DIOCTYL SODIUM SULFOSUCCINATE
First draft prepared by Dr F.S.D. Lin,
Division of Toxicological Review and Evaluation,
Center for Food Safety and Applied Nutrition,
US Food and Drug Administration.
1. EXPLANATION
Dioctyl Sodium Sulfosuccinate (DSS) is the dioctyl ester of
sodium sulfosuccinate. The pure compound is a white waxy solid,
soluble in many organic solvents and in water. It is an anionic
surface active compound, which has marked wetting characteristics.
Its detergent properties make it useful for cleaning and peeling
fruits and vegetables and cleaning food packaging. It is also used
in various pharmaceutical products. The structure of DSS is shown
in Figure 1.
Figure 1.
C2H5
'
CH2COOCH2CH(CH2)3CH3
'
NaO3S - CHCOOCH2CH(CH2)3CH3
'
C2H5
This food additive was reviewed at the twenty-second meeting of
the Committee (Annex 1, reference 47), when the temporary ADI 2.5
mg/kg/bw was withdrawn because the additional information which had
been required by the Committee at its eighteenth meeting was not
provided. The required information included: (1) the effects on
newborn animals, particularly those exposed to DSS through
lactation: (2) an adequate long-term study in a rodent species: and
(3) a study of the effects of DSS on the pulmonary vascular system.
These data were still not available at the twenty-fourth meeting
(1980) and the Committee did not prepare a monograph.
Since the last evaluation of DSS additional toxicological data
have become available to the Committee: these data are summarized
and discussed in the following monograph. The previously published
monograph from the 18th meeting is also included as part of this
monograph.
2. BIOLOGICAL DATA
2.1 Biochemical Aspects
2.1.1 Absorption, distribution, metabolism, and excretion
2.1.1.1 Rat
DSS labelled with 35S was administered orally in a single
dose (50 mg/kg) in an alcohol and water (1:1 v/v) solution to albino
rats weighing 200 g. The animals were provided with food and water
ad libitum. More than 85% of the administered DSS was excreted
within 24-48 hours post dosing and essentially all within 96-120
hours. 25%-35% of the DSS was excreted in the urine 24-48 hours
post dosing, then only trace amounts via this route. The faeces
contained over 66% of the radiolabel, indicating that the major
route of elimination is the gastrointestinal tract. The tissues of
the rats 96-168 hours post dosing contained only trace amounts of
radiolabel (Patel, 1969).
In another study, two rats were administered orally a single
dose of either 5 mg or 10 mg of DSS in water, and two rats a single
dose of DSS, 10 mg by i.v. route. A fifth rat received a single
oral dose of 5.8 mg of 2-ethylhexanol in 40% ethanol. In the first
24 hour post dosing period, in animals receiving the 5 or 10 mg oral
dose 18.6% and 15.5% of the total dose was excreted in the urine and
0.9 and 8.7 % in the faeces. Animals receiving DSS i.v. excreted
12.3-15.5% in the urine in this period and none in the faeces. The
24-48 hour urine sample from the test animals did not contain
detectable 2-ethylhexanol. Rats administered 2-ethylhexanol
excreted 3.1% of the dose in urine and 3.9% in the faeces, in the
first 24 hours post dosing (Kelly et al., 1973).
One adult male rat was administered 14C labelled DSS by
gavage, at a dose level equivalent to 10 mg/kg b.w. 64.1% of the
administered radioactivity was excreted in the urine during the
first 24 hours and approximately 1.0% during the 24-48 hour period.
37.4% and 0.9% of the administered radioactivity was excreted in the
faeces during this period. DSS undergoes extensive metabolism in
the rat since no unchanged DSS appeared to be present in the urine,
and only a small amount was present in the faeces (Kelly et al.,
1973).
2.1.1.2 Rabbit
Two female rabbits were each administered a single dose of 14C
radiolabelled DSS (4 mg), one orally, one i.v. Each route of
administration resulted in the excretion of over 90% of the
radioactivity in the urine (87% and 69.7%, 0-24 hours after dosing,
oral and i.v., respectively). Analyses of the 0-24 hour urine
sample indicated similar patterns of metabolites, irrespective of
the route of administration (Kelly et al., 1973).
