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Description of key information

Based on physicochemical properties, oral absorption seems to be possible and absorption by inhalation is considered to be negligible. Dermal absorption was assessed to be low based on physicochemical characteristics and Dermwin calculation.
The absorption, excretion and metabolism of read across substance Docusate sodium were investigated in rats, rabbits, dogs and man by means of radiolabeled read across substance Docusate sodium applied orally and intravenously. Absorption, metabolism and excretion were extensive in the rat and rabbit after oral application as two thirds of the administered radioactivity was found in the urine in the form of metabolites, and 90% of the radioactivity was detected in the urine both after oral and intravenous application. In the dog 71% of the administered radioactivity was excreted. In man, peak concentrations in serum occurred at 2 hours at comparable levels to the dog.
Literature data are available for anionic surfactants (alkyl sulfates, alkane sulfonates and α-olefin sulfonates ) which have similar breakdown products to sulfosuccinates. For these surfactants high oral absorption rates (90%) and low dermal absorption rates (<1%) were observed.
For risk characterisation, conservative absorption rates of 90, 10 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 (%):
10
Absorption rate - inhalation (%):
10

Additional information

The absorption, distribution, metabolism and excretion of Butanedioic acid, sulfo-, 1,4-dicyclohexyl ester, sodium salt 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-, 1,4-dicyclohexyl ester, sodium salt was assessed as follows based on physicochemical/toxicological data:

-It is a solid material with molecular weight of 388 g/mol and water solubility > 500 g/L. The logKow has a very low value of 0 and the particle size is rather high (X50 =792 µm).

-Based upon the ionisable and hydrophilic properties, oral absorption is considered to be limited. On the other hand, easy dissolution in the gastro-intestinal tract and toxicity observed in acute oral toxicity studies indicated that oral absorption is possible. 

-Deposition in the airways and absorption by inhalation are considered to be negligible due to the large particle size, low vapour pressure (<0.078 Pa) and high hydrophilic properties of the substance.

-Dermal absorption is considered to be possible but limited taking into account the physicochemical parameters and the fact that the substance has been shown to be a skin irritant. When QSAR (Dermwin calculation) was taken into consideration, the dermal penetration rate seems to be very slow. However, it is more expected that the test material is retained in the dermis than that it is absorbed.

For the assessment of distribution, metabolism and excretion physicochemical and toxicological properties are taken into account.

-Based upon the molecular size, high hydrophilicity and low LogP, distribution is expected to be low, but possible based on the clinical signs observed after oral acute toxicity testing. 

-There is no direct indication of bioaccumulation potential. The substance is very hydrophilic and has a low lypophilicity.

-Based upon the low logP and high water solubility excretion in the urine and bile is expected to occur after oral absorption. When dermally exposed, the test substance not expected to be absorbed, but to penetrate in the (epi)dermis and to be excreted by exfoliation.

Reference:

-ECHA Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance, November 2012 Version 1.1.

 

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). Radiolabeled compound carbon-14 was used in animal studies and unlabeled Docusate sodium in certain studies in rats, dogs and man. Using a gas chromatographic procedure, a similarity in percent excretion of dose into urine was observed in rats dosed orally and intravenously, indicating a high degree of absorption of the oral dose. A similar experiment in dogs yielded much lower values.

-Confirmation of extensive absorption of Docusate sodium in the rat was obtained through oral dosage of 10 mg/kg carbon-14 labeled compound. Two thirds of the administered radioactivity was found in the urine in the form of metabolites. 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. 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. In each case 71% of the administered radioactivity was excreted. 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.

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, alkane sulfonates and α-olefin sulfonates, have been assessed under the HPV program. These chemical 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 (fragments) for the various chain lengths, leading to fairly rapid excretion and low hazard for human health.

References:

-Wibbertmann et al., Ecotoxicology 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.

For risk characterisation, conservative absorption rates of 90, 10 and 10% were taken into account for oral, dermal and inhalation routes, respectively. See also Section 7.0: attached Justification for DNEL calculation & Annexes for support of absorption rates.