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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    TOXICOLOGICAL EVALUATION OF SOME
    FOOD COLOURS, ENZYMES, FLAVOUR
    ENHANCERS, THICKENING AGENTS, AND
    CERTAIN FOOD ADDITIVES



    WHO FOOD ADDITIVES SERIES 6







    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.

    DIMETHYLPOLYSILOXANE

    Explanation

         This compound has been evaluated for acceptable daily intake by
    the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
    Ref. No. 20) in 1969.

         Since the previous evaluation additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monograph has been expanded and is reproduced
    in its entirety below.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         Some silicone fluids may contain 5% silica. Data on methylphenyl
    or other mixed polysiloxanes are not applicable to dimethyl
    polysiloxane.

    Mouse

         Groups each of 12 male Buckberg mice which had been fasted
    four hours received a single dose of 0.5 ml/kg bw sesame oil
    containing 0 or 6 mg/kg (SiO2)x, or 0.5 ml/kg bw of Anti foam A
    or 1.67 ml/kg emulsion of Antiform A, (Antiform A is a mixture of
    polydimethylsiloxanes containing trimethylsilyl and blocks and
    18% low molecular weight species as well as dispersed silica) or
    Antifoam B (polydimethylsiloxane plus dispersed silica) or other
    polydimethylsiloxanes with or without emulsifiers. Urine was removed
    direct from the bladder and bile direct from the gall bladder 4, 12
    and 24 hours after treatment. There were no statistically significant
    differences in urinary or biliary silicon concentrations, with the
    exception of the A in oil and A emulsion groups, which were higher
    than controls. However, the amount present only represented a very
    small percentage of that available for absorption from the gut (Dow
    Corning Corp., 1974).

    Monkey

         Three rhesus monkeys maintained in metabolic chambers were
    administered a single dose of 14C-labelled polydimethylsiloxane
    (prepared from randomly labelled dimethyl cyclic siloxanes), at dose
    levels equivalent to 1.15, 13.7 and 18.0 mg/kg bw. Approximately 0.5
    to 0.9% of the dose was found in expired air. The half-life for
    pulmonary elimination was 4-6 hours. Less than 0.1% of the dose
    was lost as volatiles from urine, flatus and faecal material.

    Approximately 2.0 to 2.5% of the dose was present in urine, with a
    half-life of 24 hours. The bile contained 0.1 to 0.3% of the dose in
    the first 24 hours post dosing. Faecal material collected over a 92
    hour period contained 80-90% of the dose. Blood levels were below
    detection limit (1 g/ml).

         In another study in which the C14-labelled polydimethylsiloxane
    was essentially free of low molecular weight species, oral dosing at
    21.8, 41.8 mg/kg bw resulted in 0.01 to 0.02% recovery of the dose in
    expired air, 0.001-0.22% in urine and 93-97% in faeces. Analyses of
    the silicone fraction in the faeces indicated that no chemical change
    had occurred.

         Analyses of 40 tissues from an animal 72 hours post dosing showed
    that the total cumulative radiolabel in the tissues was less than
    0.01% of the administered dose (Dow Corning Corp., 1974).

    TOXICOLOGICAL STUDIES

    Special studies on neurotoxicity

    Rat, rabbit, monkey

         Male rats, New Zealand white rabbits and female cynomolgus
    monkeys were injected spinally with dimethylpolysiloxane fluid (Dow
    Corning MF 360). The test animals were sacrificed 30 or 90 days after
    injection. There was no evidence of neurological effect. At autopsy,
    none of the test rabbits or monkeys showed any significant
    pathological change in any of the nervous tissues. Changes observed in
    the nervous tissue of rabbits were as frequent in controls (treated
    with saline) as in test animals (Hine et al., 1969).

