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    PROPHAM

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

    EXPLANATION

           Propham, isopropyl carbanilate, is the active substance of
    several products used as herbicides and potato sprout inhibitors. It
    was previously evaluated by the JMPR in 1963 and 1965 (Annnex 1,
    references 2 and 3) at which time the data available were considered
    inadequate for allocating an ADI. 

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, and excretion

           The tissue distribution and excretion of 14C-labelled propham
    (purity > 99%, specific activity of chain-labelled molecule 4.9
    mCi/mmol and of ring-labelled molecule 4.1 mCi/mmol) were
    investigated in adult female Wistar rats (mean body-weight 270 g). A
    single oral dose (2 animals per dose) of 0, 0.67, 19, 38, or 75
    mg/kg bw 14C-labelled propham (5ÁCi in 1.0 ml of 20% aqueous
    ethanol solution) was administered by intubation. Rats were housed
    individually in glass metabolism cages; expired air was continuously
    monitored for radioactivity for 72 h. The faeces and urine samples
    were collected at 24, 48, and 72 h and analyzed for 14C by liquid
    scintillation counting. The urine was analyzed by paper
    chromatography and thin-layer chromatography. In a similar
    experiment, single rats were killed at various times (1-24 h) after
    administration of a single dose of 0.81 mg/kg bw 14C-labelled
    propham/kg bw (5ÁCi in 1.0 ml of a 20% aqueous ethanol solution).
    Tissue samples (kidneys, liver, blood, lungs, heart, spleen,
    intestine, brain, muscle, and fat) were freeze-dried, and analyzed
    for 14C by gas-flow G-M counter.

           The average 3-day excretion of radioactivity in urine, faeces,
    and CO2 was 80, 5, and 5%, respectively after chain-labelling of
    propham, and 85, 5, and 0%, respectively after ring-labelling of
    propham. There was no significant difference in the rate of
    excretion or the route of elimination among rats receiving different
    dosages. The radioactivity was distributed in all examined tissues
    with the highest concentrations in the kidneys. The average
    biological half-life of propham in most organs was short, ranging
    between 3 and 8 h. However, in brain, fat, and muscle, the half-life
    was about twice the value for other organs. Propham was metabolized
    by hydrolytic and oxidative mechanisms and the resulting metabolites
    were excreted either as free forms or as conjugates. Tentative
    identification of the metabolites indicated the following substances
    to be present in urine: (4-OH)-propham, 1-OH-2-propyl-propham, 1-
    carboxyl-1-ethyl-propham, and (4-OH)-propham-sulphate (Fang  et
     al., 1974).

    Biotransformation

           The metabolic fate of propham was investigated in male Wistar
    rats weighing approximately 250 g. The animals received a single
    dose of 15 mg 14C-labelled propham (purity 98.8%)
    intraperitoneally in 0.2 ml absolute ethanol (n=5) or orally as a
    suspension in 1.0 ml syrup (n=6). Urine, faeces and carbon dioxide

    were collected for up to 4 days after dosing, the respired gases
    being trapped in 20% sodium hydroxide solution. For biliary studies,
    bile was collected for 6 h after injection of 0.5 mg 14C-labelled
    propham in 0.25 ml 40% aqueous ethanol into the femoral vein of rats
    under urethane anaesthesia. Other rats received 50 mg neomycin
    sulphate in 0.5 ml water orally 24 h before an oral dose of 14C-
    labelled propham. The drinking-water provided for these animals
    contained 1% neomycin sulphate. Radioactivity was measured by liquid
    scintillation counting.

           After both oral and intraperitoneal doses approximately 80% of
    the administered radioactivity appeared in the urine over 4 days,
    with much smaller amounts appearing in the faeces and respired air.
    Of the urinary radioactivity about 80% was present as the sulphate
    ester of isopropyl N-(4-hydroxyphenyl)carbamate. Little or no
    isopropyl N-(2-hydroxyphenyl)-carbamate was formed. Neomycin feeding
    studies suggested that the small amount of hydrolysis which occurred
    was mediated by the animal rather than by its gut microflora.
    Biliary elimination of 14C-labelled propham was also examined,
    about 30% of an intravenous dose being excreted in the bile within
    6 h (Bend  et al., 1971).

