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    GLYCEROL ESTER OF WOOD ROSIN

    First draft prepared by
    Dr. C.B. Johnson and Dr. M.J. Bonner
    Division of Health Effects Evaluation
    Office of Premarket Approval
    Center for Food Safety and Applied Nutrition
    Food and Drug Administration, Washington, DC, USA

    Explanation
    Biological data
         Biochemical aspects
         Absorption, distribution, and excretion
    Toxicological studies
         Acute toxicity studies
         Short-term toxicity studies
         Long-term toxicity/carcinogenicity studies
         Special studies on genotoxicity
         Observations in humans
    Comments
    Evaluation
    References

    1.  EXPLANATION

         Glycerol ester of wood rosin was previously considered by the
    Committee at its eighteenth, twentieth and thirty-third meetings
    (Annex 1, references 35, 41 and 83). At its twentieth meeting, the
    Committee, in the light of the strong ester bond and anticipated
    stability of this material, expressed the view that long-term and
    reproductive toxicity studies should be done on the specific substance
    before further evaluation. Because of early concerns on the part of
    the Committee about the lack of food grade specifications for glycerol
    ester of wood rosin, plans for a further toxicological evaluation
    had to be postponed. Such specifications were adopted at the
    thirty-seventh meeting of the Committee (Annex 1, reference 94). The
    specifications define the material as a complex mixture of tri- and
    diglycerol esters of resin acids from wood rosin.

         This monograph summarizes relevant data in the previous monograph
    and data that have become available since the previous evaluation.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

    2.1.1.1  Rats

         Ester gum 8BG, a commercial preparation of glycerol ester of wood
    resin, was fed in the diet to groups of 6 male and 6 female F344 rats
    under two treatment regimens: (1) for 24 hours at concentrations of
    7000 or 28 000 mg/kg and (2) for 10 days at concentrations of 14 000
    or 28 000 mg/kg. Food consumption was measured during the treatment
    periods and ester gum 8BG intake was calculated for each of the
    treatment groups. Faeces were collected during each 24-hour treatment
    period and for subsequent 24-hour periods until no ester gum 8BG was
    detected. The bulk of ingested ester gum 8BG was excreted in the
    faeces within the first 48 h, and only small quantities were present
    in the faeces between 48 and 72 h. At the 7000 mg/kg dietary level,
    73% of the ingested ester gum 8BG was accounted for in the faeces. At
    the 14 000 and 28 000 mg/kg dietary levels, 92% and 89-96%,
    respectively, of the ingested ester gum 8BG was recovered in the
    faeces. The author postulated that the lower recovery from the
    7000 mg/kg group was due to the lack of sensitivity of the analytical
    method (HPLC of solvent extract). No necropsy was performed. The
    author concluded that in the rat gut, no measurable hydrolysis of
    ester gum 8BG took place, and that no absorption from the intestine
    was apparent (Blair, 1994).

         In recovery experiments, 4 male rats received a single oral dose
    of 100 mg (300 mg/kg bw) or 1 mg (3 mg/kg bw) tritiated resin acids
    from wood rosin (dehydroabietic, tetrahydroabietic or isopimaric
    acids) as a 5% solution in corn oil. After administration of
    dehydroabietic acid, the rats excreted on average 80% of the 100 mg
    dose in faeces and 7.2% in urine over a 15-day post-treatment period.
    Total recoveries in the 4 animals ranged from 71% to 99% at the end of
    15 days. Four additional total recovery experiments were conducted,
    utilizing a 1mg dose of labelled dehydroabietic acid, and sampling
    carried out at various times ranging from 28 to 51 h post-treatment.
    In these studies, the amount of dehydroabietic acid recovered averaged
    70% in faeces, 8% in urine, 17% in the GI tract, 0.5% in breath, and
    1% in the carcass, for a total recovery of 96.5%.

         In recovery experiments with tetrahydroabietic acid, 2 rats were
    given 45.7 Ci of the tritiated derivative and the radioactivity
    monitored at regular intervals after administration (1, 2, 3, 4, 5-8,
    9-12 and 13-16 days). Recovery of tritiated tetrahydroabietic acid
    averaged 92% in faeces, 5% in urine and 3% in breath for all average
    total recovery of 100%. In concurrent studies with isopimaric acid,
    recovery also averaged 100% total with 83% found in faeces, 15% in
    urine, and 2% in breath.

