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    ZIRAM

    First draft prepared by
    J.-J. Larsen,
    Institute of Toxicology, National Food Agency,
    Ministry of Health, Soborg, Denmark

    Explanation
    Evaluation for acceptable daily intake
       Biochemical aspects
          Absorption, distribution, and excretion
          Biotransformation
       Toxicological studies
          Acute toxicity
          Short-term toxicity
          Long-term toxicity and carcinogenicity
          Reproductive toxicity
          Developmental toxicity
          Genotoxicity
          Special studies
             Dermal and ocular irritation and dermal sensitization
             Neurotoxicity
       Observations in humans
    Comments
    Toxicological evaluation
    References

    Explanation

         Ziram was evaluated for toxicological effects by the Joint
    Meeting in 1965, 1967, 1970, 1974, 1977, and 1980 (Annex 1, references
    4, 8, 14, 22, 28, and 34). A temporary ADI of 0-0.025 mg/kg bw for
    ziram or ziram in combination with other dimethyldithiocarbamates was
    allocated in 1967, on the basis of the NOAEL in a one-year study in
    dogs. This temporary ADI was lowered to 0-0.005 mg/kg bw in 1974. A
    group ADI of 0-0.02 mg/kg bw for ferbam and ziram was allocated in
    1977 and confirmed in 1980. The compound was reviewed by the present
    Meeting within the CCPR periodic review programme. This monograph
    summarizes the data received since the previous evaluation and
    contains relevant summaries from the previous monograph and monograph
    addenda on ziram (Annex I, references 4, 9, 15, 23, 29, and 35).

    Evaluation for acceptable daily intake

    1.  Biochemical aspects

    (a)  Absorption, distribution and excretion

         A group of 71 rats were given a single oral dose of 15 mg/kg bw;
    14 daily doses of 15 mg/kg bw nonradiolabeled ziram (purity, 99%)
    followed by a single dose of 14C-ziram (radiochemical purity, 96.9%)
    on day 15; or a single dose of 352 mg/kg bw 14C-ziram. Urine, faeces,
    expired carbon dioxide, and volatile organic compounds were collected
    from all animals 0-4, 4-8, 8-12, and 12-24 h after treatment. The rats
    were killed seven days after administration of the radiolabelled
    dose. The mean recovery of radiolabel was 79-92% of the total dose
    administered. Most of the radiolabel was eliminated within 24 h after
    administration of the low dose and within 48 h of the high dose. Most
    radiolabel (36-53%) was found in expired air, with 17-35% in urine
    and 9-18% in faeces. The amounts retained in tissues and carcass
    represented 1-2% of the total dose. The highest residue levels were
    found in blood, liver, kidney, heart, lungs, spleen, and thyroid
    gland. No apparent sex-related differences were observed in the
    elimination or distribution of 14C-ziram (Cheng, 1991a).

         The extent of absorption of 14C-ziram was studied in 74 rats
    given single dermal doses of 0, 1.1, 12, or 91 mg per animal (0.086,
    0.95, or 7.25 mg/cm2). Urine, faeces, blood, skin at the application
    site, and the carcass were collected from four animals killed 0.5, 1,
    2, 4, 10, or 24 h after initiation of exposure to ziram. A mean of
    74-101% of the dose was recovered. Most of the radiolabel (68-99%) was
    washed off the skin at the application site; only 16% remained on or
    in the skin. Less than 0.3% of the administered radiolabel was
    retained in the carcass and was eliminated in the excreta within
    24 h after exposure. The mean amount absorbed (sum of radiolabel in
    urine, carcass, and skin at the test site) by 24 h was 29% of the
    administered dose in animals at 1.1 mg, 31% in those at 12 mg, and 5%
    for those at 91 mg, indicating non-linear dermal absorption (Cheng,
    1991b).

    (b)  Biotransformation

         Three lactating goats weighing about 40 kg were fed 14C-ziram
    for six consecutive days at concentrations of 0 or 300 ppm, equal to 0
    or 12.5 mg/kg bw per day. All milk, urine, and faeces were collected
    for radioanalysis. The animals were killed 6 h after the last dose and
    the organs were removed. The concentrations of radiolabel in the milk
    appeared to reach a plateau by day 3, at 0.6-1.8 ppm. In the edible
    tissues, the concentrations of radiolabel were 22-28 ppm in the liver,
    3 ppm in the kidneys, and < 1 ppm in fat and muscle. The total
    amounts of radiolabel excreted during the test period were 42-61% of
    the administered dose in faeces, 3% in urine, and 0.28-0.51% in milk.
    Dithiocarbamates represented maxima of 28 and 10% of the total

    radioactive residues in urine and liver, respectively, and
    undetectable amounts in other tissues.  N-Nitrosodimethylamine
    residues (detection limit, 1 ppb) were not found. Radiolabelled
    lactose and casein were isolated from milk and radiolabelled urea from
    urine, indicating that the metabolism of ziram in goats occurs at
    least in part via a single-carbon pathway, which results in extensive
    radiolabelling of natural products. The author concluded that the
    bound and extractable radioactivity in milk and tissues was derived
    largely from radiolabelled natural products rather than from discrete
    dithiocarbamate metabolites (Bodden, 1993).

         The expected metabolic pathways of ziram, on the basis of data on
    other dimethyldithocarbamates, are shown in Figure 1.

    FIGURE 9

    2.  Toxicological studies

    (a)  Acute toxicity

         The acute toxicity of ziram is summarized in Table 1.

    (b)  Short-term toxicity

    Mice

         Ziram (purity 97.6%) was administered orally to C57B1 and A mice
    at doses of 0 or 75 mg/kg bw twice a week (equivalent to 20 mg/kg bw
    per day) for 2.5 months. A positive control group was exposed in the
    same way to urethane. The presence of adenomas in the lungs and the
    liver was studied after the end of the exposure at intervals of 1.5
    months for six months; adenomas were found only in the lungs. In the A
    mice, adenomas occurred in 100% of animals given urethane, 51% of
    those given ziram, and 43% of the controls. The differences were not
    statistically significant. The first adenomas were seen after three
    months. In C57B1 mice, adenomas occurred in 26% of mice given
    urethane, 7.4% of those given ziram, and none of the controls. The
    results were statistically significant according to Student's  t test
    ( t = 2.08;  p = 0.05) but not according to the chi-squared test
    (chi-squared = 2.18;  p = 0.15) (Khicenko & Chernev, 1968; Annex 1,
    reference 15).

         In a range-finding study, groups of five male and five female
    Crl.CD(ICR)BR mice were fed ziram (purity, 89.5%) at concentrations of
    0, 3000, 4000, or 5000 ppm, equal to 0, 370, 510, or 740 mg/kg bw per
    day for males and 0, 420, 660, or 780 mg/kg bw per day for females,
    for four weeks. The body weight, food intake, and efficiency of food
    use were significantly reduced at all doses. The brain and heart
    weights were reduced in all female mice, and the heart weight was also
    reduced in males at 5000 ppm. There was no NOAEL (Chambers  et al.,
    1992a).