         Rats were injected intraperitoneally with 14-C labelled
    dimethyl-polysiloxane. Twenty-five days after dosing, 96.52% of the
    dose was in the tissues. None was found in accumulated urine and
    faeces samples. Most of the activity was distributed in the fat
    (51.0%). The liver contained 13.5-16.1% of the activity, presumably in
    the fat. None was present in heart or blood. C14-labelled silicone
    was administered to rats by intracisternal injection, and tissue
    distribution studied 45 days after dosing. Approximately 92% of the
    administered activity was recovered in the tissues. The largest
    fraction was present in the brain, vertebral column and spinal cord,
    41.1, 31.4 and 9.9% respectively, 10% or less was present in the fat,
    and traces of the C14 label were present in the spleen, liver and
    lungs. There was no evidence of demethylation (Hine et al., 1969).

    Acute toxicity
                                                  

                        LD100
    Animal    Route     mg/kg bw       Reference
                                                  

    Rat       s.c.      >5 000         Frazer, 1959

    "         i.m.      >5 000          "

    "         i.p.      >5 000          "

    Rabbit    s.c.      >5 000          "

    "         i.m.      >5 000          "

    "         i.p.      >5 000          "
                                                  

         Parenteral administration produced no significant gross or
    histopathological abnormalities nor was any silicate found in the
    urine of rats or rabbits (Frazer, 1959). Transient conjunctival
    irritation has been noted both in rabbits and man for 24-48 hours
    after contact (Child et al., 1951).

         The data on acute toxicity vary with the viscosity and are
    generally i.p. rat > 10 ml/kg bw (Rowe et al., 1948). Only
    hexamethyldisiloxane and dodecamethylpentasiloxane appeared to be
    toxic in acute tests and irritant on intradermal or subcutaneous
    application to rabbits. For all the silicones on test 20 percutaneous
    applications for one month produced no adverse effects (Rowe et al.,
    1948).

    Short-term studies

    Rat

         Four groups of five female rats each were fed diet containing 0%
    and 0.1% silicone for three months. No adverse effects were noted on
    general condition, body weight, growth rate, blood urea levels and
    organ weights. The histopathology of major organs was normal (Child et
    al., 1951).

         Groups of five female adult rats received 20 doses of 0, 1.0,
    2.0, 5.0, 10.0 and 20.0 g/kg bw of silicone fluid (350 cSt) over 28
    days without deleterious effects on growth, haematology, organ weights
    and histopathology (Rowe et al., 1948).

         Silicone fluids of viscosity 50, 350, 1000, 10 000, 60 000 cSt
    were fed for 90 days to five groups of 10 male and 10 female rats at a
    level of 1% in their diet. Twenty males and 20 females were controls.
    No significant adverse effects were noted on mortality and food
    consumption, body weight, haematological indices, organ weights and
    histopathology (MacDonald et al., 1960).

         Two groups of 15 rats received dimethylpolysiloxane (DC151) at
    0.3 and 1.0% of their diet with 10 rats acting as controls. Food
    consumption, haematology and mortality experience were similar for
    test and control groups. There was slight depression of body weight in
    the group receiving the highest dietary level (Pollard, 1960).

         Groups of five male and five female rats were fed a diet
    containing 1% silicone fluids of viscosity 50 and 350 cSt for one
    year. Controls consisted of 10 male and 10 female rats. No adverse
    effects were noted upon body weight, haematology, blood urea,
    nitrogen, SGPT, cholesterol, serum alkaline phosphates, urinalysis,
    organ weights. Histological findings in major organs were normal
    (Carson et al., 1966).

         A group of 10 rats (five male and five female) was fed a mixture
    (96% liquid dimethylpolysiloxane and 4% silica aerogel) in the diet at
    a level of 1% for one year. Ten male and 10 female rats served as
    control. No significant differences were found between the test and
    the control animals in growth, body weight, haematology, blood urea,
    urine analysis, serum pyruvic transaminase activity, organ weight
    (10 organs) and histopathology (13 organs) (Carson et al., 1966).

         Three groups of five male and five female rats were maintained
    for approximately 260 days on diets containing 0.0%, 0.5% and 2% of a
    silicone emulsion consisting of 50% Antifoam A (silicon eith silica)
    with 2% pentaerythritol distearate as the emulsifying agent. No
    adverse effects were noted on body weight and organ weights. Blood
    remained normal and no abnormal amounts of protein were seen on
    reproduction as measured by mating to produce and wean single sets of
    offspring in each group (Frodsham, 1956).

