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    MICROCRYSTALLINE WAX AND PARAFFIN WAX

    First draft prepared by
    Dr K.B. Ekelman
    US Food and Drug Administration
    Washington DC, USA

    1.  EXPLANATION

         Food-grade petroleum-derived hydrocarbon waxes were first
    evaluated at the thirtieth meeting of the Committee (Annex 1,
    reference 73). At that time, the Committee was informed that
    toxicity data were available on certain hydrocarbon waxes, including
    the results of long-term feeding studies in rats, but noted that
    these studies were carried out with hydrocarbon waxes that had been
    in commercial use in the 1960s. Because the Committee was not
    informed whether the hydrocarbon waxes tested in these long-term
    studies were equivalent to those currently produced by both
    traditional and newer processes, no ADI was established.

         At the thirty-third meeting (Annex 1, reference 83), the
    Committee reiterated its need to be informed whether the chemical
    composition of paraffin wax in current use met specifications for
    this substance. It decided that for newer formulations of paraffin
    wax, new specifications were required, and that adequate long-term,
    mutagenicity, and reproduction/teratogenicity studies should be
    completed (Annex 1, reference 83).

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

         Some information about the metabolism of hydrocarbon oils was
    briefly reviewed by Freeman and co-workers (1989): Studies indicate
    that normal, branched and cyclic paraffins are absorbed from the
    mammalian gastrointestinal tract and that the absorption of
    n-paraffins is inversely proportional to the carbon chain length,
    with little absorption above C30. With respect to the carbon chain
    lengths likely to be present in mineral oil, n-paraffins may be
    absorbed to a greater extent that iso- or cyclo-paraffins.

         In a recent review of hydrocarbon intestinal absorption and
    metabolism, Barrowman and co-workers (1989) stated that
    representatives of the major classes of hydrocarbons have been shown
    to be well absorbed by the gastrointestinal tract in various
    species. In many cases, the hydrophobic hydrocarbons are ingested in
    association with dietary lipids. Authors reviewed the dependence of
    hydrocarbon absorption on concomitant triglyceride digestion and
    absorption, and discussed the "hydrocarbon continuum" hypothesis,
    which asserts that a series of solubilizing phases in the intestinal
    lumen, created by dietary triglycerides and their digestion
    products, afford hydrocarbons a route to the lipid phase of the
    enterocyte membrane.

         While some hydrocarbons may traverse the mucosal epithelium
    unmetabolized and appear as solutes in lipoprotein particles in
    intestinal lymph, there is evidence that most hydrocarbons partially
    separate from nutrient lipids and undergo metabolic transformation
    in the enterocyte. Thus, Barrowman and co-workers (1989) concluded
    that the enterocyte may play a major role in determining the
    proportion of an absorbed hydrocarbon that, by escaping initial
    biotransformation, becomes available for deposition in its unchanged
    form in peripheral tissues such as adipose tissue, or in the liver.

         Barrowman and co-workers (1989) also summarized information on
    the solubility of various hydrocarbons in liquid trioleoyl glycerol;
    information in the following table is taken from Table 1 of their
    review:

        Table 1: Solubility of Various Hydrocarbons in Liquid Trioleoyl Glycerol
                                                                                  

                                 Solubility                Temperature
    Hydrocarbon              (g solute/100 g fat)             ( C)
                                                                                  

    Octadecane                     9.26                        14
                                  82.69                        27

    Eicosane                       4.02                        14
                                   9.55                        27

    Docosane                       0.60                        14
                                   2.12                        27
                                  12.69                        37
                                                                                  
    
         Results of extraction and migration tests that have been
    performed on waxes and wax-bearing products, however, indicate that
    hydrocarbon waxes consumed in the diet are unlikely to be absorbed
    or metabolized in detectable or significant amounts (Eldred, 1990;
    Eldred & Modderman, 1990; European Wax Federation, 1990; Kelly &
    Castle, 1989; Orfan, 1990; Orfan & Bonica, 1989; van Battum & Rijk,
    1979; van den Berg, 1990; van den Berg  et al., 1989; and Woldhuis
    & Kemp, 1989). For example, gum base waxes do not leach into saliva
    at a detection limit of 1 mg/kg and hydrocarbons are not extractable
    by gastric and pancreatic fluids at a detection limit of 0.5 mg/kg.

         On the basis of information about the physical characteristics
    of oils and waxes and the results of extraction and migration tests
    that have been performed on waxes and wax-bearing products, Arnold
    (1991) argues that hydrocarbon waxes are less likely to be toxic
    than hydrocarbon oils because:

    1)   they cannot be readily dispersed as emulsions at body
         temperatures, and

    2)   migration tendencies and solubility in most media is minimal or
         zero.

    Both conclusions are based on the fact that waxes generally consist
    of longer-chain hydrocarbons than the hydrocarbons in oils and,
    thus, are solids at ambient and body temperatures.