         Four rats were given 30 Ci (105 mg) dehydroabietic acid and
    quantitative chromatographic analyses were made of faeces and urine
    collected over 2 days. Analysis revealed 3 major metabolites, which
    were not identified but for convenience were called A, B, and C.
    Recovery in faeces amounted to 89% of the administered activity, of
    which 14% was dehydroabietic acid, 33% metabolite A, 8% metabolite B,
    and 14% metabolite C. Of the 8% of the administered activity recovered
    in urine, 0.13% was dehydroabietic acid, 7% was metabolite B, and
    0.55% metabolite C. In rats given labelled tetrahydroabietic or
    isopimaric acids, the bulk of the radioactivity in faeces and urine
    consisted of the unchanged acids.

         In tissue distribution studies with dehydroabietic acid, 4 male
    and 4 female rats each were given 50 mg (5.5 Ci), and distribution of
    radioactivity measured at various time intervals after administration
    (1, 2, 4 or 8 h). Radioactivity was distributed among all major
    organs, fat, and muscle, with peak levels occurring 4 h after
    administration. After 8 h, the highest concentrations of radioactivity
    were found in the liver (approximately 12%) and in kidney
    (approximately 5%) (Radomski, 1965).

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

         The results of acute toxicity studies with wood rosin are
    summarized in Table 1.

    Table 1.  Results of acute toxicity studies on pale wood rosin.
                                                                        

    Species        Route      LD50             Reference
                              (mg/kg bw)
                                                                        

    Mouse          Oral       4100             Hercules, 1974
    Rat            Oral       8400             "
    Guinea-pig     Oral       4100             "
                                                                        

    2.2.2  Short-term toxicity studies

    2.2.2.1  Rats

         In a 90-day oral toxicity study, groups of Sprague-Dawley rats
    (10/sex) were fed a stock diet containing Ester Gum 8D (prepared as a
    30% suspension in corn oil and blended into the diet) at dietary
    levels of 0.01, 0.05, 0.2, 1.0 or 5.0%, equal to 6, 31, 120, 630 or
    2660 mg/kg bw/day. The diets of controls and all ester gum 8D groups
    contained 2.3% corn oil except the diet of the 5.0% group, which

    contained 11.7% corn oil. Test parameters for the study included:
    clinical observations, mortality, body weights and body-weight gain,
    food consumption, food efficiency, haematology, urinalysis, organ
    weights and gross and microscopic pathology. During the course of this
    study no mortality occurred among treated rats or controls. No
    significant effects were noted on body weight, food intake,
    haematology, urinalysis, or gross and microscopic histology at dietary
    levels up to and including 1.0%. Food consumption at the 5.0% level
    was slightly lower than controls. This difference probably reflected
    the higher dietary corn oil concentration at this dose level. No
    microscopic pathological changes related to treatment were observed in
    any organ. The 1.0% treatment level, equal to 630 mg/kg bw/day, was
    considered to be the NOEL in this study (Kay, 1960a).

         In a 13-week oral toxicity study, groups of Charles River Fischer
    344 rats (20/sex), approximately 6 weeks of age, were fed NIH Open
    Formula Diet at ester gum 8BG dose levels of 0, 625, 1250 or
    2500 mg/kg bw/day. Test parameters included behavioural observations,
    ophthalmoscopic examinations, body weights, food consumption,
    haematological and clinical chemistry analyses (at the mid-point and
    end of the study), organ weights and macroscopic and microscopic
    pathology.

         There were no deaths among treated or control rats during the
    course of the study and no changes were observed in appearance,
    behaviour, or ophthalmoscopic examinations that were attributed to
    treatment. There were slight significant decreases noted by the author
    in body-weight gain in female rats at the 1250 and 2500 dose levels
    during the last few weeks of the study. However, these minor effects
    on body-weight gain were negligible and probably can be attributed to
    dietary dilution. Dietary dilution can probably also account for a
    slight increase in food consumption that was dose-related, present at
    all dose levels among groups of both sexes, and sometimes reaching
    statistical significance. There were no dose-related statistically
    significant differences in mean haematological and clinical chemistry
    values between treated and control groups.