         In another preliminary study, groups of 10 male and 10 female
    Crl:CD-1 mice were fed ziram (purity, 98.7%) at concentrations of 0,
    100, 300, 900, or 2700 ppm, equal to 0, 15, 44, 120, or 360 mg/kg bw
    per day for males and 0, 19, 49, 130, or 410 mg/kg bw per day for
    females, for 13 weeks. Clinical signs, body weight, food and water
    consumption, and efficiency of food use were recorded. On completion
    of treatment, all mice were sacrificed for macroscopic and microscopic
    examination. Over week 1, a reduction was noted in food consumption
    and use in animals of each sex and in the body weight of males and the
    body-weight gain of females at 2700 ppm. Lower weight gain was also
    noted during the study in males and females at 900 ppm. A lower spleen
    weight was noted in animals of each sex at 900 and 2700 ppm and in
    females at 300 ppm. Uterine weight was reduced at 2700 ppm. An
    increased incidence of hyperkeratosis of the non-glandular epithelium

        Table 1.  Acute toxicity of ziram in experimental animals

                                                                                                         

    Species     Sex            Route          Purity      LD50 (mg/kg bw)             Reference
                                                         or LC50 (mg/litre)
                                                                                                         

    Rat        Male       Oral                 98.5              380           Liggett & Allan (1989a)
               Female                                            270
    Rat        Male       Inhalation (4 h)     98.5             0.08           Jackson & Hardy (1989)
               Female                                           0.06
    Rat        Male       Inhalation (4 h)     98.4             0.18           Blagden (1991)
               Female                                           0.08
    Rabbit     NR         Oral                 NR                400           Annex I, reference 4
    Rabbit     Male       Dermal               98.5           > 2000           Liggett & Allen (1989b)
               Female                                         > 2000
                                                                                                         

    NR, not reported
        in the stomach was seen among mice given 900 or 2700 ppm. Epithelial
    hyperplasia of the limiting ridge in the stomach was also seen at
    2700 ppm. Contraction of the spleen and extramedullary haematopoiesis
    in the spleen were observed in mice at 900 and 2700 ppm. Corpora lutea
    were absent in one mouse at 900 ppm, and recent corpora lutea were
    absent in two mice at 2700 ppm and in one at 900 ppm. The uteri of
    some of these mice showed changes consistent with the ovarian changes,
    i.e. cellular stroma and reduced luminal diameter. These changes were
    not seen at 0, 100, or 300 ppm. The NOAEL was 100 ppm, equal to
    15 mg/kg bw per day, on the basis of decreased spleen weight at doses
    > 300 ppm (Powell  et al., 1993).

    Rats

         Groups of 10 male and 10 female weanling rats were fed ziram
    (purity unspecified) at concentrations of 0, 100, 500, 2500, or
    5000 ppm (equivalent to 0, 10, 50, 250, or 500 mg/kg bw per day) for
    28 days. Growth retardation was marked in animals at 2500 and
    5000 ppm; a slight retardation was also seen in those at 500 ppm, but
    growth was normal in those at 100 ppm. Except for slight anaemia at
    2500 and 5000 ppm, the haematological findings were normal and no
    significant histopathological changes were seen in any of the animals.
    The NOAEL was 100 ppm, equivalent to 10 mg/kg bw per day, on the basis
    of growth retardation at doses > 500 ppm (Annex I, reference 4).

         In a separate experiment, 10 male and 10 female rats were
    maintained for 28 days on a diet containing 0 or 2500 ppm ziram. No
    thyroid abnormalities were seen (Annex I, reference 4).

         Groups of 15 male and 15 female Wistar rats were given ziram
    (purity, 98%) by gavage at doses of 0, 3, 15, or 100 mg/kg bw per day
    for four weeks. Food consumption, efficiency of food use, and body
    weights were reduced significantly in males at the highest dose and in
    females at 15 and 100 mg/kg bw per day. End-points of haematology and
    clinical chemistry did not show clear dose-dependent changes, except
    for an increase in aspartate transaminase and alkaline phosphatase
    activities and blood urea nitrogen values at the highest dose. The
    liver weight was increased in males at this dose, and degenerative
    changes in the liver and kidneys were seen in animals of each sex.
    Degenerative liver changes were also seen in males and females at
    15 mg/kg bw per day. The NOAEL was 3 mg/kg bw per day, on the basis of
    decreased body weight, food consumption, and food use and degenerative
    liver changes at doses > 15 mg/kg bw per day (Dickhaus & Heisler,
    1980).

         In a range-finding study, groups of five male and five female
    Crl:CD(SD)BR rats were fed ziram (purity, 98.5%) at concentrations of
    0, 500, 1000, or 2000 ppm (equal to 0, 46, 90 or 170 mg/kg bw per day
    for males and 0, 46, 85, or 170 mg/kg bw per day for females) for four
    weeks. The body weight, food intake, and efficiency of food use were
    significantly reduced in animals of each sex at all doses. In males,

    the absolute weights of the liver, pituitary, and testes were reduced
    at all doses. The absolute weights of the brain in animals of each sex
    and of the uterus were also reduced at the highest dose. There was no
    NOAEL (Chambers  et al., 1992b).

         In another range-finding study, groups of 10 male and 10 female
    Crl:CD(SD)BR rats were fed ziram (purity, 98.7%) at concentrations of
    0, 100, 300, or 1000 ppm (equal to 0, 7.4, 21, or 68 mg/kg bw per day
    for males and 0, 8.8, 24, or 77 mg/kg bw per day bw for females)
    for 13 weeks. The body-weight gain, food intake, and food use were
    dose-dependently reduced at 300 and 1000 ppm. Brain weight and spleen
    weight were increased and a higher incidence of hair loss was noted at
    300 and 1000 ppm. Epithelial hyperplasia of the nonglandular stomach
    was seen at 1000 ppm. The NOAEL was 100 ppm, equal to 7.4 mg/kg bw per
    day, on the basis of decreased body-weight gain, food intake, and food
    use and increased brain and spleen weights and hair loss at doses
    > 300 ppm (Powell  et al., 1992).

    Rabbits

         Ziram (purity 98.5%) was applied to the intact skin of groups
    of five male and five female New Zealand white rabbits, weighing
    2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or
    1000 mg/kg bw per day. The test substance was moistened with distilled
    water and maintained on the backs of the rabbits for 6 h each day,
    after which the dressings were removed and the treated skin washed
    with tap-water at 30-40°C and gently blotted dry. No dermal reaction
    to the treatment was observed at any dose. Significant losses in body
    weight or low body-weight gain and reduced food consumption were
    recorded for female rabbits receiving 1000 mg/kg bw. The number of
    lymphocytes was reduced in both males and females at 1000 mg/kg bw,
    and alanine and aspartate transaminase activities were increased at
    300 and 1000 mg/kg bw. At the highest dose, significantly increased
    levels of bilirubin were found in females and of cholesterol in
    animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis
    of decreased body weight, body-weight gain, food consumption, and
    number of lymphocytes and increased bilirubin and cholesterol levels
    at 1000 mg/kg bw per day (Edwards  et al., 1989).

    Dogs

         In a range-finding study, single male and female beagle dogs were
    fed ziram (purity, 89.5%) at concentrations of 1000, 2000, or 5000 ppm
    (equal to 38, 78, or 260 mg/kg bw per day for males and 28, 91 or
    270 mg/kg bw per day for females) for four weeks; there was no control
    group. Both dogs at 5000 ppm and the female at 2000 ppm were killed
    for humane reasons due to loss of body weight and deteriorated
    condition. Convulsive episodes of up to 5-min duration were seen in
    females at 2000 ppm. Body-weight loss was seen in both animals at
    5000 ppm and in the female at 1000 ppm. Food intake and efficiency of

    food use were reduced in females at all doses and in males at
    5000 ppm. Increased liver weight in comparison with historical
    controls in the laboratory was seen in males at all doses. No
    histopathological examinations were performed. There was no NOAEL
    (McLean  et al., 1992a).