           The identification of propham metabolites was studied in six
    male Sprague-Dawley rats, weighing 220-274 g, and a lactating goat
    weighing 48 kg. Each animal was given a single dose by stomach tube
    of 100 mg/kg bw 14C-ring-labelled propham (purity 99%, 6.8-8.6 ÁCi
    in the rats and 37 ÁCi in the goat, specific activity not given).
    Faeces and urine (plus milk from the goat) were collected separately
    at 6, 24, and 48 h after dosing. The samples were analyzed together
    with fractions from the liver, heart, kidneys, intestine, intestinal
    content, and the remaining carcass for 14C by liquid scintillation
    techniques.

           Radioactivity was rapidly eliminated in the urine of both the
    rat and goat during the first 6 h after dosing. The cumulative 48-h
    excretion of radioactivity, in per cent of the dose given, in urine
    was 96% and 90% in the rat and goat, respectively, and in faeces 2%
    and 3% in rat and goat, respectively. Radioactivity in milk was
    highest during the first 6 h after dosing. The cumulative 48-h milk
    radioactivity was 0.45% of the dose. The content of radioactivity 48
    h after dosing was highest in the liver. The relative content of
    radioactivity of the heart, kidney, and intestine seemed to be quite
    different in rat and goat. The data indicated that biliary excretion
    of propham metabolites into the intestinal tract had occurred. The
    metabolites in the rat included: glucuronic acid conjugate of
    isopropyl 4-hydroxycarbanilate, sulphate ester of isopropyl 4-
    hydroxycarbanilate, sulphate ester of 4-hydroxyacetanilide and
    several other minor unidentified compounds. Goat urinary metabolites
    included the sulphate ester of isopropyl 4-hydroxycarbanilate,
    glucuronic acid conjugate of isopropyl 4-hydroxycarbanilate, another
    conjugated form of isopropyl 4-hydroxycarbanilate, a conjugate of

    isopropyl 3,4-dihydroxy-carbanilate, the sulphate ester of isopropyl
    2-hydroxycarbanilate, a conjugate of 4-hydroxyaniline, the sulphate
    ester of 2-hydroxyaniline, another conjugated form of 2-
    hydroxyaniline, the glucuronic acid conjugate of 4-
    hydroxyacetanilide, a conjugate of (2-hydroxyisopropyl)4-
    hydroxycarbanilate and several other unidentified compounds (Paulson
     et al., 1973).

    Effects on enzymes and other biochemical parameters

           No data available.

    Toxicological studies

    Acute toxicity studies

           Studies of acute toxicity following oral (animals fasted 16 h
    before dosing) or dermal administration or after inhalation of
    propham were performed (purity 98.4%) in SPF-bred Wistar rats, Bor
    strain: WISW (SPF Cpb) (body-weight 160-200 g) and acclimatized and
    randomised before use (Mihail, 1984; Pauluhn, 1984).

    Table 1. Acute toxicity of propaham
                                                                 
    Species  Strain  Sex  Route   LD50      LC50   Reference
                                  mg/kg bw  mg/l
                                                                 

    Rat      Wistar  M    oral    4300             Mihail (1984)
             Wistar  F    oral    8700

    Rat      Wistar  M    dermal  > 5000           Mihail (1984)
             Wistar  F    dermal  > 5000

    Rat      Wistar  M    inhal.            > 2.1  Pauluhn (1984)
             Wistar  F    inhal.            > 2.1
                                                                 

    Short-term toxicity studies

           Four groups of 10 Wistar rats (Bor strain, WISW/SPF Cpb)/sex, 4
    to 5 weeks old were fed dietary concentrations of 0, 200, 1000 or
    5000 ppm (equal to 0, 14, 70 or 384 mg/kg bw/day for males and 0,
    21, 109 or 576 mg/kg bw/day for females) 99.3% purity propham for 13
    weeks. Stability and homogeneity in the diet were based on parallel
    studies (dietary concentrations, 100 and 15 000 ppm), which
    indicated acceptable results (i.e. ▒10% of nominal values). Body-
    weight, food and water intake were monitored weekly. Haematology,
    clinical biochemistry, gross pathological examinations and
    histopathological examinations were performed. 