         A recent description of the accumulation of long-chain alkanes
    (C29, C31, and C33) in a patient who had died of heart disease
    led the author to conclude that these hydrocarbons were of dietary
    (plant) origin as judged by the tissue distribution of the alkanes
    (Salvayre  et al., 1988).

    2.2  Toxicological studies

    2.2.2  Short-term studies

         No information available.

    2.2.3  Long term/carcinogenicity studies

         Groups of fifty 6-8 week old male and female Sprague-Dawley
    rats were fed diets containing 10% ground wax (petrolatum; 5
    samples) for two years. In addition, 157 female and 140 male rats
    served as untreated controls. Waxes were chosen to represent the
    range of polycyclic aromatic hydrogen content of waxes in commercial
    use (0-0.64 ppm). The rats were observed and weighed every other
    week, and all gross lesions were recorded. Rats were observed until
    spontaneous death or were killed  in extremis; necropsies were
    performed on all animals and histologic examination was performed on
    all abnormal tissues. Survival rates and average weights of
    experimental groups did not differ significantly from those of
    control animals, and the incidence of tumours observed in
    experimental animals was consistently similar to incidences of these
    tumours in control animals. No other wax-associated toxic effects
    were identified by histopathology (Shubik  et al., 1962). Recent
    personal communications from two of the authors of this study
    (Shubik and Saffiotti) confirm that findings in recent 90-day
    studies on mineral oils - deposition in the reticuloendothelial
    system and granulomas in the livers of rats - were not observed in
    the two-year oral toxicity study of waxes in rats.

         Shubik and co-workers (1962) also reported that five petrolatum
    waxes were negative for local and systemic carcinogenicity or
    toxicity in skin painting studies in mice and rabbits (applied 3
    times each week until death of the animals), and that wax disk
    implants, but not ground wax implants, were associated with the
    development of fibrosarcomas at the implantation site. Neither of
    the studies is directly relevant to determining the likely effects
    of ingestion of hydrocarbon waxes.

         A series of 180-day rat feeding studies were performed over a
    period of approximately 15 years (beginning in 1955) on chewing gum
    bases containing a hydrocarbon wax at proportions varying from 2 to
    57% of the gum base. In total, there were 16 series of control rats
    (120 males and 120 females) and 27 series of experimental animals
    (186 males and 195 females). Male and female rats were 4 weeks old

    at the beginning of the studies. Calculated feeding levels for the
    waxes were reported to vary from 0.16% to 4.75% of the diet. Test
    animals were fed diets consisting of 75% basal diet, 8.3% gum base,
    and 16.67% wood flour. Endpoints measured included body weight, food
    consumption, urinalysis, gross pathology and histopathology (organs
    examined were the heart, liver, spleen, adrenal, gonad, kidney,
    small intestine and large intestine). A total of 78 control rats and
    109 experimental rats from these studies were maintained up to
    19 months of age following the conclusion of the feeding study;
    these animals were examined for late-occurring pathologic changes
    that may be associated with the test compound.

         A summary report of these studies noted that an influenza
    epidemic in the animal colony in the first part of 1957 increased
    the number of intercurrent deaths and pulmonary lesions in test
    animals. The following non-significant findings were described: (1)
    3/120 control males and 7/186 test males demonstrated impaired
    testicular function (decreased spermatogenesis, reduced testicular
    weight, or both); (2) malignant tumours were found in 5/241 controls
    and 4/381 experimental rats; and (3) haemorrhagic manifestations,
    usually in association with pulmonary lesions, and prolonged
    prothrombin times were reported for 4/241 controls and 5/381
    experimental rats (particularly during the pneumonia epidemic noted
    above). For the complete set of experiments, and for those
    experiments in which hydrocarbon wax was a high percentage of the
    chewing gum base, the authors reported that no compound-related
    effects were observed (Davidsohn & Stern, 1960; Wrigley Co., 1959).

    3.  COMMENTS

         At the present meeting, the Committee concluded that waxes
    tested in previous studies contained a broader spectrum of waxes
    than those in use today; two specifications for food-grade
    petroleum-derived hydrocarbon waxes were prepared (paraffin wax and
    microcrystalline wax. Because these specifications limit the number
    of waxes that can be used for food applications as compared with
    those tested in previous studies, the Committee concluded that
    previous long-term toxicity studies were suitable for evaluating the
    safety of hydrocarbon waxes in current use. Additional long-term and
    mutagenicity studies on paraffin wax and microcrystalline wax were
    therefore not required. The results of extraction and migration
    tests performed on waxes or wax-bearing products indicated that
    hydrocarbon waxes consumed in the diet are not absorbed or
    metabolized in significant amounts.

         In a long-term feeding study with Sprague-Dawley rats, no
    wax-related effects were observed. In a series of 180-day feeding
    studies in rats that were performed over a period of approximately
    15 years (beginning in 1955) on chewing-gum bases containing
    hydrocarbon wax in proportions varying from 2% to 57% of the gum
    base, no compound-related effects were observed.