         In another range-finding study, groups of four male and four
    female beagle dogs were fed ziram (purity, 98.5%) in the diet at
    concentrations of 0, 100, 300, or 1000 ppm (equal to 0, 4.1, 12, or
    42 mg/kg bw per day for males and 0, 4.3, 13, or 41 mg/kg bw per day
    for females) for 13 weeks. One of the four dogs at 1000 ppm suffered a
    seizure and was killed for humane reasons, and another had tremors.
    Animals at this dose showed reduced body weight and food intake;
    lowered erythrocyte count, packed cell volume, and haemoglobin; and
    elevated circulating reticulocyte counts, with associated slight
    polychromasia, hypochromasia, and anisocytosis. Activated partial
    thromboplastin time was increased in male dogs at 300 or 100 ppm.
    Alkaline phosphatase activity was elevated in females at 1000 ppm, and
    the cholesterol level was elevated in females at 300 and 1000 ppm. The
    albumin concentration was decreased and that of globulin increased in
    some dogs at all doses during week 13. The liver weight was increased
    in male and female dogs at 1000 ppm and in one dog at 300 ppm. Focal
    myocardial necrosis with acute inflammation and haemorrhage were seen
    in the dog at 1000 ppm that was killed for humane reasons. Focal
    necrosis in the liver with loss of cells and dilated sinusoids were
    seen in one dog at 1000 ppm, and focal necrosis was also seen in a dog
    receiving 300 ppm. Minimal amounts of pigment in Kupffer cells were
    observed in two dogs at 300 ppm and in three dogs at 1000 ppm. The
    NOAEL was 100 ppm, equal to 4.1 mg/kg bw per day, on the basis of
    increased liver weight, focal liver necrosis, pigment in Kupffer
    cells, increased activated partial thromboplastin time, and an
    elevated cholesterol level at doses > 300 ppm (McLean  et al., 1992b).

         Groups of four male and four female beagle dogs were fed ziram
    (purity, 98.5%) in the diet to give concentrations of 0, 50, 180, or
    700/500 ppm (equal to 0, 1.6, 6.6, or 17 mg/kg bw per day for males
    and 0, 1.9, 6.7, or 21 mg/kg bw per day for females) for one year. The
    highest dose was reduced from 700 to 500 ppm in week 12 due to
    treatment-related deaths. All animals were killed and necropsied after
    one year. Body-weight gain was reduced in females at 180 and 500 ppm.
    Alanine transaminase, alkaline phosphatase, and, occasionally,
    aspartate transaminase activities were elevated in males receiving 180
    or 500 ppm; and the liver weights of males receiving 500 ppm were
    increased. Reduced albumin values and raised cholesterol levels were
    found for male dogs receiving 500 ppm. In the liver, some foci of
    degenerated hepatocytes were seen in a female at 180 ppm and in a
    number of dogs at 500 ppm, single-cell necrosis was seen in one male
    dog at 500 ppm, and inflammatory-cell infiltration around the central
    veins and branches of the hepatic veins was seen in a proportion of

    these dogs. An increase in centrilobular fibrocytes was seen in one
    male dog at 180 ppm and three males at 500 ppm. Aggregates of
    pigmented Kupffer cells were observed in the livers of dogs of each
    sex in a dose-related incidence, including one male and one female at
    50 ppm. An increased incidence and degree of pigmented macrophages
    were seen in the spleens of male dogs at 180 and 500 ppm. The NOAEL
    was 50 ppm, equal to 1.6 mg/kg bw per day, on the basis of decreased
    body-weight gain, degenerated hepatocytes, and increases in
    centrilobular fibrocytes, spleen macrophages, alanine transaminase and
    alkaline phosphatase activities, and pigmented Kupffer cells at doses
    > 180 ppm (Smith  et al., 1993).

    (c)  Long-term toxicity and carcinogenicity

    Mice

         Groups of 49 or 50 male and female B6C3F1 mice were fed ziram
    (purity, 89%; containing 6.5% thiram, 2% other zinc salts, and 2%
    unidentified additional impurities) at concentrations of 0, 600, or
    1200 ppm (equal to 0, 120, or 200 mg/kg bw per day for males and 0,
    130, or 250 mg/kg bw per day for females) for 103 weeks. All animals
    were observed daily for clinical signs, and body weight and food
    consumption were recorded monthly. At termination, necropsies were
    performed on all animals, and selected organs and tissues from most
    animals were examined microscopically. The survival of treated mice
    was not adversely affected. The body-weight gain of male mice at 600
    and 1200 ppm and of female mice at 600 ppm was reduced, and food
    consumption was reduced in both males and females at 1200 ppm. The
    incidence of alveolar or bronchiolar adenomas was statistical
    significantly increased in female mice (2/50 controls, 5/49 at the low
    dose, 10/50 at the high dose), and the combined incidence of alveolar
    and bronchiolar adenomas and carcinomas in female mice showed a
    statistically significant, positive trend. The incidence in males at
    1200 ppm was significantly higher than that in the controls (4/50
    controls, 6/49 at the low dose, 11/50 at the high dose). Pulmonary
    adenomatous hyperplasia consistent with chronic Sendai viral infection
    was observed in control and treated animals. The authors concluded
    that any interpretation of the increase in lung tumours is complicated
    by the presence of intercurrent viral infection (National Toxicology
    Program, 1983).

         Groups of 50 male and 50 female Crl:CD-1(ICR)BR mice were fed
    ziram (purity, 98.7%) in the diet to give concentrations of 0, 25, 75,
    225, or 675 ppm (equal to 0, 3, 9, 27, or 82 mg/kg bw per day for
    males and 0, 4, 11, 33, or 95 mg/kg bw per day for females) for 80
    weeks. The concentrations of ziram given to the groups at 25 and
    75 ppm were greater than the nominal concentration in order to
    compensate for losses during storage. Statistically significant
    reductions in body-weight gain and food intake were seen in males and
    females receiving 225 or 675 ppm. Dose-related, statistically

    significant decreases in the absolute brain weight of males receiving
    225 or 675 ppm and the brain weight adjusted for final body weight
    of females receiving 75, 225, or 675 ppm were noted. Macroscopic
    examination of all animals that died or were killed at termination
    revealed increased incidences of reduced adipose tissue in males
    that died, irregular cortical scarring of the kidneys in males at
    terminal sacrifice, brown kidneys in males, and roughened and white
    forestomachs in females, all receiving the highest dose. An increased
    incidence of centrilobular and/or generalized hepatocellular
    enlargement was seen in all treated groups, and an increased incidence
    of urinary bladder epithelial hyperplasia was seen in males and
    females receiving 675 ppm and in males at 225 ppm. No treatment-
    related neoplastic effects were seen. The NOAEL was 25 ppm, equal
    to 3 mg/kg bw per day, on the basis of reduced brain weight and
    hepatocellular enlargement at doses > 75 ppm (Powell  et al., 1994a).

    Rats

         Groups of 25 male and 25 female weanling rats were fed ziram at
    concentrations of 0, 25, 250, or 2500 ppm (equivalent to 0, 1.3, 13,
    or 125 mg/kg bw per day) for two years. The growth rate and life span
    were normal in all groups. Neurological changes were observed at
    2500 ppm, but no cystic lesions were seen in the brain  post mortem.
    No neurological changes were seen at the lower doses. In some males,
    the testes were atrophied and there was a slight indication of thyroid
    hyperplasia, notably at 2500 ppm. There was no increase in tumour
    incidence in the treated animals (Annex I, reference 4).

         Groups of 50 Fischer 344/N rats were fed ziram (purity, 89%;
    containing 6.5% thiram, 2% other zinc salts, and 2% unidentified
    additional impurities) at concentrations of 0, 300, or 600 ppm (equal
    to 0, 11, or 22 mg/kg bw per day for males and 0, 13, or 26 mg/kg bw
    per day for females) for 103 weeks. All animals were observed daily
    for clinical signs, and body weights and food consumption were
    recorded monthly. At termination, necropsies were performed on all
    animals, and selected organs and tissues from most animals were
    examined microscopically. The survival, body weight, and food
    consumption of treated rats were not adversely affected. C-Cell
    carcinomas of the thyroid occurred in male rats, with a statistically
    significant, positive trend ( p < 0.01); the incidence among animals
    at 600 ppm was significantly greater than that in controls (0/50
    controls, 2/49 at the low dose, 7/49 at the high dose). The combined
    incidence of C-cell adenomas and carcinomas in males also showed a
    statistically significant, positive trend (4/50 controls, 9/49 at the
    low dose, 12/49 at the high dose). No significant histopathological
    changes were found in the follicular cells. There was no NOAEL, since
    the combined incidence of C-cell adenomas and carcinomas of the
    thyroid in males showed a statistically significant, positive trend at
    300 ppm, the lowest dose tested (National Toxicology Program, 1983).