         At necropsy, the author noted minor differences between controls
    and high-dose groups in male caecum(full)/body weight and in female
    liver, thymus and thymus/brain weight. However, these differences were
    small and did not appear to be an important effect of treatment. There
    were no macroscopic or microscopic changes in any organs that were
    related to treatment and none of the organs for which weight changes
    were noted had histological abnormalities. The NOEL in this study was
    2500 mg/kg bw/day (Blair, 1991, 1992).

         In a 90-day study, groups of Sprague-Dawley rats (10/sex) were
    fed a stock diet containing 0, 0.01, 0.05, 0.2, or 1.0% N-wood rosin
    (added to the diet as a 40% suspension in corn oil), equal to 0, 6.4,
    36, 119, or 674 mg/kg bw/day, respectively. Two identical control
    groups were utilized. Feeding at a 5.0% level was attempted, but
    discontinued early in the study, as all the animals died during the
    first 8 days of the treatment period. Final corn oil content was 2.3%
    in all test and control diets (except for 11.7% in the 5.0% test
    diet). Test parameters included clinical observations, food
    consumption, body weights, haematology, urinalyses, organ weights and
    gross and microscopic pathology. There was no mortality in controls or
    in animals receiving lower doses of wood rosin, and no significant
    differences between treated groups and controls were observed in
    analyses for haemoglobin, haematocrit, total leucocyte count,
    differential leucocyte count or urine analysis parameters.

         Body weights were significantly reduced throughout the study for
    male and female rats fed 1.0% wood rosin. The decrement in weight gain
    at this level occurred during the first 2 weeks of the study;
    thereafter, weight gains of this group were comparable to controls.
    However, in males fed 1.0% wood rosin, body weight was only
    significantly lower when compared to the first control group but not
    the second control group. Organ weights revealed statistically
    significant increases in both liver to body-weight and brain to
    body-weight ratios for male and female rats at the 1.0% wood rosin
    level when compared to control groups. However, brain to body-weight
    ratio for female rats at the 1.0% level were only significantly
    increased compared to those of the second control group but not the
    first. No pathological lesions, either macroscopic or microscopic,
    related to wood rosin treatment were observed in any of the organs of
    treated animals (Kay, 1960b).

    2.2.3  Long-term toxicity/carcinogenicity studies

    2.2.3.1  Rats

         Groups of weanling Sprague-Dawley rats (30/sex, individually
    housed) were ted dietary levels of 0, 0.05, 0.2 or 1% rosin in corn
    oil for 24 months, equal to 0, 24, 88 or 434 mg/kg bw/day. Final corn
    oil content was 2.3% in all test and control diets. At the end of
    12 months, 5 animals of each sex were sacrificed for gross and
    microscopic pathology studies. All surviving animals were killed at 24
    months, organ weights were recorded and pathological examinations were
    conducted.

         At both 12 and 24 months, body weights were significantly lower
    than controls in both males and females at the 1% diet level. The
    decreased body weight may reflect the reduced food consumption also
    noted at the 1% diet level, which was attributed to non-palatability.
    There were no significant differences between wood rosin treated

    groups and controls with respect to mortality, tumour rate,
    haematology, urinalysis, gross or microscopic pathology. Elevated
    liver to body-weight ratios were noted in high-dose females, with some
    sporadic significant differences noted between treated groups and one
    or other of the control groups with respect to organ to body-weight
    ratios for the kidneys, spleen and gonads (Kohn, 1962a).

    2.2.3.2  Dogs

         Groups of beagle dogs (3/sex) were fed dietary levels of 0.05% or
    1.0% (equal to 14 or 260 mg/kg bw/day) N-wood rosin in corn oil for 24
    months. A control group consisting of 6 animals of each sex received
    the basal diet. Test parameters included body weight, food consumption,
    mortality and behavioural changes, haematology and urine analysis,
    liver and kidney function tests, and gross and microscopic pathological
    examinations. No significant effects were seen on any test parameter
    other than weight, except at the 1.0% level, where some increase in
    liver and kidney size was noted (although no pathology was present).
    Both mean body weight and food consumption in high-dose males were
    approximately 30% less than in low-dose males, which would be
    consistent with lack of diet palatability. The author concluded that
    the NOEL in this study was 1.0% (Kohn, 1962b).