2.1.1.3 Dog
Two male beagle dogs were dosed with 4 mg/kg b.w. 14C
radiolabelled DSS, one orally, one i.v. Analyses of blood for 2-
ethylhexanol compounds indicated that in the case of the i.v.
injected dog the blood level of these compounds fell off rapidly
during the first hour and was zero at eight hours. Oral
administration of the DSS led to the appearance of small amounts of
this compound in the blood after one hour, but the level was zero at
eight hours. Each route of administration led to similar excretion
patterns and metabolic profile. About 21% of the label was excreted
in the urine in the first 24 hours, the bulk of the radiolabel being
excreted in the faeces (about 70%) in the 24-48 hour post dosing
(Kelly et al., 1973).
2.2 Toxicological studies
2.2.1 Acute oral toxicity
Species Acute Toxicity Reference
g or ml/kg/b.w.
Mouse 4.8 g/kg Hooper et al., 1949
Mouse 2.64 g/kg Case et al., 1977
Mouse 1.50 g/kg Schultz, 1941
Rat 3.98 g/kg Lundholm & Svedmyr, 1959
Rat 1.80 g/kg Olsen et al., 1962
Rat 4.3 g/kg Hazleton Laboratories, 1954
Rat 3.08 g/kg American Cyanamid, 1966
Rat 7.5 ml/kg* Huntingdon Research, 1977a
Rat 5.7 g/kg* Huntingdon Research, 1977a
Rat 4.2 ml/kg** Huntingdon Research, 1977b
* Compound tested was Aerosol/OT-80 PG which consists of 80%
DSS 20%, propylene glycol solvent and less than 1% sodium
sulfate.
** Compound tested was Aerosol OT-100 which consists of 100% DSS.
DSS is practically nontoxic when given orally to mice and rats;
its acute toxicity ranging from 2.64 to 5.7 g/kg bw. In most cases,
the gross pathological examination did not reveal any observable
lesions except that the gastrointestinal tract of some animals that
died were filled with clear fluid. In addition, some animals had
diarrhoea or showed signs of intestinal irritation.
2.2.2 Short-term studies
2.2.2.1 Rat
In a 9-week study rats that received 25% of DSS in the diet
showed a decrease in growth rate. The authors suggested that this
effect was due to impalatability of the DSS treated diet since this
group showed a decrease in food consumption. Necropsy revealed no
visible lesions in the G.I. tract (Guerrant, 1937).
Groups of five male and five female rats were given 0, 0.19,
0.37, 0.55, 0.75, and 0.87 g/kg of DSS in their diet for 24 weeks.
No deaths occurred but there was some initial lag in body weight
gain compared to the controls. No significant haematological
effects were noted. Histology of the liver, spleen, kidney,
pancreas, stomach, and gut, bladder, gonads, heart, lung, brain and
spinal cord showed nothing remarkable (Benaglia et al., 1943).
Groups of five male weanling rats were given diets containing
0, 2%, 4%, and 8% DSS for 16 weeks. There was marked growth
retardation at the 2% level without mortality, but only one animal
survived at 4% and all animals died within one week at the 8% level
from severe gastrointestinal distrubances (Fitzhugh & Nelson, 1948).
Several short-term studies that were conducted in rats
administered DSS in the diets of 28 days at dose levels up to 1%
revealed no significant effects. (Hazleton Laboratories, 1959).
In a further experiment, groups of 12 male and 12 female
weanling rats were provided with diets containing 0, 0.5% 1.04% and
1.5% DSS for 26 weeks. There were no significant differences
between test and control groups regarding body weight gain with the
exception of female animals which showed some slight reduction at
the 1.0% and 1.5% level during the third week. No adverse effects
appeared in the findings of haematology, urinalysis, food
consumption, the weight of spleen, liver, adrenal, kidney, gonads,
or in the histology of the heart, lung, liver, spleen, kidney,
adrenal, bladder, thyroid, pancreas, lymph nodes, gut, muscle, bone,
marrow, gonads and thymus. Two controls and four test animals in
the 1.5% group died, two of the latter from haemorrhagic
gastroenteritis (Taylor, 1966).
2.2.2.2 Rabbit
Seven rabbits were given intragastrically 0.124 g DSS/kg bw
daily for 24 weeks. Higher doses were not tolerated because of
gastrointestinal irritation. No abnormal pathological findings were
seen on gross and histopathological examination of the liver,
spleen, pancreas, kidney, gut, bladder, gonads, heart, lung and CNS
(Benaglia et al., 1943).