         Five petrolatum waxes were negative for local and systemic
    carcinogenicity or toxicity in skin-painting studies in mice and
    rabbits. However, wax disk implants, but not ground wax implants,
    were associated with the development of fibrosarcomas at the
    implantation site in rats.

    4.  EVALUATION

         Because long-term toxicity studies indicated that
    petroleum-derived paraffin and microcrystalline waxes are non-toxic
    and non-carcinogenic, the Committee established a group ADI "not
    specified" for microcrystalline wax and paraffin wax for the uses
    indicated in the specifications (chewing-gum base, protective
    coating, defoaming agent, and surface finishing agent).

         The Committee was informed that a 90-day study on hydrocarbon
    waxes made both by newer processes and by traditional methods was
    under way, and asked to be informed of the results when they became
    available.

    5.  REFERENCES

    ARNOLD, F.V. (1991) Reasons to differentiate fully refined petroleum
    waxes from white oils. European Wax Federation.

    BARROWMAN, J.A., RAHMAN, A., LINDSTROM, M.B., & BORGSTRON, B. (1989)
    Intestinal absorption and metabolism of hydrocarbons.  Prog. Lipid
     Res., 28: 189-203.

    DAVIDSOHN, I. & STERN, K. (1960). Letter to J.I. Weeks.

    ELDRED, J.S. (1990) Letter to D. Lees. Keller and Heckman,
    Washington, DC.

    ELDRED, J.S. & MODDERMAN, J.P. (1990) Letter to D. Lees. Keller and
    Heckman, Washington, DC.

    EUROPEAN WAX FEDERATION (1990) Specifications for petroleum derived
    hydrocarbon waxes - Food grade (Petroleum Waxes E905c).

    FREEMAN, J.J., BILES, R.W., CRAGIN, D.W., McKEE, R.H., NIKIFOROV,
    A.I. & SMITH, J.H. (1989) Liquid mineral hydrocarbons in food:
    Review of current issues, EXXON Corporation's toxicological data,
    and consideration of potential human health effects. EXXON
    Biomedical Sciences, Inc. Technical Report, East Millstone, NJ.

    KELLY, M. & CASTLE, L. (1989) Mineral hydrocarbons levels in waxed
    cheese and in skinless sausages. FScL Internal Report 89/28.

    ORFAN, C.P. (1990) Laboratory Report 7b, 13b: Hydrocarbon extraction
    of paraffin wax and microcrystalline wax in gum base and finished
    gum, alone and when combined with cocoa butter and/or chocolate, by
    simulated saliva, gastric, and intestinal fluids. L.A. Dreyfus
    Company.

    ORFAN, C.P. & BONICA, V.C. (1989) Laboratory Report 7b, 13b:
    Hydro-carbon extraction in gum base and finished gum by synthetic
    gastric and intestinal fluids. L.A. Dreyfus Company.

    RUSTIGE, J. (1991) Letter to J.L Herrman. European Wax Federation.

    SALVAYRE, R., NEGRE, A., ROCCHICCIOLI, F., DUBOUCHER, C., MARAT, A.,
    VIEU, C., LAGARON, A., POLONOVSKI, J. & DOUSTE-BLAZY, L. (1988). A
    new human pathology with visceral accumulation of long-chain
    n-alkanes; tissue distribution of the stored compounds and
    pathophysiological hypotheses.  J. Biochim. Biophys. Acta, 958:
    477-483.

    SHUBIK, P.  ET AL. (1962). Studies on the toxicity of petroleum
    waxes.  Tox. and Appl. Pharm., 1-62.

    SIMPSON, B. (1990) Draft protocol for 90-day feeding study with
    mineral hydrocarbons. The oil companies' European organization for
    environmental and health protection (CONCAWE), Brussels, Belgium.

    VAN BATTUM, D. & RIJK, M.A.H. (1979) Report B77/2694A: Migration
    experiments with waxed papers; Fifth report; Results obtained with
    various foodstuffs. Central Institute for Nutrition and Food
    Research (TNO)

    VAN DEN BERG, G. (1990) Is there any significant migration of wax
    into cheese? NIZO-EDE.

    VAN DEN BERG, G., OLIEMAN, C. & VAN RIEL, J. (1989) Investigation of
    the possible migration of wax components into cheese. NIZO-EDE.

    WHITE PAPER: Mineral hydrocarbon waxes used in chewing gum. Prepared
    for possible presentation by EACGI or CAOBISCO to the European
    Community's Scientific Committee for Food and to Commission staff.
    Anonymous, undated.

    WOLDHUIS, J. & KEMP, G. (1989) Hydrocarbon content of cheese rind by
    comparative GPC and GC analysis. European Wax Federation, Brussels,
    Belgium.

    Wm WRIGLEY Jr. COMPANY (1959). Report on toxicity tests; ingredients
    used in the manufacture of the Wrigley brands of chewing gum;
    history and complete data (1959).


    See Also:
       Toxicological Abbreviations