IPCS INCHEM Home

    PROPINEB

    EXPLANATION

         The toxicology of propineb was previously reviewed by the Joint
    Meeting in 1977, 1980, and in 1983 (Annex 1, FAO/WHO, 1978a, 1981a, &
    1984). A toxicological monograph was prepared by the Joint Meeting in
    1977 (Annex 1, FAO/WHO, 1978b) and a monograph addendum was prepared
    in 1980 (Annex 1, FAO/WHO, 1981b). Because of concern of the meeting
    in 1977 regarding the potential for thyrotoxicity and tumourigenicity
    of propylene thiourea (PTU), a breakdown product of propineb, the
    Meeting recommended a temporary ADI of 0.005 mg/kg b.w. Although no
    new toxicity data were provided in 1980, the Meeting took into account
    available data on ethylene thiourea (ETU), an analogous breakdown
    product of the ethylenebisdithiocarbamates. Further evaluation of
    propineb was postponed pending the submission of additional data.
    After examining the available data in 1983, the Meeting concluded that
    a complete evaluation was not possible. Adequate data for evaluation
    was required by 1985. Meanwhile, the temporary ADI was extended an
    additional 2 years to 1985.

         Data submitted for evaluation in 1985 consisted of long-term
    mouse and rat studies, mutagenicity studies, and a special study on
    the effect of PTU on DNA. In addition, data previously submitted for
    evaluation in 1983 were re-examined. These data included several
    studies on propineb (acute and subacute toxicity studies, short-term
    studies on thyroid function in rats, mutagenicity studies, and an
    oncogenicity study on mice) and on PTU (pharmacokinetic studies on
    rats and a long-term thyroid-function study on rats).

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, and excretion of propylene thiourea 

         Radiolabeled 14C-propylene thiourea was orally administered to
    groups of 5 male Sprague-Dawley rats at dosage levels of 0.5 to
    50 mg/kg. Additional groups of rats were given i.v. doses of 5 or
    10 mg/kg. Intraduodenal doses of 5 mg/kg were also administered to
    rats with bile duct fistulas. Radioactivity in urine, faeces, exhaled
    air, and bile was measured for up to 10 days. Radioactivity was also
    monitored in body tissues/organs for up to 10 days. Whole-body
    autoradiograms were prepared. Inasmuch as radioactivity was directly
    measured, with no prior extraction procedures, all results were for
    unchanged parent compound plus metabolites.

         Total recoveries of radioactivity in experiments ranged from 86%
    to 98%. More than 95% of orally-administered doses was absorbed.
    Absorption and excretion of radioactivity were rapid. At 48 hours,
    85-92% of orally- or i.v.-administered doses was recovered in the
    urine, 7-14% in the faeces, < 0.2% in exhaled air, and only 1-2%
    remained in the body. The elimination half-life for the first 48 hours
    was about 6 hours. After 5 days, the elimination half-life was 2-2.5
    days, which indicated a biphasic elimination pattern. Biliary
    excretion was also observed, as was evidence for entero-hepatic
    circulation. Two hours after oral doses of 5 mg/kg, radioactivity was
    essentially uniformly distributed in body tissues/organs, with the
    exception of the thyroid, which had a 12-fold higher level of
    radioactivity. Thyroid levels of radioactivity reached a peak at 8
    hours, which was about double that observed at 2 hours, and
    radioactivity remained considerably higher than levels in other
    tissues/organs for the remainder of the 10-day study. By 48 hours,
    radioactivity levels in body tissues/organs, with the exception of the
    thyroid, declined about 50-fold. Somewhat higher levels of
    radioactivity were observed in the kidney and liver. Selective uptake
    and accumulation of radioactivity in the thyroid was apparent
    throughout the 10-day study (Weber et al., 1978).

    Toxicological studies

    Special study on carcinogenicity

    Mouse

         Technical grade propineb of 82.9% purity was administered in the
    feed to NMRI mice for 104 weeks at dosage levels of 0, 50, 200, or
    800 ppm. Each control and test group contained 50 mice of each sex.
    The animals were observed daily for mortality, general appearance, and
    signs of toxicity. Body weights were determined weekly for 6 weeks and
    biweekly thereafter. Feed consumption was measured weekly. Clinical
    laboratory examinations were performed on satellite groups of 10
    mice/sex/group prior to initiation of dosing and at 6, 12, 18, and 24
    months. Haematological examinations consisted of erythrocyte counts,
    haemoglobin determinations, leukocyte counts, and differential
    leukocyte counts. Clinical chemistries consisted of alkaline
    phosphatase and glutamate-pyruvate transaminase activity
    determinations. Urinalyses consisted of semiquantitative
    determinations of protein, glucose, haemoglobin, urobilin-ogen, and
    pH. Gross necropsies were performed on nearly all mice. At terminal
    sacrifice, absolute organ weights and relative organ/body-weight
    ratios were determined for brain, heart, lung, liver, spleen, kidneys,
    adrenals, thyroids, and gonads. Approximately 36 organs or tissues
    from each of 37 to 47 mice in each group were histopathologically
    examined.

         No meaningful differences in mortality were observed between male
    and female control and test groups, respectively. The number of male
    mice surviving to termination of the study were 19, 20, 19, and 25 for
    the control, low-, mid-, and high-dose groups, respectively.
    Comparable numbers for female mice were 5, 4, 13, and 7, respectively.
    The causes of death of animals that died during the study were
    attributed in numerous instances to pulmonary tumours, malignant
    lymphomas, or amyloid nephrosis. Daily observations did not indicate
    any differences between test and control mice. Mean feed consumption
    was similar in male and female control and test groups, respectively.
    No apparent differences in mean body weights were observed between
    male and female control and test groups, respectively. Haematological,
    clinical chemistry, and urinalysis examinations did not reveal any
    effects attributable to the test material. Gross necropsies were
    reported to be negative for lesions attributable to the test material,
    but documentation was lacking. Organ weights and organ/body-weight
    ratios did not reveal any differences that could be related to the
    test material. Possibly increased mean thyroid weights and
    thyroid/body-weight ratios in all treated female groups were noted,
    but could not be related to the test material because too few female
    mice survived to termination of the study.

         Non-neoplastic lesions were not reported in the histopathological
    evaluation; therefore, this study cannot be used as a chronic feeding
    study. Percentages of female mice with tumours of any kind were 65,
    66, 73, and 88 for the contol, low-, mid-, and high-dose groups,
    respectively. A similar increase was not observed in treated male
    mice. Frequently-observed neoplasms were pulmonary adenomas and
    malignant lymphomas in male and female mice and benign granulosa cell
    tumours in the ovaries of female mice.

         Increased incidences of pulmonary adenomas were observed in the
    treated female mice. Percentages were 19, 27, 30, and 50 for the
    control, low-, mid-, and high-dose female groups, respectively.
    Pulmonary carcinomas were not increased. The increase in adenomas in
    the high-dose female group may possibly be related to treatment. A
    similar increase was not observed in treated male mice.

