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EC number: 247-873-6
CAS number: 26650-05-5
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
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
acid, sulfo-, 4-[2-[(1-oxo-10-undecenyl)amino]ethyl]
ester, disodium salt
is assessed on three levels:
Based 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
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.
acid, sulfo-, 4-[2-[(1-oxo-10-undecenyl)amino]ethyl] ester, disodium
salt was assessed as follows based on physicochemical/toxicological data.
substance is a sulfosuccinate with moleucular formulaC17-H29-N-O8-S.2Na.
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:
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
upon the low vapor pressure, low log P, deposition in the airways and
absorption by inhalation is considered to be negligible.
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.
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.
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.
There is no direct indication of bioaccumulation potential.
Excretion: Excretion via the urine and bile might be expected because of
the high water solubility.
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
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
species and man. Testing laboratory: American Cyanamid. Report no.:
07066. Owner company:
Study number: 7235-03. Report date: 1973-04-10.
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
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
SIDS Initial Assessment Report for SIAM 25, Category of Alkyl sulfates,
Alkane sulfonates andα-Olefin sulfonates,
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
calculation & Annexes for support of absorption rates.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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