    2.2.4  Special studies on genotoxicity

         The results of genotoxicity assays on glycerol ester of wood
    rosin and resin acids present in wood rosin are summarized in Tables 2
    and 3, respectively.

    2.3  Observations in humans

         Medical doctors reported that a 22-year old woman developed
    papules, dryness and pigmentation on the lips after application of a
    lipstick several times a day. Patch tests showed that the woman tested
    positive for only one of the ingredients in the lipstick, ester gum at
    a level of 0.1%. In further patch testing she did not show positive
    reactions for rosin, balsam of Peru, nor oil of turpentine. The
    subject was diagnosed as sensitized to ester gum in the lipstick
    (Ogino  et al., 1989).

         A medical doctor reported a case of an 8-year old boy who
    suffered from recurring perioral dermatitis for 18 months; the subject
    frequently chewed gum before each episode of dermatitis developed.
    Patch testing was positive to cobalt, rosin, fragrance-mix, oakmoss,
    and isoeugenol as well as chewing gum and bubble gum. The perioral
    dermatitis improved but did not disappear after the child stopped
    chewing gum. Possible sensitivity to allergens other than rosin could
    not be ruled out (Satyawan  et al., 1990).

        Table 2.  Results of genotoxicity assays on glycerol ester of wood rosin.
                                                                                              

    Test System       Test Object         Concentration       Results      Reference
                                                                                              

    Ames test (1)     S. typhimurium      10 000 g/plate     Negative     Ishidate et al.,
                      TA92, TA94                                           1984
                      TA98, TA100
                      TA1535, TA1537

    Ames test (1)     S. typhimurium      2.5-500 g/plate    Negative     Jagannath,
                      TA98, TA100                                          1988
                      TA1535, TA1537
                      TA1538

    Chromosome        Chinese hamster     8000 g/ml          Negative     Ishidate et al.,
    aberration        fibroblast                                           1984

    CHO/Cytogenetic   Chinese hamster     127-507 g/ml       Negative     Murli, 1988
    assay (1)         ovary

    Unscheduled DNA   rat primary         5.1-102 g/ml       Negative     Cifone, 1988
    synthesis         hepatocyte
                                                                                              

           Note that application of treatment in above experiments was single dose.
    (1)    Both with and without rat liver S-9 fraction.

    Table 3.  Results of genotoxicity assays on resin acids present in wood rosin
                                                                                              

    Test System      Test Object          Concentration     Results                Reference
                                                                                              

    Ames test (1)    S. typhimurium       250-1000          Positive for           Nestmann
                     TA98, TA100          g/plate          neoabietic acid in     et al., 1979
                     TA1535, TA1537                         absence of S-9
                     TA1538                                 activation

    Mutagenicity     Yeast strains D7,    50-2000           Positive for           Nestmann &
    test             XV185-14C            g/ml             neoabietic acid in     Lee, 1983
                                                            XV185-14C cells
                                                                                              

    (1)     Both with and without rat liver S-9 fraction.
    
         A dentist reported a case of a 33-year old man with contact
    allergy to rosin from a periodontal dressing. Periodontal surgery was
    performed with no post-operative complications. One week after the
    first operation a new surgical dressing was applied. Four days later
    the patient began to experience both oral and dermatological symptoms,
    but the symptoms disappeared 24 h after the periodontal dressing was
    replaced with a wax packing. Patch tests showed that the patient had
    contact allergy to rosin, but not to eugenol or zinc oxide which were
    also components of the original periodontal dressing (Lysell, 1976).

         Patch testing in dental patients who exhibited stomatitis after
    repeated applications of periodontal dressing revealed some
    sensitization to colophony (rosin). Out of 18 patients (6 men and 12
    women, aged 33-71 years), 3 (17%) had a positive reaction to colophony
    (Koch  et al., 1971).

         A total of 133 dental patients who were preoperatively negative
    to medication and materials used in dentistry showed negligible
    sensitization to colophony, with only one (0.8%) positive result in
    patch tests (Koch  et al., 1973).

         A patch testing study in 150 women investigated contact allergy
    caused by cosmetics and toiletries (including those containing rosin).
    The type of rosin was not identified in the report. Only one positive
    reaction to rosin (0.7%) was observed out of the 150 women tested
    (De Groot  et al., 1988).