         Malignant lymphomas in male mice ranged from 26 to 28%, and in
    female mice from 30 to 38%. Benign granulosa cell tumours in the
    ovaries of female mice ranged from 14 to 32%, but their incidence was
    not dose-related and could not be related to the test material. A
    suggestive increase in pituitary adenomas was noted in the high-dose
    female mice. Percentages were 3, 0, 2, and 10 for the control, low-,
    mid-, and high-dose female groups, respectively. Thyroid or adrenal
    tumours were not increased in treated male or female mice.

         An increased incidence of hepatocellular adenomas was observed in
    the high-dose male group. Percentages were 6, 7, 0, and 20 for the
    control, low-, mid-, and high-dose male groups, respectively.
    Hepatocellular carcinomas in male mice ranged from 0 to 4%, but their
    incidence was not dose-related. Historical control data presented by
    the testing laboratory for hepatocellular adenomas in NMRI mice ranged
    from 4 to 12%. The increase in hepatocellular adenomas in the high-
    dose male group may possibly be related to treatment with the test
    material. Hepatocellular tumours were not increased in treated female
    mice (Brune et al., 1980).

    Special studies on mutagenicity

         Propineb was tested in the mutagenicity studies listed in
    Table 1.

    Special studies on effect upon thyroid function

    Rat

         Propineb of unknown purity was administered in the feed for 62
    days to 5 groups of 80 male Wistar TNO/W74 rats at dosage levels of 0,
    2, 10, 50, or 250 ppm. The rats were 40-50 days old at the beginning
    of the study and had a mean body weight of 113 grams. Ten rats per
    group were sacrificed at 7 days and at 21 days. Gross necropsies,
    organ-weight determinations, and clinical laboratory examinations were
    performed on these animals. An additional 10 rats per group were also
    sacrificed at 7, 21, and 62 days and given a "thyroid function test",
    which was reported separately (see Weber & Dressier, 1980). The
    remaining animals were sacrificed at 62 days. Animals were examined
    daily. Body weights and feed consumption were determined weekly.
    Clinical laboratory examinations consisted of lactate dehydrogenase,
    creatinine phos-phokinase, total thyroxin, calcium, magnesium, and
    inorganic phosphate-level determinations. Animals were necropsied and
    organ weights were determined for thyroids, adrenals, and liver.
    Histopathological examinations were performed on 30 control and 29
    high-dose animals. Liver, adrenals, thyroid, para-thyroid, skeletal
    muscle, and grossly-apparent lesions were examined.

        Table 1.  Mutagenicity assays with propineb
                                                                                               
    Study type               Dosage level and/or           Results        Reference
                              conditions
                                                                                               

    Bacteria tests

    Reverse mutation,        Dosage levels up to 2.5       Negative       Herbold, 1980a
    S. typhimurium,          mg/plate, w/o and with
    strains TA1535,          metabolic activation1
    TA100, TA1537,
    & TA98

    Reverse mutation,        Dosage levels up to           Negative       Hatano Institute,
    S. typhimurium,          0.864 mg/plate, w/o                          1978
    strains TA1535,          and with metabolic
    TA100, TA1537,           activation2
    TA1538, & TA98.
    E. coli, strain WP2.

    Preferential toxicity,   Dosage levels up to 0.864     Negative       Hatano Institute
    B. subtilis,             mg (on filter disc)/plate,                   1978
    strains M45, H17         w/o metabolic activation2

    In vivo study

    Micronucleus test,       2 oral doses of 1000 or       Negative       Herbold, 1982
    male and female mice     2000 mg/kg, 24h apart3
                                                                                               

    1    Purity of test material, 84.3%
    2    Purity of test material, unknown
    3    Purity of test material, 85.7%
    
         No mortalities occurred during the study. Daily examinations
    indicated no effects that could be attributed to the test material.
    Mean body weights of animals in the 250-ppm group were slightly but
    consistently lower than those of the control group throughout the
    entire study. Feed consumption was unaffected. Lactate dehydrogenase
    and creatinine phosphokinase levels were decreased in all treatment
    groups at 7, 21, and 62 days when compared to the control group.
    Calcium, magnesium, and inorganic phosphate levels were unaffected.

         Total thyroxin was decreased in the 50- and 250-ppm groups at 21
    and 62 days. Thyroid weights were decreased in the 250-ppm group at 7
    days, but later increased in the 50- and 250-ppm groups at 62 days.

    These findings suggest a reduction in thyroid function at 50 and 250
    ppm, which initially resulted in lower thyroid weights, but later in
    higher thyroid weights, possibly due to increased production of
    pituitary thyrotropic hormone.

         Gross necropsies were negative. Adrenal and liver weights were
    unaffected. Histopathological examinations revealed no effects that
    could be attributed to the test material (Krotlinger et al., 1980).

         Ten male rats per group from the just-described study were each
    tested at 7, 21, and 62 days. In addition, iodine accumulation in the
    thyroid was assayed 24 hours after oral intubation of 0.2 µCi of
    131I-NaI tracer by measuring radioactivity in excised and weighed
    thyroid tissue. Concentrations of triiodothyronine (T3) and of
    tetraiodothyronine (T4) in the serum were also determined by use of a
    commercially-available 125iodine radioimmunoassay test system.

         Mean thyroid weights were increased above control values in the
    50-ppm group at 62 days (+25%), and in the 250-ppm group at 21 days
    (+22%) and at 62 days (+27%). A decrease in mean thyroid weights was
    observed in the 2-ppm group at 7 days (-14%). Mean iodine accumulation
    in the thyroid, expressed as the amount of radioactive iodine per mg
    of tissue, was decreased below control values in the 50-ppm group at
    62 days (-20%) and in the 250-ppm group at 21 days (-32%) and at 62
    days (-25%). Mean T3 concentrations were increased above control
    values in the 2-ppm group at 7 days (+26%) and in the 10-ppm group at
    7 days (+20%). A decrease in mean T3 was observed in the 250-ppm group
    at 62 days (-25%). Mean T4 concentrations were decreased below control
    values in the 250-ppm group at 7 days (-32%), at 21 days (-42%), and
    at 62 days (-16%).

         The study results indicate that propineb inhibits thyroid
    function at all dosage levels tested. The effect appears to be dose-
    related. At 50 ppm and 250 ppm, iodine accumulation in the thyroid was
    reduced and at 250 ppm, T3- and T4 serum levels were also reduced. A
    compensatory reaction occurred, however, at these dosage levels, as
    evidenced by increased thyroid weights and a return toward control
    values for several of the other parameters. Compensation was more
    complete in animals in the 50-ppm group than in those in the 250-ppm
    group. At 2 and 10 ppm, inhibition of thyroid function was indicated
    by the increased levels at 7 days of T3, the more biologically-active
    form of the thyroid hormone (Weber & Dressier, 1980).

    Special studies on carcinogenicity of propylene thiourea

    Mouse

         Propylene thiourea of 99.3% purity was administered in the diet
    to groups of CF1/W74 mice at dosage levels of 0, 1, 10, or 100 ppm for
    24 months. An additional group of mice received 1000 ppm in the diet,
    which was regularly alternated on a weekly basis with control diet.

