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Description of key information

The toxicokinetics of Butanedioic acid, sulfo-, 4-C12-14-(even numbered)-alkyl esters, disodium salts was assessed based on the physicochemical parameters and information from toxicokinetic literature from structural analogue substances. 
In summary, the substance is anticipated to be orally absorbed to a high extent, whereas inhalation or dermal uptake is very unlikely. The substance may be distributed within the organism, but accumulation is unlikely. Hydrolysis will take place at the ester site of the substance causing it to split in a polar and non-polar part. Eventually, it is expected that these parts will break down to water, CO2 and sulfur.. The major path of excretion seems to be via kidney, although some excretion via the bile is also possible. This was confirmed by experimental study of read-across substance Docusate sodium (CAS 577-11-7), demonstrating rapid and extensive metabolism and excretion in the urine in the form of metabolites. As more than 90% of the radioactivity was detected in the urine both after oral and intravenous application, oral absorption was considered to be relevant and therefore also the most relevant route of testing. Literature data for other anionic surfactants (e.g. alkyl sulfates, alkane sulfonates and α-olefin sulfonates) demonstrated a similar toxicological and toxicokinetic/metabolic profile as for the sulfosuccinate esters/amides. For these surfactants high oral absorption rates (90%) and low dermal absorption rates (<1%) were observed. For risk characterisation of the registered substance, conservative absorption rates of 90, 2 and 10% were taken into account for oral, dermal and inhalation routes, respectively.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
90
Absorption rate - dermal (%):
2
Absorption rate - inhalation (%):
10

Additional information

The absorption, distribution, metabolism and excretion of Butanedioic acid, sulfo-, 4-C12-14-(even numbered)-alkyl esters, disodium salts is assessed on three levels:

1) Based on the physicochemical properties of the compound itself

2) Read-across to Docusate sodium (‘Butanedioic acid, sulfo-, 1,4-bis(2-ethylhexyl) ester’, or ‘sodium salt dioctyl sodium sulfosuccinate’)

3) Literature review of other anionic surfactants

 

Part 1: Physicochemical properties

Absorption of Butanedioic acid, sulfo-, 4-C12-14-(even numbered)-alkyl esters, disodium salts was assessed as follows based on physicochemical/toxicological data following ECHA guidance 7c (ECHA Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, November 2012 Version 1.1).

The substance is an UVCB consisting mainly (50-80%) of C12 chains. Therefore molecular formula and molecular weight are based on the C12 chain. The compound is a solid material with a molecular weight of 420 g/mol and water solubility of 7.2 g/L. The log Pow is around -0.9 and the mean particle size is 76 µm. The vapour pressure is 0.0026 Pa. The structure of the substance shows ionisable groups, the surface tension of a watery solution is 41.3 mN/m and the substance is readily biodegradable.

-Oral/GI absorption:

Based upon the ionisable and hydrophilic properties, oral absorption might be considered to be limited, however the good solubility in GI fluids and the molecular weight below 500 g/mol are factors in favor of oral absorption. Furthermore the observed toxicity in acute oral toxicity studies indicated a systemic availability of the substance underlining an oral absorption. Nevertheless the extent of absorption remains unclear.

-Respiratory absorption:

The respiratory absorption is limited by the amount of inhalable substance and the fraction reaching the lower respiratory system. Due to the large particle size and low vapour pressure (0.0026 Pa) inhalation and/or deposition of significant amount of the substance seems unlikely. Additionally, the high hydrophilic properties of the substance may retain the substance in the upper mucosa. As a result the respiratory uptake and absorption is assumed to be limited.

- Dermal absorption:

Due to the molecular weight below 500 g/mol and the water solubility between 1-100 g/L a dermal absorption can be expected. Nevertheless the LogPow below 0 makes it impossible for the substance to cross the lipophilic areas of the stratum corneum. The surface tension is above 10mN/m pointing to no enhanced absorption, however due to the low vapor pressure a dermally attached substance may stay on the skin for a longtime. No skin irritations were observed for structural analog substances or with in vitro tests performed with the target substance. Therefore a limited dermal absorption is expected from this information. Calculation shows a very slow dermal absorption and low penetration coefficient Kp (see attachments) . In summary, the dermal absorption is assumed to be very limited due to the high hydrophilicity and based on the irritation test information received.

 

For the assessment of distribution, metabolism and excretion physicochemical and toxicological properties are also taken into account according to ECHA guidance 7c (ECHA Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, November 2012 Version 1.1).

-Metabolism:

Hydrolysis will take place at the ester site of the substance causing it to split in a polar and non-polar part. Eventually, it is expected that these parts will break down to water, CO2 and sulfur.

-Distribution:

Based on the molecular size of above 400g/mol and the high hydrophilicity a less wide distribution is expected but cannot be excluded. Nevertheless the low LogPow of below 0 indicates that a distribution into cells is less likely. However from the clinical signs observed after oral acute toxicity testing, distribution in the body is expected to take place. 

-Accumulation:

Based on the hydrophilicity and the large diameter of the substance, the substance is not expected to accumulate in the lung. Based on the low log Pow the accumulation in adipose tissues is also unlikely as well as accumulation in the stratum corneum. As the substance is no metal, accumulation in bones is also not expected. Taken together there is no direct indication of bioaccumulation potential.