         In a study of toxicity, involving groups of 20 CD(SD)BR rats of
    each sex, and carcinogenicity, involving groups of 50 rats of each
    sex, the animals were fed diets containing ziram (purity, 98.7%)
    providing concentrations of 0, 60, 180, or 540 ppm (equal to 0,
    3.0/2.5, 9.1/7.7, or 27/24 mg/kg bw per day for males and 0, 3.9/3.4,
    12/10, or 38/35 mg/kg bw per day for females), for 12 or 24 months.
    Clinical signs, body weight, and food consumption were observed
    weekly, and ophthalmoscopic, haematological, biochemical, and urinary
    investigations were performed at certain intervals. At termination,
    the organ weights, haematological parameters, and the results
    of clinical chemical, urinary, and macroscopic and microscopic
    examinations were recorded. Body-weight gain, food intake, and food
    conversion ratios were reduced in a dose-dependent fashion in male and
    female rats at 180 and 540 ppm. The erythrocyte count was reduced
    dose-dependently in animals of each sex at 60, 180, and 540 ppm, and a
    dose-dependent decrease in thromboplastin time was observed in males
    at all three doses. At 180 and 540 ppm, packed cell volume and
    haemoglobin were reduced in females and thromboplastin time in males.
    Tri-iodothyronine, thyroxine, albumin, total protein, and calcium
    levels were reduced and that of blood urea nitrogen was increased
    at 180 and 540 ppm in animals of each sex. Haemangiomata in the
    mesenteric lymph nodes, hypertrophy with vacuolation of the adrenals,
    and C-cell hyperplasia of the thyroids were observed in males at
    540 ppm. In females, cortical cystic degeneration of the adrenals was
    seen at 540 ppm. Dose-dependent adipose replacement, narrowing of the
    myofibres in skeletal muscle, haemosiderosis in the spleen, adipose
    tissue replacement in the pancreas, prominent ultimobranchial cysts in
    the thyroids, and epithelial hyperplasia and subepithelial oedema in
    the nonglandular part of the stomach were observed in animals at 60,
    180, or 540 ppm. There was no NOAEL, since decreased erythrocyte
    counts and thromboplastin time, haemosiderosis in the spleen,
    ultimobranchial cysts in the thyroids, and epithelial hyperplasia in
    the stomach were seen at 60 ppm, the lowest dose tested (Powell
     et al., 1994b).

    (d)  Reproductive toxicity

    Mice

         Groups of 10 CH3 or AK male mice were given ziram (purity
    unspecified) by gavage at concentrations of 0 or 0.2 mg% (equivalent
    to 0 or 0.02 mg/kg bw per day) for 21 days before mating with
    untreated females of the same strain. The males were then killed for
    histopathological examination. Some of the female mice were killed on
    day 17 of gestation in order to examine the numbers of corpora lutea,
    nidation places, and dead and live embryos; the other females were
    kept alive to breed. Newborn mice were immediately sacrificed and
    stained with alizarin for examination of skeletal abnormalities. Ziram
    increased the incidence of sterility: only 20% of the C3H and 80% of
    the AK females, but all of the controls, were fertilized. The mean

    number of embryos was reduced from 11.1 in controls to 7.5 in the CH3
    mice and from 11.2 in controls to 9.1 in the AK mice. The calculated
    embryonic mortality was 4.5% in the CH3 strain and 6.3% in the AK
    strain (Abbota's formula). When the numbers of corpora lutea and of
    live and resorbed embryos were included, embryonic mortality rates of
    27% for C3H mice and 32% AK mice were found (method of dominant
    lethals). Analysis of the testes showed atrophy of the seminiferous
    tubules and impaired spermatogenesis. Examination of meiotic
    chromosomes in diakinesis showed the presence of tetravalent and
    univalent chromosomes and frequent pyknosis, demonstrating the
    clastogenic effect of ziram on future gametes. The offspring of both
    CH3 and AK strains had anomalies of the spine, cyphosis, scoliosis,
    sternum ossification failure, branching ribs (some of which were
    incompletely ossified), assymetry of the cranium, microcephalus, and
    eviscerations. The bone dimensions of the CH3 mice were greater than
    those of the controls. There was no NOAEL for male fertility, because
    of decreased fertility, atrophy of seminiferous tubules, and impaired
    spermatogenesis, or for developmental toxicity, because anomalies of
    the spine, cyphosis, scoliosis, and sternum ossification failure were
    seen in the offspring at 0.02 mg/kg bw per day, the lowest dose tested
    (Cilievici  et al., 1983). In the absence of important information on
    the design of the study, this report was not considered in establishing
    the ADI.

         Groups of six Swiss albino male mice, aged 12-14 weeks, received
    ziram (purity unspecified), dissolved in 5% dimethyl sulfoxide,
    intraperitoneally as single doses of 0, 50, or 100 mg/kg bw or
    repeated doses of 25 mg/kg bw per day for five days. The mice were
    killed one month after the treatment. The epididymides were isolated,
    minced in 4 ml NaCl, and dispersed by slow aspiration. The tissue
    particles were filtered out, and smears were made on clean, dry slides
    for microscopy. A minimum of 2000 sperm was scored per animal, and the
    abnormalities were classified. The frequency of abnormal sperm was
    1.6% in the controls, 5.6% in animals at 50 mg/kg bw, 8.2% in those
    at 100 mg/kg bw, and 8.4% following repeated doses of 25 mg/kg bw
    per day. The abnormalities included sperm with acrosomes bent
    upwards, acrosomes bent downwards, and without acrosomes. Many head
    abnormalities, including double heads, banana heads, amorphous heads,
    microcephaly, and macrocephaly, were found, and a high frequency of
    coiled sperm was seen. The abnormalities observed were considered to
    be due either to changes in the genes responsible for spermatogenesis
    or to changes in differentiation during gene expression involving
    post-transcriptional stages and thereafter in the translation of the
    genetic message. There was no NOAEL, as sperm abnormalities were seen
    at 25 mg/kg bw per day, the lowest dose tested (Hemavathi & Rahiman,
    1993).

    Rats

         In a two-generation study of reproductive and developmental
    neurotoxicity, groups of 30 male and 30 female Crl:CD BR Sprague-
    Dawley rats were fed ziram at concentrations of 0, 72, 210, or 540
    ppm, equal to 0, 3, 10, or 25 mg/kg bw per day for males and 0, 5, 13,
    or 32 mg/kg bw per day for females. The parental animals received the
    diets from about six weeks of age for the F0 generation and on day 22
    postnatally for the F1 generation, for at least 70 days before mating
    and throughout all subsequent phases of the study until termination of
    the generation. All animals were observed twice daily for appearance
    and behaviour. Body weights and food consumption were recorded at
    appropriate intervals. All females were allowed to deliver and rear
    their pups to weaning on lactation day 21. Offspring from the pairing
    of the F0 animals (30 pups of each sex per group) were selected to
    constitute the F1 generation. Thirty F2 pups of each sex per group
    were selected for testing of developmental landmarks and behaviour,
    neuropathological examination, and brain weight measurement. Surplus
    F1 pups were killed and necropsied on postnatal day 28, and surplus
    F2 pups were killed and necropsied on postnatal day 22. The F0 and
    F1 parental animals and selected F2 pups that were not allocated for
    measurements underwent detailed gross necropsy; and the weights of
    the brain, kidneys, liver, pituitary gland, ovaries, or testes and
    epididymides (F0 and F1 only) were recorded. Designated tissues from
    the controls and from F0 and F1 parental animals at 540 ppm and F2
    pups selected for neuropathological evaluation were evaluated for
    histopathological changes.