    The latter group was referred to as the 1000-ppm group. Sixty male and
    60 female mice were treated at each dosage level. Mice were 5 to 6
    weeks old at the start of the study. The mean starting body weight for
    male mice was 22 grams and for female mice it was 23 grams. Powdered
    feed and tap water were available ad libitum. At 12 months, 8 to 10
    pre-designated mice/sex/group were sacrificed and examined. General
    examinations for mortality, appearance, behaviour, and signs of
    toxicity were performed daily. Body weights were determined weekly for
    13 weeks and tri-weekly thereafter. Feed consumption was monitored
    weekly. Clinical laboratory examinations (haematology and clinical
    chemistries) were performed on 10 mice/sex/group at 12 and 24 months.
    Haematological examinations consisted of erythrocyte count, leucocyte
    count, thrombocyte count, reticulocyte count, haemoglogin,
    haematocrit, differential blood count, mean corpuscular haemoglobin,
    mean cell volume, and mean corpuscular haemoglobin concentration.
    Clinical chemistries consisted of alkaline phosphatase (ALP),
    glutamate-oxaloacetate transaminase (GOT), glutamate-pyruvate
    transaminase (GPT), creatinine, urea, blood sugar, cholesterol,
    bilirubin, and total protein. No thyroid function tests (e.g. protein-
    bound iodine) were performed. Urinalyses were not performed. Body
    temperatures were not determined. Gross necropsies were performed on
    nearly all mice in the study regardless of time or manner of death.
    Absolute organ weights, determined at the 12-month interim sacrifice,
    were for thyroid, heart, lung, liver, spleen, kidneys, and testes.
    Thyroid weights were not determined, however, from the animals
    sacrificed at 24 months. Organ/body-weight ratios were calculated for
    individual animals, but means were not presented. Twenty
    organs/tissues plus grossly-observed lesions from nearly all mice in
    the study were routinely excised, fixed, and microscopically examined.

         Based on mean feed consumption and body weights at 12 months,
    daily intakes of test material in mg/kg b.w. were calculated to be
    0.16 and 0.21 for 1-ppm male and female mice, respectively, 1.56 and
    2.06 for 10-ppm mice, and 17.09 and 21.54 for 100-ppm mice. General
    examinations did not indicate any notable differences between test and
    control animals. Mean feed consumption of 1000-ppm male mice was
    increased compared to control male mice (6.94 g/animal/day vs 6.39)
    and of 1000-ppm female mice (7.71 g/animal/day vs 6.22). Mean body
    weights for 1000-ppm male mice were consistently about 2 grams lower
    than those of control male mice from week 16 to termination of the
    study. This decreased mean body weight was attributed to the test
    material. No other meaningful mean body-weight differences were
    observed for any of the groups. Mortality was equivalent in all test
    and control groups for male and female mice, respectively. The numbers
    of surviving male mice at 24 months were 14/50, 11/50, 15/50, 11/49,
    and 16/50 for the control, 1-, 10-, 100-, and 1000-ppm groups,
    respectively. The respective numbers for female mice were 21/50,
    25/50, 19/50, 20/51, and 18/50. Haematological examinations did not
    reveal any meaningful differences between control and test-group male
    or female mice. Occasional statistically-significant differences were

    observed, but without consistency. ALP-activity levels in 1000-ppm
    male and female mice were increased at 12 and 24 months, suggesting
    the possibility of liver damage. ALP levels in other dose groups were
    generally similar to control levels. GOT and GPT were not increased
    above control levels in any consistent pattern. Cholesterol levels
    were increased in 1000-ppm male and female mice at 12 and 24 months,
    suggesting the possibility of altered lipid metabolism. Bilirubin,
    total protein, urea, creatinine, and glucose levels in test male and
    female mice were generally similar to control levels.

         Gross necropsies on mice sacrificed at 12 months revealed
    clearly-enlarged thyroids in 1000-ppm male mice. For mice dying or
    moribund-sacrificed during the study, increased incidences of enlarged
    or swollen livers, sometimes with nodes, were observed in 10-, 100-,
    and 1000-ppm male and female groups. For mice sacrificed at 24 months,
    dose-related increased incidences of enlarged or swollen livers and/or
    nodular alterations were observed in all treated male and female
    groups. These livers also tended to be partly hardened and brittle.
    Absolute thyroid weights were significantly increased in 1000-ppm male
    mice (p < 0.01), but not in female mice, at 12 months. Thyroid
    weights at 24 months were not determined "in order to avoid artifacts
    arising during preparation which might hinder histopathological
    appraisal". Absolute liver weights of 1000-ppm male mice were
    significantly increased at 12 months (p < 0.01) and at 24 months
    (p < 0.05), and of female mice at 24 months (p < 0.01). Absolute
    liver weights of 100-ppm male and female mice were also significantly
    increased at 24 months (p < 0.01). All thyroid and liver effects
    described above were considered to be attributable to the test
    material. Absolute kidney weights from female mice were significantly
    increased at 24 months at 1000 ppm (p < 0.05), at 100 ppm (< 0.01),
    and possibly also at 10 ppm (p < 0.05). Absolute heart, lung, spleen,
    and testes weights were comparable from test and control male and
    female groups, respectively.

         Histopathological examination revealed increased incidences of
    thyroid hypercellularity in the high-dose male mice at the interim
    12-month sacrifce and at the terminal sacrifice. This effect is most
    likely related to the test material. In the spleen, an apparent dose-
    related increased incidence of lymphoid hyperplasia was observed in
    treated female mice. Percentages were 0, 5, 8, 9, and 10 for the
    control, 1-, 10-, 100-, and 1000-ppm female groups, respectively.

         Frequently-observed non-neoplastic lesions occurring with
    similar incidences in control and all treated groups included focal
    hepatitis and focal necrosis in the liver, chronic nephropathy and
    hydronephrosis in the kidneys, myocardial degeneration in the heart,
    interstitial pneumonitis and congestion in the lungs, "reactive"
    tissue in the spleen, gastritis in the stomach, atrophy of the
    pancreas, subcapsular cell hyperplasia in the adrenals, tubular

    degeneration in the testes, cystic fibrosis in the ovaries, cystic
    endometrial hyperplasia in the uterus, osteopathy in the bone, and
    vascular canalization of compact bone (in females).

         With respect to neoplasia, male and female mice in all treated
    groups had higher percentages of animals with any kind of neoplasm,
    with multiple tumours, and with malignant neoplasms than did
    respective control groups. Dose-response relationships, however, were
    not evident.

         In the liver, clearly-increased incidences of hepatocellular
    tumours were observed in treated male and female groups. For male
    mice, percentages of animals with adenomas were 0, 11, 10, 7, and 26,
    and of animals with carcinomas were 0, 13, 29, 31, and 21 for the
    control, 1-, 10-, 100-, and 1000-ppm groups, respectively. For female
    mice, comparable percentages for adenomas were 0, 10, 13, 32, and 18,
    and for carcinomas they were 2, 2, 5, 26, and 38, respectively. The
    increased incidences of hepatocellular adenomas in male mice at
    1000 ppm and in female mice at 100 and 1000 ppm, and of hepatocellular
    carcinomas in male mice at 10, 100, and 1000 ppm and in female mice at
    100 and 1000 ppm, were considered to be related to administration of
    the test material.