         A patch testing study in 1785 patients investigated contact
    sensitivity to several suspected allergens, including colophony
    (rosin). The specific type of rosin tested was not identified. A total
    of 50 patients (2.8%) tested positive for colophony 48 or 72 h post
    application. On a gender basis, males experienced a 1.8% incidence
    (11/613) and females a 3.3% incidence (39/1172); this difference in
    sex distribution was not considered to be significant. Sensitivity to
    colophony occurred at a higher incidence (4.4%) in patients aged 50 or
    older (Young  et al., 1988).

    3.  COMMENTS

         Several recent studies, including a metabolic study in rats, a
    13-week toxicity study in rats and mutagenicity studies, have been
    conducted on glycerol ester of wood rosin. In the 13-week toxicity
    study, the NOEL was 2500 mg/kg bw/day, the highest dose tested.
    Mutagenicity studies were negative.

         The results of the recent metabolic study showed that glycerol
    ester of wood rosin given to rats in the diet was, for the most part,
    recovered unchanged in the faeces, and suggested that it was not
    hydrolyzed in the gut to a significant extent and was largely
    unabsorbed. However, the lack of sensitivity of the analytical method
    used was such that a firm conclusion could not be reached as to the
    non-bioavailability of glycerol ester of wood rosin and/or its
    component resin acids.

         Absorption studies with tritiated resin acids from wood rosin
    (e.g., dehydroabietic, tetrahydroabietic and isopimaric acids)
    indicated that more than 90% were recovered in urine or faeces within
    2 weeks (most within 4 days) after oral administration. The small
    amount of dehydroabietic acid absorbed appeared to have been
    metabolized in the liver to three or four uncharacterized metabolites,
    which were then excreted in the bile and urine. Little evidence was
    found to show that tetrahydroabietic and isopimaric acids were
    metabolized.

    4.  EVALUATION

         The Committee noted the absence of adequate long-term toxicity/
    carcinogenicity studies and reproductive toxicity studies on glycerol
    ester of wood rosin. Because of the limited toxicological information
    available, the Committee was unable to establish an ADI. It is
    considered that, as a minimum, studies demonstrating the metabolic
    stability and non-bioavailability of glycerol ester of wood
    rosin under conditions resembling those present in the human
    gastrointestinal tract would be required to permit further evaluation
    of this material.

    5.  REFERENCES

    BLAIR, M (1991). Ester Gum 8BG. 13-week dietary toxicity study in
    rats. Unpublished report No. 548-007 from International Research and
    Development Corporation, Mattawan, MI, USA. Submitted to WHO by
    Hercules Inc., DE, USA.

    BLAIR, M. (1992). Ester Gum 8BG. 13-week dietary toxicity study in
    rats. Amendment to the Final Report. Unpublished report No. 548-007
    from International Research and Development Corporation, Mattawan,
    MI, USA. Submitted to WHO by Hercules Inc., DE, USA.

    BLAIR, M. (1994). A dietary excretion study with Ester Gum 8BG in
    Fischer 344 Rats. Unpublished report No. 3352.1 from Springborn
    Laboratories, Inc., Spencerville, OH, USA. Submitted to WHO by
    Hercules Inc., DE, USA.

    CIFONE, M.A. (1988). Mutagenicity test on Ester Gum 8BG in the rat
    primary hepatocyte unscheduled DNA synthesis assay. Unpublished Report
    No. 10349-0-447 from Hazleton Laboratories America, Inc., Kensington,
    MD, USA. Submitted to WHO by Hercules Inc., DE, USA.

    DE GROOT, A.C., BEVERDAM, E.G.A., AYONG, C.T., COENRAADS, P.J. &
    NATER, J.P. (1988). The role of contact allergy in die spectrum of
    adverse effects caused by cosmetics and toiletries.  Contact
     Dermatitis, 19: 195-201.

    HERCULES POWDER CO (1974). Unpublished report submitted to WHO.

    ISHIDATE, M., Jr., SOFUNI, T., YOSHIKAWA, K., HAYASHI, M., NOHMI, T.,
    SAWADA, M. & MATSUOKA, A. (1984). Primary mutagenicity screening of
    food additives currently used in Japan.  Fd. Chem. Toxic.,
    22: 623-636.

