg bw available for magnesium sulfonate read across substance CAS 71786-47-5, which shows that the substance is not acutely toxic after oral exposure.

Inhalation route

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

Benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts has a low vapour pressure (1.0 * 10E-2 Pa at 25°C), which 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 and 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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts is marginally available in the air for inhalation and any inhaled substance is expected not to be absorbed.

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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium 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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, which is absorbed following dermal exposure into the stratum corneum is unlikely to be transferred into the epidermis. Although the substance does show characteristics of a surfactant, the magnesium sulfonate target substance is not irritating to skin and eyes, and therefore this does not enhance dermal absorption.

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 115733-09-0via the skin is low (acute dermal toxicity, LD50 value of > 2000 and > 5000 mg/kg bw for rats, respectively).

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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium 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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, no 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 so high. Therefore, the distribution is expected to be limited.

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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium 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 magnesium 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 for benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts. 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., 2013). According to the modelling results, benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, containing the structural alerts: cation, anion, 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, where it branches, 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 also subject to aliphatic hydroxylation.

Moreover, it is possible that the long carbon chains are subject to initial omega- and then successive beta-oxidation, probably 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.

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

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 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 benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts no data is available concerning its elimination. Concerning the fate of the metabolites formed of benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, the metabolites should be eliminated mainly via the urine and to a smaller extent via the bile.

The following information is taken into account for any hazard/ risk assessment

The magnesium sulfonate target substance is expected to be absorbed to a limited extent after oral exposure, based on its high molecular weight, its low water solubility and its high LogPow. Concerning the absorption after exposure via inhalation, as the chemical is considered to have a low vapour pressure, 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 magnesium sulfonate target substanceis also not expected to be absorbed following dermal exposure into the epidermis, due to its low water solubility and its fairly high molecular weight. Concerning its distribution in the body the magnesium sulfonate target substanceis expected to be distributed into the intravasal compartment and possibly also into the intracellular compartment. The substance does not indicate a significant potential for accumulation, when taking into account the predicted behaviour concerning absorption and metabolism.The magnesium sulfonate target substanceis expected to be extensively metabolised (metabolism by cytochrome P450 enzymes, followed by omega- and beta-oxidation and cleavage of the aromatic ring and desulfonation) andto be eliminated mainly via the urine and also via the bile.

Prediction using TOXTREE

A representative chemical structure of benzenesulfonic acid, mono-C20 -24 -alkyl derivs., magnesium salts was assessed by Toxtree (v.2.5.0) modelling tool for possible metabolism. SMART Cyp is a prediction model, included in the tool, which identifies sites in a molecule that are labile for the metabolism by Cytochromes P450.

Benzenesulfonic acid, mono-C20-24-alkyl derivs., magnesium salts, containing the structural alerts: cation, anion, 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, where it branches, 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.

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 akylbenzene sulfonates (LAS), alpha-olefin sulfonates (AOS) and alkyl sulfonates (AS) 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]DOBS 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 (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 also was 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 the magnesium sulfonate target substance and the magnesium and calcium sulfonate read across substances indicate that oral and dermal absorption is expected to be limited. 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.