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    PESTICIDE RESIDUES IN FOOD - 1983


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1983





    Data and recommendations of the joint meeting
    of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the
    WHO Expert Group on Pesticide Residues
    Geneva, 5 - 14 December 1983

    Food and Agriculture Organization of the United Nations
    Rome 1985


    BITERTANOL

    TOXICOLOGY

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, Distribution and Excretion

    Rat

         A single oral dose (100 mg/kg) of 14C-phenyl-labelled bitertanol
    in propylene glycol was administered by gavage to five male and five
    female Wistar rats. Pooled urine and faeces were collected at 4, 8 and
    24 h after dosing and then at subsequent 24-h intervals until
    sacrifice. In each case, recovered radioactivity exceeded 99 percent
    of the administered radioactivity, thus confirming that little, if
    any, 14C-respiration occurs. Over seven days, 92.1 percent and
    91.9 percent of radioactivity was excreted in the faeces and 7.4
    percent and 8.0 percent appeared in the urine of male and female rats,
    respectively; 73.2 percent and 71.4 percent of administered
    radioactivity appeared in the faeces after 48 h. The urine contained a
    number of metabolites, which were not identified. The faeces also
    contained numerous metabolites, including two that co-chromatographed
    with bitertanol. After hydrolysis, mass spectrometry indicated that
    the faeces contained metabolites formed by mono- and di-hydroxylation
    of the biphenyl ring system and t-butyl moieties. At sacrifice, seven
    days after dosing, tissues contained low levels of radioactivity; the
    higher levels, expressed as bitertanol equivalents, occurred in
    excretory organs, liver and kidney (male 0.6 ppm and female 3.06 ppm).
    Blood contained smaller amounts of radioactivity (male 0.24 ppm and
    female 0.32 ppm) while bone, brain, adipose tissue, gonads, heart,
    muscle, and spleen each contained less than 0.2 ppm (Puhl et. al.
    1979).

    TOXICOLOGICAL STUDIES

    Special Studies on Embryotoxicity

    Rat

         Groups of 20 to 22 Long Evans FB 30 rats received daily oral
    doses of bitertanol (96.5 percent pure) emulsion by gavage at 0, 10,
    30 and 100 mg/kg from day 6 to 15 of gestation. Foetuses were
    delivered by Caesarean section on day 20. The body weight gain of the
    dams was significantly reduced at 30 and 100 mg/kg during treatment,
    and throughout the gestation period at 100 mg/kg. Resorption rates,
    foetal deaths, placental weights and sex ratio were unaffected by

    treatment. However, foetal weights were significantly reduced at
    100 mg/kg and significant foetal stunting occurred at 30 mg/kg and
    100 mg/kg. A wide variety of foetal abnormalities occurred at
    100 mg/kg, including three litters with cleft palate, one litter with
    hydrocephalus and two litters with rib dysplasia. A simple case of
    hydrocephalus also occurred at 30 mg/kg, indicating a no-effect level
    of 10 mg/kg (Machemer 1977).

         In separate experiments, groups of 23 to 25 Long Evans FB 30 rats
    were exposed to average concentrations of 0, 2.9, 6.4, 22.4 and 0,
    27.6, 60 and 115 mg/m3 of bitertanol aerosol for 4 h daily from day 6
    to 15 of gestation. The foetuses were delivered by Caesarean section
    on day 20 of gestation. The rate of body weight increase of the dams
    was unaffected by treatment. The average foetal weights were reduced
    significantly by exposure to 115 mg/m3 and foetuses with stunted
    growth were found at aerosol concentrations above 22.4 mg/m3.
    Implantation rates, resorption rates, placental weights, skeletal
    anomalies, malformation rates and sex ratios were unaffected by
    treatment. Treatment-related teratogenic effects were not observed and
    6.4 mg/m3 was considered the no-effect level (Machemer & Thyssen
    1979).

