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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION





    SAFETY EVALUATION OF CERTAIN FOOD
    ADDITIVES AND CONTAMINANTS



    WHO FOOD ADDITIVES SERIES: 44





    Prepared by the Fifty-third meeting of the Joint FAO/WHO
    Expert Committee on Food Additives (JECFA)





    World Health Organization, Geneva, 2000
    IPCS - International Programme on Chemical Safety



    GLAZING AGENT



    HYDROGENATED POLY-1-DECENE1

    First draft prepared by E. Vavasour

    Chemical Hazard Assessment Division, Bureau of Chemical Safety, Food
    Directorate, Health Protection Branch, Health Canada, Ottawa, Ontario,
    Canada

    Explanation
    Biological data
         Biochemical aspects
              Absorption, distribution, and excretion
         Toxicological studies
              Acute toxicity
              Short-term studies of toxicity
              Genotoxicity
         Observations in humans
    Comments
    Evaluation
    References

    1.  EXPLANATION

         Hydrogenated poly-1-decene is a mixture of synthetic
    branched-chain hydrocarbons (isoparaffins) which are produced by the
    oligomerization of 1-decene to the tri-, tetra-, and penta-decene
    molecules followed by hydrogena-tion to full saturation of the
    oligomer. Hydrogenated poly-1-decene has been proposed for use in
    foods as a substitute for white mineral oil in its use as a glazing or
    polishing agent for dried fruits and certain sugar confectionery, such
    as fruit gums and jellies. Other uses are as a release ('non-stick')
    coating in bread tins, as a lubricant in dough-dividing machines, as
    an anti-dusting and anti-foaming agent, and as a plasticizer in films
    that are to be used in contact with food.

         Since hydrogenated poly-1-decene is a synthetic product, its
    composition is well defined. The oligomer distribution of the product
    is 16-35% trimer, 42-61% tetramer, 12-23% pentamer, and 1-9% hexamer;
    the dimer concentration is less than 1%.

                 

    1  The Committee gratefully acknowledges the contribution of Dr H.
       Blumenthal, who prepared the working paper on this substance
       before the forty-ninth meeting. That working paper was
       incorporated into this monograph.

         Hydrogenated poly-1-decene was evaluated by the Committee at its
    forty-ninth meeting, when the results of two studies of 28 and 90
    days' duration in rats given repeated doses were reviewed (Annex 1,
    reference  131) and considered to be inadequate to support use of the
    product as a food additive. In view of the potentially high intake
    from its use, the Committee concluded that adequate data were required
    to establish that the oily coats observed on rats fed hydrogenated
    poly-1-decene were not the result of systemic absorption. It also
    requested data that clearly demonstrated the lack of absorption of
    this substance in humans. In the absence of these data, the Committee
    noted that the results of long-term studies of toxicity and
    reproductive toxicity and information on the metabolism, distribution,
    and excretion of hydrogenated poly-1-decene would be required. The
    only study submitted was an investigation of the distribution and
    excretion of hydrogenated poly-1-decene and of the origin of the oily
    coats on rats in the 90-day study. All relevant data, including those
    reviewed at the forty-ninth meeting, were evaluated at the present
    meeting.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

         A study was conducted with 3H-radiolabelled hydrogenated
    poly-1-decene (purity not stated; oligomer distribution: 18% trimer,
    56% tetramer, 29% pentamer, 5% hexamer) to determine its absorption,
    pharmacokinetics in plasma, distribution in a limited number of
    tissues, and excretion after oral ingestion. In the main study, single
    oral doses of 30, 210, or 1500 mg/rat were administered to groups of
    33 male Fischer 344 rats weighing 200-250 g, and radiolabel was
    determined in plasma, tissues (fat, kidney, liver, lymph node, spleen,
    gut wall and contents), urine, faeces, carcass, skin, and fur for 168
    h after dosing. In three additional studies, radiolabel was determined
    in plasma for 168 h after dosing in three rats that received 30 mg
    hydrogenated poly-1-decene intravenously and in three rats that
    received an oral dose of 210 mg per day of unlabelled compound for 14
    days followed by a single oral dose of labelled compound; and biliary
    excretion of hydrogenated poly-1-decene was determined for 168 h in
    three rats that received a single oral dose of 210 mg.

