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    TOXICOLOGICAL EVALUATION OF CERTAIN FOOD ADDITIVES



    WHO FOOD ADDITIVES SERIES 10





    The evaluations contained in this document were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives*
    Rome, 21-29 April 1976



    Food and Agriculture Organization of the United Nations

    World Health Organization




    *Twentieth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Geneva, 1976, WHO Technical Report Series No. 599, FAO Food
    and Nutrition Series No. 1.

    BUTYLATED HYDROXYANISOLE

    Explanation

         Butylated hydroxyanisole was evaluated for acceptable daily
    intake for man by the Joint FAO/WHO Expert Committee on Food Additives
    in 1961 and 1973 (see Annex 1, Ref. No. 6, p. 41; No. 33, p. 148).

         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

    Absorption, distribution and excretion

         Butylated hydroxyanisole (BHT) was absorbed from the
    gastrointestinal tract, and there was some evidence that the feeding
    of amounts 100-500 times the levels generally permitted in fats for
    human consumption (in the United States of America 200 mg/kg fat)
    caused deposition in depot fat, the stability of which was thereby
    increased (Johnson et al., 1958). However, there was no evidence of
    cumulation in other tissues (Astill et al., 1960; Bunnell et al.,
    1955; Hodge et al., 1964). In the rabbit, BHA was conjugated mainly
    with glucuronic acid or sulfuric acid (Dacre et al., 1956); a small
    amount of unchanged BHA was excreted in the urine.

         In rats the 2-tert-butyl isomer was chiefly excreted as
    glucuronide, while the 3-tert-butyl isomer was excreted mainly as
    ethereal sulfate (Astill et al., 1960). Thus, these animals
    effectively detoxicated BHA. The changes described occurred in the
    liver. No evidence has been found to suggest that BHA produces any
    adverse biochemical or metabolic effect in the animal body (Dacre,
    1960).

         Dogs excreted 60% of a 350 mg/kg dose unchanged in the faeces
    within three days. The remainder was excreted in the urine mainly as
    sulfate conjugates of BHA, tert-butyl-hydroquinone and an unidentified
    phenol. Only 5.5% of the dose was excreted in urine as the glucuronide
    (Astill et al., 1962). Rats were injected intra-peritoneally with a
    single dose of tritium-labelled BHA. Approximately 90% of the
    radioactivity was recovered in the urine within four days (Golder et
    al., 1962).

         Pigs fed 0.1% BHA in the diet for four months, and pullets fed
    0.1% BHA in the diet for eight weeks, showed no accumulation in
    muscle, liver, kidney or the reserve fat (Francois & Pihet, 1960).

    Effects on enzymes and other biochemical parameters

         Rats administered 500 mg/kg bw (seven daily doses) of BHA, showed
    no change in liver glucose-6-phosphatase activity. BHA at dose levels
    of 100 mg/kg or more (seven daily doses) caused increase in liver
    weight of male rats, but in females only at doses greater than
    200 mg/kg bw (seven daily doses). Liver weight was comparable to
    control within 14 days of withdrawal of BHA from the diet. No fatty
    changes were observed (Feuer et al., 1965a), Rats administered BHA
    (500 mg/kg/day) for two days showed no increased activity of
    microsomal processing enzymes (aminopyrine demethylase) hexabarbitine
    oxidase and nitro-anisol demethylase (Gilbert & Golberg, 1965). In
    another study, rats fed 0.1, 0.25 or 0.5% BHA in the diet for 12 days,
    showed no increased liver weight, but there was an increase in liver
    biphenyl-4-hydroxylase activity in the 0.5% group (Creaven et al.,
    1966).

         Groups each of eight rats (SPF Carworth strain) equally divided
    by sex were administered by intubation daily for one week, BHA
    dissolved in arachis oil, at a dose level equivalent to 0, 50, 100,
    200, or 500 mg/kg body weight. BHA had no effect on the growth of
    the animals. Twenty-four hours after administration of the final
    dose the animals were sacrificed and liver preparations assayed
    for glucose-6-phosphatase, glucose-6-phosphate dehydrogenase,
    hexabarbitone oxidase, nitro-anisol demethylase and aminopyrine
    demethylase activities. BHA had no effect on these enzyme activities.
    Histochemical studies showed that BHA caused no fatty changes in liver
    (Feuer et al., 1965b).