         Reproductive parameters (fertility, mating, and days between
    pairing and coitus, gestation, and parturition) in the F0 and F1
    generations were not adversely affected by concentrations of 72, 210,
    or 540 ppm ziram. All F0 and F1 parental animals survived to the
    scheduled necropsies, and no adverse clinical signs attributable to
    treatment were observed. The mean body weights and body-weight gains
    of F0 males at 540 ppm were reduced early in the treatment period,
    and the mean body weights and body-weight gains of F1 males at
    540 ppm were generally reduced. The mean body weights and body-weight
    gains of F0 and F1 females at 540 ppm were generally reduced before
    breeding, during gestation and lactation, and after weaning. No adverse
    effects were seen on the body weights or body-weight gains of animals
    in either generation at 72 or 210 ppm. The food consumption of F0 and
    F1 males at 540 ppm was generally reduced throughout each generation.
    The food consumption of F0 and F1 females at 540 ppm was reduced
    before breeding, during gestation and lactation, and after weaning of
    the F0 and F2 generations. No adverse effects on food consumption
    were observed in males or females given ziram at concentrations of 72
    and 210 ppm in either generation. No treatment-related, macroscopic 
    internal changes were found in treated F0 or F1 animals, and no
    adverse effects on organ weights were observed at any dose. No
    microscopic lesions attributable to treatment were observed in 

    tissues from animals at 540 ppm on histopathological examination.
    Microscopic examination of gross lesions seen at the scheduled
    necropsies of animals at 540 ppm did not reveal any adverse effects.

         The mean body weights of F1 and F2 pups in the litters of
    animals at 540 ppm were slightly reduced (usually statistically
    significantly) during lactation and throughout the remainder of the
    study until postnatal day 70 (selected F2 pups). The F1 and F2 pup
    sex ratios, live litter sizes, number of dead pups on lactation day 0,
    viability indices, general physical condition, and brain weight
    (selected F2 pups) were not adversely affected by parental treatment
    at any concentration. The findings at necropsy of F1 and F2 pups
    that died or were killed at the scheduled postnatal necropsies did not
    suggest any correlation with parental treatment. Various indicators
    of physical and functional development and behavioural responses
    in the selected F2 pups were comparable to those in controls.
    Neuropathological examinations on postnatal days 11 and 70 showed no
    gross or microscopic treatment-related lesions in the F2 pups. The
    NOAEL for maternal toxicity was 210 ppm, equal to 10 mg/kg bw per day,
    on the basis of reduced food consumption and body-weight gain; that
    for neonatal toxicity was 210 ppm, equal to 10 mg/kg bw per day, on
    the basis of reduced body weight; and that for reproductive and
    developmental neurotoxicity was 540 ppm, equal to 25 mg/kg bw per day
    (Nemec, 1996).

    (e)  Developmental toxicity

    Rats

         In a preliminary study, groups of 10 pregnant Crl:CD(SD)BR rats
    were given ziram (purity, 98.9%) by gavage at doses of 0, 5, 20, or
    80 mg/kg bw per day on days 6-15 of gestation. Dams were observed for
    clinical symptoms, body weight, and food and water consumption, and
    were killed on day 20 and examined for congenital abnormalities and
    macroscopic pathological changes in organs. The ovaries and uteri
    were examined to determine the number of corpora lutea, the number
    and distribution of live young, and the number of early and late
    embryo-fetal deaths and fetal abnormalities. Live young were examined
    externally and weighed; no further examinations were done. Dams showed
    body-weight loss up to day 8, decreased food intake, and increased
    water intake at doses of 5, 20, and 80 mg/kg bw per day. Hair loss
    was observed in dams at 20 and 80 mg/kg bw per day. Salivation and
    increased postimplantation losses were seen in dams at 80 mg/kg bw per
    day. Reduced litter and fetal weights were seen at 20 and 80 mg/kg bw
    per day. The dose range was considered to be too high for the main
    study (Smith  et al., 1990).

         Groups of 25 pregnant Crl:CD(SD)BR rats were given ziram (purity,
    98.9%) by gavage at doses of 0, 1, 4, 16, or 64 mg/kg bw per day on
    days 6-15 of gestation and were then observed for clinical symptoms,
    body weight, and food and water consumption. On day 20, the animals
    were killed and examined for congenital abnormalities and macroscopic
    pathological changes in organs. The ovaries and uteri were examined to
    determine the number of corpora lutea, the number and distribution of
    live young, and the number of early and late embryo-fetal deaths and
    fetal abnormalities. Live young were examined externally and weighed.
    One-half of the fetuses were subsequently examined for visceral and
    the other half for skeletal abnormalities. Dams showed dose-related
    body-weight loss up to day 8, followed by retarded weight gain
    throughout treatment; decreased food consumption and increased water
    consumption and salivation were seen at 16 and 64 mg/kg bw per day.
    Pre- and postimplantation losses were unaffected by treatment. At
    4 mg/kg bw per day, only marginally increased water consumption was
    observed during treatment. Significantly lower litter and fetal
    weights were seen at 64 mg/kg bw per day; litter size and the
    incidences of skeletal and visceral anomalies were unaffected by
    treatment. The NOAELs were 4 mg/kg bw per day for maternal toxicity,
    on the basis of decreased body weight and food intake, increased water
    intake, and salivation at doses > 16 mg/kg bw per day, and 16 mg/kg
    bw per day for developmental toxicity, on the basis of decreased
    litter and fetal weight at 64 mg/kg bw per day. No teratogenicity was
    seen (Smith  et al., 1990).

    Rabbits

         In a preliminary study, groups of five pregnant New Zealand white
    rabbits were given ziram (purity, 98.0%) by gavage at doses of 0, 5,
    10, or 20 mg/kg bw per day on days 7-19 of gestation. All animals
    were observed for clinical symptoms, body weight, and food consumption.
    On day 28, the animals were killed, dissected, and examined
    macroscopically for abnormalities. The ovaries and uteri were removed
    and examined to determine the gravid uterine weight, number of corpora
    lutea, and the distribution of live young and of early and late
    embryo-fetal deaths. Live young were examined externally for
    abnormalities and weighed. Two animals at 20 mg/kg bw per day died,
    and one aborted. Treatment had no effect on the clinical condition or
    findings at necropsy for animals that survived to term. Marked
    reductions in weight gain and food intake, particularly at the start
    of treatment, were observed in animals at 20 mg/kg bw per day. Slight,
    temporary reductions in weight gain and food intake were also observed
    at 10 mg/kg bw per day. At 20 mg/kg bw per day, postimplantation
    losses were increased and litter size, litter weight, and fetal weight
    were reduced. Because maternal toxicity was observed at 20 mg/kg bw
    per day, the high dose for the main study was < 20 mg/kg bw per day
    (Barker, 1985).

         Groups of 16 pregnant New Zealand white rabbits were given ziram
    (purity, 98.1%) by gavage at doses of 0, 3, 7.5, or 15 mg/kg bw per
    day on days 7-19 of gestation. All animals were observed for clinical
    symptoms, body weight, and food consumption. On day 28, the animals
    were killed, dissected, and examined macroscopically for abnormalities.
    The ovaries and uteri were removed and examined to determine the gravid
    uterine weight, the number of corpora lutea, and the distribution of
    live young and of early and late embryo-fetal deaths. Live fetuses were
    weighed and examined for abnormalities before alizarin staining.
    Significant reductions in maternal body-weight gain and food intake
    were observed from the start of treatment at 15 mg/kg bw per day;
    slight reductions in weight gain and food intake were also observed
    during the early part of the treatment period in animals at 7.5 mg/kg
    bw per day. At 15 mg/kg bw per day, postimplantation loss was slightly
    increased and litter size, litter weight, fetal weight, and the
    crown-rump length were reduced. There was no teratogenic effect. The
    NOAEL for maternal and developmental toxicity was 7.5 mg/kg bw per day,
    on the basis of decreased body-weight gain and food intake, increased
    postimplantation loss, and reduced litter size, litter weight, fetal
    weight, and crown-rump length at 15 mg/kg bw per day (Barker, 1986).