           Appearance, behaviour and mortality of the rats were unaffected
    by dosages of up to 5000 ppm. Food intake of females was slightly
    increased at all three dose levels, but the increase was not dose-
    dependent. At 5000 ppm the body-weight gain in males was slightly
    but statistically significantly reduced. A significant and dose-
    dependent decrease was seen in the erythrocyte counts, haemoglobin,
    haematocrit and mean cell haemoglobin concentration and an increase
    was seen in the mean cell volume in males receiving 1000 and 5000
    ppm and in females receiving 5000 ppm. Cholesterol concentrations
    were increased in females at 5000 ppm. Males dosed with 1000 and
    5000 ppm had a significantly increased relative adrenal weight and
    at 5000 ppm increased relative liver and spleen weights. In females
    a significant increase in relative liver weight was observed at 1000
    ppm and a significant increase in relative kidney and liver weight
    at 5000 ppm. At 1000 and 5000 ppm a treatment-related effect on
    liver function (liver weight and ASAT activity) was seen in both
    sexes. A dose-dependent increase in haemosiderin content in the
    spleen was seen in both sexes at 1000 and 5000 ppm. Based on the
    effects on the blood parameters a NOAEL of 200 ppm equal to 14 and
    21 mg/kg bw/day in males and females, respectively, was determined
    (Hahnemann & Vogel, 1984).

           Four groups of 20 SPF Wistar rats (Bor strain, WISW/SPF
    Cpb)/sex, 5 to 6 weeks old and weighing 68 to 124 g (males) or 84 to
    116 g (females) were fed dietary concentrations (99.4% purity
    propham) of 0, 10, 30 or 100 ppm equal to 0, 0.6, 1.8 or 5.8 mg/kg
    bw/day for males and 0, 0.7, 2.4 or 7.8 mg/kg bw/day for females for
    12 months. Homogeneity in the 10 and 100 ppm diet was within ▒10%
    and stability of diets stored under similar conditions to those in
    the study were within ▒3% of original concentrations. Body-weight,
    food and water intake were monitored weekly up to week 13 and
    biweekly thereafter. Haematology, clinical biochemistry, urinalysis,
    and ophthalmoscopy were performed and gross pathological
    examinations and histopathological examinations were carried out.
    The body-weight was unaffected in both sexes at all dose levels as
    were mortality and clinical signs. Haematological data indicated no
    significant effects at 10 and 30 ppm. At certain times during the
    treatment with 100 ppm statistically significantly reduced
    erythrocyte counts, leucocyte cell counts, per cent lymphocytes in
    differential blood count and haematocrit were observed.
    Statistically significantly increased values for mean MCH and MCHC
    compared to control values were noted. Haemosiderosis in spleen was
    more severe in the propham-treated males compared to control
    animals. A NOAEL of 100 ppm, equal to 5.8 or 7.8 mg/kg bw/day for
    males and females respectively, was determined (Eiben, 1988a). 

    Long-term toxicity/carcinogenicity studies

    Rats

           Four groups of 20 SPF Wistar rats (Bor strain, WISW/SPF
    Cpb)/sex, 4 to 5 weeks old, and weighing 72 to 110 g (males) or 73
    to 107 g (females) were fed dietary concentrations (99.3% purity
    propham) of 0, 100, 500 or 2500 ppm equal to 0, 5.7, 29 or 150 mg/kg
    bw/day for males and 7.6, 37 or 200 mg/kg bw/day for females, for 24
    months. Ten additional rats/sex/dose level were fed similar diets
    and were sacrificed at 12 months. Homogeneity based on diet
    containing 100 or 15 000 ppm was within ▒10% and stability under
    conditions of storage similar to those used in the present study
    indicated 101 to 109% of initial concentrations. Body-weight, food
    and water intake were monitored weekly up to week 13 and biweekly
    thereafter. Haematology, clinical biochemistry, urinalysis, and
    ophthalmoscopy were performed and gross pathological examinations
    and histopathological examinations were carried out. No treatment-
    related incidences of clinical signs and symptoms, changes in food
    and water intake or mortality were observed up to the dosage of 2500
    ppm. Body-weight gain was comparable to control rats up to 2500 ppm
    (males) and 500 ppm (females). At 2500 ppm, weight gain was slightly
    decreased in females during the second half of the study. No
    evidence of any treatment-related adverse effects on the blood or
    haematopoietic organs was found in the 100 ppm dosage group. At and
    above 500 ppm, evidence of increased haemopoiesis was observed in
    the spleen and liver. Reduced erythrocyte and haematocrit counts and
    increased spleen weights were also recorded in the 2500 ppm groups.
    At 2500 ppm mineralization in the kidneys and increased relative
    kidney weights were observed most often in the females. No adverse
    effects were noted for any other organ systems. Ophthalmological
    investigations revealed age-related eye changes which were fairly
    evenly distributed over all groups. No carcinogenic potential of
    propham could be inferred from the type, frequency or time of onset
    of benign or malignant tumours. Based on the effects on the blood
    parameters, a NOAEL for propham of 100 ppm, equal to 5.7 and 7.6
    mg/kg bw/day in males and females respectively was determined.
    Carcinogenicity was not demonstrated (Eiben, 1989).