         A suspension of technical bitertanol (95 percent pure) was
    administered daily to groups of 25 Sprague-Dawley rats by gavage at
    levels of 0, 10, 25 and 65 mg/kg on days 6 to 15 after mating. No
    signs of reaction to the treatment were observed. Necropsy was
    performed at day 20 of gestation. Body weight gain was unaffected at
    10 mg/kg but a significant decrease was observed in dams receiving
    25 mg/kg. The 65 mg/kg group displayed a significant reduction in body
    weight gain, which persisted after treatment. At necropsy, no effects
    were observed on the numbers of corpora lutea, implants, live
    foetuses sex ratio, foetal and placental weights, or foetal mortality.
    Dose-related increases in the incidences of lumbar (14th) ribs
    occurred at 25 and 65 mg/kg. The no-effect level was therefore
    established as 10 mg/kg (Nagumo et. al. 1981).

    Rabbit

         Emulsified bitertanol (96.7 percent pure) was administered daily
    to groups of 12 Himalayan rabbits during 6 to 18 days after mating at
    0, 10, 30 and 100 mg/kg b.w. Caesarean sections were performed on day
    29 of gestation. Although dams treated at 100 mg/kg failed to gain
    weight during treatment, and occasionally had reduced feed
    consumption, diarrhoea or blood in their urine, pregnancy rates were
    unaffected. One dam died. Placental weight, foetal survival and foetal
    weight were all reduced at the highest treatment rate. Treatment-
    related skeletal malformations were not observed. However, in 12
    litters one instance of several pulmonary lobes and another of aplasia
    of one lung associated with hypoplasia of the other lung were
    observed. The no-effect level determined in this study was 30 mg/kg
    (Roetz 1982).

         Groups of 15 Himalayan rabbits were treated daily with an
    emulsion of bitertanol (93.9 percent pure) at 0, 10, 30 and 100 mg/kg
    from day 6 to 18 after mating by gavage. Foetuses were removed on day
    29 of pregnancy. Treatment had no effect on behaviour, appearance and
    body weight gain of the dams. At 100 mg/kg only, the conception rate
    was reduced and the resorption rate increased. Teratogenic effects,
    cleft palate and pigeon chest were also observed at the highest
    treatment rate. In eight litters, two of the pups had cleft palate
    associated with pigeon chest, another had pigeon chest and another had
    cleft palate alone. This study confirmed 30 mg/kg as the no-effect
    level for bitertanol in the rabbit (Schlueter 1983).

    Special Studies on Reproduction

         Bitertanol (95.0 percent pure) was fed in the diet to groups of
    10 male and 20 female Long Evans PB 30 rats at 0, 20, 100 and 500 ppm.
    The animals were maintained on their respective diets prior to mating
    for about 70 days. The diet was fed continually throughout three
    generations producing two litters in each generation. Pups of the F3b
    generation and their F2b parents were necropsied after four weeks
    lactation. Although fertility was unaffected by treatment, birth
    weight and maternal lactation rate, pup growth and survival were
    reduced by treatment at 100 ppm. At 500 ppm, litter size, birth
    weights, pup growth rate and viabilities were reduced. At necropsy
    maternal liver weight was increased at 100 ppm, confirming 20 ppm as
    the no-effect level in rats (Loeser & Eiben 1981).

    Special Studies on Mutagenicity

         Bitertanol (93.7 percent pure), when tested at 4, 20, 100, 500
    and 2 500 g/plate in Salmonella assays with and without metabolic
    activation with 4 LT2 mutants, TA98, TA100, TA1535 and TA1537, was
    not found to be mutagenic. Bitertanol was found to be bacteriostatic
    above 100 g/plate in strains TA100 and TA1535 (Herbold 1979).

         Bitertanol (95.0 percent pure) was found neither to affect DNA
    repair in Bacillus subtilis H17 and M45 nor to be mutagenic
    in reverse mutation tests, with or without metabolic activation,
    employing Escherichia coli WP2 hcr and Salmonella
    typhimurium strains TA1535, TA1537, TA1538, TA100 and TA98 (Shirasu
    et. al. 1981).

         There was no indication that the cellular DNA of E. coli
    strains W3110/pol A+ and p3478/pol A- was modified when bitertanol
    was tested with and without S-9 microsome fraction at doses of 100 g,
    333.3 g, 1.0 mg, 3.3 mg, 10.0 mg and 33.3 mg per plate. However,
    precipitation occurred above 333.3 g/plate (Riach 1981).