    (f)  Genotoxicity

         The results of studies on the genotoxicity of ziram are
    summarized in Table 2. Ziram is mutagenic in bacteria. It induced
    chromosomal aberrations in some, but not all, studies with cultured
    mammalian cells and did not induce unscheduled DNA synthesis in
    hepatocytes.  In vivo, ziram induced DNA single-strand breaks in the
    livers of rats but not mice. Chromosomal aberrations were not
    induced in mice  in vivo in bone-marrow cells or spermatogonia, and
    micronuclei were not induced in bone-marrow cells or peripheral
    erythrocytes. Studies for clastogenicity have not been conducted in
    rats  in vivo. Consequently, the Meeting was unable to reach a
    conclusion about the genotoxicity of ziram.
        Table 2.  Results tests for the genotoxicity of ziram

                                                                                                                                      

    End-point                   Test system                  Concentration                Purity    Results       Reference
                                                                                            (%)
                                                                                                                                      

    In vitro

    Reverse mutation            S. typhimurium               < 100 µg/plate               NR        Positivea     Hedenstedt
                                TA98, TA100, TA1535,                                                at 10, 50,    et al. (1979)
                                TA1537, TA1538                                                      100 µg/
                                                                                                    plate

    Reverse mutation            S. typhimurium               < 50 µg/plate                98.5      Positiveb     Jones et al.
                                TA98, TA100, TA1535,                                                at 15, 50     (1990)
                                TA1537, TA1538                                                      µg/plate

    Reverse mutation            S. typhimurium               < 90 µg/plate                98.5      Positivea     Crebelli et al.
                                TA98, TA100, TA102, TA1537,                                         at 7.5-90     (1992)
                                TA1950, TA1975, TA1535                                              µg/plate

    Reverse mutation            S. typhimurium               15-90 µg/plate               NR        Positiveb     Franekic et al.
                                TA98, TA100, TA102,                                                               (1994)
                                TA104, TA1535, TA1538

    Chromosomal                 Saccharomyces                5-50 µg/ml                   NR        Negative      Franekic et al.
    malsegregation              cerevisiae                                                                        (1994)

    Cell division               Shallot root-tip             0.5-50 µg/ml                 NR        Positive      Franekic et al.
                                cells                                                                             (1994)

    Chromosomal aberration      Chinese hamster              < 1.5 µg/ml                  98.5      Negative      Brooker &
                                ovary cells                                                                       Akhurst (1989)

    Chromosomal aberration      Chinese hamster              < 1.75 µg/ml                 86.2      Positivea     Gulati et al.
                                ovary cells                                                                       (1989)
                                                                                                                                      

    Table 2.  (Cont'd)

                                                                                                                                      

    End-point                   Test system                  Concentration                Purity    Results       Reference
                                                                                            (%)
                                                                                                                                      

    Chromosomal aberration      Chinese hamster              < 10 µg/ml                   98.5      Positiveb     Mosesso et al.
                                ovary cells                                                                       (1994)

    Chromosomal aberration      Chinese hamster              < 2.15 µg/ml                 98.5      Positiveb     Mosesso et al.
                                epithelial liver cells                                                            (1994)

    Unscheduled DNA synthesis   Rat hepatocytes              < 100 µg/ml                  98.5      Negative      Proudlock (1989)

    In vivo

    Chromosomal aberration      Male and female NMRI         40, 120, 400 mg/kg bw        98.4      Negative      Völkner (1992a)
                                mice, bone-marrow cells

    Chromosomal aberration      Male NMRI mice, germ cells   20, 67, 200 mg/kg bw         98.4      Negative      Völkner (1992b)

    Micronucleus formation      Male and female Crl:CD-1     3.8, 11, 34, 101 mg/kg bw    98.8      Negative      Proudlock &
                                mice, erythrocytes                                                                Taylor (1992)

    Micronucleus formation      Male and female B6C3F1       2.5, 5.0, 10, 20 mg/kg bw    98.5      Negative      Crebelli et al.
                                mice, bone-marrow cells                                                           (1992)

    Single-strand DNA breaks    Male Swiss mice,             13, 25, 50, 100 mg/kg bw     NR        Negative      Scarabelli et al.
                                liver cells                                                                       (1993)

    Single-strand DNA breaks    Male Wistar rats,            13, 25, 50, 100 mg/kg bw     NR        Positive      Scarabelli et al.
                                liver cells                                                                       (1993)
                                                                                                                                      

    NR, Not reported
    a    In the presence or absence of metabolic activation
    b    In the presence of metabolic activation
        (g)  Special studies

    (i)  Dermal and ocular irritation and dermal sensitization

    Rabbits

         The irritancy of ziram to the skin was tested in New Zealand
    white rabbits. About 24 h before application of the test substance,
    hair was removed from the dorsal lumbar region. Ziram (purity, 98.5%)
    was applied at a dose of 0.5 g under a 2.5-cm2 gauze pad moistened
    with 0.5 ml distilled water to one skin site on each of six animals,
    and each treatment site was occluded with an elastic adhesive dressing
    for 4 h. The animals were not restrained during the exposure and were
    returned to their cages. At the end of treatment, the semiocclusive
    dressing and gauze pads were removed and the treatment sites were
    washed with water to remove any residual test substance. The treated
    skin was examined for erythema and oedema on days 1, 2, 3, and 4. None
    of the animals showed a response to treatment (Liggett & McRae,
    1990a).

         The irritancy of ziram to the eye was tested in New Zealand white
    rabbits. The eyes of the animals were examined before instillation of
    80 mg ziram (purity, 89.5%) in 0.1 ml into the lower everted lid of
    one eye. Ocular lesions were graded and scored 1 and 24 h after
    instillation. As the first rabbit had a severe ocular reaction
    (irridal inflammation and opacity), the study was terminated on humane
    grounds (Liggett & McRae, 1990b).

    Guinea-pigs

         The skin sensitizing potential of ziram (purity, 99.0%) was
    examined in 30 adult female Dunkin-Hartley guinea-pigs. After
    induction by epicutaneous applications of the test substance (25% w/w
    in corn oil) and challenge with 10, 5, or 1% (w/w) in corn oil, six
    guinea-pigs showed a positive skin response (grade 2 or more) to the
    10% concentration. Five of these animals also reacted positively to
    the 5% dose and three to the 1% concentration. No positive reactions
    were observed in the control animals. Thus, a sensitization rate of
    30% was obtained. The author considered that ziram has moderate
    sensitizing properties (Daamen, 1988).

    (ii)  Neurotoxicity

    Rats

         The neurotoxicity of repeated doses of ziram was studied in
    groups of 10 Crl:CD(SD)BR rats fed diets containing ziram (purity,
    97.9%) providing concentrations of 0, 72, 210, or 540 ppm, equal to 0,
    5, 14, or 34 mg/kg bw per day for males and 0, 6, 16, or 40 mg/kg bw

    per day for females, for 91 days. Five animals of each sex per group
    were allocated for evaluation of neurotoxic esterase and five for
    evaluation of neuropathological changes. Viability, clinical signs,
    body weight, and food consumption were recorded for all animals.
    The results of a functional observational battery (home cage,
    handling, open field, sensorimotor, neuromuscular, and physiological
    observations) and of tests for total and ambulatory motor activity
    were recorded for all animals during week 3, 7, and 12 of exposure.
    The body weights and food consumption of male and female rats at
    540 ppm were reduced, but no treatment-related effects indicative of
    neurotoxicity were apparent. Brain neurotoxic esterase activity was
    47% lower than that in controls in males and 38% lower in females at
    540 ppm. The NOAEL for brain neurotoxic esterase inhibition was
    210 ppm, equal to 14 mg/kg bw per day (Nemec, 1993).