2.2.2.3 Monkey
Three monkeys were given intragastrically 0.125 g DSS/kg bw
daily for 24 weeks. Higher doses were not tolerated because of
gastrointestinal irritation. No abnormal pathological findings were
seen on gross and histopathological examination of the liver,
spleen, and pancreas, kidney, gut, bladder, gonads, heart, lung and
CNS (Benaglia et al., 1943).
2.2.2.4 Dog
When 4 male and 4 female Beagle dogs were given 30 mg/kg doses
of DSS via gavage for a period of one year, no treatment-related
signs of toxicity were observed at any period when the dogs were
examined. Gross and microscopic examination of tissues and organs
of the G.I. tract did not reveal any toxic changes, nor were there
any serum enzyme changes indicative of chronic liver toxicity (Case
et al., 1977).
2.2.2.5 Guinea pig
Groups of 3 guinea pigs were given 0.1, 0.5, and 1.0 g/1
solutions of DSS (Alphosol OT) as a replacement for drinking water
for a period of 15 months. The growth rate of the animals was not
affected, once they were adjusted to the taste of DSS. Necropsies
did not reveal any pathological alterations in organs and tissues of
the treated animals (Bengalia, 1943).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Rat
Groups of 12 male and 12 female weanling rats were given 0,
0.25%, 0.5% and 1.0% DSS in their diet for two years. Body weight
gain was slightly reduced in the 1% test group during the first
three months and became more pronounced during the first year. No
pathological changes were noted at gross examination or in the
histology of lung, heart, liver, spleen, pancreas, stomach and gut,
kidney, adrenal, testes, thyroid, parathyroid, lymph nodes, bone,
muscle, and marrow (Fitzhugh & Nelson, 1948).
When given orally to inbred Charles River Fischer 344 rats as
1.0% of the diet, DSS exhibited no promotional activity in rats
treated with s.c. injections of 1,2,-dimethylhydrazine (DMH) at 20
mg/kg/wk for 20 weeks. Reducing the dose of DMH to 10 mg/kg/wk
decreased significantly the number of gastrointestinal tumours per
rat in the DSS treated group at the 5th and 6th month necropsies
(Karlin, 1980).
2.2.4 Reproduction studies
2.2.4.1 Rat
DSS was fed in the diet to groups of 40 male and 40 female rats
(Carworth Farms, CFE strain) for three successive generations at
levels of 0, 0.5, or 1.0%. Pairs of rats were mated to produce two
litters per generation with the exception of the F1b generation
which was bred once to produce a single F2 generation. The F2
generation was maintained on the test diet until three to four
months of age before mating. For the first mating of the F0
generation and the F2 generation, the dams were continuously fed
the test diets, and the pups weaned directly onto the test diets.
For the other three matings (F1b, F2 and F3a pups), DSS was
removed from the diet of the dams before they were expected to cast
their litters. After weaning, the pups were placed on test diets.
Reproduction performance was evaluated in terms of fertility index,
gestation index, viability index and lactation index. Litter size
was reduced to 10 pups at day 5. Pups from all litters, including
those which died before weaning, were examined for gross defects.
Autopsies were performed on pups from the first mating of the F2
animals. Portions of all major organs from one female and one male
from each litter were examined histologically. Carcasses of the
other pups were cleared and skeletons stained and examined for
defects.
The first mating of the F0 generation and F2 generation (dams
continuously fed DSS and pups weaned to test diet), resulted in
fertility indices and gestation indices that were high and
comparable. The viability index was good, but slightly depressed
for F3b pups. The lactation index was depressed for both of these
matings (64, 46, 42 for F1a pups at 0, 0.5, 1.0% test diet
respectively, and 71, 59, 53 for F3b pups for the respective
diets). Also, for these groups, mean weight of pups decreased with
increasing concentrations of DSS in the diet of the dams.
For the other three matings (F1b, F2, F3a pups), the
viability and lactation indices and the mean weight of pups from
dams on test diets were less than those of control for the F1b
pups, but similar to controls for the F2 and F3a pups.
The lowering of survival rate and mean body weight of F3b pups
was attributed to impairment of nutrition, because of the taste of
DSS secreted in the milk of the dams.