         Two strains of Sordaria brevicollis, mo-C70 notl+ and mo+ S6
    notl-, did not exhibit meiotic aneuploidy when exposed to 0, 0.1,
    0.25, 0.5, 1.0 and 2.5 mg/l bitertanol (95.0 percent pure). Spore
    maturation was affected at 5 mg/l and spore fertility reduced at
    10 mg/l (Bond & McGregor 1981).

         Bitertanol did not increase the mutation frequency at the
    thymidine kinase gene locus when L5178Y mouse lymphoma cells were
    exposed to 10 concentrations ranging from 1.95 to 1 000 g/ml, with or
    without S-9 mix (Bootman & Rees 1983).

         In a micronucleus assay, the incidence of Howell-Jolly bodies
    among polychromatic erythrocytes was unchanged on treatment of five
    male and five female NMRI mice with two oral doses, 24 h apart, of
    1 000 and 2 000 mg/kg bitertanol (93.7 percent pure) (Herbold 1978b).

         In a dominant lethal assay, male NMRI strain mice in groups of 50
    were dosed orally with 1 000 mg/kg bitertanol emulsion and
    sequentially mated with a series of 12 virgin females. Fourteen days
    after mating, the females were examined for pre- and post-implantation
    losses. No effects were observed on fertilization quotas,
    preimplantation and postimplantation losses or viable implants
    (Herbold 1978a).

    Special Study on Carcinogenicity

    See under long-term studies.

    Special Studies on Skin Sensitization

    Guinea pig

         A 1 percent emulsion (0.1 ml) of bitertanol was injected
    intradermally, with and without Freund's adjuvant, into 20 male and 20
    female guinea pigs. After one week, topically applied 25 percent
    bitertanol emulsion did not induce a dermal response. Subsequent
    dermal challenge after a further two weeks with a 25 percent
    bitertanol emulsion failed to provoke an allergic response (Flucke
    1981).

         Following an initial administration of 0.05 mg/kg, nine repeated
    intracutaneous injections of emulsified bitertanol (0.1 mg/kg) over
    three consecutive weeks did not produce a significant response.
    Intracutaneous injection of an additional 0.05 mg/kg after a further
    two-week period also failed to produce signs of dermal sensitization
    (Thyssen 1977).

    Dog

         Oral administration of bitertanol at 35 and 70 mg/kg produced
    significant hair loss and reddening of the gums in beagle dogs. After
    a six-week withdrawal period, re-treatment with 1.75 mg/kg for 14 days
    produced hair loss and gingivitis at an unspecified time towards the
    end of the treatment period. Observations on individual animals were
    not reported (Hoffman 1977).

         Dermal or mucosal irritation were not observed in an inhalational
    study in which male beagle dogs were subjected to 15  4 h exposures
    to bitertanol dust, averaging 28.8 mg/m3. Subsequent re-exposure
    after 10 days to dust concentrations averaging 47.1 mg/m3 also failed
    to produce signs of dermal irritancy or sensitization (Thyssen &
    Kimmerle 1977a).

    Special Studies on Potentiation of Acute Toxicity

         Since bitertanol can be used in combination with other fungicidal
    compounds, acute combination toxicity studies were performed with
    Wistar rats. The compounds tested in combination with bitertanol were
    captan (Mihail 1982a), triadimenol (Mihail 1982b) and fuberidazole
    (Flucke 1980). After determination of the oral LD50 for each
    compound, Wistar rats were treated with each test compound in
    combination with bitertanol. Groups of 10 rats were used per dose and
    the post observation period was 14 days. From the LD50 values for the
    individual components, the theoretically expected LD50 was calculated
    for each combination. The mixtures were administered in equitoxic
    doses, according to their acute toxicity. Slight synergistic effects
    were observed for the combination of bitertanol and captan only.

    Acute Toxicity

         The acute toxicity of bitertanol is generally low. No significant
    sex differences were observed. Sheep are the most sensitive to its
    oral toxicity but dermal toxicity is uniformly low in those species
    tested. Bitertanol is moderately toxic to rats and mice by
    intraperitoneal injection. The LD50 in various species by several
    routes appear in Table 1.

