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    WORLD HEALTH ORGANIZATION

    WHO Food Additives Series 1972, No. 1




    TOXICOLOGICAL EVALUATION OF SOME 
    ENZYMES, MODIFIED STARCHES AND 
    CERTAIN OTHER SUBSTANCES




    The evaluations contained in this publication were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
    16-24 June 19711





    World Health Organization

    Geneva

    1972





                   

    1 Fifteenth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Wld Hlth Org. techn. Rep. Ser., 1972, No. 488; FAO
    Nutrition Meetings Report Series, 1972, No. 50.

    The monographs contained in the present volume are also issued by the
    Food and Agriculture Organization of the United Nations, Rome, as FAO
    Nutrition Meetings Report Series, No. 50A

    (c) FAO and WHO 1972



    HYDROXYPROPYL STARCH

    Modification is carried out by propylene oxide at levels up to 25 per
    cent. and the resultant starch is usually lightly oxidized, bleached
    or acid modified after etherification.  Substitution may amount to a
    maximum of 40 ether linkages per 100 glucopyranose units if 25 per
    cent. propylene oxide is used, and 4-6 ether linkages per 100
    glucopyranose units if 5 per cent. propylene oxide is used.

    Biological data

    Biochemical aspects

    In vitro digestibility by pancreatin was estimated by comparing
    the amount of reducing material liberated with that formed from native
    wheat starch.  No significant difference could be detected between low
    (1 in 10) and high (4 in 10) substituted starches compared with
    unmodified starch (Kay & Calandra, 1962).  In contrast the
    digestibility by pancreatin was found to decrease with increased
    substitution degree.  At 0.04 degree the digestibility was 80 per
    cent. of that of unmodified starch (Leegwater & Luten, 1971).  Corn
    starch treated with propylene oxide -2-C14 to produce
    hydroxypropyl starch (degree of substitution 0.12) was given to a male 
    rat by gavage.  Ninety-two per cent. of the radioactivity was excreted 
    in the faeces and 3.6 per cent. in the urine over the next 50 hours.  
    The urinary activity was probably derived from propyleneglycol in the 
    test material.  Further investigation of the degradation products in 
    the faeces revealed hydroxypropyl maltose to be the major metabolite
    in vitro and in vivo (Leegwater, 1971).

    Short-term studies

    Rat

    Groups of 10 male and 10 female rats were fed for 90 days diets
    containing 0, 2, 5, 10 and 25 per cent. of highly modified starch (25
    per cent. propylene oxide) and 25 per cent. unmodified starch.  No
    systemic toxicity was noted.  There were no adverse effects regarding
    mortality, urinalysis or haematology at any level.  There was slight
    reduction in growth rate at the highest dietary level with lower food
    utilization and without an equivalent increase in food consumption.
    Mild diarrhoea occurred at 25 per cent. dietary level.  No adverse
    effects occurred at any other level.  At autopsy there were no
    significant differences in the organ weights of liver, kidney, spleen,
    gonad, heart or brain.  The observed increased ratios at 25 per cent.
    dietary level for liver/body-weight and kidney/body-weight were due to
    the relatively lower body-weight.  Gross and histological examination
    of all major tissues revealed no abnormalities due to the feeding of
    highly modified starch (Kay & Calandra, 1961).  In another experiment
    groups of 10 male and 10 female rats were fed for 90 days on diets
    containing 0, 5, 15 and 45 per cent. of low modified starch (5 per
    cent. propylene oxide).  Haematological findings at 12 weeks were

    comparable for all groups.  Body-weights did not differ significantly
    from controls but were consistently lower in male rats only.  Feed
    efficiency was similar in all groups.  Caecal enlargement was seen at
    the 45 per cent. and very slightly at the 15 per cent. level.  No
    histological abnormalities were detected in any major organs, which
    were due to the test substance.  The enlarged caeca showed no evidence
    of inflammation or changes in the muscular coat (Feron et al., 1967).

    Long-term studies

    None available.

    SUPPLEMENTARY INFORMATION

    Biological data on propylene chlorohydrin

    Biochemical aspects

    Propylene chlorohydrin was identified as the residue formed in foods
    fumigated with propylene oxide (Wesley et al., 1965).  The
    chlorohydrin is formed by the reaction of the epoxide with the
    chloride of food.  Previously, it had been believed that propylene
    glycol, formed by reaction with water in the food, was the residue.
    Propylene chlorohydrin is also formed in starches modified by
    hydroxypropylation.  Both propylene chlorohydrin isomers have been
    identified in fumigated foods (Ragelis et al., 1966).

    When volatilization was precluded, a combination of high temperature
    and prolonged time in cooking did not appreciably alter the propylene
    chlorohydrin content of food, but when volatilization was possible,
    the chlorohydrin content was reduced 50 per cent. by cooking (Wesley
    et al., 1965).  When propylene chlorohydrin was added to a standard
    ground laboratory rat diet, 20 minutes of mixing in an open mixer at
    room temperature resulted in a 65 per cent. decrease in the propylene
    chlorohydrin content (USFDA, 1966).