         In the lungs, pulmonary adenomas were frequently observed in all
    control and treated male and female groups. Incidences were similar in
    all groups. No relationship to treatment with the test material was
    evident. In the thyroid, only 2 adenomas (both in the 1-ppm male
    group) and 2 adenocarcinomas (1 in the 100-ppm female group and 1 in
    the 1000-ppm female group) were observed.

         Other tumours frequently observed at similar frequencies in
    control and test mice were malignant lympohoma/leukemia complex (males
    and females), adenomas in the adrenals (males), theca granulosa cell
    tumours in the ovaries (females), and osteomas in the bone (females).
    None of these tumour types were attributed to treatment with the test
    material (Bomhard & Loser, 1981).

    Rat

         Propylene thiourea of approximately 99% purity was incorporated
    into the feed and offered ad libitum to Wistar TNO/W74 rats for 24
    months at dosage levels of 0, 1, 10, 100, or 1000 ppm. The control
    group consisted of 100 rats/sex/group and each of the test groups of
    50 rats/sex/group. Additional satellite groups of 25 rats/sex/group
    were used for clinical laboratory studies. The rats were 5 to 6 weeks
    old at initiation of treatment. The mean body weight of the male rats
    was 76 g and of the female rats 78 g. All animals were examined at
    least daily for mortality, physical appearance, behaviour, and signs
    of toxicity. Body weights were recorded weekly for 26 weeks and
    biweekly thereafter. Food consumption was recorded weekly. Clinical

    laboratory studies (haematology, clinical chemistries, and urinalyses)
    were performed on 5 rats/sex/group at 1, 3, 6, and 12 months and on
    10 rats/sex/group at termination of the study at 24 months.
    Haematological examinations consisted of erythrocyte count, leucocyte
    count, thrombocyte count, reticulocyte count, haemoglogin,
    haematocrit, differential blood count, mean corpuscular haemoglobin,
    mean corpuscular volume, and thromboplastin time (at termination
    only). Clinical chemistries consisted of determinations of ALP, GOT,
    GPT, glutamate dehydrogenase (GLDH; at termination only), creatinine,
    urea, blood sugar, cholesterol, bilirubin, total protein in
    plasma, and protein-bound iodine (PBI). Urinalysis consisted of
    semiquantitative determinations of glucose, blood, protein, pH, ketone
    bodies, bilirubin, urobilinogen, microscopic examination of sediment,
    and a quantitative determination of protein in urine. In addition,
    rectal body temperatures were recorded of 20 rats/sex/group at 3, 6,
    12, and 24 months. Gross necropsies were performed of nearly all rats
    in the study, regardless of time or type of death. Organ weights were
    recorded only of rats sacrificed at termination of the study. Organs
    weighed were thyroid, heart, lung, liver, spleen, kidneys, adrenals,
    testes, and ovaries. Organ/body-weight ratios were not calculated.
    Approximately 31 organs/tissues plus macroscopically-identified
    lesions from nearly all rats in the study were routinely excised,
    fixed, and microscopically examined.

         The 1000-ppm dosage level was clearly excessive. From the third
    week onward, animals in this group gained little or no body weight and
    were cachectic. Feed consumption was substantially below that of
    control animals. Most rats had a ruffled hair coat and/or heavy loss
    of hair. The skin of some rats was covered with a brownish scale.
    Mortalities commenced at 3 months. For male rats, 31/50 died by 6
    months and 34/50 by 12 months. For female rats, 38/50 died by 6 months
    and 40/50 by 12 months. At 64 weeks, the mean body weight of the
    surviving male rats was approximately 150 g and of the surviving
    female rats was approximately 100 g. At 65 weeks the last survivors in
    this group, 12 male and 3 female rats, were sacrificed. Haematological
    examinations on male and female rats in this dose group revealed a
    marked and widespread decrease in haematopoiesis, which was
    characterized by decreased erythrocyte counts, haemoglobin levels,
    haematocrits, reticulocyte counts, thrombocyte counts, and leucocyte
    counts (in males only). Differential blood counts revealed a relative
    increase in mature polymorphonuclear neutrophils and a relative
    decrease in lymphocytes. Clinical chemistries indicated highly-
    increased ALP levels in male and female rats, which suggested liver
    damage, but GOT, GPT, and GLDH levels were not affected. Urea,
    creatinine and cholesterol levels were increased in male and female
    rats. Urinalyses revealed decreased protein in the urine of male rats,
    although haemoglobin was detected more frequently in the urine of male
    than female rats. Body temperatures of male and female rats were
    clearly lower than those of control rats, but PBI levels were not
    affected. Gross necropsies revealed greatly-enlarged thyroids in some

    animals. Histopathological examination of organs/tissues revealed the
    following non-neoplastic lesions, which were considered to be
    related to treatment with the test material: nodular and generalized
    hyperplasia of the thyroid (males and females), calculi and
    vacuolation of tubular cells in kidneys (males and females), aplasia
    and decreased haemato-poiesis in marrow (particularly in males),
    vacuolation of hepatocytes in liver (particularly in males), and
    atrophy and reduced spermatogenesis in testes. Nine male rats (of 42
    examined) had thyroid adenomas. Two female rats (of 25 examined) also
    had thyroid adenomas and 1 additional female rat had a thyroid
    cystadenoma. The thyroid adenomas/cystadenoma were considered to have
    been induced by the test material. It should be recalled, however,
    that the dosage level at which these tumours were observed was above
    the maximum tolerated dose.

         Calculations based on mean feed consumption and mean body weights
    at week 53 indicated the following daily intake of test material for
    the remaining animals in the study: 1-ppm dose group, 0.06 and
    0.07 mg/kg b.w. for male and female rats, respectively; 10-ppm dose
    group, 0.56 and 0.74 mg/kg b.w.; 100-ppm dose group, 5.70 and
    7.26 mg/kg b.w. Daily observations of these animals indicated no
    differences from the control animals. Mean feed consumption was also
    similar in test and control groups. Mean body weights of 100-ppm male
    rats were consistently 10 to 20 g lower than those of control male
    rats from week 20 to termination of the study. This decrease in mean
    body weights of the 100-ppm male group is considered to be related to
    ingestion of the test material. Mean body weights of all other test
    groups were similar to those of the respective control groups. A
    suggestion of slightly increased mortality in the 100-ppm male group
    was observed at 18 and 24 months. Mortalities were equivalent in all
    other test and control groups. The number of male rats surviving to
    termination of the study were 85/100, 41/50, 44/50, and 38/50 for the
    control, 1-, 10-, and 100-ppm groups, respectively. The respective
    numbers for female rats were 83/100, 40/50, 42/50, and 43/50.