          The pattern of excretion of 3H-hydrogenated poly-1-decene was
    similar whether it was administered as a single dose or for 15 days.
    After 168 h, less than 1% of the administered dose had been excreted
    in urine, whereas 92-102% was excreted in the faeces and the total
    recovered was 93-102%. Biliary excretion accounted for only 0.01% of
    the 210-mg dose at 48 h, while 0.16% was present in urine, 70% in
    faeces, and 25% in the gut contents. After oral administration of
    hydrogenated poly-1-decene, the radiolabel in plasma showed a large
    increase during the first 4-8 h in all treated groups. In the groups

    given 30 or 210 mg, the maximum concentration (Cmax) was achieved
    after 8 and 4 h, respectively, while in the group given 1500 mg the
    plasma concentration of radiolabel continued to rise slightly over the
    next 24-72 h. The half-liveswere 81 h at 210 mg and 93 h at 1500 mg.
    Most of the plasma radiolabel was associated with 3H2O after 8 h at
    30 mg, 4 h at 210 mg, and 2 h at 1500 mg. The authors reported that
    the half-lives of plasma radiolabel were similar to those of 3H2O in
    the body water, 3.5 days. The plasma concentrations of radiolabel
    measured in rats given 30 mg hydrogenated poly-1-decene intravenously
    were similar to or lower than those measured in rats receiving the
    same dose orally, but no further comment was made on this result. A
    large proportion of the administered radiolabel was associated with
    the gut and its contents during the first 4-24 h after dosing. The
    liver and lymph nodes had higher concentrations of radiolabel than
    plasma at the Tmax for each dose; at lower doses, the amount of
    radiolabel in liver remained high at 24 h while that in the lymph
    nodes started to decline. At the high dose, the amount of radiolabel
    in the liver remained high at 72 h, but the trend in accumulation of
    radiolabel in the lymph nodes at this dose could not be ascertained as
    it was measured only at 72 h. The concentrations of radiolabel in fat,
    spleen, and kidneys was similar to that in plasma. Animals at 210 or
    1500 mg had transient oiliness of the fur. In those at 210 mg, the
    oiliness was generally restricted to the base of the tail, became
    apparent about 6 h after dosing, and had disappeared within 24 h. At
    the higher dose, all rats showed oiliness of the fur 1 h after dosing,
    and at 4 h the oiliness was clearly apparent and oily patches were
    observed over the entire body. The oiliness decreased during 48-72 h
    after dosing and had disappeared by 96 h. The radiolabel was
    distributed over the fur but the highest amounts were found in the
    lower parts of the body, especially in animals at the high dose in
    which radiolabel was clearly distributed on the lower abdomen >
    mid-abdomen > thorax > head. The proportion of radiolabel found on
    the fur was much higher in animals at the high dose, with a maximum of
    11% of the administered dose found on the fur at 4 h. At the
    intermediate dose, the largest amount appearing on the fur was 1.1% of
    that administered 8 h after dosing. It is likely that the continued
    small increase in plasma radiolabel in rats at the high dose seen
    after 8 h was due to reingestion of radiolabel during grooming. The
    presence of a larger proportion of the administered radiolabel on the
    fur of rats at the high dose indicates limited absorption of the test
    material and is consistent with the observation that the increase in
    plasma radiolabel with dose was not proportional to the dose itself:
    thus, the ratio of dose was 1:7:50, while the area under the curve of
    concentration-time at 168 h (AUC168) for total plasma radiolabel was
    1:2.3:7.6 (Runacres, 1999).