         The principal signs of acute intoxication, altered behaviour,
    sedation, motility disturbance, convulsions and dyspnoea, were
    consistent with central nervous system toxicity. Signs of
    gastrointestinal irritation, vomiting and diarrhoea also occurred and,
    in some cases, gastric irritation and mucosal haemorrhage were found
    at necropsy.

        Table 1  Acute Toxicity of Bitertanol in Animals
                                                                                               

    Species      Route               LD50             References
                                     (mg/kg b.w.)
                                                                                               

    Mouse        oral                4 202-4 488      Thyssen & Kimmerle 1977b; Iyatome 1980

    Mouse        intraperitoneal     520-670          Iyatome 1980

    Mouse        subcutaneous        >1 000->5 000    Thyssen & Kimmerle 1977b; Iyatome 1980

    Mouse        dermal              >5 000           Iyatome 1980

    Rat          oral                3 300->5 000     Mihail 1982a,b; Iyatome 1980; Thyssen &
                                                      Kimmerle 1977b; Flucke 1980; Flucke 1978;
                                                      Heimann 1981; Heimann 1983

                 dermal              >5 000           Thyssen & Kimmerle 1977b; Iyatome 1980

                 intraperitoneal     560-1 160        Thyssen & Kimmerle 1977b; Iyatome 1980

    Rabbit       dermal              >2 000           Hixson 1979

    Sheep        oral                ca 1 000         Hoffmann 1981a

    Dog          oral                >5 000           Hoffmann 1981b
                                                                                               
    
    Short-Term Studies

    Rat

         Groups of 20 male and 20 female Wistar rats were dosed daily by
    stomach tube for 28 days at 0, 30, 100 and 300 mg/kg bitertanol
    (96.5 percent pure). Half the animals were sacrificed and the other
    half were observed for a further 28 days. Although mortality was
    unaffected, significant treatment-related effects were observed above
    30 mg/kg, particularly in females. Body weight gains were reduced at
    100 and 300 mg/kg; at the higher dosage female rats lost hair and had
    disturbed behaviour. Also at 300 mg/kg, rats of both sexes had a
    moderate leucocytosis and females had reduced haemoglobin and
    thrombocyte levels compared with the controls; the males had
    relatively increased weight of thyroid, liver and testes while female
    rats had increased liver weight but decreased weight of heart,
    kidneys, adrenals, ovaries and uterus. Furthermore, four of the female
    rats treated at 300 mg/kg showed hyperkeratosis and parakeratosis,

    with dilated epithelia of the forestomach and accompanying round cell
    and granulocyte infiltration of the epithelial and subepithelial
    strata. This study indicated 30 mg/kg as the no-effect level in rats
    (Thyssen & Kaliner 1977).

         In a subsequent feeding study, groups of 20 male and 20 female
    Wistar rats received 0, 150, 600 and 2 400 ppm technical bitertanol
    (90.2 percent pure) in their diet for three months. No effects were
    observed on behaviour, but food intake in treated females and in males
    treated at 2 400 ppm were reduced. Body weight gain was reduced in
    treated males and in females treated at 600 and 2 400 ppm. Mortality
    was not affected by treatment. At 2 400 mg/kg, haemoglobin
    concentration, haematocrit and reticulocyte count were significantly
    reduced; also, male rats had reduced erthyrocyte and leucocyte counts
    while females had a significant reduction of lymphocytes and segmented
    neutrophils accompanying a slightly reduced MCH. Altered liver
    function occurred at 2 400 ppm, serum cholesterol and alkaline
    phosphatase were elevated and serum protein concentration was reduced.
    Male rats had elevated glutamic-oxaloacetic transaminase while female
    rats had significantly elevated glutamate dehydrogenase and increased
    liver weight at autopsy. The reduced weights of other organs, e.g.
    heart, lung, spleen, kidney, adrenal, ovary and testes, corresponded
    to the reduced body weight at 2 400 ppm. A no-effect level was not
    established in this study (Bomhard & Loeser 1978).