         Haematological examinations on the 100-ppm male rats strongly
    suggested decreased haematopoiesis at irregular times during the
    study. Intermittent decreases in erythrocyte count, haemoglobin level,
    haematocrit, thrombocyte count, and leucocyte count were observed. In
    contrast to the 1000-ppm animals, however, reticulocyte counts tended
    to be increased. In the 10-ppm male group, decreased thrombocyte
    count, decreased leucocyte count, and increased reticulocyte count
    were observed at termination of the study. For 100-ppm female rats,
    decreased haematopoiesis was only suggested by marginal and
    intermittent decreases in erythrocyte count, haemoglobin level, and
    thrombocyte count, and an increase in reticulocyte count. Differential
    blood counts in 100-ppm male and female rats revealed a relative
    increase in mature polymorphonuclear neutrophils and a relative
    decrease in lymphocytes. A similar shift was also observed in 10-ppm
    male rats. Clinical chemistries did not reveal increases in enzyme

    levels (ALP, GOT, GPT, or GLDH) indicative of liver damage. Bilirubin
    and cholesterol levels were increased, however, in 10-ppm and 100-ppm
    male rats and possibly bilirubin levels also in 1-ppm male rats. Other
    clinical chemistries were negative. Urinalyses were negative. Body
    temperatures were not decreased and PBI levels were not affected.

         Gross necropsies performed on 100-ppm male and female rats
    revealed enlarged thyroids in numerous rats. Mean absolute thyroid
    weights from 100-ppm male and female rats were significantly increased
    (p < 0.01). From 100-ppm male rats, the mean thyroid weight was 31 mg
    compared to 22 mg from the control male group. In 100-ppm female rats,
    the mean thyroid weight was 24 mg compared to 19 mg in the control
    female group. Mean absolute adrenal weights were significantly
    decreased (p < 0.05) in 100-ppm male rats. For these animals, the
    mean adrenal weight was 41 mg compared to 48 mg in the control male
    group. Other organ-weight differences were unremarkable.

         Histopathological examination of thyroids from male and female
    rats revealed lesions and/or effects attributable to the test material
    at all dosage levels. At 1 ppm, 10 ppm, and 100 ppm, increased
    incidences of "many small follicles" were observed. For male rats,
    incidences were 7/95 (7.4%), 9/47 (19.1%), 10/45 (22.2%), and 8/47
    (17.0%) for the control, 1-, 10-, and 100-ppm groups, respectively.
    Respective incidences for female rats were 1/90 (1.1%), 11/45 (24.4%),
    23/49 (46.9%), and 1/46 (2.2%). For 100-ppm male and female rats,
    increased incidences of "colloid cysts" (up to 6/46), "large
    follicles" (up to 6/46), "tall columnar cells lining the follicles"
    (up to 2/47, in males only), "vacuolation of epithelial cells" (up to
    4/47), and "nodular hyperplasia" (up to 5/47) were also observed.
    "Colloid cysts" (2/47) and "nodular hyperplasia" (3/47) were also
    reported in 1-ppm male rats, but not in 10-ppm male rats. "No colloid"
    was reported in 1-ppm male rats (2/47), "solid areas" in 1-ppm female
    rats (2/45) and "vacuolation of epithelial cells" in 10-ppm female
    rats (1/49). All of the thyroid lesions described above occurred at a
    higher incidence than in the respective male and female control
    groups.

         Microscopic lesions observed in adrenals from male and female
    rats were also attributed to treatment with the test material at
    dosage levels of 10 ppm and 100 ppm. For male rats, "vacuolation of
    cortical cells" was noted in 9/94 (9.6%), 4/47 (8.5%), 12/47 (25.5%)
    and 8/45 (17.8%) for the control, 1-, 10-, and 100-ppm groups,
    respectively. Respective incidences for female rats were 26/88
    (29.5%), 8/43 (18.6%), 25/43 (58.1%), and 19/48 (39.6%). "Cortical
    cysts" in the adrenals were also reported for female rats at
    respective incidences of 33/88 (37.5%), 17/43 (39.5%), 26/43 (60.5%),
    and 17/48 (35.4%). In addition, "haemorrhage" was increased in 100-ppm
    female rats (10/48) compared to control female rats (9/88). Other non-
    neoplastic microscopic lesions possibly related to the test material
    were "areas of necrosis" in the liver of 100-ppm female rats (4/50 vs.

    3/99 in control female rats), "increased haematopoiesis" in the spleen
    of 100-ppm female rats (9/50 vs. 6/95 in control female rats),
    "pituitary hyperplasia" in 10-ppm (but not 100-ppm) female rats (5/44
    vs. 2/92 in control female rats), "pituitary cysts" in 10-ppm (but not
    100-ppm) female rats (4/44 vs. 2/92 in control female rats) and
    "testicular atrophy" in 100-ppm male rats (3/50 vs. 2/100 in control
    male rats).

         Additional non-neoplastic lesions observed at higher incidences
    in test animals than in control animals, but probably not related to
    the test material, were pneumonia in the lungs (males and females),
    leucocyte infiltration in the lungs (females), and submucosal
    leucocytosis in the trachea (males and females). Other frequently-
    observed lesions that occurred with similar incidences in test and
    control rats included emphysema, thickened alveolar walls, and
    pneumonitis in the lungs (males and females); bile duct hyperplasia
    and hepatocyte vacuolation in the liver (particularly in males);
    glomerulonephrosis and fibrosis in the kidneys (males and females);
    pituitary cysts (particularly in males); ovarian cysts; cystic
    endometrial hyperplasia, pyometra, and cysts in the uterus; and
    dilated mucosal glands in the stomach (males and females).

         Neoplastic lesions, total numbers of tumours (benign and/or
    malignant), and total numbers of animals with tumours (benign and/or
    malignant) were not increased in test rats compared to control rats,
    with the possible exception of male rats with benign tumours;
    incidences were 13/100 (13.0%), 11/49 (22.4%), 3/50 (6.0%), and 11/50
    (22.0%) for the control, 1-, 10-, and 100-ppm groups, respectively.
    Thyroid adenomas were increased in treated male and female rats. For
    male rats, the incidences were 1/95 (1.1%), 2/47 (4.3%), 1/45 (2.2%),
    and 0/47 (0.0%) for the control, 1-, 10-, and 100-ppm groups,
    respectively. For female rats, the respective incidences were 2/90
    (2.2%), 2/45 (4.4%), 2/49 (4.1%), and 2/46 (4.3%). In addition, 2/90
    (2.2%) control female rats and 2/46 (4.3%) 100-ppm female rats had
    thyroid cystadenomas. In view of the clearly-increased incidence of
    thyroid tumours in the 1000-ppm male and female rats, and the
    substantially-increased incidences of thyroid lesions in the lower-
    dose male and female rats, it is likely that the thyroid tumours in
    the lower-dose groups, although not dose-related, may nevertheless be
    related to treatment with the test material. Pituitary adenomas were
    observed in control and test animals at incidences up to 9/44 (20.5%).
    For female rats, the incidences were 12/92 (13.0%), 7/43 (16.3%), 8/44
    (18.2%), and 9/44 (20.5%) for the control, 1-, 10-, and 100-ppm
    groups, respectively. Interstitial cell tumours of the testes were
    observed at incidences of 3/100 (3.0%), 2/48 (4.2%), 1/50 (2.0%), and
    4/50 (8.0%) for the respective groups. The possible relationship of
    pituitary adenomas in female rats and of testicular tumours in 100-ppm
    male rats to the test material is problematical. Pheochromocytomas and

    medullary tumours of the adrenal were observed in the control and test
    animals at equivalent incidences which did not exceed 2/47 (4.3%) in
    any group. Other tumour types occurred at low incidences and were not
    related to the test material.

