The evaluations contained in this publication were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
    4-13 June 19741

    World Health Organization     Geneva     1975


    1  Eighteenth Report of the Joint FAO/WHO Expert Committee on
    Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 557.
    FAO Nutrition Meetings Report Series, 1974, No. 54.




         No data are available on the absorption and excretion mechanisms
    for this substance although surface-active agents are known to be
    absorbed through the skin and probably through mucous membranes
    (Smythe et al., 1941).


         DSS labelled with 35S was administered orally in a single dose 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 radio-label,
    indicating that the major route of elimination is the gastrointestinal
    tract. The tissues of rats 96-168 hour post dosing contained only
    trace amounts of radiolabel (American Cyanamid Co., 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-ethyl-hexanol in 40% ethanol. 18.6% and 15.5% of the total
    dose was excreted in the urine and 0.9 and 8.7% in the faeces, in the
    first 24 hour post dosing period, in animals receiving the 5 or 10 mg
    oral dose. 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-ethyl-hexanol. Rats
    administered 2-ethyl-hexanol excreted 3.1% of the dose in urine and
    3.9% in the faeces, in the first 24 hour post dosing (American
    Cyanamid Co., 1973).

         One adult male rat was administered 14C labelled DSS by gavage,
    at a dose level equivalent to 10 mg/kg bw. 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 (American Cyanamid Co., 1973).


         Two female rabbits were administered a single dose of 14C radio-
    labelled 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 (American Cyanamid Co., 1973).


         Two male beagle dogs were dosed with 4 mg/kg bw. 14C radio-
    labelled DSS, one orally, one i.v. Analyses of blood for 2-ethyl-
    hexanol 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 (American Cyanamid Co.,


    Special studies on reproduction

         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 was bred
    twice to provide an F3a and F3b litter. The Fo generation was
    maintained on the test diet until three to four months of age before
    mating. For the first mating of the Fo generation and the F2
    generation, the dams were continuously fed the test diets, and the
    pups weaned directly onto 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 male from each litter were examined histologically.
    Carcasses of the other pups were cleared and the skeletons stained and
    examined for defects.

         The first mating of the Fo generation and the 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 depressed for both 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 the pups decreased with increasing concentration of DSS in
    the diet of 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 the 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 sternebra in the sternum between the fifth and sixth
    sternebra (1/29, 7/30, and 4/29 at 0, 0.5 and 1.0% 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).

    Studies on the effect of DSS in the gut

         When tested on isolated rabbit jejunum in an organ bath, DSS had
    a distinct inhibitory effect on the 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).

    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 effect of
    laxatives containing anthraquinone derivatives (Lundholm & Svedmyr,

    Acute toxicity
    Animal         (mg/kg bw)          References
    Rat            ca 1 800 p.o.       Olsen et al., 1962

    Mice           ca 3 980 p.o.       Lundholm & Svedmyr, 1959

    Mouse          1 500 p.o.          Schultz, 1941

         Mice have been shown to tolerate 0.2 ml 5% solution s.c.,
    although ulceration and necrosis developed at the injection site, or
    0.5 ml of 0.2% DSS i.p. or 0.25 ml of 0.5% DSS i.v. which often
    produced severe haemolysis (Lorenz et al., 1940).

         Human patch tests using 1% DSS showed non-irritancy.

    Short-term studies


         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 disturbances (Fitzhugh & Nelson, 1948).

         In another experiment groups of five male and five female rats
    were given 0, 0.19, 0.37, 0.55, 0.75 and 0.87 g/kg body weight of DSS
    in their diet for 24 weeks. No deaths occurred but there was some
    initial lag in body weight gain compared with controls. No significant
    haematological effects were noted. Histology of liver, spleen, kidney,
    pancreas, stomach and gut, bladder, gonads, heart, lung, brain and
    spinal cord showed nothing remarkable (Benaglia et al., 1943).

         In a further experiment groups of 12 male and 12 female weanling
    rats were treated with diets containing 0, 0.5%, 1.04% and 1.5% DSS
    for 26 weeks. There was no significant differences between tests and
    controls 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 findings of
    haematology, urinalysis, food consumption, weight of spleen, liver,
    adrenal, kidney, gonads, as well as the histology of 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).


         Seven rabbits were given intragastrically 0.5 g DSS/kg bw daily
    for 24 weeks. Three animals died from severe diarrhoea and anorexia,
    two from unrelated causes and two survived without showing any
    pathological findings on gross and histological examination of liver,
    spleen, kidney, pancreas, gut, bladder, gonads, heart, lung, CNS
    (Benaglia et al., 1943).