         In another feeding study, groups of 15 male and 15 female Wistar
    rats received technical bitertanol (purity unspecified) for three
    months at 0, 30, 100 and 300 ppm in the diet. The animals were then
    sacrificed. At 300 ppm, body weight gain of both male and female rats
    was reduced. No toxicologically significant treatment-related effects
    were found on serum biochemistry, haematological parameters, serum
    cholesterol, blood sugar level or urinalysis. No specific effects were
    found at necropsy, indicating 100 ppm in the diet as the no-effect
    level (Kroetlinger et al. 1978).

         In an inhalational study, groups of 10 male and 10 female Wistar
    rats were exposed daily five days per week for three weeks for six
    hours to an aerosol of technical bitertanol of unknown purity at an
    average concentration of 17.9, 63.3 and 197.9 mg/m3. At the highest
    aerosol concentration the male rats had reduced body weight gains but
    were without symptoms; the females suffered an impairment of general
    condition, however. At necropsy, there were significant increases in
    the relative weight of lung in the males and of liver, kidney and
    adrenal in females exposed to 197.7 mg/m3; adrenal weights were
    slightly but significantly increased at 63.3 mg/m3, indicating
    17.9 mg/m3 as the no-effect level for inhalational toxicity of
    bitertanol to the rat. Treatment-related histopathological changes
    were not observed (Mihail & Kimmerle 1977).

    Dog

         Encapsulated bitertanol (90.2 percent pure) was administered
    orally to groups of four male and four female beagle dogs for 13 weeks
    at concentrations of 0, 1, 5 and 25 mg/kg. Water consumption was
    unaffected but food consumption was reduced, particularly at 25 mg/kg,
    at which dosage treated dogs actually lost weight. Although mortality
    was not affected, treatment caused significant effects at 5 and
    25 mg/kg, including alopecia, erythema, dermal scale formation,
    mucosal irritation, gingivitis, conjunctivitis and lachrymation, as
    well as elevation of serum glutamate-pyruvate transaminase and
    alkaline phosphatase. Treatment-related changes in haematological and
    urinalysis parameters were not observed. At necropsy, increased
    hepatic N-demethylase and cytochrome P-450 activities accompanied
    increased liver weight at 25 mg/kg. Histologically, at 5 and 25 mg/kg
    there was dose-related distension of the dermal stratum epithelium
    with some increase in keratinization. In addition, males, which had
    dose-related reduction of prostate weight, had corresponding
    histopathological changes consistent with reduced maturation at these
    doses, indicating 1 mg/kg as the no-effect level (Hoffmann & Schilde
    1979).

    Long-Term Studies

    Mouse

         A long-term study was conducted over 24 months to investigate
    chronic effects and carcinogenic potential. Four groups of 50 male and
    50 female SPF CFI/W strain mice were fed bitertanol (ca. 94 to 95
    percent pure) at dietary concentrations of 0, 20, 100 and 500 ppm.
    Behaviour, feed consumption, mortality and haematology were not
    affected by the treatment. However, at 500 ppm body weight was reduced
    and serum alkaline phosphatase was significantly elevated in both
    sexes. The latter enzyme concentration was also higher in male mice
    treated at 100 ppm, making 20 ppm the level causing no toxicological
    effects. Ocular changes were not recorded. At necropsy, hepatic
    weights were increased at 500 ppm; the liver was enlarged in females
    with an increase in eosinophilic foci microscopically. No dose-related
    increase in neoplasia was observed (Bomhard & Loeser 1981b).

    Rat

         In a combined chronic toxicity/carcinogenicity study, bitertanol
    (94 to 95 percent pure) was fed in the diet at concentrations of 0,
    20, 100 and 500 ppm to groups of 50 male and 50 female SPF Wistar rats
    for 24 months. Rats of both sexes exhibited growth retardation at
    500 ppm only, but food consumption, behaviour and physical appearance
    were unaffected, making 100 ppm the no-effect level. Ocular changes
    were not recorded. Haematological parameters, blood chemistry and
    urinalysis were not significantly affected. Mortality was not

    adversely influenced by treatment; organ weights, gross pathological
    and microscopic examination of the tissues showed no compound-related
    effects. There was no indication of an increase in the incidence of
    neoplastic lesions (Bomhard & Loeser 1981a).

