Benzenesulfonic acid, mono-C10-13-alkyl derivs., compds. with diethanolamine

Endpoint summary

Description of key information

There are no data available on the test item. Therefore, toxicokinetic propteries are assessed based on its physico chemical properties and on available data on read-across substances. For Read-across justification please refer to IUCLID chapter 13.

Based on its physico-chemical properties the test item is not expected to have a bioaccumulation potential. However, the read-across substance DEA was observed to accumulate in liver and kidney presumably by an endogenous pathway phospholipid genesis of cell membranes. It cannot be ruled out completely that this mechanism also applies for the test item.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic analysis of Benzenesulfonic acid, mono-C10-13-alkyl derivs., compds. with diethanolamine (CAS 90194-39-1)

 

Experimental data on toxicokinetic properties of the substance is not available. Therefore, an analysis on toxicokinetics is performed based on physico chemical properties of the substance as well as on experimental data of the two read across substances, source substance 2 (Benzenesulfonic acid, C10-13-alkyl derivs., sodium salts, LAS Na) and source substance 3 (diethanolamine, DEA). For details on the read-across approach please refer to the read-across justification attached in IUCLID chapter 13.

Toxicokinetic assessment of read-across source substance 1 (Benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., compds. with triethanolamine, LAS TEA) is based on a read-across approach itself with LAS Na and TEA and is therefore not taken into account here.

 

The test substance is a slight yellow, viscous liquid at room temperature. Since the substance is an UVCB molecular weight is not determinable. However, based on its constituents molecular weight is not expected to exceed 500 g/mol. Relative density of the test item was determined to be 1.09. The melting point of the test item is 16 °C and the boiling point is greater than 176 °C (decomposition) at 1013 hPa. The substance is very well soluble in water, as water solubility is 337 g/L at 20 °C. Higher concentrations in water lead to gel formation. Partition coefficient (logPow) of the substance was determined to be 2.5. Vapor pressure of the substance was determined to be 190 Pa at 20 °C. The test item is considered as surface active substance based on its surface tension of 33.0 mN/m.

 

 

 

1.1 Absorption

 

Oral route

Bioavailability via oral route is strongly linked to physico-chemical properties of the substance (ECHA Guidance, 2008). Generally, oral absorption is favored for molecular weights below 500 g/mol and with a logPow in the range of -1 to 4. Furthermore, the water solubility of a substance has to be taken into account when estimating the potential for a substance to diffuse through biological membranes.

The test item is an UVCB with a logPow of 2.5. In addition, water solubility was determined to be 337 g/L. Therefore, the test item is expected to be readily absorbed in the gastrointestinal tract. Since the substance is surface active it possibly forms micelles and enters the circulation via the lymphatic system, bypassing the liver (ECHA Guidance R7c). Absorption of surface active substances may be enhanced.    

Source substance 2 has a logPow of 1.4 and a molecular weight of 334.5 g/mol. Therefore, the substance is expected to be readily absorbed in the intestine. Furthermore, water solubility of the substance is 250 mg/L which also favors bioavailability via the gastrointestinal tract. These considerations are confirmed by oral absorption studies conducted in the rat and monkey, respectively (Cresswell, 1978; Michael, 1968). In the rat, almost full absorption of the test item was observed, meaning 80 - 90 % of the orally administered dose.

 

Source substance 3 has an even better water solubility of 1000 mg/L and a lower molecular weight of 105.1 g/mol. The logPow of the substance is -2.46, which does actually not favor the passage through biological membranes anymore. However, available experimental data demonstrate well absorption (57 %) of the substance when orally administered to rats (Mendrala, 2001).