    Hamsters

           The Meeting determined that the data available in a published
    carcinogenicity study on golden hamsters (Van Esch & Kroes, 1972)
    were inadequate to permit evaluation. The authors concluded that
    there was no indication of a carcinogenic effect of propham in
    hamsters at a dose level of 200 mg/kg bw/day given daily for 33
    months.

    Reproduction studies

           In a two-generation, two-litter per generation Wistar rat (Bor
    strain, WISW/SPF Cpb) reproduction study, 4 groups of 25 rats/sex
    (initial age 4 to 6 weeks, weighing 62-93 g) were fed diets
    containing 0, 200, 1000 or 5000 ppm, 99.3-99.4% purity propham,
    equal to 0, 20, 80 or 100 mg/kg bw/day in the F0 generation and 0,
    20, 100 or 550 mg/kg bw/day in the F1 generation. Homogeneity and
    stability were determined in parallel studies for dietary
    concentrations of 100 and 15 000 ppm. Homogeneity was within ▒10%
    and stability data indicated 101 and 109% of nominal values. F0
    animals were inspected daily for clinical signs and were weighed
    weekly mating (after approximately 16 weeks on test for F0 animals
    and at about 100 days of age for F1b parents) was determined by
    vaginal smear. Lactation period was 4 weeks. F1a, F2a and F2b
    pups were sacrificed at weaning and subject to gross and
    histopathological examination. 

           At dietary concentrations up to 5000 ppm there were no effects
    on appearance, behaviour, general condition, mortality, fertility,
    insemination rate, gestation, viability, duration of pregnancy or
    sex ratio. No malformations were observed and incidence of
    stillbirths was unaffected. The lactation index and mean litter size
    at birth were comparable to those of the controls up to 1000 ppm. At
    5000 ppm, the lactation index was in some cases significantly
    depressed and the litter size was reduced. Body-weight gain was not
    retarded in the parent animals or in the pups up to 1000 ppm. The
    body-weight of parents and pups in the 5000 ppm group increased more
    slowly during the rearing period. Food intake was unaffected up to
    1000 ppm. Following 5000 ppm F1b rats consumed less food. The
    macroscopic examination of the dissected F1b and F2b pups
    revealed no changes of organs related to the treatment. The
    histopathological investigations revealed indications of increased
    breakdown of the red blood cells from 200 ppm upwards in F0 and
    F1b parents, which was identified by an increased incidence of
    siderosis in the liver and/or spleen. At 5000 ppm increased
    extramedullary haematopoiesis was frequently observed and increased
    spleen weights were recorded. At 200 ppm and above (F1b) and from
    1000 ppm and above (F0) spleens were commonly dark in colour. No
    indications of organ damage were found in the other organs of parent
    animals in the gross pathology examinations nor on the basis of the
    organ weights or histopathological investigations. In all dosage
    groups, therefore, signs of increased breakdown of erythrocytes were
    found. The dose of 200 ppm of propham was therefore toxic to
    parental animals. Based on effects on lactation index, food intake
    and body-weight gain, a NOAEL for reproduction of 1000 ppm equal to
    80 mg/kg bw/day, was determined. The NOAEL for maternal toxicity
    (haematological effects) was < 200 ppm (equal to 20 mg/kg bw/day)
    (Eiben, 1988b).