         A NOEL was not established in this study. Possibly-increased
    bilirubin levels in 1-ppm male rats and non-neoplastic lesions in the
    thyroid of male and female rats were observed at the lowest dosage
    level tested (1 ppm). In addition, it is likely that thyroid tumours
    observed in male and female rats at this dosage level and at 10 ppm
    and 100 ppm (females only) may have been related to the test material.
    Suggestive increased incidences of pituitary adenomas in female rats
    and interstitial cell tumours in the testes of 100-ppm rats were
    problematical. In male and female rats at 1000 ppm, which was a
    clearly-excessive dosage level, thyroid tumours were definitely
    related to the test material (Bomhard & Loser, 1980).

    Special studies on mutagenicity of propylene thiourea

         Propylene thiourea of 99.5% purity was tested in the mutagenicity
    studies listed in Table 2.

        Table 2.  Mutagenicity assays with propylene thiourea
                                                                                            

    Study type               Dosage level and/or              Results          Reference
                             conditions
                                                                                            

    Bacteria tests

    Reverse mutation,        Dosage levels up to 12.5         Negative         Herbold, 1980b
    S. typhimurium,          mg/plate, without and with
    strains TA1535,          metabolic activation (from
    TA1537, TA100, &         rat liver homogenates)
    TA98

    Reverse mutation,        Dosage levels up to 12.5         Inconclusive     Herbold, 1981a
    S. typhimurium,          mg/plate, without and with
    strains TA1535,          metabolic activation (from
    TA1537, TAlO0, &         CFW1 male mouse liver
    TA98                     homogenates)

    Pol A1 test,             Dosage levels up to 1 mg         Inconclusive     Herbold, 1981b
    E. coli, strains         (on filter disc)/plate,
    p3478, W3110             with and without metabolic
                             activation
                                                                                            
    
    Special study on effect of propylene thiourea on thyroid function

    Rat

         Propylene thiourea of about 99% purity was administered in the
    feed for up to 24 months to groups of male and female Wistar rats at
    dosage levels of 0, 1, 10, 100, or 1000 ppm. Each group contained 40
    male and 40 female rats. At 3, 7, and 14 days, and at 1, 3, 6, 12, and
    24 months, 5 rats/sex/group were subjected to thyroid function tests.
    Twenty-four hours following oral administration of 2 µCi of 125I-NaI
    tracer, the rats were sacrificed. Accumulation of iodine by the
    thyroid was determined by measuring radioactivity in excised and
    weighed thyroid tissue. PBI was also assayed by measuring
    radioactivity in plasma protein precipitated by trichloroacetic acid.

         Propylene thiourea inhibited thyroid function in a dose-related
    manner. Both sexes were affected to about the same degree. Initial
    effects were observed at all dose levels at 3 days, as evidenced by
    dose-related decreases in iodine uptake by the thyroid and by
    decreased PBI levels. By 7 days, compensatory reactions, presumably
    due to increased pituitary production of thyrotropic hormone, were
    observed to have started in the 1000-ppm and 100-ppm groups.

         In the 1000-ppm group, thyroid weights increased approximately
    6-fold over control weights, reaching peak levels at 6 months in the
    female rats and at 12 months in the male rats. Iodine uptake by the
    thyroid, expressed as the amount of radioactive iodine per mg of
    tissue, decreased to about 10% of the control levels at these times.
    PBI, after an initial decrease to approximately 20% of the control
    levels, later rose to control levels by 1-3 months. Mean body weights
    in this group were significantly decreased from 7 days to the end of
    the study. In the 100-ppm group, thyroid weights increased 2-3-fold
    over control weights, reaching peak levels at 6 months. Iodine
    concentration in the thyroid, however, remained similar to control
    levels throughout the study. PBI levels that were initially decreased
    later increased to 2-3 times control levels at 1 month. At 10 ppm,
    initially-reduced iodine uptake and PBI levels recovered to control
    levels at 7 days and remained similar to control levels for the
    remainder of the study. At 1 ppm, results were ambiguous (Weber &
    Patzschke, 1979).

    Special study on DNA with propylene thiourea

         The potential effects of propylene thiourea on DNA metabolism and
    binding in the spleen and liver of CF1 male mice were studied. Only
    brief summaries of the procedures and results, as reported by the
    author, were available to the Meeting, and are presented here.

         Fasted male CF1 mice were treated by gavage with PEG 200
    (negative control group), 100 mg/kg propylene thiourea dissolved in
    PEG 200 (test group), or i.p. with 100 mg/kg cyclophosphamide
    (positive control group). Two hours after dosing with PEG 200,
    without and with test material, or 24 hours after dosing with
    cyclophosphamide, the mice were sacrificed, their spleens removed, and
    cell suspensions prepared. Potential primary damage induced by
    propylene thiourea to genetic material in the spleen cells was then
    studied by the following methodologies. The results presented below
    are directly quoted from the author.

         Programmed DNA synthesis (semi-conservative DNA synthesis):
    Incorporation of 3H-thymidine into DNA of mouse spleen cells during
    the synthesis phase of the cell cycle was measured. Results - "Test
    substance group: significantly increased 3H-thymidine incorporation
    in the DNA of the cells compared with the controls. Reference
    substance group: significant suppression of incorporation by
    cyclophosphamide compared with the control."

         Suppressed programmed DNA synthesis: Incorporation of
    3H-thymidine into DNA of mouse spleen cells pre-treated with
    hydroxyurea, which suppresses programmed DNA synthesis by about 90%,
    was measured. The measurable radioactivity remaining is due, in part,
    to continuous DNA repair. Results - "Test substance group: no
    significant difference from the control group. Reference substance
    group: no significant difference from the control groups."

         Unprogrammed DNA synthesis (DNA excision repair): Incorporation
    of 3H-thymidine into DNA of mouse spleen cells previously damaged by
    gamma or ultraviolet light irradiation was measured. Pre-treatment of
    cells with hydroxyurea permitted differentiation between programmed
    DNA synthesis and unprogrammed DNA synthesis. Results - "Test
    substance group: no significant difference from the control group.
    Reference substance group: significant suppression of unprogrammed DNA
    synthesis of the spleen cells compared with the control group."

         DNA sedimentation in alkaline saccharose gradient (DNA strand
    healing): Irradiated spleen cells pre-labeled with 3H-thymidine in
    DNA were lysed and the DNA dissociated into individual strands.
    Molecular weights of DNA strands were then determined by linear
    gradient centrifugation. Breaks in DNA strands that have been repaired
    result in restoration of original molecular weights. Results - "Test
    substance group: no difference from the control group. Reference
    substance group: clear effect on sedimentation of the spleen cell DNA
    in the saccharose gradient."