 

 

Dermal route

 

According to ECHA guidance on toxicokinetics, there are no exclusion criteria for skin permeability. In general, skin absorption of 100 % is applied as default. However, a molecular weight of > 500 g/mol and a logPow of > 4 are given as indicators for low absorption (10 % or less). Both parameters do not apply for the test item. In fact the test items logPow is 2.5 and its molecular weight is not expected to be greater than 500 g/L. Therefore, based on the test items physico- chemical properties, dermal absorption could be possible in theory. As the surface tension of the substance was determined to be 33 mN/m it is considered as surface active, but not yet as surfactant (< 10mN/m). Therefore, enhanced potential for dermal uptake or enhanced absorption of other compounds is not expected.

 

There are no data available on dermal absorption of source substance 2. However, this endpoint was addressed with data on an analogue substance (CAS 25155-30-3). For more detailed information please refer to the REACH registration dossier of CAS 68411-30-3. Dermal absorption was investigated in rats and found to be less than 0.3 % 24 hours after exposure. Furthermore, percutaneous penetration was studied in human skin in vitro systems and assessed to be less than 0.7 % after 2, 6, 24 and 48 hours, respectively. Based on these findings, source substance 2 is considered to highly unlikely become bioavailable via the dermal route. Based on its surface tension Source substance 2 is also considered as surface active substance. However, enhanced potential of dermal absorption is not supported by available experimental data.

 

Experimental data on source substance 3 revealed that the substance facilitates its own dermal absorption in a dose dependent manner (Mathews, 1997). Higher doses were found to be more completely absorbed than lower doses. However, overall the substance is absorbed to a lower degree after dermal administration than via the oral route (3-16% in rats; 25 – 60% in mice). Source substance 3 applied to skin preparations in vitro showed penetration rates of 6.7% (mouse) > 2.8% (rabbit) >0.56% (rat) > 0.23% (human) (Sun, 1996).

 

Taking into account available experimental data on skin penetration properties of both source substances, it can be stated that the test item is not expected to be well absorbed by the human skin. Experimental data for both source substances demonstrated only poor dermal absorption in vitro and in vivo. And it is unlikely that the test substance itself would facilitate substantially better absorption through skin than the source substances.

 

 

Inhalation route

 

The test substance is a liquid with a low vapour pressure of 190 Pa and a boiling point of greater than 176 °C. Therefore, it is very unlikely that the substance is available as a vapour. Thus, regarding inhalation, exposure is not relevant since the substance is not considered to form inhalable dust. However, if the case of inhalation should occur the substance is expected to probably pass the mucosal membranes of the respiratory tract in the same manner as it is considered via the oral route.

 

No experimental data for source substance 2 are available for exposure by inhalation. Vapour pressure of source substance 2 was calculated to be 3E-13 Pa. Therefore, the substance is not expected to be available as a vapour. Even though source substance 2 is a solid it is not handled and marketed in a solid or granular form. Therefore, human exposure by small particle dust of the substance is not relevant.

 

Source substance 3 was investigated in acute and repeated dose toxicity inhalation studies. Based on experimental findings, it can be stated that the substance is absorbed when inhaled. For more detailed information please refer to the REACH registration dossier of CAS 111-42-2.

 

 

1.2 Distribution

 

As outlined above, the physico-chemical properties of the test item indicate that it will likely become bioavailable via the oral route and probably via inhalation route as well. But to a less extend via the dermal route.           
After being absorbed, the test item is likely distributed into cells and intracellular concentrations may be higher than extracellular concentrations due to its slightly lipophilic properties (logPow of 2.5). As its logPow is smaller than 4, the test item is not highly lipophilic and therefore it is unlikely to have a potential for bioaccumulation.

 

Due to its good water solubility, source substance 2 is expected to be distributed basically by body fluids such as the blood. Extracellular concentrations may be higher than intracellular concentrations. In the rat 35 % of orally administered substance was observed to be eliminated via the bile and then reabsorbed (Michael,, 1968). However, the substance is not expected to accumulate in the body as demonstrated by an OECD 305 study with fish. Corresponding BCF values were increasing with increasing alkyl chain length but not exceeding critical values (2-1000 L/kg). Furthermore, toxicokinetic studies in the monkey showed sufficient metabolism and rapid excretion of the substance or its metabolites within 5 days (71 % via urine and 23 % via faeces) (Cresswell, 1978).