           The effect of propham on the haematopoietic organs was
    investigated in a 6-month reproduction study in rats, since a NOAEL
    in this context had not been determined in the previous 2-generation
    study. Propham (purity 99.1-99.4%) was administered at dietary
    concentrations of 0, 20, 60 or 180 ppm to F0 males (25
    animals/dosage group) and F0 females (25 animals/dosage group),
    their F1 litters until weaning and for a further 6 months to 20
    male and 20 female weaned F1 rats from these litters. The dosages
    in the F1 generation were equal to 0, 1.8, 5.3, or 16 mg/kg bw/day
    in the males and 0, 2.3, 6.7, or 21 mg/kg bw/day in the females.
    SPF-bred Wistar rats, Bor strain: WISW (SPF Cpb), were acclimatized
    before use. All animals were randomized in order to obtain
    comparable groups. At the start of the study, the rats had an age of
    11-16 weeks and a body-weight of 300-349 g (F0 males) and 189-217
    g (F0 females). Test for homogeneity from a parallel study showed
    a mean propham concentration of 97%, 90%, and 99% of nominal values
    in feed containing 20, 100, and 15 000 ppm, respectively. Tests for
    stability from a parallel study resulted in 105%, 101%, and 109% of
    nominal values in feed containing 20, 100, and 15 000 ppm,
    respectively. The animals were inspected daily for general clinical
    signs and specific behaviours. The body-weight and food intake was
    recorded weekly during study. Mating was determined by presence of
    sperm in vaginal smears or by finding of vaginal plugs. The body-
    weight of each of the F1 litter was determined weekly and each pup
    underwent inspections for malformations. Blood samples were taken
    from 10 animals per group for haematological examination. Organ
    weights were determined and histopathological examinations were
    carried out on selected tissues.

           Dietary concentrations of 180 ppm propham were tolerated
    without any adverse effect on general behaviour, mortality or any of
    the reproduction parameters of the F0 generation (fertility,
    gestation, viability, lactation, litter size and litter weight). No
    malformations or increase in the number of still-births were
    observed. Feed intake, appearance, behaviour, body-weight gain
    (lactation period and 6 months treatment period) and mortality of
    adult F1 rats remained unaffected at dosages up to 180 ppm.
    Haematological investigations were negative. No findings were
    obtained at autopsy which indicated any treatment-related organ
    damage or changes in organ weights of liver, spleen or kidney.
    During the histopathological examination of liver, spleen, kidneys
    and bone marrow, no treatment-related pathological findings were
    observed up to 180 ppm. Detection of ferruginous pigment in liver,
    kidney and spleen was within the normal variability.

           Administration of 180 ppm propham equal to 16 and 21 mg/kg
    bw/day in males and females, respectively, was tolerated with no
    adverse effects during the ante-natal development phase, the rearing
    period and the following 6 months. NOAELs for reproduction and
    maternal toxicity exceeded 180 ppm, equal to 16 mg/kg bw/day (Eiben,
    1988c). 

    Special studies on genotoxicity

           Data are shown in Table 2.
        Table 2.  Results of genotoxicity assays on propham
                                                                                               
    Test system                Test object        Concentration     Purity  Results   Reference
                                                  of propham
                                                                                               

    In vitro

    Ames test (with and        Salmonella         300-4800          99.6%   Negative  Herbold
    without metabolic          typhimurium        Ág/plate                  (▒ S9)    (1992)
    activation)

    Sister chromatid exchange  Human lymphocytes  10-4, 10-5,       n.g.    Negative  Lindahl-
    (without metabolic                            10-6 M                              Kiessling
    activation)                                                                        et al.
                                                                                      (1989)

    Gene mutation              S-49               1.1 - 2.2 M       n.g.    Negative  Friedrich
    (dexamethasone             Mouse                                                  & Nass
    resistance) (without       lymphoma cells                                         (1983)
    metabolic activation)

    In vivo

    Micronucleus test          Mouse (NMRI)       2 x 1000 mg/kg    99.9%   Negative  Machemer
                                                  bw and 2 x 2000                     (1977)
                                                  mg/kg bw orally.
                                                  The two doses
                                                  were administered
                                                  with an interval
                                                  of 24 h
                                                                                               

    n.g. = not given
        Special studies on teratogenicity.