    COMMENTS

         After oral administration, the rat excreted radio-labelled
    bitertanol and its metabolites, mostly in the faeces. After seven
    days, tissues contained low levels of radioactivity. Hydroxylated
    metabolites were identified in the faeces but details of the degree of
    absorption and the metabolic fate of these compounds of the rat were
    not elucidated.

         Bitertanol is of low acute toxicity to the mouse, rat, rabbit,
    sheep and dog. The symptoms of acute intoxication are consistent with
    central nervous system toxicity. Gastrointestinal irritation occurs at
    high doses after oral administration.

         Subchronic oral administration of bitertanol to dogs induced
    significant dermal lesions, including inflammation, scale formation
    and hair loss, as well as conjunctival and gingival irritation at
    doses above 1 mg/kg/day.

         In chronic studies, the rat was less susceptible to bitertanol
    toxicity than the mouse. There was no evidence of carcinogenicity in
    either species at the doses tested. A battery of short-term
    mutagenicity investigations did not indicate any mutagenic potential.

         Bitertanol produced maternal toxicity and some evidence of
    teratogenicity in rats receiving more than 10 mg/kg/day and in rabbits
    at more than 30 mg/kg/day. Clear separation of maternal toxicity and
    teratogenicity could not be achieved. Maternal toxicity and
    embroyotoxicity, but not teratogenicity, were observed in the rat
    multi-generation reproduction study at dietary levels above 20 ppm.

    TOXICOLOGICAL EVALUATION

    Level Causing no Toxicological Effect

    Mouse:    20 ppm in the diet, equal to 3 mg/kg b.w.

    Rat:      20 ppm in the diet, equal to 1 mg/kg b.w.

    Rabbit:   30 mg/kg b.w./day (based on reproduction)

    Dog:      1 mg/kg b.w./day

    Estimate of Temporary Acceptable Daily Intake for Man

    0 - 0.005 mg/kg b.w.

    FURTHER WORK OR INFORMATION

    Required (by 1987)

    1.   Metabolism studies to clarify the metabolic pathway of bitertanol
         in mammals.

    2.   Oral toxicity study in the dog with a minimum duration of one
         year.

    3.   Chronic toxicity and carcinogenicity studies in rats at an
         appropriate dosage.

    Desirable

         Observations in humans.

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    Roetz, R. Study of embryotoxic (and teratogenic) effects on rabbits
    1982      after oral administration- KWG 0599. Bayer AG, Institute of
              Toxicology, Report No. 10979. Submitted to WHO by Bayer AG.
              (Unpublished)

    Schlueter, G. Studies to determine embryotoxic and teratogenic effects
    1983      to rabbits following oral administration - KWG 0599. Bayer
              AG, Institute of Toxicology, Report No. 11548. Submitted to
              WHO by Bayer AG. (Unpublished)

    Shirasu, Y., Moriya, M. & Ohta, T. Bitertanol - report of a microbial
    1981      mutagenicity study. Department of Toxicology, Institute of
              Environmental Toxicology, Japan. Submitted to WHO by Bayer
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    Thyssen, J. Intracutaneous allergy test on guinea pigs - KWG 0599.
    1977      Bayer AG, Institute of Toxicology, Report No. 7113.
              Submitted to WHO by Bayer AG (Unpublished)

    Thyssen, J. & Kaliner, G. Subacute oral cumulative toxicity study on
    1977      rats - KWG 0599. Bayer AG, Institute of Toxicology, Report
              No. 7153. Submitted to WHO by Bayer AG. (Unpublished)

    Thyssen, J. & Kimmerle, G. Report on subacute inhalational toxicity
    1977a     study on dogs. Bayer AG, Institute of Toxicology. Submitted
              to WHO by Bayer AG. (Unpublished)

    Thyssen, J. & Kimmerle, G. Acute toxicity studies - KWG 0599. Bayer
    1977b     AG, Institute of Toxicology, Report No. 6546. Submitted by
              Bayer AG to WHO. (Unpublished)


    See Also:
       Toxicological Abbreviations
       Bitertanol (Pesticide residues in food: 1984 evaluations)
       Bitertanol (Pesticide residues in food: 1987 evaluations Part II Toxicology)
       Bitertanol (JMPR Evaluations 1998 Part II Toxicological)