    Rabbit

         In a similar experiment the same mixture was fed to a group of
    six rabbits (three male and three female) at a level of 1% in the diet
    for eight months. Six male and six female rabbits served as control.
    No significant differences were found between the test and the control
    animals in any of the parameters listed in the rat study (Carson,
    1966).

         Groups of three male and three female rabbits were fed diets
    containing 1% silicone fluids of viscosity 50 and 350 cSt for eight
    months. Controls consisted of six male and six female rabbits. No
    adverse effects were noted upon body weight, haematology, blood urea,
    nitrogen, SGPT, cholesterol, serum alkaline phosphatase, urinalysis,
    organ weights. Histological findings on major organs were normal
    (Carson et al., 1966).

    Dog

         Groups of two adult dogs were each fed doses of 0, 300, 1000 or
    3000 mg/kg bw silicone fluid five days each week for six months. Apart
    from moist and frequent loose stools in test dogs no abnormal effect
    on body weight was noted. Small amounts of silicone could be recovered
    from the faeces of the group fed 3000 mg/kg bw. Haematology and
    urinalysis gave no abnormal findings. Gross and histopathology
    revealed nothing abnormal. The liver of all dogs fed silicone fluid
    but not of controls presented brown/black deposits of iron-free bile
    in the Kupffer cells and parenchyma, the quantities being directly
    related to the silicone dose administered. Similar deposits were also
    found in the interlobular bile ducts of dogs fed the highest dose. The
    significance of these observations remains unexplained (Child et al.,
    1951).

         Two adult male dogs received daily 1.0 and 313 g/kg bw
    dimethylpolysiloxane (DC151) in divided doses for eight months. No
    abnormalities were detected regarding behaviour, body weight,
    haematology and urinalysis. Monthly biopsies of liver, spleen, kidney
    and bone marrow were normal in all respects (Pollard, 1960).

    Monkey

         Two groups of two monkeys were fed dimethylpolysiloxane (DC151)
    five days a week for eight months either 100 or 300 g/day. One monkey
    was used as control. All monkeys exhibited occasional diarrhoea. No
    other abnormalities were observed (Pollard, 1960).

    Long-term studies

    Rat

         Groups of 25 male and 25 female rats were kept on a diet
    containing 0% or 0.3% silicone fluid for two years. There was no
    difference between tests and controls regarding appearance, growth,
    survival or morbidity, haematology, blood urea, liver lipids, organ
    weights, macroscopic and microscopic pathology (Rowe et al., 1950). In
    another study three groups of 30 female and 10 male rats were fed a
    diet containing 0%, 0.01% and 0.1% silicone fluid and observed for two
    years. Two further generations were reared and fed the same diets. The
    F1 generation was autopsied at 28 weeks, the F2 generation at 25

    weeks. There were no consistent adverse effects as regards body
    weights, gross and histopathology. The consistent slight weight
    increase of the small gut was not statistically significant. No silica
    was found in the gut wall or any undue rise in other organs. Tumoric
    incidence was not abnormal. Liver function tests, urinalysis, fat
    absorption, renal function tests and haematology were not remarkable
    for F1 and F2 tests and controls (Frazer, 1959).

         Two groups of 10 weanling rats were kept on a diet containing 0%
    and 0.1% silicone fluid for two years. There was no consistent adverse
    effect as regards body weight, behaviour and histopathology (Gloxhuber
    & Hecht, 1955).

    OBSERVATIONS IN MAN

         Preparations containing dimethylpolysiloxane have been used
    therapeutically in man to reduce foaming during gastroscopy and as
    anti-flatulence treatment at doses of up to 200 mg/day (Dailly &
    Rider, 1954; Garry, 1956; Oswald, 1961; Hock, 1962; Entine, 1962;
    Reinhardt, 1961). Twenty-seven patients received 48 ml
    dimethylpolysiloxane (DC151) in divided doses for 3-13 months without
    significant toxic effects except occasional nausea (Pollard, 1960).