         Groups each of two to three rhesus monkeys (macaca mulatta) one
    month old infant or sexually immature juvenile, of both sexes, were
    administered BHA at a dose level of 500 mg/kg body weight for four
    weeks. Another group of juveniles received 50 mg BHA/kg body weight
    for the same period. Controls received equivalent amounts of corn oil.
    Urine and blood analyses were normal with the exception of serum
    cholesterol which was elevated at the high dose at week 3 of the
    study, but which returned to normal at week 4. The livers of all test
    animals were enlarged. No other organ showed any pathological change.
    Ultrastructurally, infant and juvenile monkeys treated at the high
    dose level showed pronounced proliferation of the hepatic smooth
    endoplasmic reticulum. Infants and juveniles treated with BHA
    (500 mg/kg) had lower levels of liver lipids than corn oil controls.
    Nitro-anisol demethylase activity was increased and glucose-6-
    phosphatase activity was decreased in BHA treated juveniles but
    unaffected in infant monkeys (Allen & Engblom, 1972). No changes were
    observed in DNA, RNA and cytochrome P450 levels.

         Additional biochemical tests were carried out on the liver and
    plasma of these monkeys. BHA treated animals showed higher plasma
    triglyceride levels than controls. There was a significant decrease

    in the level of liver cholesterol, as well as a lowering of the
    cholesterol/lipid-phosphorus ratio of the liver, in the test animals.
    Liver succinic dehydrogenase was also lowered in BHT treated animals
    (Branen et al., 1973).

         Hepatic microsomal preparations were made from female mice (A/HcJ
    strain) fed a diet of 0 and 0.5% BHA for 14 days. The aryl hydrocarbon
    hydroxylase activity (AHH) of the preparations was similar. However,
    microsomal preparations from the BHA fed mice showed greater
    sensitivity to in vitro inhibition of AHH activity by alpha-
    naphthafluorine, and continued increased amounts of cytochrome
    P450 per unit weight, than preparations from control mice (Speier
    & Wattenberg, 1975).

         Rats were maintained on a diet supplemented with 20% lard, and
    containing 0, 0.1, 0.2, 0.3, 0.4, 0.5% BHA, for a period of six weeks.
    BHA caused an increase in the total serum cholesterol at the 0.1%
    level, but no further elevations occurred at higher doses. There was a
    relatively greater increase in the amount of serum-free cholesterol
    than of ester-cholesterol. BHA produced enlarged adrenals in males at
    all levels, but no histological changes were observed. Increased liver
    weight at the higher dietary BHA levels was accompanied by an increase
    in the absolute lipid content of the liver. However, BHA had no effect
    on the concentration in liver of total and esterified cholesterol, or
    the composition of the polyunsaturated fatty acids (Johnson & Hewgill,
    1961).

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenicity

         Groups each of 100 mice (equally divided by sex) were given
    single s.c. injections (10 mg/mouse) of BHA in trioctanoin and
    observed for up to 575 days. Another group was given weekly skin
    applications of 0.1 mg or 10 mg of BHA in acetone, for a period of
    309-459 days. Microscopic examination of the skin from the test mice
    showed no evidence of tumours (Hodge et al., 1966).

         BHA in lanolin applied to the ears of guinea-pigs once daily for
    periods of two to six weeks, resulted in a microinvasion of basal cell
    pseudopods with destruction of the superficial connective tissue and
    fragmentation of the collagen. BHA alone did not cause these changes
    (Riley & Seal, 1968).

    Special studies on mutagenicity

    (a) Cytogenetics

         Butylated hydroxyanisole (BHA) was investigated at concentrations
    of 2.0, 20.0 and 200 g/ml, in vitro, employing WI-38 human

    embryonic lung cells for anaphase abnormalities. It was also
    investigated in vivo by the cytogenetic analysis of metaphase cells
    from rat bone marrow at dosages of 15, 150 and 1500 mg/kg. BHA did not
    produce any significant increases in abnormalities above the control
    values in either assay (Fabrizio, 1974).

    (b) Host-mediated assay

         In vitro-Salmonella TA-1530, and G-46, together with
    Saccharomyces D-3 were employed. A 10% concentration was tested. BHA
    was non-mutagenic for Salmonella TA-1530 and G-46. Tests with
    Saccharomyces D-3 demonstrated a biologically significant increase
    in the frequency of recombinants. This result could not be repeated
    upon subsequent testing and was therefore thought to be spurious
    (Fabrizio, 1974).