    JAGANNATH, D.R. (1988). Mutagenicity test on Ester Gum 8BG in the Ames
     salmonella/microsome reverse mutation assay. Unpublished report
    No. 10349-0-401 from Hazleton Laboratories America, Inc.,
    Kensington, MD, USA. Submitted to WHO by Hercules Inc., DE, USA.

    KAY, J.H. (1960a). Ninety-day subacute oral toxicity of Ester Gum 8D.
    Unpublished Report (no study no. given) from Industrial Bio-Test
    Laboratories Inc., Northbrook, IL, USA. Submitted to WHO by Hercules
    Inc., DE. USA.

    KAY, J.H. (1960b). Ninety-day subacute oral toxicity of N-wood rosin.
    Unpublished report (no study no. given) from Industrial Bio-Test
    laboratories, Inc., Northbrook, IL, USA. Submitted to WHO by Hercules
    Inc., DE, USA.

    KOCH, G., MAGNUSSON, B. & NYQUIST, G. (1971). Contact allergy to
    medicaments and materials used in dentistry (II).  Odont. Revy,
    22: 275-289.

    KOCH, G., MAGNUSSON, B., NOBRUS, N., NYQUIST, G. & SDERHOLM, G.
    (1973). Contact allergy to medicaments and materials used in dentistry
    (IV).  Odent. Revy, 24:109-114.

    KOHN, F.E. (1962a). Two-year chronic oral toxicity of N-wood rosin -
    albino rats. Unpublished report (no study no. given) from Industrial
    Bio-Test Laboratories, Inc., Northbrook, IL, USA. Submitted to WHO by
    Hercules Inc., DE, USA.

    KOHN, F.E. (1962b). Two-year chronic oral toxicity of N-wood rosin -
    dogs. Unpublished report (no study no. given) from Industrial Bio-Test
    Laboratories, Inc., Northbrook, IL, USA. Submitted to WHO by Hercules
    Inc., DE, USA.

    LYSELL, L. (1976). Contact allergy to rosin in a periodontal dressing.
     J. Oral Medicine, 31: 24-25.

    MURLI, H. (1988). Mutagenicity test on Ester Gum 8BG OSR in an
     in vitro cytogenetic assay measuring chromosomal aberration
    frequencies in Chinese hamster ovary (CHO) cells. Unpublished report
    No. 10349-0-437 from Hazleton Laboratories America, Inc., Kensington,
    MD, USA. Submitted to WHO by Hercules Inc., DE, USA.

    NESTMANN, E.R., LEE, E.G., MUELLER, J.C. & DOUGLAS, G.R. (1979).
    Mutagenicity of resin acids identified in pulp and paper mill
    effluents using the  Salmonella/mammalian-microsome assay.  Environ.
     Mutagen., 1: 361-369.

    NESTMANN, E.R. & LEE, E.G. (1983). Mutagenicity of constituents of
    pulp and paper mill effluent in growing cells of  Saccharomyces
     cerevisiae. Mutat. Res., 119: 273-280.

    OGINO, Y., HOSOKAWA, K., SUZUKI, M., MATSUNAGA, K., HIROSE, O.,
    ARIMA, Y. & HAYAKAWA, R. (1989). Allergic contact dermatitis due to
    ester gum in a lipstick.  Skin Research, 31(Suppl. 6): 180-184.

    RADOMSKI, J.L. (1965). The absorption, fate and excretion of
    dehydroabietic acid, isopimaric acid and tetrahydroabietic acid in
    rats. Unpublished report (no Study No. given) from University of Miami
    School of Medicine, Coral Gables, FL, USA. Submitted to WHO by
    Hercules Inc., Wilmington, DE, USA.

    SATYAWAN, I., ORANJE, A.P. & VAN JOOST, T. (1990). Perioral dermatitis
    in a child due to rosin in chewing gum.  Contact Dermatitis,
    22: 182-183.

    YOUNG, E., VAN WEELDEN. H. & VAN OSCH, L. (1988). Age and sex
    distribution of the incidence of contact sensitivity to standard
    allergens.  Contact Dermatitis, 19: 307-308.
    


    See Also:
       Toxicological Abbreviations
       Glycerol ester of wood rosin (WHO Food Additives Series 37)
       GLYCEROL ESTER OF WOOD ROSIN (JECFA Evaluation)