         Polydimethylsiloxanes A and M compounds either in sesame oil or
    emulsified were administered orally in single doses (100 mg/kg or
    30 mg/kg solids for emulsions) to humans under conditions of
    controlled dietary and fluid intake. Administration of the test
    compound M did not result in a statistically significant increase in
    total or organosoluble urinary silicon eliminated in the 72 hours
    following administration of the test compound. This compound does not
    contain low M.W. polymers. Administration of compound A, which
    contains low M.W. polymers, resulted in increased urinary output of
    silicon and organosoluble urinary silicon during the 72 hour post
    dosing period. 1.8-3.3% of the administered dose was excreted in the
    urine. About 25% of this was in the form of a soluble organosilicon
    compound that has not been identified.

         Examination of expired air indicated no organosilicon compounds
    were exhaled by individuals receiving compound M. In the case of
    compound A, approximately 0.35% of the dose was exhaled in the eight-
    hour post dosing period. The exhaled material contained principally
    octamethylcyclotetrasiloxane and a small amount of
    decamethylcyclopentasiloxane (Anonymous, 1974).

    Comments:

         Studies have been carried out on silicone fluids with and
    without the addition of silica. The presence of silica did not
    raise any toxicological problems nor did it affect the results
    of the experiment in a significant way. Short-term studies have

    been carried out in several species, including one study on an
    emulsion of dimethylpolysiloxane. An adequate long-term study with
    dimethylpolysiloxane has been carried out in the rat. None of these
    studies has revealed any significant toxicity. The metabolic studies,
    including those in man, indicate that the orally administered
    dimethylsiloxanes are mainly excreted unchanged in the faeces. The
    provision of this data meets the requirements of the committee for
    metabolic studies.

    EVALUATION

    Level causing no toxicological effect

         Rat: 0.1% (= 1000 ppm) in the diet equivalent to 150 mg/kg bw

    Estimate of acceptable daily intake for man

         0-1.5 mg/kg bw

    REFERENCES

    Anonymous (1974) Report No. 4244 from Dow Corning Corp., Sines 10030
         Project No. 0831

    Carson, S., Weinberg, M. S. & Oser, B. L. (1966) Proceedings of the
         Scientific Section of the Toilet Goods Association, No. 45, 8-19

    Child, G. P., Paquin, H. O., jr & Deichmann, W. B. (1951) Arch.
         industr. Hyg., 3, 479

    Dailly, M. E. & Rider, J. A. (1954) J.A.M.A., 155, 859

    Entine, J. H. (1962) J. Abdom. Eng., 4, 123

    Frazer, A. C. (1959) Unpublished report dated November

    Frodsham, J. (1956) Unpublished report No. IHR/63, Imperial Chemical
         Industries Ltd., Industrial Hygiene Research Laboratories

    Garry, M. W. (1956) Amer. J. Gastroent., 25, 733

    Gloxhuber, C. & Hecht, G. (1955) Arzneimittel. Forsch., 5, 10

    Hine, C. H. et al. (1969) Tox. App. Pharm., 15, 566

    Hode, C. W. (1962) Med. Times, 90

    MacDonald, W. E., Lainer, G. E. & Deichmann, W. B. (1960) Arch.
         industr. Hyg., 21, 514

    Oswald, W. J. (1961) Curr. Ther. Res., 3, 443

    Paul, J. & Pover, W. F. R. (1960) Brit. J. industr, Med., 17, 149

    Pollard, H. M. (1960) Unpublished report supplied by Dow Corning Co.

    Reinhardt, W. I. (1961) Med. Times, 89, 1099

    Rowe, V. K., Spencer, H. C. & Bass, S. L. (1948) J. industr. Hyg., 30,
         332

    Rowe, V. K., Spencer, H. C. & Bass, S. L. (1950) Arch. industr. Hyg.,
         1, 539


    See Also:
       Toxicological Abbreviations
       Dimethylpolysiloxane (FAO Nutrition Meetings Report Series 46a)