    2.2  Toxicological studies

    2.2.1  Acute toxicity

         The results of studies of the toxicity of single doses of
    hydrogenated poly-1-decene are shown in Table 1.

    2.2.2  Short-term studies of toxicity

         Rats

         A 28-day range-finding study was conducted to establish an
    appropriate range of doses for a 90-day study in rats. Diets
    containing 0, 8000, 20 000, or 50 000 mg/kg (0, 0.8, 2, and 5%)
    hydrogenated poly-1-decene (32% trimer, 47% tetramer, 17% pentamer, 4%
    hexamer) were fed to groups of five male and five female Fischer 344
    rats for 29 days, resulting in intakes of test material equal to 0,
    1000, 2500, and 6200 mg/kg bw per day for males and 0, 1000, 2500, and
    6800 mg/kg bw per day for females, respectively. Five animals of each
    sex were housed per cage, observed twice daily for clinical signs, and
    palpated weekly; body weights were measured twice weekly, and mean
    weekly food consumption was measured for each cage. Gross autopsy at
    sacrifice included an extensive inventory of the weights of the
    kidney, liver, heart, spleen, and mandibular and mesenteric lymph
    nodes from all animals; the liver and mesenteric lymph nodes of all
    controls and all animals at the highdosewere examined histologically
    but with no special staining techniques or use of polarized light to
    allow visualization of accumulated material.

    Table 1. Acute toxicity of hydrogenated poly-1-decene
                                                               

    Speciesa       Route          Chain length        LD50
                                                      (mg/kg bw)
                                                               

    Rat            Oral           C10-11              > 10 000
    Rat            Oral           C11-13              > 10 000
    Rat            Oral           C9-11               > 34 600
    Rat            Oral           C10-13              > 34 600
    Rat            Oral           C9-12               > 25 000

    Rabbit         Dermal         C10-11               > 3 200
    Rabbit         Dermal         C11-13               > 3 200
    Rabbit         Dermal         C9-11                 15 400
    Rabbit         Dermal         C10-13                15 000
    Rabbit         Dermal         C9-12                > 5 000
                                                               
    From Mullion et al. (1990)

    a Sex unspecified 

         No clinical signs or deaths related to treatment were observed
    during the study. The body weights were not affected by treatment, but
    female rats at the high dose showed slightly elevated food
    consumption, with no effect on food conversion efficiency, probably
    due to compensation for the reduced nutritional quality of the diet. A
    dose-related decrease in the absolute and relative weights of the

    mandibular lymph nodes was seen in both male and female rats, which
    was statistically significant ( p < 0.05) in females at the high
    dose. A slight, dose-related decrease in the weights of the mesenteric
    lymph nodes was also noted which was more pronounced in female rats.
    There were no macroscopic or microscopic findings in the liver or
    mesenteric lymph nodes that were related to treatment (Cooper, 1994).

         Diets containing 0, 1000, 7000, or 50 000 mg/kg (0, 0.1, 0.7, and
    5%) hydrogenated poly-1-decene, equal to 0, 78, 550, or 4200 mg/kg bw
    per day in males and 0, 86, 610, and 4600 mg/kg bw per day in females,
    respectively, were fed to groups of 10 Fischer 344 rats of each sex
    for 13 weeks. Additional groups of five rats of each sex received the
    control and high-dose diets for 13 weeks, after which they were put on
    control diets for a four-week recovery period. Five animals of each
    sex were housed per cage, observed twice daily for clinical signs of
    toxicity, and palpated weekly; body weights were recorded weekly, and
    mean weekly food consumption was measured for each cage.
    Ophthalmoscopic examination was made before treatment of all animals
    and at week 12 for the control and high-dose animals. At week 12 of
    treatment, blood samples were collected from 10 animals of each sex
    per group and assessed for clinical chemical parameters; however,
    serum vitamin E and other lipid-soluble nutrients were not measured.
    Bone-marrow samples were collected from the femur at sacrifice. Urine
    samples were collected from 10 animals of each sex per group for
    analysis after 11 weeks of treatment. Gross autopsy at sacrifice
    included an extensive inventory of the weights of the kidney, liver,
    heart, spleen, and mesenteric lymph nodes from all animals.
    Histopatho-logical examination was made of 20 tissues and organs.
    Samples of liver, kidneys, duodenum, jejunum, ileum, caecum, rectum,
    heart, spleen, Peyer patches, and mandibular and mesenteric lymph
    nodes were stained with oil red 'O' and examined for accumulation of
    oil [sic].