Autopsy and skeletal studies of the pups indicated no
significant changes, with the exception of the occasional presence
of an extra vertebra in the sternum between the fifth and sixth
sternebrae (1/29, 7/30, and 4/29 at 0, 0.5 and 1% test levels of
DSS). This is considered to be a truly accessory sternebra, and not
caused by parental exposure to DSS (American Cyanamid Co., 1970).
DSS was administered to Sprague-Dawley rats at levels of 1.0 or
2.0% in the diet on days 6 and 15 of gestation. There were no
effects observed at the 1% dose level. However, at 2% DSS produced
growth retardation in the dams, significant increase in fetal
resorptions, and a significantly higher percentage of externally
malformed fetuses. The external anomalies in pups that were derived
from DSS treated dams were said to consist primarily of exencephaly
of varying degrees of severity, and this malformation was frequently
associated with spina bifida and microphthalmia (Hoechst Roussel
Pharmaceuticals, 1976).
In another study pregnant rats which received 2% DSS in the
diet from day 6 to day 16 of gestation showed decreased maternal
food consumption and weight gain as well as decreased fetal body
weights and crown-rump distances compared to control groups. In
addition, DSS caused delayed ossification of sternebrae in the
foetuses. However, there was no reported incidence of exencephaly
at the 2% dose level (Hoechst Roussel Pharmacueticals, 1979).
Three generations of 30 male and 30 female immature Charles
River CD Sprague-Dawley rats were fed diets containing 0, 0.1, 0.5
or 1% DSS for 10 and 2 weeks in the parent generation, and at least
10 weeks post weaning in successive generations. The original
parents, F0 animals, were mated to produce an F1 litter: F1
animals produced F2 animals, and F3 animals were produced from F2
animals. In each generation the same regimen for DSS exposure was
repeated, and the study terminated with the F3 weanlings. All
adults and the F3 weanlings (one/sex/litter) were necropsied and
examined for gross lesions and abnormalies.
There were no effects on the reproductive function of parental
animals of either sex during any of the three generations of the
study. At the 1% level, body weights were lower than the controls
during the premating period of males in all three generations and
for F1 and F2 females. Body weights for F1 and F2 males and
females of the 0.5% dose group were slightly lower than controls
during the premating period. Pup weights on day 0 of lactation were
lower in the treated groups than in the control group, but the
difference was significant only for the high dose (1%) group of the
third generation. Lower pup weights in the 0.5 and 1% groups
resulted in significantly lower pup weights on day 21 for all three
generations. Pup survival (91-100%) was comparable between treated
and control groups of all generations.
The above results indicate that DSS at 0.5% and 1% levels
caused a reduction in body weight for parental males of all
generations and for F1 and F2 females, and weanling pup weights at
these dose levels were lower than the controls in all three
generations. However, there were no adverse effects on reproductive
function of the test animals and nor were there treatment-related
microscopic lesions or effects on antemortem function of either sex
in any generation (MacKenzie et al., 1990).
2.2.5 Special studies on DSS in the gut
It has been demonstrated that DSS within the isolated
intestinal lumen of rats (organ bath) produced definite inhibition
of muscular and glandular functions. The segment of gut when
flushed with DSS inhibited acetylcholine stimulation by 92%, and in
the quiescent gut the inhibition was 71%. The theory was that the
inhibitory action of DSS was mediated by a hormone released from the
intestinal mucosa (Lish, 1961).
When tested on isolated rabbit jejunum in an organ bath, DSS
had a distinct inhibitory effect on pendular movements at a
concentration of 0.7 mg/ml; at a concentration of 7 mg/ml these
movements were virtually suppressed (Lundholm & Svedmyr, 1959).
In a study on isolated ileum and colon of 14 male Sprague
Dawley rats, DSS induced the secretion of water and sodium and
increased the short circuit current in 13 of 14 preparations. It
was thought that the actions were mediated by mucosal cyclic
adenosine monophosphate (Donowitz 1975).
When segments of human and rat small and large intestines were
given DSS in concentrations of which may be obtained when fed to
humans at 0.5mM, DSS blocked water absorption. In human jejunum the
inhibition was 80%. In the rat jejunum, ileum and colon the degree
of inhibition was linear with the concentration of DSS (Saunders,
et al., 1975).