         The neurotoxicity of a single dose of ziram was studied in groups
    of 12-16 Crl:CD(SD)BR rats given single doses of 0, 15, 300, or
    600 mg/kg bw ziram (purity, 97.8%). Viability, clinical signs, and
    body weight were recorded for all animals. The results of a functional
    observational battery (home cage, handling, open field, sensorimotor,
    neuromuscular, and physiological observations) and tests for total and
    ambulatory motor activity were recorded for all animals before and 4 h
    after treatment and on days 7 and 14. Five controls and five animals
    at 600 mg/kg bw were selected for evaluation of neuropathological
    changes. Four males and seven females at 600 mg/kg bw and one female
    at 300 mg/kg bw died. At these doses, body weight was reduced, and
    several treatment-related clinical signs (e.g. cyanosis, hypothermia,
    enophthalmus, unkempt appearance, gait alterations, hypoactivity,
    ptosis, and abdomal respiration) were observed. Remarkable differences
    from the controls were seen in the functional observational battery
    for animals at 300 and 600 mg/kg bw. Most of the responses were
    observed 4 h after treatment (e.g. altered posture, palpebra closure,
    and faecal consistency) or daily during the first week after dosing
    (e.g. lacrimation, salivation, changes in fur appearance, altered
    palpebral closure, changes in respiratory rate, and altered gait).
    Ambulatory and total motor activity counts were reduced in males and
    females at 300 and 600 mg/kg bw. No treatment-related microscopic
    lesions were observed in the central and peripheral nervous tissues
    examined. The NOAEL for neurotoxicity was 15 mg/kg bw, on the basis of
    mortality, reduced body weight, ambulatory, and total motor activity,
    and clinical signs at doses > 300 mg/kg bw (Lamb, 1994).

    3.  Observations in humans

         The ability of ziram to induce chromosomal aberrations in
    peripheral leukocytes was studied in four men and five women who had
    been exposed for three to five years to ziram at a concentration of
    2-4 mg/m3 air. The control group consisted of three women and one
    man. The exposed group had 5.9% cells with aberrations and the
    controls, 0.75% (Pilinskaya, 1970; Annex I, reference 15).

    Comments

         In experiments with 14C-labelled ziram in rats, elimination was
    essentially complete within 48 h. Excretion occurred mainly in expired
    air, urine, and faeces. Less than 2% of the administered dose remained
    in the tissues. The biotransformation of ziram has not been studied
    in rodents. In goats, it is metabolized at least in part via a
    single-carbon pathway, which results in extensive radiolabelling of
    natural products.

         The primary effects of short- and long-term treatment with ziram
    in mice, rats, and dogs were on the liver, thyroid gland, and testis.
    The hepatic effects were increased liver weight, degeneration, and
    focal-cell necrosis. Effects in the thyroid were C-cell hyperplasia
    and carcinomas, and that on the testes was sterility.

         Ziram had moderate acute oral toxicity in rats and rabbits (LD50
    = 200-400 mg/kg bw). WHO has classified ziram as 'slightly hazardous'
    (WHO, 1996).

         In a four-week study of toxicity in mice given dietary
    concentrations of 0, 3000, 4000, or 5000 ppm, an NOAEL was not
    identified. Reductions in body weight, food intake, efficiency of food
    use, and brain and heart weight occurred at all doses.

         In a 13-week study of toxicity in mice given dietary
    concentrations of 0, 100, 300, 900, or 2700 ppm, the NOAEL was
    100 ppm, equal to 15 mg/kg bw per day, on the basis of lowered spleen
    weight at higher doses. At 900 and 2700 ppm, the number of corpora
    lutea was reduced, which was consistent with cellular changes in the
    uterus.

         In two four-week studies of toxicity in rats either given diets
    providing doses of 0, 100, 500, 2500, or 5000 ppm or treated by gavage
    with 0, 3, 15 or 100 mg/kg bw per day, the NOAEL was 3 mg/kg bw, on
    the basis of degenerative liver changes. At 100 mg/kg bw, degenerative
    changes in the kidneys and reductions in body weight, food intake,
    efficiency of food use, and absolute weights of the liver, pituitary,
    testes, brain, and uterus were seen.

         In a 13-week study of toxicity in which rats received dietary
    levels of 0, 100, 300, or 1000 ppm, the NOAEL was 100 ppm, equal to
    7.4 mg/kg bw per day, on the basis of reduced body-weight gain, food
    intake, and food use and increased brain and spleen weights at higher
    doses.

         In a four-week study of toxicity in dogs given diets providing
    doses of 0, 1000, 2000, or 5000 ppm, an NOAEL was not identified.
    Increased liver weight occurred at all doses. At 2000 ppm, convulsive
    episodes were observed.

         In a 13-week study of toxicity in dogs given diets providing 0,
    100, 300, or 1000 ppm, the NOAEL was 100 ppm, equal to 4.1 mg/kg bw
    per day, on the basis of increased liver weight, focal liver necrosis,
    pigment in Kupffer cells, activated partial thromboplastin time, and
    elevated cholesterol level at higher doses.

         In a one-year study of toxicity in which dogs were fed diets
    providing doses of 0, 50, 180, or 500 ppm, the NOAEL was 50 ppm, equal
    to 1.6 mg/kg bw per day, on the basis of reductions in body-weight
    gain, degeneration of hepatocytes, and increased activity of alanine
    and aspartate aminotransferases and alkaline phosphatase at doses
    > 185 ppm. At 500 ppm, single liver-cell necrosis was observed, and
    the liver weight and cholesterol values were increased; albumin values
    were reduced. Inflammatory cell infiltration around the hepatic vein
    and its branches and aggregates of pigmented Kupffer cells were
    observed in the liver.

         Two long-term studies of toxicity and carcinogenicity in mice
    have been reported. One was considered inadequate for evaluating
    the carcinogenicity of ziram. In the other, mice were given diets
    providing doses of 0, 25, 75, 220, or 680 ppm for 80 weeks. The NOAEL
    was 25 ppm, equal to 3 mg/kg bw per day, on the basis of reduced brain
    weight at doses > 75 ppm. There was no evidence of carcinogenicity.

         In a two-year study of toxicity and carcinogenicity in rats at
    dietary concentrations of 0, 25, 250, or 2500 ppm, the NOAEL was
    250 ppm, equivalent to 12 mg/kg bw per day, on the basis of testicular
    atrophy and thyroid hyperplasia at 2500 ppm. There was no evidence of
    carcinogenicity.

         In a two-year study of toxicity and carcinogenicity in Fischer
    344 rats with dietary concentrations of 0, 300, or 600 ppm, an NOAEL
    was not identified, since the combined incidence of C-cell adenoma
    and carcinoma of the thyroid in males showed a positive trend. This
    finding was considered to represent an extension of the known toxicity
    of the compound to the thyroid, to which the rat is particularly
    sensitive, and not to indicate carcinogenic potential for humans.

         In a study of toxicity and carcinogenicity in CD rats treated
    with 0, 60, 180, or 540 ppm in the diet for 12-24 months, an NOAEL was
    not identified because dose-related changes in organ weights and
    histopathological and haematological changes were observed at 60 ppm,
    equal to 2.5 mg/kg per day. Other effects included reduced body
    weight, erythrocyte count, and triiodothyronine and thyroxine
    activity. Cysts in the thyroids, epithelial hyperplasia, hypertrophy
    with vacuolation, cortical cystic degeneration of the adrenals, and
    C-cell hyperplasia of the thyroid were also demonstrated. The tumour
    incidence was not increased.

         In a study of sperm quality in mice treated intraperitoneally
    with ziram at a single dose of 0, 50, or 100 mg/kg bw or repeated
    doses of 25 mg/kg bw per day for five days, severe morphological
    abnormalities were observed. The frequency of abnormal sperm was 1.6%
    in the controls, 5.6% at 50 mg/kg bw, 8.2% at 100 mg/kg bw, and 8.4%
    after repeated doses of 25 mg/kg bw.