         No unscheduled deaths occurred during the study. Animals of each
    sex at the high dose appeared ungroomed during the second week of
    treatment, and the coats of all of these animals were oily from week 3
    to the end of the study. Several animals at the intermediate dose also
    had oily coats. Hair loss was seen in all treated groups, although it
    was not related to dose, and females at the high dose were more
    severely affected. During the first week of the recovery period, rats
    at the high dose and particularly females had oily coats, and the
    females still had hair loss and appeared ungroomed. Animals of each
    sex at the high dose and occasionally females at the intermediate dose
    had soft faeces from the second week of treatment. The body weights of
    treated animals were comparable to those of controls. The food
    consumption of rats at the high dose was slightly increased during
    treatment. The food conversion efficiency was slightly reduced in
    these groups throughout treatment and increased only slightly during
    the recovery period. The increased consumption was probably due to the
    reduced nutritional content of the high-dose diet. Male rats at all
    doses showed significantly increased haemoglobin and erythrocyte

    counts, but only the increase in haemoglobin count was dose-related.
    The lymphocyte counts were reduced in all treated females, but
    significantly so only at the low and intermediate doses, with no
    dose-related trend. The platelet count of males and females at the
    high dose was also significantly increased. After the recovery period,
    no such changes were seen. The myeloid:erythroid ratio and the
    cellularity and composition of the bone marrow were comparable in all
    groups. None of the haematological changes was considered to be
    toxicologically significant as they were slight and fell within the
    reference ranges. Clinical chemical and urinary parameters showed no
    effect of treatment. After 13 weeks, both the absolute weight of the
    liver and that relative to body weight were significantly lower in
    males at the high dose than in controls, but the difference
    disappeared after the recovery period. A non-significant decrease in
    the weight of mesenteric lymph nodes was seen in males at the
    intermediate and high doses and in females at the high dose, and the
    effect persisted in females at the end of the recovery period. The
    weights of the mandibular lymph node were not assessed. The only
    histopatho-logical findings were made females at the high dose, which
    had a low incidence of necrosis of individual hepatocytes in the
    livers (3/10 vs 0/10) and a significant decrease in fat retention by
    hepatocytes in the right caudal lobe of the liver  (2/10 vs 8/10). No
    accumulation of test material was reported in lymphoid,
    gastrointestinal, hepatic, or splenic tissue.

         The NOEL was 7000 mg/kg, equal to 550 mg/kg bw per day, on the
    basis of effects on the condition of coats, the reversible effects on
    liver weight in males, and histopathological observations in the
    livers of females at the high dose (Cooper, 1995).

    2.2.3  Genotoxicity

         The results of studies of the genotoxicity of hydrogenated
    poly-1-decene are shown in Table 2.

    2.3  Observations in humans

         Semi-occluded patch testing was carried out in humans with 50%
    solutions in petrolatum of materials of chain lengths of C10-11,
    C11-12, and C12-15. Defatting of the skin and irritation were seen,
    but there was no evidence of sensitization, phototoxicity, or
    photosensitization in over 100 test subjects (cited by Mullin et al.,
    1990).