-Excretion:

Derived from the molecular weight (below 500 g/mol) the high hydrophilicity and low logPow excretion in the urine is expected to be the favourable route. Nevertheless also excretion via bile is expected to occur after oral absorption but in less amounts than via urine. As the substance has a low vapour pressure, exhalation is not expected. Nevertheless the cleavage products of the substance may be included in the energy cycle and exhalation as CO2 may be possible

 

Part 2: Read-across to Docusate sodium

No test data were available for current substance, however read across data were available from Docusate sodium. Justification for read across with the category of Di-ester sulphosuccinates is documented in a separate document attached in Section 13.

- The absorption, excretion and metabolism of read across substance Docusate sodium have been investigated in rats, rabbits, dogs and man (Kelly, 1973). Radiolabelled compound carbon-14 was used in animal studies and unlabelled Docusate sodium in certain studies in rats, dogs and man. Both studies show a good absorption of the compound. From the studies with unlabelled Docusate sodium in the rat, the percent excretion of metabolites (2-ethylhexanol derivatives) seem to be similar after oral and intravenous administration demonstrating the good absorption of the compound. Confirmation of extensive absorption was obtained through oral dosage of 10 mg/kg carbon-14 labelled compound.

A comparison of an intravenous and an oral dose of 4 mg/kg of radiolabeled Docusate sodium in the rabbit also indicated a high degree of absorption following oral dosage in this species. Each route of administration resulted in the excretion of over 90% of the radioactivity in the urine after 48 hours. After 24 hours 89.4% and 72.8% are found after intravenous and oral administration respectively. As in the case of the rat, extensive metabolism was observed in the rabbit. A comparison of an oral and an intravenous dose of 4 mg/kg carbon-14 Docusate sodium in the dog yielded remarkably similar excretion patterns and metabolic profiles. However compared to the rat and rabbit, excretion via feces is higher than via urine. After 96 hours around 25% is excreted in the urine (20% after 24 hours), while around 71% is excreted in the feces (65-70% after 48 hours). Countercurrent distribution curves on the urine of these animals were almost identical.

- In man, peak concentrations of Docusate sodium in serum occurred at 2 hours after dosage with 200 mg. These values, in two men, were 7.9 and 5.5 µg/mL, similar in magnitude to the plasma concentration seen at 1 hour in the orally dosed dog (7.4 µg/mL) which received 4 mg/kg. The analysis of human serum was done by gas chromatography and that of dog plasma by the radiometric method. The excretion of 2-ethylhexanol derivatives in the urine of man accounted for only a very small amount of the administered dose of Docusate sodium, a finding similar to that seen in the urine of the dog. An attempt to compare the urine of man and the dog by analysis of 2-ethylhexanol forming compounds in countercurrent distribution fractions did not yield fruitful results. The metabolites found in dog urine are assumed to be incompletely hydrolysed ester derivatives of Docusate sodium.

Reference:

-Kelly R. G. (1973). The pharmacokinetics and metabolism of dioctyl sodium sulfosuccinate in several animal species and man. Testing laboratory: American Cyanamid. Report no.: 07066. Owner company: Cytec. Study number: 7235-03. Report date: 1973-04-10.

 

Part 3: Literature review of anionic surfactants (alkyl sulfates, alkane sulfonates and α-olefin sulfonates)

Anionic surfactants, including alkyl sulfates and alkane sulfonates and α-olefin sulfonates, have been assessed under the HPV program. These chemicals were shown to have low acute and repeated dose toxicity, no evidence of genetic or reproductive toxicity or carcinogenicity. The toxicological profile was similar to the sulfosuccinate esters/amides, and the absorption rate was high in both situations (90% absorption was demonstrated for a sulfosuccinate ester). Therefore, the toxicokinetic profile of the anionic surfactants can also be used for the sulfosuccinate esters and amides, with special emphasis on the low dermal absorption rate (<1%) and the common metabolic breakdown after oral absorption. The common physiological pathways result in structurally similar breakdown products ((butyric-, propionic-and pentanoic acid-5-sulfate fragments) for the various chain lengths, leading to fairly rapid excretion and low hazard for human health.

References:

- Wibbertmann et al., Ecotoxicolog  y and Environmental Safety 74 (2011) 1089-1106, Toxicological properties and risk assessment of the anionic surfactants category: alkyl sulfates, primary alkane sulfonates andα-olefin sulfonates.

- SIDS Initial Assessment Report for SIAM 25, Category of Alkyl sulfates, Alkane sulfonates andα-Olefin sulfonates, 2007

- Howes, D., J. Soc. Cosmet. Chem. 26 (1975) 47-63, The percutaneous absorption of some anionic surfactants.

Conclusion for the absorption rates

Based on the physicochemical properties, read across and literature, it can be concluded that the registered substance is well absorbed after oral administration (90%). For the other routes, absorption rates were assessed to be lower both after inhalation (assumed 10%) and dermal application (calculated 2%). Although the values were not based on experimental data of the registered substance, they were based on sound scientific background data and still conservative. See also Section 7.0: attached Justification for DNEL calculation & Annexes for support of absorption rates.