         In vivo-BHA was tested at 15, 150 and 1500 mg/kg in ICR Swiss
    mice employing as indicator organisms Salmonella G-46, and TA-1530,
    and Saccharomyces D-3. BHA was non-mutagenic for Salmonella but
    demonstrated a biologically significant increase in the frequency of
    recombinants. In as much as the host-mediated assay is no longer
    recommended for routine use, this suggested mutagenic effect was
    investigated using more sensitive (in terms of detection) procedures.
    In this study BHA was investigated employing Salmonella typhimurium
    strains TA-1535, TA-1537 and TA-1538, and Saccharomyces D-4 with and
    without metabolic activations, in plate and suspension tests. The
    percent concentrations (w/v) employed were .00375, .0075, .0150 for
    Salmonella and 0625, 1250 and 02500 for Saccharomyces. Under the
    conditions of this investigation BHA was non-mutagenic (Fabrizio,
    1974).

    (c) Dominant lethal test

         Sprague-Dawley C-D strain male rats were used. Dosages of 15, 150
    and 1500 mg/kg were employed.

         Acute study - a single dose was administered with subsequent
    mating for each of eight weeks. BHA produced random statistical
    increases in dominant lethality. These were discounted due to the
    unusually low negative control values (Fabrizio, 1974).

         Subacute - five daily doses were administered (5  15, 5  150
    and 5  1500 mg/kg) and males subsequently mated for each of seven
    weeks. BHA produced a statistically significant increase in
    pre-implantation loss in weeks 6 and 7. This effect occurring
    alone is not demonstrative of mutagenicity (Fabrizio, 1974).

    Special studies on teratogenicity

         Groups of rats or mice of various strains were given BHA in
    accordance with one of three different regimes, viz., daily
    administration for seven weeks, before pairing continuing until day 18
    of pregnancy or daily administration on days 1-20 of pregnancy or
    single administration on day 9, 11 or 13 of pregnancy. Dosage ranged
    from 250 to 1000 mg/kg bw. No teratogenic effects were observed at
    dose levels as high as 300-500 mg/kg bw administered for as long as
    seven weeks, although under these conditions the mortality was 25%. 
    At a higher dose level (750 mg/kg) mortality was 75% (Clegg, 1965).
    Pregnant rats receiving a total dose of 0.5 g of BHA in the diet
    showed less resorptions than rats on control diets (Telford et al.,
    1962).

    Other special studies

         BHA at concentrations as low as 8  10-10 mole/litre can inhibit
    the guinea-pig's smooth muscle contraction caused by bradykinin
    (Posati & Pallanich, 1970).

         Groups of mated pairs of Swiss-Webster mice (Mus musulus) were
    maintained on diets containing 0, or 0.5% BHA. The litters obtained
    from the mated pairs were weaned at 21 days and then maintained on a
    diet similar to that of their mother. At six weeks of age the mice
    were subjected to behavioural tests. The BHA treated offsprings showed
    increased exploration, decreased sleeping, decreased self-grooming,
    slower learning and a decreased orientation complex than did the
    control group (Stokes & Scudder, 1974).

         Using an in situ method of perfusion for rat intestine, BHA at
    a level of 2 mg/ml has been shown to reduce the absorption of glucose
    and methionine, but not butyric acid (Fritsch et al, 1975a). BHA at
    levels of 400 g/ml caused an inhibition of the metabolism (as
    measured by gas evolution) of culture of bacteria isolated from the
    cecal flora of rats (Fritsch et al, 1975b).

    Acute toxicity

                          LD50
    Animal    Route     (mg/kg bw)          References
                                                                        

    Mouse     oral      2 000               Bunnell et al., 1955;
                                            Lehman et al., 1951

    Rat       oral      2 200-5 000         Bunnell et al., 1955;
                                            Lehman et al., 1951
                                                                        

    Short-term studies

    Rat

         No effect on potassium excretion, as described below for the
    rabbit was observed in a short-term feeding study in the rat (Dacre,
    1960).

         Groups of seven recently weaned rats were fed for six months on
    rations containing 0, 0.5, 1, 2 and 3% of BHA. The rats at the 3%
    level did not eat enough to gain weight and were put on to the 2%
    diet for a time, then returned to 3%. Even at the 2% level, food
    consumption was not optimal. Histopathological examination revealed no
    pathological condition attributable to BHA (Wilder & Kraybill, 1948).