         Nucleoid sedimentation in saccharose gradient (supercoiled DNA):
    Untreated and irradiated spleen cells were gently lysed in a manner
    which preserved the secondary structure of the double helix and also
    the tertiary structure of the superhelix as present in the

    chromosomes. The supercoiled nucloids thus obtained, which were
    largely separated from muclear protein, were then centrifuged in a
    saccharose gradient. Undamaged nucleoids form a sediment faster than
    damaged nucleoids, whose DNA contains strand breaks or incisions, thus
    producing a loss of supercoils. Nucleoid sedimentation rate was
    monitored by a photometer. Results - "Test substance group: no
    significant difference from the control group. Reference substance
    group: significant shift in sedimentation profile of the nucleoids ...
    compared with the control group."

         In addition, potential binding of propylene thiourea to liver DNA
    was studied by the following methodology: Isolated cleaned liver DNA
    from CF1 male mice was incubated with 14C-propylene thiourea.
    Binding to DNA was determined by measurement of radioactivity in the
    DNA. Results - "Test substance group: no binding of the test substance
    (PTU) to the DNA. In relation to the quantity of 14C-PTU used binding
    is at a level of only two hundred thousanths of the substance to the
    DNA."

         Cyclophosphamide, the positive control substance, affected nearly
    all the parameters of DNA metabolism in the CF1 mouse spleen cells in
    this study. The only effect of propylene thiourea was a significantly-
    increased programmed DNA synthesis. Possible explanations offered by
    the author for this effect include: (i) possible activation by
    propylene thiourea of endogenous nucleases, which may stimulate DNA
    synthesis; (ii) possible activation by propylene thiourea of
    replicons, which may induce thymidine incorporation into DNA; and
    (iii) possible reaction by propylene thiourea with hormone receptors,
    which may also lead to increased DNA synthesis (Klein, 1981).

    Acute toxicity

         Technical-grade propineb of 84-87% purity was tested in the
    toxicity studies outlined in table 3.

    Short-term studies

    Rat

          Male and female TNO/W74 rats were exposed to propineb aerosols
    at analytically-determined concentrations of 0, 5, 8, 29, or 44 mg/m3
    five times per week for 3 weeks. Each exposure was for 6 hours. Ten
    rats/sex/group were exposed. Animals were examined daily, and weekly
    body weights were determined. After the last exposure, standard
    haematological examinations, clinical chemistries, and urinalyses were
    performed on 5 rats/sex/group. Gross necropsies were conducted and
    organ weights determined for thyroid, heart, lung, liver, spleen,
    kidneys, adrenals, testes, and ovaries. Histopathological examinations
    of 16 to 26 organs/tissues were performed on 5 rats/sex/group.

        Table 3.  Acute toxicity of propineb
                                                                                            

                                            LD50                LC50
    Species        Sex       Route          (mg/kg b.w.)        (mg/m3)        Reference
                                                                                            

    Mouse          M/F       Oral           > 5000                             Thyssen &
                                                                               Kimmerle, 1978

    Mouse          M/F       s.c.           1500-2000                          Thyssen &
                                                                               Kimmerle, 1978

    Mouse          M         Inhalation                         > 391          Thyssen &
                                                                (1 × 4 h)      Kimmerle, 1978

    Rat            M/F       Oral           > 5000                             Thyssen &
                                                                               Kimmerle, 1978

    Rat            F         Oral           5900                               Flucke &
                                                                               Kimmerle, 1977

    Rat            M/F       Dermal         > 5000                             Thyssen &
                                                                               Kimmerle, 1978

    Rat            M/F       i.p.           102-141                            Thyssen &
                                                                               Kimmerle, 1978

    Rat            M/F       Inhalation                         > 522          Thyssen &
                                                                (1 × 1 h)      Kimmerle, 1978

    Rat            M/F       Inhalation                         > 693          Thyssen &
                                                                (1 × 4 h)      Kimmerle, 1978

    Rat            M/F       Inhalation                         > 193          Thyssen &
                                                                (5 × 4 h)      Kimmerle, 1978

    Hamster        M         Inhalation                         > 391          Thyssen &
                                                                (1 × 4 h)      Kimmerle, 1978

    Cat            M         Oral           > 500                              Thyssen &
                                                                               Kimmerle, 1978

    Sheep          M/F       Oral           2500                               Hoffman, 1983

                                                                                            
    

         Rats exposed to 44 mg/m3 exhibited severely-disturbed behaviour
    including, in particular, paralysis of the extremities. All the female
    rats and 1 male rat at this exposure level died by the 13th exposure.
    Animals that died had sharp losses in body weight and were cachectic.
    Gross necropsies revealed small spleens and livers, enlarged adrenals,
    and inflamed lungs. Histopathology revealed acute vasculature
    congestion in the lungs, liver, kidneys, and bronchial lymph nodes,
    indicating that the cause of death was cardiovascular failure. One
    male rat at 29 mg/m3 also exhibited hindlimb paralysis but survived
    to the end of the study. The remaining test animals did not differ
    from control animals with respect to appearance, behaviour or body-
    weight gains. Haematological examinations, clinical chemistries, and
    urinalyses were negative, as were results of gross necropsies, organ-
    weight determinations, and histopathological examinations (Thyssen,
    1979).

    Rabbit

         Technical grade propineb of 87.3% purity was dermally-applied to
    the shaven backs of male and female New Zealand White rabbits 5 times
    per week for 3 weeks at dosage levels of 0, 50, or 250 mg/kg/day. Each
    exposure was for 7 hours. Each dosage group contained 6 male and 6
    female rabbits, one-half of which had intact and one-half abraded skin
    test sites. The test material was emulsified in Cremophor EL and
    distilled water prior to application. Animals were observed daily and
    treated skin was scored daily by the Draize system. Weekly body
    weights were recorded. Prior to dosing and after the final dose,
    standard haematological, clinical chemistry, and urinalysis
    determinations were made on all rabbits. Gross necropsies included
    organ-weight determinations for heart, lung, liver, spleen, kidneys,
    thyroid, adrenals, testes, and ovaries. Histopathological examination
    of 11 tissues/organs from control and 250-mg/kg/day animals was
    performed. Treated and non-treated skin from all rabbits was also
    microscopically examined.

         Three male rabbits died during the study of severe pneumonitis.
    Daily observations, including skin readings, revealed no effects
    attributable to the test material. No differences in body weights
    between control and test animals were observed. All clinical
    laboratory tests and gross necropsies were negative. With the
    exception of slightly-increased absolute and relative liver weights in
    the 250-mg/kg/day female rabbits, organ weights in control and test
    animals were similar. Histopathological examinations of tissues/
    organs were negative (Mihail & Kaliner, 1979).

    COMMENTS

         A mouse oncogenic study with propineb indicated increased
    haepatocellular adenomas in male mice and increased pulmonary adenomas
    in female mice at 800 ppm in the diet, the highest dosage level
    tested. These increases in tumours may have been related to
    administration of the test material. Thyroid tumours were not induced
    in treated mice in this study. A NOEL for non-neoplastic effects could
    not be determined in this study, however, due to insufficient data.

         In a long-term study on mice with PTU, an increased incidence of
    hepatocellular adenomas was observed in male mice at 1000 ppm in the
    diet, the highest dosage level tested. Increased incidences of
    hepatocellular carcinomas were also observed in male mice at 10 ppm
    and higher. In the same study, increased incidences of hepatocellular
    adenomas and carcinomas were observed in female mice at 100 ppm and
    higher. Thyroid tumours attributable to PTU were not observed, but
    increased thyroid hypercellularity was noted in male mice at 1000 ppm.