    3.  COMMENTS

         3H-Hydrogenated poly-1-decene (97% radiochemical purity),
    administered as a single oral dose of 30, 210, or 1500 mg/kg bw to
    rats, was eliminated almost entirely in the faeces, with 0.2, 0.05,
    and 0.6%, respectively, excreted in the urine; 0.07% was eliminated in
    the urine of rats pretreated with 210 mg/kg bw per day for 14 days.

    Negligible amounts were detected in the bile. The very low
    concentrations of radiolabel in plasma and tissues did not increase in
    direct proportion to dose, suggesting limited absorption of high
    doses. After 8 h, 60-80% of the 3H in plasma was present as 3H2O,
    so that the label had a half-life of 80-90 h. The ratio of 3H in
    liver or lymph nodes (site unspecified) to that in plasma was
    approximately 5, indicating that the material within these tissues was
    not simply 3H2O and further suggesting that the material had been
    absorbed from the gastrointestinal tract through the lymphatic system.
    The absorbed 3H was not characterized further, and the results of
    administration of an intravenous dose did not provide useful
    information on the disposition of the parent compound through the
    circulation. The study indicated very little absorption of
    hydrogenated poly-1-decene in rats after oral administration but was
    uninformative with regard to the disposition of any of the compound
    that was absorbed intact. The study established that the oiliness of
    the fur observed within 1-6 h of dosing was associated with
    radiolabelled material originating from the anal region which was
    spread by grooming activity.

         In the 90-day study, rats of each sex that received diets
    containing hydrogenated poly-1-decene at a concentration of 50 000
    mg/kg of feed had ungroomed coats during the second week of treatment
    and then oily coats from the third week of treatment to the first week
    of the recovery period. The animals also showed hair loss during the
    treatment period, which persisted throughout recovery for animals at
    the high dose. Some marginal effects on haematological parameters were
    noted. Treatment with hydrogenated poly-1-decene was associated with a
    significant, but reversible, reduction in the weights of the livers of
    males at the high dose, which was not associated with any unusual
    histopathological observations. Treatment of females with the high
    dose resulted in necrosis of individual hepatocytes and in a decrease
    in the fat content of hepatocytes, as assessed histologically, with no
    effect on liver weights. A dose-related decrease in the weights of
    mandibular lymph nodes was noted in the 28-day study, which reached
    statistical significance in females at the high dose but was not
    associated with histopathological changes. This parameter was not
    evaluated in the 90-day study. Accumulation of saturated hydrocarbons
    was not observed in lymphoid, gastrointestinal, hepatic, or splenic
    tissue.

    4.  EVALUATION

         The Committee noted that the study of the disposition of
    hydrogenated poly-1-decene did not allow clear definition of the fate
    or deposition of any absorbed material. Therefore, the Committee was
    unable to establish an ADI. The Committee requested an adequate study
    of the absorption and deposition of hydrogenated poly-1-decene in
    order to determine whether further studies were required.


        Table 2. Results of assays for genotoxicity with some low-molecular-mass isoparaffins
                                                                                                                  

    Test system        Test object           Chain       Concentration        Results            Reference
                                             length
                                                                                                                  

    In vitro

    Reverse            S. typhimurium        C11-13      7.7-77 000 g/       Negative           Xerox Corp.
    mutationa          TA98, TA100,                      plate                                   (1981)
                       TA1535, TA1537, 
                       TA1538 

    Reverse            S. typhimurium        C10-11      7.5-75 000 g/       Negative           Xerox Corp.
    mutationa          TA98, TA100,                      plate                                   (1983)
                       TA1535, TA1537, 
                       TA1538

    Reverse            S. typhimurium        C10-13      < 10 000 g/         Negative           Phillips
    mutationa          TA98, TA100,                      plate                                   Petroleum
                       TA1535, TA1537,                                                           Co (1990)
                       TA1538

    DNA                E. coli, Pol A+/A-    C11-13      7.7-77 000 g/       Negative           Xerox Corp.
    damage                                               plate                                    (1981)

