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EC number: 947-655-7
CAS number: -
Table 1. 24 hour excretion of
2-ethylhexanol-forming compounds by the rat after oral dosage with DSS
% of dose excreted
-: not determined
The absorption, excretion and metabolism of
read-across substance dioctyl sodium succinate (DSS) have been
investigated. Unlabeled DSS and radiolabeled compound (carbon-14) were
used. 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. Confirmation of extensive absorption of DSS was obtained through
oral dosage of 10 mg/kg carbon-14 labeled compound. Two thirds of the
administered radioactivity was found in the urine at 24 hours after
dosage. All of the activity was in the form of metabolites
(2-ethylhexanol forming compounds).
The toxicokinetics of Butanedioic acid, sulfo-, 4-[1-methyl-2-[(1-oxo-9-octadecenyl)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. 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 sullfosuccinate 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
absorption, distribution, metabolism and excretion of Butanedioic acid,
sulfo-, 4-[1-methyl-2-[(1-oxo-9-octadecenyl)amino]ethyl] ester, disodium
salt is assessed on three levels:
on the physicochemical properties of the compound itself
to Docusate sodium (‘Butanedioic acid, sulfo-, 1,4-bis(2-ethylhexyl)
ester’, or ‘sodium salt dioctyl sodium sulfosuccinate’)
review of other anionic surfactants
1: Physicochemical properties
of Butanedioic acid, sulfo-,
4-[1-methyl-2-[(1-oxo-9-octadecenyl)amino]ethyl] ester, disodium salt
was assessed as follows based on physicochemical/toxicological data.
substance is a sulfosuccinate with molecular formula C25H45NO8SNa2. The
freeze-dried substance is a white lumpy powder and is marketed or used
in a non solid or granular form.. The substance has a molecular weight
of 563.66 g/mol and water solubility is 10-50 g/L (OECD TG 105). The Log
P is -2 to -1.3 (OECD TG 107). The vapour pressure is 3.63E-19 Pa at
25°C (EPIwin calculation). The surface tension was determined with the
plate method according to EC A.5 and DIN 14370. The surface tension of a
1g solid content /L solution at 20°C was 28.16 mN/m.
the substance is considered to be less favourable for oral absorption
based on physicochemical properties (ionisable, high molecular weight,
high water solubility, low Log P), toxicological data indicate systemic
availability after oral absorption.
upon the granular form, low vapuor pressure high water solubility, low
Log P, deposition in the airways is assumed to be absent and absorption
by inhalation is considered to be negligible.
upon the physicochemical parameters dermal absorption is considered to
be limited. When QSAR material was taken into consideration (Dermwin:
see below), 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.
the assessment of distribution, metabolism and excretion physicochemical
and toxicological properties are also taken into account according to
ECHA guidance 7c (2017).
upon water solubility and toxicological data, distribution in the body
is expected to take place.
Metabolism & accumulation potential:
on the hydrophilicity , 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. Taken
together there is no direct indication of bioaccumulation potential.
the assumptions above, excretion via the urine and bile might be
expected because of the high water solubility. Another route of
excretion may be applicable (e.g. skin after dermal application).
However this is of less relevance.
2: Read-across to Docusate sodium
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.
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.
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.
3: Literature review of anionic surfactants (alkyl sulfates, alkane
sulfonates and α-olefin sulfonates)
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.
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 and
SIDS Initial Assessment Report for SIAM 25, Category of Alkyl sulfates,
Alkane sulfonates and α-Olefin sulfonates, 2007
Howes, D., J. Soc. Cosmet. Chem. 26 (1975) 47-63, The percutaneous
absorption of some anionic surfactants.
for the absorption rates
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
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