 

Based on its good water solubility and low logPow source substance 3 is not expected to bioaccumulate. This was also demonstrated by corresponding QSAR calculation. Investigations with source substance 3 revealed that distribution to the tissues was similar via all routes examined (oral, dermal and intravenous) (Mathews, 1997). The highest concentrations are observed in liver and kidney (Mathews, 1995). The substance is cleared from the tissues with a half-life of approximately 6 days. Because of structural similarities to endogenous ethanolamine incorporation mechanisms of diethanolamine in cells of liver and kidney are assumed. Ethanolamine is a normal constituent of phosphoglycerides, main components in biological membranes. DEA is incorporated as the head group to form aberrant phospholipids, presumably via the same enzymatic pathways that normally utilize ethanolamine.

 

 

1.3 Metabolism

 

Since the test substance is an UVCB, composed of source substance 2 and 3 as constituents, its metabolism is considered to follow similar principles as the metabolism of both source substances 2 and 3.

 

Source substance 2 is an UVCB of Benzensulfphonic acid sodium salts alkylated in para position with a hydrocarbon chain consisting of 10 to 13 carbons. In a toxicokinetic study with monkeys metabolites were found in urine and faeces but not completely identified. However, glucuron- or sulfon-conjugates could be excluded (Cresswell, 1978). Metabolism studies in the rat with source substance 2 revealed that sulfophenyl butanoic acid and sulfophenyl pentanoic acid are formed (Michael, 1968). As metabolic pathway omega-oxidation with subsequent catabolism through beta-oxidation is proposed.

 

Source substance 3 is mainly not metabolized in the rat. After oral administration unchanged DEA was found in the urine and smaller proportions of N-methyl-DEA (N-MDEA), N,N-dimethyl-DEA (N’N-DMDEA) and DEA-phosphates co-eluting with phosphatidyl ethanolamine and phosphatidyl choline (Mathews, 1997 and 1995). After digestion 30% of the phospholipids were identified as ceramides and the remaining 70% as phosphoglycerides.

 

1.4 Elimination

 

With source substance 2 60 - 65 % elimination via the urine was found after 72 h following oral administration in the rat. 35 % were eliminated via the bile (Michael, 1968). Similar proportions were observed in the monkey, with 71 % via urine and 23 % via bile within 5 days after oral administration (Cresswell, 1978).

 

Source substance 3 is excreted primarily in urine as unchanged parent molecule (25-36% 96 h post dosing), with less amounts of O-phosphorylated and N-methylated metabolites (Mendrala, 2001).

 

Based on kinetic and metabolism studies with both source substances outlined above, the test item itself is considered to be rapidly metabolized and eliminated mainly via the urine in regards to benzensulphonic acid alkyl derivates. The constituent DEA, however, will be eliminated mainly unchanged but also via the urine.

 

 

2     Summary

Based on its physico chemical properties as well as on experimental data of the two read-across source substances 2 and 3 the following toxicokinetic properties of the test item can be assumed:  

The test item is probably well absorbed via the oral but only poorly via the dermal route. Exposure via inhalation is not expected, however absorption by the mucosal membranes of the respiratory tract cannot be excluded.   

Both source substances as well as the test item itself are well soluble in water with a relative low logPow, respectively. Therefore, distribution via the body fluids can be expected. Based on their physico-chemical properties, bioaccumulation would not be expected for any of the three substances. However, DEA accumulation in liver and kidney is observed. Mechanistically, it is assumed that the endogenous phosphoglycerine pathway utilizes diethanolamine instead of physiological ethanolamine. Occurrence of this mechanism cannot be ruled out completely for the test item.       
Source substance 2 was demonstrated to be rapidly metabolized and eliminated primary via the urine. Whereas source substance 3 was found to be excreted via the urine mainly unchanged. Only a small amount was metabolized by N-methylation or O-phosphorylation.