         Combinations of BHA with other food additives, such as chlorine
    dioxide, sodium propionate, propyl gallate, or polyoxyethylene-8-
    stearate, at 50 times the normal levels of use in bread, had no
    deleterious effects when they were fed in bread to groups of 26 rats
    for a period of 32 weeks. The treated bread formed 75% of the animals'
    diet. The daily dosage levels of BHA were from 3.3 to 7.0 mg/kg bw
    (Graham et al., 1954; Graham & Grice, 1955).

         Rats were maintained on test diets containing 0, or the
    equivalent of 500-600 mg/kg bw BHA (1/5 of the LD50), for a
    period of 10 weeks. The test animals showed decreased growth rate,
    and reduced activity of the blood enzymes, catalase, peroxidase and
    cholinesterase. Chemical analysis of livers of test animals showed a
    decrease in the amount of phospholipid as compared to controls, but
    there was no lipid accumulation. Histological examination of the
    tissues and organs did not show any compound-related effects
    (Karplyuk, 1962).

    Rabbit

         In rabbits, a dose of 1 g given daily for five to six days by
    stomach tube caused a ten-fold increase in sodium excretion and a 20%
    increase in potassium excretion in the urine. Extracellular fluid
    volume fell, and this prevented any marked change in the plasma sodium
    level. The serum potassium fell after five days' treatment and
    potassium was being replaced by sodium in muscle cells. In heart
    muscle the changes occurred later than in skeletal muscle and were
    less marked. The antioxidant may have a direct effect on the kidney;
    the adrenal cortex showed changes in the zona glomerulosa and there
    was increased excretion of aldosterone in the urine, associated with
    the sodium and potassium loss (Denz & Llaurado, 1957).

    Dog

         When BHA was fed to dogs at dose levels of 0, 0.3, 30 and
    100 mg/kg bw for one year, no ill-effects were observed. Renal
    function, haematology and histopathology of the main tissues were
    normal. Organ weights were within normal limits and there was no
    demonstrable storage of BHA.  The urine did not contain a demonstrable
    increase of reducing substances, even when 100 mg/kg bw of BHA was
    fed. Groups of three dogs were used at each dose level for these
    experiments (Hodge et al., 1964).

         Groups each of four weanling dogs were fed BHA at 0, 5, 50 and
    250 mg/kg for 15 months. General health and weight gains of the dogs
    were within normal range, as were haematologic parameters. Urine from
    test dogs contained higher ratios of total to inorganic sulfate, and
    glucuronates than controls. At autopsy, microscopic examination of
    tissues and organs showed that three/four of the animals at the
    highest dose level tested had a liver cell degeneration and a diffuse
    granulocytic infiltration. The lobular structure of the livers of
    these animals was normal, and there was no excessive connective tissue
    proliferation (Wilder et al., 1960).

    Monkeys

         A group of six adult female rhesus monkeys were maintained on a
    test diet containing a mixture of BHT and BHA that provide an intake
    equivalent to 50 mg BHT and 50 mg BHA/kg body weight. Another group of
    six adult female rhesus monkeys were used as controls. The monkeys
    were fed the diet for one year prior to breeding and then for an
    additional year, including a 165 day gestation period. Haematologic
    studies including haemoglobin, haematocrit, total as well as
    differential white blood cell count, cholesterol, Na+, K+, total
    protein, serum glutamic pyruvic transaminase, and serum glutamic
    oxylacetic transaminase, were carried out at monthly intervals. Body
    weights were taken at monthly intervals. Records of menstrual cycles
    were maintained through the test period.

         After one year the females were bred to rhesus males not
    receiving test diets. During pregnancy complete blood counts were done
    on days 40, 80, 120 and 160 of gestation and on days 30 and 60 post-
    partum. A total of five infants were born to the experiment monkeys
    and six to the control monkeys. Haematological evaluations were made
    on infants of the test and control monkeys at days 1, 5, 15, 30 and
    60, and observations of the infants were continued through two years
    of age. Two experimental and two control infants, three months of age,
    were, removed from their mothers for one month of psychological home
    cage observations. No clinical abnormalities were observed in parent
    and offspring during the period of study. The gestation of test
    animals was free of complications and normal infants were delivered.
    Adult females continued to have normal infants. Infants born during

    the exposure period remained healthy, with the exception of one infant
    that died from unrelated causes. Home cage observations at the third
    month of life did not reveal any behavioural abnormalities (Allen,
    1974).