         In long-term rat studies with propineb, previously reviewed by
    the JMPR, an increased incidence of thyroid benign tumours was
    observed at 1000 ppm and higher in the diet. Non-neoplastic thyroid
    effects were observed in the same study at 100 ppm and higher. In
    another study, increased liver and kidney weights were observed at
    100 ppm and higher. A NOEL of 10 ppm was determined. In a long-term
    study on rats with PTU, thyroid tumours were not related to treatment
    with PTU except at 1000 ppm in the diet, which was a clearly-excessive
    dosage level. Goitrogenic effects in the thyroid were observed,
    however, at dosage levels as low as 1 ppm, the lowest dosage level
    tested. A NOEL could not be determined in this study.

         Short-term studies on thyroid function in rats with propineb did
    not establish an unequivocal NOEL for effects on the thyroid. In a
    long-term study on thyroid function in rats with PTU, effects on the
    thyroid were observed at 1000 ppm in the diet. Ambiguous effects were
    observed at lower dosage levels. Pharmacokinetic studies on rats with
    PTU demonstrated preferential uptake of radioactivity from
    14C-labeled PTU by the thyroid.

         Mutagenic studies on propineb and PTU were negative or
    inconclusive. A special study on the effect of PTU on DNA demonstrated
    increased DNA synthesis in mouse spleen cells. PTU did not bind to the
    DNA of mouse liver cells.

    TOXICOLOGICAL EVALUATION

         In view of the carcinogenic response in the liver of mice to PTU
    and the lack of a NOEL for thyroid effects of propineb in a long-term
    study in mice, in short-term studies in rats, and for PTU in a long-
    term study in rats, the Meeting recommended that the temporary ADI for
    propineb be withdrawn.

    REFERENCES

    Bomhard, E. & Loser, E. Propylene thiourea, chronic toxicity study on
    (1980)    rats (two-year feeding experiment). Bayer AG Institute of
              Toxicology, Report No. 9345. Unpublished report submitted to
              WHO by Bayer AG.

    Bomhard, E. & Loser, E. Propylene thiourea, chronic toxicity study
    (1981)    with mice (feeding study over two years). Bayer AG Institute
              of Toxicology, Report No. 10102. Unpublished report
              submitted to WHO by Bayer AG.

    Brune, H., Deutsch-Wenzel, R., & Mohr, U. Toxicology examination of
    (1980)    propineb in a chronic feeding study on NMRI mice. Biological
              laboratory of Dr. Brune (Hamburg), Report No. R 1792.
              Unpublished report submitted to WHO by Bayer AG.

    Flucke, W. & Kimmerle, G. Propineb (LH 30/Z), triadimefon (MEB 6447),
    (1977)    study for acute toxicity after simultaneous administration
              of both active ingredients. Bayer AG Institute of
              Toxicology, Report No. 7065. Unpublished report submitted to
              WHO by Bayer AG.

    Hatano Institute. Mutagenicity study of propineb. Food and Drug Safety
    (1978)    Center, Hatano Institute, Japan. Unpublished report
              submitted to WHO by Bayer AG.

    Herbold, B. Propineb, Salmonella/microsome test to evaluate for point
    (1980a)   mutations. Bayer AG Institute of Toxicology, Report No.
              9321. Unpublished report submitted to WHO by Bayer AG.

    Herbold, B. Propylene thiourea, Salmonella/microsome test for
    (1980b)   detection of point mutagenic effects. Bayer AG Institute of
              Toxicology, Report No. 9563. Unpublished report submitted to
              WHO by Bayer AG.

    Herbold, B. Propylene thiourea, Salmonella/microsome test to
    evaluate
    (1981a)   for point mutations employing liver homogenates from strain
              CFW1 male mice. Bayer AG Institute of Toxicology, Report No.
              10116, Unpublished report submitted to WHO by Bayer AG.

    Herbold, B. Propylene thiourea, Pol A1 - test on E. coli to evaluate
    (1981b)   for DNA damage. Bayer AG Institute of Toxicology, Report No.
              10146. Unpublished report submitted to WHO by Bayer AG.

    Herbold, B. Propineb, micronucleus test on the mouse to evaluate for
    (1982)    mutagenic effects. Bayer AG Institute of Toxicology, Report
              No. 10974. Unpublished report submitted to WHO by Bayer AG.

    Hoffmann, K. (1983). LH 30/Z (Antracol(R) active ingredient), acute
    (1983)    toxicity for sheep after oral administration. Bayer AG
              Institute of Toxicology, Report No. 11463. Unpublished
              report submitted to WHO by Bayer AG.

    Klein, W. Study for the effect of PTU on DNA metabolism. Seibersdorf
    (1981)    Research Centre, Institute of Biology, Project No. PS/2277,
              Bayer Study No. T 4003 443 (PTU). Unpublished report
              submitted to WHO by Bayer AG.

    Krotlinger, F., Loser, E., & Kaliner, G. Propineb (Antracol(R) active
    (1980)    ingredient), subchronic toxicological study to establish the
              dose-time-effect relationship for the thyroid. Bayer AG
              Institute of Toxicology, Report No. 9313. Unpublished report
              submitted to WHO by Bayer AG.

    Mihail, F. & Kaliner, G. LH 30/Z (Antracol(R) active ingredient),
    (1979)    subacute dermal cumulative toxicity study on rabbits. Bayer
              AG Institute of Toxicology, Report No. 8322. Unpublished
              report submitted to WHO by Bayer AG.

    Thyssen, J. Antracol(R) active ingredient, subacute inhalation study on
    (1979)    rats. Bayer AG Institute of Toxicology, Report No. 8334.
              Unpublished report submitted to WHO by Bayer AG.

    Thyssen, J. & Kimmerle, G. (1978). Antracol(R) active ingredient (LH
    (1978)    30/Z), acute toxicological study. Bayer AG Institute of
              Toxicology, Report No. 7208. Unpublished report submitted to
              WHO by Bayer AG.

    Weber, H. & Dressier, H.F. Effect on thyroid function of male rats on
    (1980)    sub-chronic administration of propineb (Antracol(R) active
              ingredient). Bayer AG Institute of Pharmacokinetics, Report
              No. 9268. Unpublished report submitted to WHO by Bayer AG.

    Weber, H. & Patzchke, K. Effect of long-term administration of
    (1979)    propylene thiourea (PTU) on thyroid function of male and
              female rats. Bayer AG Institute of Pharmacokinetics, Report
              No. 8494. Unpublished report submitted to WHO by Bayer AG.

    Weber, H., Patzschke, K., & Wegner, L.A. Propylene thiourea-14C,
    (1978)    biokinetic study on rats. Bayer AG Institute of
              Pharmacokinetics, Report No. 7397. Unpublished report
              submitted to WHO by Bayer AG.
    


    See Also:
       Toxicological Abbreviations
       Propineb (Pesticide residues in food: 1977 evaluations)
       Propineb (Pesticide residues in food: 1984 evaluations)
       Propineb (Pesticide residues in food: 1993 evaluations Part II Toxicology)