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Description of key information

The toxicokinetics of Butanedioic acid, sulfo-, 4-[2-[(1-oxo-10-undecenyl)amino]ethyl] ester, disodium salt 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. 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-[2-[(1-oxo-10-undecenyl)amino]ethyl] ester, disodium 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

According to chapter R.7C (Version 3.0 June 2017) of the endpoint specific guidance of REACH, physicochemical data may be used for a qualitative TK assessment. The data below were used for a qualitative toxicokinetic assessment.

Absorption of Butanedioic acid, sulfo-, 4-[2-[(1-oxo-10-undecenyl)amino]ethyl] ester, disodium salt was assessed as follows based on physicochemical/toxicological data.

The substance is a sulfosuccinate with moleucular formulaC17-H29-N-O8-S.2Na. The compound is a non-granular solid (or liquid formulation) material with a molecular weight of 451 g/mol and water solubility 200.0 g/L at 23.0 °C and log P-3.10 (experimental). The vapour pressure is1.75 x 10E-18 hPa at 25°C (EPIWIN). The structure of the substance shows ionisable groups, the surface tension of a watery solution is31.7 ± 0.82 mN/m at 20°C at a concentration of 1 g/L.and the substance is readily biodegradable.Based on the physicochemical (and toxicological) characteristics, following was concluded:

-       Oral/GI absorption: Based upon the ionisable and hydrophilic properties and rather high molecular weight of the molecule, oral absorption is considered to be limited. Toxicity was only observed at very high dosages (> limit dose of 2000 mg/kg bw).  

-       Respiratory absorption: Based upon the low vapor pressure, low log P, deposition in the airways and absorption by inhalation is considered to be negligible.

-       Dermal absorption: Based upon the physicochemical parameters (solid or liquid, low log P and low vapour pressure) and skin irritation data, dermal absorption is considered to be possible but limited. When QSAR material was taken into consideration (Dermwin), 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.

-       Metabolism: Based upon the high molecular weight, low log P and hydrophilicity, distribution is expected to be rather limited, however from the toxicity of slimier subtsance, distribution in the body is expected to take place. 

-       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 LogP 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: There is no direct indication of bioaccumulation potential.

- Excretion: Excretion via the urine and bile might be expected because of the high water solubility.

 

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.

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