    Long-term studies

    Rat

         Groups of 15 or more newly weaned rats were placed on diets
    containing 0, 0.05, 0.5 and 1% BHA in lard (0, 0.003, 0.03 and 0.06%
    of the total diet) for 22 months. Weight gain was comparable in all
    groups. Reproduction was normal, and young rats kept on the same
    ration grew normally. Number, size, weight, weight gain and mortality
    of the litters were comparable for animals of all groups. After one
    year on test, the colony suffered from an infectious respiratory
    disease and many died. There was no significant difference in
    mortality among the groups. After 22 months, the remaining animals
    were killed; histopathological examination revealed no changes
    attributable to the antioxidant (Wilder & Kraybill, 1948).

         A similar series of tests was undertaken, with an additional
    group on a diet of 2% BHA in lard (0.12% of the total diet). There
    were 17 rats in each group. After 21 months, the survivors were
    killed. Histopathological examination revealed no significant
    differences compared with the control animals. The rate of gain in
    weight during the growing period was unchanged, and all rats appeared
    normal in every respect (Wilder & Kraybill, 1948).

         In another rat feeding test carried out over a period of two
    years on groups of 40 rats, there was a small reduction in the mature
    weight and an increase in relative liver weight in some cases with the
    highest level of BHA used (0.5% of the diet), but there were no
    effects on any of the following: the reproductive cycle; histology of
    the spleen, kidney, liver, or skin; ratio of weight of heart, spleen,
    or kidneys to total body weight:mortality. The toxicity of BHA was not
    affected by the dietary fat load (Brown et al., 1959).

         Rats were maintained on diets containing 0, and the equivalent of
    500-600 mg/kg bw BHA (1/5 of the LD50) for a period of one year.
    During the course of this study, rats were bred to produce three
    successive generations. Two generations were maintained on the test
    diet for six months. BHA had no effect on reproductive performance, as
    measured by litter size, birth weight, date of appearance of incisors,
    and opening of eyes. Autopsy and histological examination of tissues
    and organs of parents and offsprings at the termination of the study
    did not reveal any compound-related effect (Karplyuk, 1962).

    OBSERVATIONS IN MAN

         Human volunteers were dosed with 0.5-0.7 mg/kg bw BHA. 22-77% was
    excreted in the urine as the glucoronide within 24 hours. Less than 1%
    was excreted in the urine as unchanged BHA, and no dealkylation or
    hydroxylation products were detected (Astill et al., 1962). In
    another study, human volunteers were administered a single dose of
    14C-labelled BHA (approximately 0.5 mg/kg bw). 60-70% of the
    radioactivity was excreted in the urine within two days, and by day
    11 post-dosing, 80-86.5% of the radioactivity was recovered in the
    urine (Daniel et al., 1967).

    Comments

         Several metabolic studies with orally administered BHA are
    available in rats, mice and monkeys. In the rat, at the levels tested,
    there appeared no change in the activity of the liver enzymes studied.
    In the case of mice, although there appeared no increase in aryl
    hydrocarbon hydroxylase, there was an increase in cytochrome P450 and
    the nature of the enzyme appears altered. With monkey, on the other
    hand, cytochrome P450 levels appeared unaffected whereas some enzyme
    activities were affected. In this regard, infant monkeys, as opposed
    to juveniles, did not show these changes. BHA appeared to lower liver
    cholesterol whereas plasma triglycerides were increased.

         Female monkeys maintained on a dietary intake of 50 mg/kg body
    weight for one year prior to breeding, and bred to untreated males,
    gave birth to normal offspring. BHA had no effect on any of the
    indices tested. These included haematology and clinical biochemistry
    as well as behavioural observations on the young.

         Mutagenic activity of BHA has been tested in several in vitro
    and in vivo systems. The collective assessment of these tests does
    not show BHA to be mutagenic.

         The previously stated requirement that studies on the effect on
    reproduction of mixtures of BHA, BHT and propyl gallate was considered
    to be no longer necessary.

    EVALUATION

    Level causing no toxicological effect

         Rat: 5000 ppm (0.5%) in the diet equivalent to 250 mg/kg bw.

    Estimate of acceptable daily intake for man

         0-0.51 mg/kg bw.2

    FURTHER WORK OR INFORMATION

    Required by 1980.

         A multigeneration reproduction study.