           Four groups of 25 pregnant Wistar rats (strain, Bor WISW/SPF
    Cpb) were dosed orally with a 0.5% aqueous suspension of propham at
    0, 30, 100 or 300 mg/kg bw/day on days 6-15 of pregnancy. Fetuses
    were removed by caesarean section on day 20 of pregnancy. 

           The body weight, clinical signs and pregnancy rate of the dams
    were unaffected by propham. There were no treatment-related
    mortalities among the fetuses. Malformations occurred in three
    fetuses of two dams in the 300 mg/kg bw group and in one fetus of a
    dam in the 30 mg/kg bw/day group and in none of the control or 100

    mg/kg bw/day group. One of the three fetuses had multiple skeletal
    anomalies and two fetuses had exencephaly and some other
    malformations The Meeting concluded that this study was inadequate
    for evaluation (Renhof, 1984). 

    Special studies on skin-sensitizing effect

           Propham was tested in female guinea-pigs for skin sensitizing
    properties using Magnusson and Kligman's Maximization Test. SPF-bred
    DHPW female guinea-pigs were used. The animals were acclimatized for
    at least 7 days before start of treatment. At the start of treatment
    the guinea-pigs were 4-7 weeks old and weighed 276-358 g. The
    animals were observed daily throughout the study for clinical signs
    and body-weights were recorded before and at the end of study.
    Propham (purity 99.6%) was formulated in Cremophor EL (2% v/v) in
    physiol-ogical NaCl solution. The stability of propham was
    satisfactory. An analysis showed that 95-97% of the active substance
    in the test solution was found after 24 h storage. The homogeneity
    of test solutions was also satisfactory. The mean content of three
    samples from each of two test solutions was 93-108% of the nominal
    values. The test animal group consisted of 10 guinea-pigs, and two
    control groups consisted of 10 animals each. The following propham
    concentrations were used: intradermal induction: 2.5%, topical
    induction: 25%, and challenge: 25%. Following shaving of the backs
    and flanks of the guinea-pigs three intradermal injections
    (injection volume 0.1 ml) with a distance of 1-2 cm were given in a
    row per side to the left and right of the spinal column. Topical
    induction with propham in cremophor/saline solution was performed
    one week after intradermal induction. Challenge exposure (0.5 ml)
    was performed three weeks after intradermal induction. A
    hypoallergenic dressing soaked in the 25% test article formulation
    was placed for 24 h on the left flank of propham animals and first
    control group. A control dressing was placed on the right flank. The
    criterion for sensitization was a higher incidence and intensity of
    skin reaction in test animals compared to control animals. All
    animals tolerated the treatment without signs of toxicity and no
    skin reactions occurred among the test or control animals. There is
    thus no indication of a skin sensitizing effect of propham (Diesing,
    1989).

    Observations in humans

           No data available.

    COMMENTS

           Following oral administration to rats, propham was rapidly
    eliminated via the urine (80-96%), faeces (5%), and expired air
    (5%). Metabolism proceeds by hydrolysis and oxidation. 

           Propham had a low acute oral toxicity in rats. The World Health
    Organization has classified propham as unlikely to present acute
    hazard in normal use (WHO, 1992). 

           In short-term toxicity studies in rats at dietary
    concentrations of 0, 200, 1000, or 5000 ppm for 13 weeks or of 0,
    10, 30, or 100 ppm for 12 months, effects were observed on
    haematological parameters, ASAT and relative weight of the adrenals,
    liver and spleen. Increases in haemosiderin content in the spleen
    were seen. On the basis of the haematological effects the NOAEL was
    100 ppm, equal to 5.8 and 7.8 mg/kg bw/day in males and females,
    respectively. 

           In a 2-year long-term toxicity/carcinogenicity study in rats at
    dietary concentrations of 0, 100, 500, or 2500 ppm propham, effects
    on haematological parameters and spleen weight were observed.
    Increased haemopoiesis was seen in the spleen and liver. On the
    basis of the effects on the haematological parameters the NOAEL was
    100 ppm, equal to 5.7 and 7.6 mg/kg bw/day in males and females,
    respectively. There was no evidence of carcinogenicity. 

