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EC number: 259-515-6
CAS number: 55184-72-0
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 registered product 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. Major
suggested metabolites are 2-ethylhexanol derivatives, 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,
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, 10 and 10% were taken into account for oral,
dermal and inhalation routes,
absorption, distribution, metabolism and excretion of registred product
is assessed on three levels:
Based on the physicochemical properties of the compound itself
Read-across to Docusate sodium (CAS 577 -11 -7)
Literature review of other anionic surfactants
1: physicochemical properties
was assessed as follows based on physicochemical/toxicological data
following ECHA guidance 7c (ECHA Guidance on information requirements
and chemical safety assessment. Chapter R.7c: Endpoint specific
guidance, November 2012 Version 1.1). The substance is a solid material
with molecular weight of 584.83 g/mol and water solubility > 170 g/L.
The log Pow is around 0.47 and the mean particle size is 30000-40000 µm.
The vapour pressure is 0.0048 Pa. The structure of the substance shows
ionisable groups, the surface tension of a watery solution is 25.2 mN/m.
The substance is not readily biodegradable, but strongly binding and
hence removed from the environment.
upon the molecular weight above 500g/mol, the ionisable and hydrophilic
properties, oral absorption might be considered to be limited, however
the good solubility in GI fluids and a logPow between -1 and 4 are
factors in favor of oral absorption. Furthermore the observed toxicity
in acute oral toxicity studies indicated a systemic availability of the
substance underlining an oral absorption. Nevertheless the extent of
absorption stays unclear.
respiratory absorption is limited by the amount of inhalable substance
and the fraction reaching the lower respiratory system. Due to the large
particle size and low vapour pressure (0.0048 Pa) inhalation and/or
deposition of significant amount of the substance seems unlikely.
Additionally the high hydrophilic properties of the substance may retain
the substance in the upper mucosa. As a result the respiratory uptake
and absorption is assumed to be very limited.
to the molecular weight of above 500, the high water solubility (>100
mg/mL) dermal absorption is not expected to be a favorable route.
However the LogPow between -1 and 4 makes it possible for the substance
to cross the lipophilic areas of the stratum corneum. The surface
tension is above 10mN/m pointing to no enhanced absorption, however due
to the low vapor pressure a dermally attached substance may stay on the
skin for a longtime. No skin irritations were observed for structural
analog substances or with in vitro tests performed with the target
substance. Therefore a limited dermal absorption is expected from this
information. Also QSAR information (Dermwin) shows a very slow dermal
absorption. The dermal penetration coefficient Kp was calculated to be
1.68.10-6 cm/h. In summary, the dermal absorption is assumed to be very
limited due to the high hydrophilicity and based on the irritation test
the assessment of distribution, metabolism and excretion physicochemical
and toxicological properties are taken into account according to ECHA
guidance 7c (ECHA Guidance on information requirements and chemical
safety assessment. Chapter R.7c: Endpoint specific guidance, November
2012 Version 1.1).
will take place at the ester site of the substance causing it to split
in a polar and apolar part. Eventually, it is expected that these parts
will break down to water, CO2 and sulfur.
on the molecular size of above 500g/mol and the high hydrophilicity a
less wide distribution is expected but cannot be excluded. Nevertheless
the LogPow is very close to 0 which 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
on the hydrophilicity and the large diameter of the substance, 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. As the substance is no metal,
accumulation in bones is also not expected. Taken together there is no
direct indication of bioaccumulation potential.
from the high hydrophilicity and low logPow excretion in the urine is
expected to be the favourable route. Nevertheless also excretion via
bile is expected to occur after oral absorption but in less amounts than
via urine. As the substance has a low vapour pressure, exhalation is not
expected. Nevertheless the cleavage products of the substance may be
included in the energy cycle and exhalation as CO2 may be possible.
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.
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 oral 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.
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.
risk characterisation, conservative absorption rates of 90, 2 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.
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
Initial Assessment Report for SIAM 25, Category of Alkyl sulfates,
Alkane sulfonates andα-Olefin sulfonates, 2007
D., J. Soc. Cosmet. Chem. 26 (1975) 47-63, The percutaneous absorption
of some anionic surfactants.
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