    REFERENCES

    Allen, J. R. (1976) Annual Report of the University of Wisconsin Food
         Research Institute 1974, pp. 308-315

    Allen, J. R. & Engblom, J. F. (1972), Fd. Cosmet. Toxicol., 10, 769

    Astill, B. D. et al. (1962) J. Ag. & Food Chem., 10, 315

    Astill, B. D., Fassett, D. W. & Roudabush, R. L. (1960) Biochem. J.,
         75, 543

    Branen, A. L. et al. (1973) Fd. Cosmet. Toxicol., 11, 797

    Brown, W. D., Johnson, A. R. & O'Halloran, M. W. (1959) Aust. J. exp.
         Biol. med. Sci., 37, 533

    Bunnell, R. H. et al. (1955) Poultry Sci., 34, 1068

    Clegg, D. J. (1965) Fd. Cosmet. Toxicol., 3 387

    Creaven, P. J., Davies, W. H. & Williams, R. T. (1966) J. Pharm.
         Pharmacol., 18, 485

    Dacre, J. C. (1960) N. Z. J. Inst. Chem., 24, 161

    Dacre, J. C., Denz, F. A. & Kennedy, T. H. (1956) Biochem. J., 64, 777

    Daniel, J. W. et al. (1967) Fd. Cosmet. Toxicol., 5, 475

    Denz, F. A. & Llaurado, J. G. (1957) Brit. J. exp. Path., 38, 515

              

    1    As BHA, BHT or the sum of both.

    2    Temporary.

    Fabrizio, D. P. A. (1974) Mutagenic evaluation of compound FDA 71-24:
         Butylated hydroxyanisole. Unpublished report from Litton
         Bionetics, Inc., Kensington, Md. US, submitted to the World
         Health Organization by the US Food and Drug Administration

    Feuer, G. et al. (1965) Fd. Cosmet. Toxicol., 3 457

    Feuer, G., Golberg, L. & LePelley, J. R. (1965a) Fd. Cosmet. Toxicol.,
         3, 235

    Francois, A. C. & Pihet, A. (1960) Ann. ind. natl. recherche agron.
         Ser., D9, 195

    Fritsch, P., de Saint-Blanquat, G. & Derache, R. (1975a) Eur. J. Tox.,
         8, 169

    Fritsch, P., Lamboeuf, Y. & de Saint-Blanquat, G. (1975b) Toxicology,
         4, 341

    Gilbert, D. & Golberg, L. (1965) Fd. Cosmet. Toxicol., 3, 417

    Golder, W. S., Ryan, A. J. & Wright, S. E. (1962) J. Pharm.
         Pharmacol., 14, 268

    Graham, W. D. & Grice, H. C. (1955) J. Pharm. (Lond.), 7, 126

    Graham, W. D., Teed, H. & Grice, H. C. (1954) J. Pharm. (Lond.), 6,
         534

    Hodge, H. C. et al. (1966) Toxicol. appl. Pharmacol., 9, 583

    Hodge, H. C. et al. (1964) Toxicol. appl. Pharmacol., 6, 512

    Johnson, A. R. & Hewgill, E. R. (1961) Aust. J. exp. Biol. med. Sci.,
         39, 353

    Johnson, A. R., O'Halloran, M. W. & Hewgill, F. R. (1928) J. Amer. oil
         Chem. Soc., 35, 496

    Karplyuk, I. A. (1962) Tr. 2-01 (Vtoroi) Nauchn. Konf. po Vopr. Probl.
         Zhira v Pitanii, Leningrad, 1962, 318

    Lehman, A. J. et al. (1951) Advanc. Food Res., 3, 197

    Posati, L. P. & Pallansch, M.J. (1970) Science, 168, 121

    Riley, P. A. & Seal, P. (1968) Nature, 220, 922

    Speier, J. L. & Wattenberg, L. W. (1975) J. nat. Cancer Inst., 55, 469

    Stokes, J. D. & Scudder, C. L. (1974) Development Psychobiology, 7,
         343

    Telford, I. R., Woodruff, C. S. & Linford, R.H. (1962) Amer. J. Anat.,
         10, 29

    Wilder, O. H. M., Ostby, P. C. & Gregory, B. A. (1960) J. Ag. & Food
         Chem, 8, 504

    Wilder, O. H. M. & Kraybill, H. R. (1948) Summary of toxicity studies
         on butylated hydroxyanisole, American Meat Institute
         Foundation, University of Chicago


    See Also:
       Toxicological Abbreviations
       Butylated hydroxyanisole (WHO Food Additives Series 5)
       Butylated hydroxyanisole (WHO Food Additives Series 21)
       Butylated hydroxyanisole (WHO Food Additives Series 24)
       BUTYLATED HYDROXYANISOLE (JECFA Evaluation)