    Acute toxicity

                                                                     

    Animal    Route             LD50                    Reference
                          (mg/kg body-weight)
                                                                     

    rat       oral               218                    USFDA, 1969

    dog       oral        150 mg/kg - no deaths         USFDA, 1969
                          200 mg/kg - 1/7 deaths
                          250, 300 mg/kg - 6/6 deaths
                                                                     

    Short-term toxicity

    Rat

    Groups of 10 male and 10 female five-week-old rats were fed, for 25
    weeks, diets to which propylene chlorohydrin had been added.  The
    planned dietary levels were 0, 1000, 2500, 5000 and 10 000 ppm, but
    analysis of the 10 000 ppm diet after mixing in the test compound
    (open mixer, 20 minute mixing time, room temperature) showed an actual
    concentration of 3568 ppm or 35 per cent. of the planned level.  The
    2-chloro isomer constituted 27 per cent. of the total found.  The
    actual level in this diet, after 7 days exposure to laboratory
    conditions, was reduced to 838 ppm, with 32 per cent. of the 2-chloro
    isomer, or less than 10 per cent. of the planned concentration. 
    Weight gain in both sexes on the 5000 and 10 000 ppm levels was
    depressed.  The depression was slight in the males on the 5000 ppm
    level and both groups of females and moderate in the males on the     
    10 000 ppm level. Food consumption was slightly decreased in these
    groups but food efficiency was normal.  The average liver and kidney
    weights of the males and the liver weight of the females on the 10 000
    ppm level were decreased but the organ weight/body-weight ratios were
    normal.  The decreased spleen weights and spleen/body-weight ratios in
    the males and other minor organ weight variations appeared to be
    unrelated to the treatment.  No effects on haematological values,
    mortality, or gross or microscopic lesions in the tissues were
    observed (USFDA, 1969).

    Propylene chlorohydrin was administered to groups of 10 male and 10
    female eight week old rats by stomach tube in doses of 0, 25, 50, 75
    and 100 mg/kg/day for 22 weeks.  The dose for the high level was
    increased from 100 mg/kg to 150 mg/kg in the eleventh week, to 200
    mg/kg in the fourteenth week, and to 250 mg/kg in the sixteenth week.
    Doses of 200 mg/kg and less did not increase mortality.  All the rats
    on the high level were dead by the nineteenth week with all but one of
    the deaths occurring between the sixteenth and nineteenth weeks after
    the dose had been increased to 250 mg/kg.  On the high level, weight
    gain was moderately depressed in the males and slightly depressed in
    the females while the dose was 100 or 150 mg/kg.  Both sexes lost
    weight when the dose was increased to 200 mg/kg. Weight gain was
    slightly, but not significantly, decreased in both sexes on the 75
    mg/kg level.  Food consumption was slightly decreased in the males of
    the high level while the dose was 100 mg/kg and decreased to a greater
    extent when the dose was raised.  The females on the high level also
    showed a slight decrease in food consumption when the dose was
    increased. With the rats losing weight when the dose was increased to
    200 mg/kg, the food efficiency values have no meaning.  The liver
    weight/body-weight ratios of both males and females on the 75 mg/kg
    dose and the liver weight and liver weight/body-weight ratio of the
    males on the 25 mg/kg dose were increased, but this increase was not
    accompanied by gross or microscopic alterations in the liver.  Other
    organ weight and organ weight/body-weight ratio changes did not appear
    to be related to the treatment.  No haematological effects or gross or
    microscopic effects on the tissues of the treated rats, at a dose of

    75 mg/kg or less, were seen.  The tissues of the high level rats were
    not examined microscopically (USPDA, 1969).

    Comments

    Short-term feeding studies with rats show that even the most highly
    modified starch tested is well utilized.

    The metabolic study in rats using radio-labelled material shows that
    most of the radio-labelled hydroxypropyl containing moiety is excreted
    in the faeces.  No long-term study on this modified starch is
    available but collateral evidence from the long-term study in rats
    with hydroxypropyl distarch glycerol, a more high modified starch,
    indicates that the propylene glycol moiety is causing no adverse
    effects.  The available evidence for the group of modified starches
    considered suggests that caecal enlargement without associated
    histopathological changes is of little toxicological significance.

    EVALUATION

    Temporarily not limited.*

    Further work required by 1973

    Histological report to complete the two-year rat study on
    hydroxypropyl distarch glycerol.

    Histological report to complete the reproduction study on
    hydroxypropyl distarch glycerol.

    REFERENCES

    Feron, V. J., Til, H. P. & de Groot, A. P. (1961) Unpublished report
    No. R 2456 by Centraal Instituut voor Voedingsonderzoek

    Kay, J. H. & Calandra, J. C. (1961) Unpublished report by Industrial
    Bio-Test Laboratories, Inc.

    Kay, J. H. & Calandra, J. C. (1962) Unpublished report by Industrial
    Bio-Test Laboratories, Inc.

    Leegwater, D. C. (1970) Unpublished report No. R 3209 by Centraal
    Instituut voor Voedingsonderzoek

    Leegwater, D. C. (1971) Unpublished report No. 3441 by Centraal
    Instituut voor Voedingsonderzoek


                   

    *Except for good manufacturing practice.

    Leegwater, D. C. & Luten, J. B. (1971) Unpublished report No. 3440 by
    Centraal Instituut voor Voedingsonderzoek

    Majors, P. A. & Ruben König, H. L. (1959) Unpublished report by Hill
    Top Research Institute, Inc.

    Ragelis, E. P., Fisher, B. S. & Klimeck, B. A. (1966) J.O.A.C., 49,
    963

    United States Food and Drug Administration (1969) Unpublished report

    Wesley, P., Rourke, B. & Darbishire, O. (1965) J. Fd. Sci., 30, 1037

    


    See Also:
       Toxicological Abbreviations
       Hydroxypropyl starch  (FAO Nutrition Meetings Report Series 46a)
       Hydroxypropyl starch (WHO Food Additives Series 5)
       Hydroxypropyl starch (WHO Food Additives Series 17)
       HYDROXYPROPYL STARCH (JECFA Evaluation)