    DNA                E. coli, Pol A+/A-    C10-11      7.5-75 000 g/       Negative           Xerox Corp. 
    damage                                               plate                                   (1981)

    Reverse            E. coli, WP2          C10-11      7.5 -75 000 g/      Negative           Xerox Corp.
    mutationa                                            plate                                   (1981)

    Cell               Mouse lymphoma        C10-13      < 1000 g/ml         Negative           Phillips Petroleum
    mutationa          L5178Y cells,                                                             Co. (1990)
                       Tk+/- locus

    Sister             Chinese hamster       C10-13      < 50 g/ml           Negative           Phillips 
    chromatid          ovary cells                                                               Petroleum 
    exchangea                                                                                    Co. (1990)

    Table 2. (continued)
                                                                                                                  

    Test system        Test object           Chain       Concentration        Results            Reference
                                             length
                                                                                                                  
    In vivo

    Micronucleus       Mouse bone            C10-11      19 g/kg bw,          Negative           Xerox Corp. 
    formationb         marrow                            intraperitoneally                       (1983)

    Dominant           Sprague-Dawley        C10-11      0, 300, 900 ppm,     Negative           Exxon Corp. 
    lethal             rat                               6 h/day, 5 d, by                        (1978)
    mutation                                             inhalation
                                                                                                                  

    a In the presence and absence of Arochlor-induced rat liver microsomal fraction
    b Sacrificed at 48 and 72 h
    

         No studies of genotoxicity have been conducted with the test
    material; however, the results of tests for genotoxicity with related
    isoparaffinic compounds of lower molecular mass showed that they had
    no effect on a variety of end-points. Consequently, the Committee
    concluded that tests for the genotoxicity of hydrogenated
    poly-1-decene were not required.

         Patch tests on human skin with the same low-molecular-mass
    isoparaffins did not indicate sensitization.

    5.  REFERENCES

    Cooper, S. (1994) NEXBASE 2006 FG: Preliminary toxicity study by
    dietary administration to F-344 rats for four weeks. Unpublished
    report No. 93/1140 from Pharmaco-LSR Ltd, Eye, Suffolk, United
    Kingdom. Submitted to WHO by Neste Alfa OY, Espoo, Finland.

    Cooper, S. (1995) NEXBASE 2006 FG: Toxicity study by dietary
    administration to F-344 rats for 13 weeks followed by a four week
    reversibility period. Unpublished report No. 95/NEY002/0090 from
    Pharmaco-LSR Ltd, Eye, Suffolk, United Kingdom. Submitted to WHO by
    Neste Alfa OY, Espoo, Finland.

    Exxon Corp. (1978) Cited by Mullin et al. (1990).

    Mullin, L.S., Ader, A.W., Daughtrey, W.C., Frost, D.Z. & Greenwood,
    M.R. (1990) Toxicology update: Isoparaffinic hydrocarbons: A summary
    of physical properties, toxicity studies and human exposure data.
     J. Appl. Toxicol., 10, 135-142.

    Phillips Petroleum Co. (1990) Unpublished data submitted to WHO by
    Neste Alfa OY, Espoo, Finland.

    Runacres, S. (1999) 3H-NEXBASE 2006 FG (3H-hydrogenated
    poly-1-decene). Absorption study in the rat after single and repeated
    doses. Unpublished report No. NEY 014/984811 from Huntingdon Life
    Sciences, Huntingdon, Cambridgeshire, United Kingdom. Submitted to WHO
    by Neste Alfa OY, Espoo, Finland.

    Xerox Corporation (1981) Unpublished data submitted to WHO by Neste
    Alfa OY, Espoo, Finland.

    Xerox Corporation (1983) Unpublished data submitted to WHO by Neste
    Alfa OY, Espoo, Finland.
    


    See Also:
       Toxicological Abbreviations
       Glazing agent: Hydrogenated poly-1-decene (JECFA Food Additives Series 48)