         In a two-generation study of reproductive toxicity and
    developmental neurotoxicity, rats were fed ziram at concentrations of
    0, 72, 210, or 540 ppm. The NOAEL for maternal toxicity was 210 ppm,
    equal to 10 mg/kg bw per day, on the basis of reduced food consumption
    and body-weight gain at 540 ppm. The NOAEL for neonatal toxicity was
    210 ppm, equal to 10 mg/kg bw per day, on the basis of reduced body
    weight gain at 540 ppm. The NOAEL for reproductive toxicity and
    developmental neurotoxicity was 540 ppm, equal to 25 mg/kg bw per day.

         In a study of developmental toxicity, rats were given ziram at 0,
    1, 4, 16, or 64 mg/kg bw per day on days 6-15 of gestation. The NOAEL
    for maternal toxicity was 4 mg/kg bw per day for maternal toxicity, on
    the basis of decreased body-weight gain and food intake and increased
    water intake and salivation at doses > 16 mg/kg bw per day. The
    NOAEL for developmental toxicity was 16 mg/kg bw per day, on the basis
    of decreased litter weight and fetal weight at 64 mg/kg bw per day. No
    teratogenicity was seen.

         In a study of developmental toxicity in rabbits given ziram at
    doses of 0, 3, 7.5, or 15 mg/kg bw per day on days 7-19 of gestation,
    the NOAEL for maternal toxicity and developmental toxicity was 7.5
    mg/kg bw per day, on the basis of decreased body-weight gain and food
    intake in the dams and post-implantation loss, reduced litter size,
    litter weight, fetal weight, and crown-rump length at 15 mg/kg bw per
    day. There was no evidence of teratogenicity.

         Ziram is mutagenic in bacteria. It induced chromosomal
    aberrations in some, but not all, studies with cultured mammalian
    cells but did not induce unscheduled DNA synthesis in hepatocytes.
     In vivo, ziram induced single-strand breaks in DNA in the livers of
    rats but not mice. Chromosomal aberrations were not induced in mice
     in vivo in bone-marrow cells or spermatogonia, and micronuclei were
    not induced in bone-marrow cells or peripheral erythrocytes. Studies
    for clastogenicity have not been conducted in rats  in vivo. In an
    old study of nine workers exposed for three to five years to ziram at
    a concentration of 2-4 mg/m3 air, the percentage of peripheral
    leukocytes with chromosomal aberrations was 5.9%; in a control group,
    the percentage was 0.75%. The Meeting was unable to reach a conclusion
    about the genotoxicity of ziram.

         Ziram caused severe ocular irritation but no dermal irritation in
    rabbits and moderate skin sensitization in guinea-pigs.

         In two studies of neurotoxicity in rats treated with single doses
    of 0, 15, 300, or 600 mg/kg bw or 0, 72, 210, or 540 ppm for 91 days,
    behavioural effects indicative of neurotoxicity were apparent after
    the single high doses but not after repeated dosing at a lower level.
    The NOAEL was 210 ppm, equal to 14 mg/kg bw per day, on the basis of
    reduced body weight and food consumption and inhibition of brain
    neurotoxic esterase activity at 540 ppm.

         An ADI of 0-0.003 mg/kg bw was established on the basis of
    long-term toxicity in the rat. In this study, effects were seen at all
    doses, the LOAEL being 60 ppm, equal to 2.5 mg/kg bw per day. In view
    of the absence of an NOAEL, a safety factor of 1000 was used. The
    NOAEL of 1.6 mg/kg bw per day observed in a long-term study of
    toxicity in dogs supported this ADI, which served as the basis for the
    group ADI that was established for ziram alone or in combination with
    ferbam.

    Toxicological evaluation

    Levels that cause no toxic effect

         Mouse:    25 ppm, equal to 3 mg/kg bw per day (80-week study of
                   toxicity and carcinogenicity)

         Rat:      NOAEL could not be determined: lowest effective dose,
                   60 ppm, equal to 2.5 mg/kg bw per day (12-24-month
                   study of toxicity, various effects)

                   100 ppm, equal to 7.4 mg/kg bw per day (13-week study
                   of toxicity)

                   250 ppm, equivalent to 12 mg/kg bw per day per day
                   (two-year study of toxicity and carcinogenicity)

                   210 ppm, equal to 10 mg/kg bw per day (maternal
                   toxicity in a study of reproductive toxicity)

         Rabbit:   7.5 mg/kg bw per day (maternal toxicity and
                   embryotoxicity in a study of developmental toxicity)

         Dog:      50 ppm, equal to 1.6 mg/kg bw per day (one-year study
                   of toxicity)

                   100 ppm, equal to 4.1 mg/kg bw per day (13-week study
                   of toxicity)

    Estimate of acceptable daily intake for humans

         0-0.003 mg/kg bw (for ferbam and ziram)

    Studies that would provide information useful for continued evaluation
    of the compound

         1.   Further studies on long-term toxicity in the rat

         2.   Further studies on genotoxicity in rats

         3.   Further studies on male reproductive toxicity

         4.   Further observations in humans

        Toxicological criteria for estimating guidance values for dietary and non-dietary exposure to ziram

                                                                                                                                      

           Exposure               Relevant route, study type, species                        Results, remarks
                                                                                                                                      

    Short-term (1-7 days)      Oral, toxicity, rat                           LD50 = 270 mg/kg bw
                               Inhalation, toxicity, rat                     LC50 = 0.06 mg/litre
                               Dermal, irritation, rabbit                    Not irritating
                               Ocular, irritation, rabbit                    Severely irritating
                               Dermal, sensitization, guinea-pig             Moderately sensitizing

    Medium-term (1-26 weeks)   Repeated oral, 13 weeks, toxicity, mouse      NOAEL = 15 mg/kg bw per day, decreased spleen weight
                               Repeated oral, 4 weeks, toxicity, rat         NOAEL = 3 mg/kg bw per day, reduced body weight and
                                                                             food consumption, degenerative hepatic changes
                               Repeated oral, 13 weeks, toxicity, rat        NOAEL = 7.4 mg per kg bw per day, reduced body weight
                                                                             and food consumption, increased brain and spleen weight
                               Repeated oral, 13 weeks, toxicity, dog        NOAEL = 4.1 mg/kg bw per day, hepatic toxicity
                               Repeated oral, reproductive toxicity and      NOAEL = 25 mg/kg bw per day, reproductive toxicity
                               developmental neurotoxicity, rat              and development neurotoxicity
                                                                             NOAEL = 10 mg/kg bw per day, maternal and neonatal
                                                                             toxicity (reduced body weight)
                               Repeated oral, developmental toxicity, rat    NOAEL= 16 mg/kg bw per day, developmental toxicity
                                                                             (reduced fetal weight)
                                                                             NOAEL = 4 mg/kg bw per day, maternal toxicity
                                                                             (reduced body weight)
                               Repeated oral, developmental toxicity,        NOAEL = 7.5 mg/kg bw per day, developmental and
                               rabbit                                        maternal toxicity (reduced fetal and maternal weight)
                               Repeated oral, neurotoxicity, rat             NOAEL = 14 mg/kg bw per day, inhibition of
                                                                             neuropathy target esterase activity

    Long-term (> 1 year)       Repeated oral, 18 months, toxicity, mouse     NOAEL = 3 mg/kg bw per day, reduced brain weight and
                                                                             hepatic toxicity
                               Repeated oral, 2 years, toxicity and          No NOAEL; LOAEL = 2.5 mg/kg bw per day, haematological
                               carcinogenicity, rat                          toxicity and toxic effects on the thyroid
                               Repeated oral, 1 year, toxicity, dog          NOAEL = 1.6 mg/kg bw per day, reduced body weight and
                                                                             hepatic toxicity
                                                                                                                                      
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    See Also:
       Toxicological Abbreviations
       Ziram (ICSC)
       Ziram (FAO Meeting Report PL/1965/10/1)
       Ziram (FAO/PL:1967/M/11/1)
       Ziram (IARC Summary & Evaluation, Volume 53, 1991)