         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 histological examination of liver, spleen, pancreas,
    kidney, gut, bladder, gonads, heart, lung, CNS (Benaglia et al.,


         Groups of three dogs received 0.1 or 0.25 mg DSS/kg bw in their
    food for 24 weeks. Higher doses caused gastrointestinal irritation.
    All dogs lost some weight but this was not considered due to the DSS.
    Gross and histopathology showed nothing abnormal in liver, spleen,
    pancreas, kidney, gut, bladder, gonads, heart, lung, CNS (Benaglia et
    al., 1943).

    Long-term studies


         Groups of 12 male 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 and in the histology of lung, heart, liver,
    spleen, pancreas, stomach and gut, kidney, adrenal, testes, thyroid,
    parathyroid, lymph nodes, bone, muscle, marrow (Fitzhugh & Nelson,


         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 (JAMA, 1956). Others have suggested 50 mg/day
    as optimum (Firing & short, 1956).

         Two male volunteers were each administered two 100 mg capsules of
    DSS. Peak serum values of 2-ethyl-hexanol compounds were observed two
    hours post dosing and these compounds were still present in the serum
    eight hours post dosing. Excretion of 2-ethylhexanol derivates in the

    urine of man only accounted for 2.5 to 5.5% of the administered dose,
    during the 48 hours post dosing. The urinary metabolites, as separated
    by counter-current distribution, did not resemble those from dog
    (American Cyanamid Co., 1973).


         Metabolism studies indicate that dioctyl sodium sulfosuccinate
    (DSS) is rapidly absorbed from the gastrointestinal tract and
    undergoes extensive metabolism. In man, as in the dog, the major route
    of excretion of the DSS metabolites is in the faeces, whereas in the
    rat and rabbit, a larger percentage of the metabolites appear to be
    excreted in the urine. However, the number of animals employed was
    small and the results quite variable. A multigeneration reproduction
    study in the rat indicates a no-effect level when the offspring are
    not exposed to dioctyl sodium sulfosuccinate or its metabolites
    through mother's milk. The long-term study in rats is inadequate as
    regards the number of animals used and only one sex was used. It has
    been used in man as faecal softener for many years. Because of the
    possibility that high dietary intakes may affect faecal consistency,
    uses should be carefully allocated. Recent findings with highly active
    surface agents suggest the possibility of adverse effects on the
    pulmonary circulation, particularly if rapidly absorbed into the
    systemic circulation.


    Level causing no toxicological effect

         Rat: 0.5% (= 5000 ppm) in the diet equivalent to 250 mg/kg bw.

    Estimate of acceptable daily intake for man

         0-2.5 mg/kg bw*


         Required (by June 1978)

         Effects on neonatal animals particularly those exposed to dioctyl
    sodium sulfosuccinate through the milk. Adequate long-term study in a
    rodent species. Investigation of pulmonary circulatory effects
    including pulmonary hypertension.


    *    Temporary.


    American Cyanamid Co. (1969) Unpublished data

    American Cyanamid Co. (1970) Report No. 70-239 Unpublished data

    American Cyanamid Co. (1973) P.R. vol. 18, 1220 Unpublished data

    AMA (1956) JAMA, 161, 63

    Benaglia, A. E. et al. (1943) J. Ind. Hyg Tox., 25, 175

    Firing & Short (1956) Anal. Chem., 28, 1827

    Fitzhugh, O. G. & Nelson, A. A. (1948) J. American Pharm. Ass. Sci.,
         37, 29

    Lorenz, E. et al. (1940) Nat. Cancer Inst., 1, 355

    Lundholm, L. & Svedmyr, N. (1959) Acta Pharmacol. et Toxicol., 15, 373

    Olson, K. J. et al. (1962)

    J. Soc. Geo. Chem., 13, 469

    Schultz, F. H. jr (1941) (personal communication quoted in 5)

    Smyth, H. F. jr Seaton, J. & Fisher, L. (1941) J. Ind. Hyg. Tox., 23,

    Taylor, R. E. (1966) Report from Harris Laboratory dated 1/2/66

    Wilson, J. L. & Dickinson, D. G. (1955) JAMA, 158, 261

    Yasuna, A.D. & Halpern, A. (1957) Amer. J. Gastroent., 28, 530

    See Also:
       Toxicological Abbreviations