           A 33-month study in hamsters was inadequate for evaluation.

           In a two-generation reproduction study in rats at dietary
    concentrations of 0, 200, 1000, or 5000 ppm propham, the NOAEL was
    1000 ppm, equal to 80 mg/kg bw/day, on the basis of effects on
    lactation index, food intake, and body-weight gain.

           An oral teratogenicity study in rats was inadequate for
    evaluation. 

           Although the data were not fully adequate, the Meeting
    concluded that propham was not likely to be genotoxic.

           The available toxicological data on propham were not adequate
    to allocate an ADI.

    Studies without which the determination of an ADI is impractible

    1.     A biotransformation study in rats.

    2.     Short-term toxicity study in a non-rodent species.

    3.     A test specifically for aneuploidy.

    4.     Teratogenicity study in two species.

    5.     Available observations in humans.

    REFERENCES

    Bend, J.R., Holder, G.M. & Ryan, A.J. (1971) Further studies on the
    metabolism of isopropyl N-phenylcarbamate (propham) in the rat.  Fd.
     Cosmet. Toxicol., 9: 169-177.

    Diesing, L. (1989) Studies on skin-sensitizing effect in guinea-
    pigs. Unpublished report No. 17537 from Institute of Toxicology,
    Agrochemicals, Department of Toxicology, Bayer AG, Friedrich-Ebert
    Str. 217-333, D-5600 Wuppertal 1, Germany. Submitted to WHO by Bayer
    AG, Wuppertal, Germany.

    Eiben, R. (1988a) Chronic toxicity study in Wistar rats.
    Supplementary study to investigate effects on the spleen.
    Unpublished report No. 17170 from Institute of Toxicology for
    Industrial Chemicals, Fachbereich Toxicology, Bayer AG, Friedrich-
    Ebert Str. 217-333, D-5600 Wuppertal 1, Germany. Submitted to WHO by
    Bayer AG, Friedrich-Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.

    Eiben, R. (1988b) Two-generation study in rats. Unpublished report
    No. 16880 from Institute of Toxicology for Industrial Chemicals,
    Fachbereich Toxicology, Bayer AG, Friedrich-Ebert Str. 217-333, D-
    5600 Wuppertal 1, Germany. Submitted to WHO by Bayer AG, Friedrich-
    Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.

    Eiben, R. (1988c) Six month feeding study after intrauterine
    pretreatment (supplementary study to clarify haemotoxic effects).
    Unpublished report No. 16877 from Institute of Toxicology for
    Industrial Chemicals, Fachbereich Toxicology, Bayer AG, Friedrich-
    Ebert Str. 217-333, D-5600 Wuppertal 1, Germany. Submitted to WHO by
    Bayer AG, Friedrich-Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.

    Eiben, R. (1989) Chronic toxicity and carcinogenicity investigations
    in Wistar rats. Unpublished report No. 17947 from Institute of
    Toxicology for Industrial Chemicals, Fachbereich Toxicology, Bayer
    AG, Friedrich-Ebert Str. 217-333, D-5600 Wuppertal 1, Germany.
    Submitted to WHO by Bayer AG, Friedrich-Ebert Str. 217-333, D-5600
    Wuppertal 1, Germany.

    Fang, S.C., Fallin, E., Montgomery, M.L. & Freed, V.H. (1974)
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    female rat.  Pesticide Biochemistry and Physiology, 4: 1-11.

    Friedrich, U. & Nass, G. (1983) Evaluation of a mutation test using
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    Mihail, F. (1984) Study for acute oral and dermal toxicity.
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    Pauluhn, J. (1984) Study for acute inhalation toxicity and
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    Paulson, G.D., Jacobsen, A.M., Zaylskie, R.G. & Feil, V.J. (1973)
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    Renhof, M. (1984). Study for embryotoxic effect on the rat following
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    Van Esch, G.J. Van & Kroes, R. (1972). Long-term toxicity studies of
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    See Also:
       Toxicological Abbreviations
       Propham (FAO Meeting Report PL/1965/10/1)
       Propham (IARC Summary & Evaluation, Volume 12, 1976)