Alcohols, C18-22, reaction products with maleic anhydride and sodium bisulfite

Endpoint summary

Description of key information

The toxicokinetics of Disodium C18-C22 sulfosuccinate was assessed based on the existing information on the substance 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 into the original alcohol and the sulphosuccinic acid. 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 30% 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 (%):

30

Additional information

The absorption, distribution, metabolism and excretion of Disodium C18-C22 sulfosuccinate is assessed based on the following data:

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 (See attachment)

Part 1: Physicochemical properties

The substance is a white powder solid, witha low solubility in water.

Due to the high insolubility and the value of melting point, and the complexity of the substance, vapour pressure is indicated with the estimation value of2.98E-015 Pa at 25°C

The partition coefficient was determined by the estimation and it is estimated to be 2.73 at room temperature 25°C (ca.).

The density has been measured as 0.839 g/ml

This substance is considered to be a surface-active material, based on a surface tension of similar substances. A masurement has not been performed due to the solubility, that is very low. It is considered stable in organic solvent and dissociation constant doesn’t need to be calculated.

Based on those data the substance is expected to be orally absorbed, while dermal absorption is expected to be very low based on the molecular weight at around 500 d and the ionic characterr of the substance and inhalatory exposure is not expected

-ADME:
Distribution can not be assessed properly, based on the fact that repeated dose testing on similar substance didn't reported sistemic toxicity or accumulation in specific tissues, at the tested doses. The substance, when assumed orally, is hydrolised in the sulphosuccinic part, whose metabolism and distribution has been extensively studied and excretion at very high evels has been measured. While the long chain alcoholic part is presumably absorbed, oxidised to the corresponding fatty acid moyety and it will enter in the fatty acid metabolic cycle.

Part 2: Read-across to Docusate sodium
No test data were available for current substance, however read across data were available from Docusate sodium. Data from docusate sodium can be taken into account to follow the sulphosuccinic portion that will generate afer hydrolysis in the stomach after oral uptake.

- 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 radiolabelled 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.