In a study where portions of jejunum of Sprague-Dawley rats
were exteriated and a section was delineated with sutures, DSS was
applied to the serosa at various concentrations. Thirty days post
treatment samples were taken of the treated and untreated guts and
the number of ganglion cells were counted. The results showed that
there were ganglion loss in the DSS treated areas of 0.01, 0.1 and
1.0% with the loss rate compared to untreated as 61%, 85%, and 100%,
respectively. It was concluded that DSS ablated the myenteric
neurons leading to a depletion of peptidergic neurons and an
alteration in the electrical parameters of the gut (Fox et al.,
1983).
2.2.6 Special studies on the laxative action of DSS
In studies with normal rats, as well as those with a tendency
to constipation induced by opium drugs, DSS potentiated the effects
of laxatives containing anthraquinone derivatives (Lundholm &
Svedmyr, 1959).
2.2.7 Special studies on pulmonary circulatory system
2.2.7.1 Rabbit
When rabbits were exposed to an aerosol containing 5% DSS in
95% ethanol and isotonic saline the pulmonary clearance of
technetium-99m-labeled diethylenetriamine pentaacetate (99m-Tc-DPTA)
from aveoli to blood was accelerated by DSS without affecting gas
exchange or lung mechanics. (Evander et al., 1987).
In a second study 56 mongrel dogs were evaluated for the
effects of DSS on pulmonary oedema. In the study, DSS was
administered as a 1% aerosol in 95% ethanol and isotonic saline.
Two hours post treatment the pulmonary extravascular water volume
was increased indicating that there was a loss of surfactant
activity and an increase in alveolar surface tension (Nieman et
al., 1985).
Neither of the above studies on the activity of DSS in the lung
is considered relevant to the safety evaluation of DSS as a direct
food additive.
2.3 Observation in humans
DSS has been used as a faecal softener in a large number of
cases for many years since 1943 in infants, children and adults
(Wilson & Dickinson, 1955).
In chronic constipation it is used as a non-laxative softener
but action does not become apparent for one to two days after taking
it. Dosage employed is 10-20 mg daily for infants and children, 10-
60 mg daily for adults, exceptionally 100 mg/day. Up to 300 mg can
be taken without adverse effects (Anon, 1956). Others have
suggested 50 mg/day as optimum (Fairing & Short, 1956).
Two human subjects were given 200 mg/kg of DSS orally. Peak
concentrations in the serum occurred two hours post dosing, and
concentrations of DSS found in the plasma of the subjects were
similar to those observed in dogs one hour after an oral dose 4
mg/kg (Kelly et al., 1973).
When patients with T-tube biliary drainage were given doses of
100 mg or 200 mg DSS orally the results of gas chromatography
analysis indicated that DSS was present in the bile at
concentrations of 2 to 4 x 10-5M (Dujovne & Shoemans, 1972).
In a human panel where drugs were prescribed to 6,937 women
during the first trimester of pregnancy, 473 received DSS
(docusatesodium), and only one gave birth to a child with
unspecified congenital disorder (Jick et al., 1981).
3. COMMENTS
The Committee noted that results from a three-generation
reproduction study with DSS in rats did not reveal any adverse
effects on the reproductive function of either sex at dose levels up
to 10 g/kg in the diet. Neither was there any evidence of adverse
affects on the offspring both as a result of prenatal and postnatal
exposure to DSS. However, DSS did cause a reduction in parental
body weight as well as weanling pup weight at dose levels of 5 g/kg
and above in the diet. It was concluded that the no-observed-effect
level of DSS was 1 g/kg in the diet, equivalent to 50 mg per kg of
body weight per day.
In a long-term study, DSS did not exhibit tumour promotional
activity in rats pre-exposed to a model gastrointestinal carcinogen.
However, a full carcinogenicity bioassay that meets modern standards
is still lacking.
Two inhalation studies in which rabbits and dogs were exposed
to DSS were reviewed by the Committee. No adverse pulmonary or
systemic effects were indicated from the results.
4. EVALUATION
The Committee based its evaluation of DSS on the no-observed-
effect level found in the three-generation reproduction stduy in
rats, to which a safety factor of 200 was applied. A temporary ADI
of 0-0.25 mg per kg of body weight was allocated to DSS, pending the
evaluation, in 1995, of the results of the long-term study in a
rodent species that was requested earlier.
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See Also:
Toxicological Abbreviations