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    MECARBAM

    EXPLANATION

         Mecarbam was evaluated for acceptable daily intake by the Joint
    Meeting in 1980, and reviewed in 1983 and 1985 (Annex 1, FAO/WHO,
    1981a, 1984, and 1986a). A toxicological monograph was published after
    the 1980 Meeting (Annex 1, FAO/WHO, 1981b) and a monograph addendum
    was published after the 1983 Meeting (Annex 1, FAO/WHO, 1985a). In
    1980, a temporary ADI of 0.001 mg/kg b.w. was established. The 1983
    JMPR extended the temporary ADI and required an adequate delayed
    neurotoxicity study in hens, a full report of the metabolic studies
    that had been performed in rats, complete metabolic studies in
    laboratory animals other than the rat, and a ruminant metabolism
    study. Since the required data were not made available to the 1985
    Joint Meeting, the temporary ADI was reduced to 0.0005 mg/kg b.w. and
    extended until 1986. This monograph addendum summarizes the requested
    data that were submitted to the 1986 Joint Meeting.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

    Rats

         The absorption, biotransformation, and excretion of
    14C-mecarbam (97.6% pure, radiolabelled on the carbamoyl group) were
    studied in 3 male and 3 female Sprague-Dawley-derived rats
    (CR1:CD(SD)BR strain) after single oral doses of 10 mg/kg b.w. Within
    96 hours after dosing, a total of approximately 85 and 91% of the
    administered radioactivity was recovered in the urine (78 and 82%), in
    the faeces (3 and 2.6%), and in the cage washings (3.4 and 5.9%) from
    the males and females, respectively. Negligible radioactivity was
    recovered in expired carbon dioxide within 48 hours after dosing
    (0.4 and 0.3% from males and females, respectively). Most of the
    administered radioactivity was eliminated in the urine within 24 hours
    after dosing in males (74%) and within 48 hours in females (82%). TLC
    and HPLC analysis of rat urine showed no significant differences
    between the sexes in the number of radiolabelled metabolites. After
    TLC using 4 different solvent systems, 11 radiolabelled products were
    observed that were more polar than either the parent compound or any
    of its metabolites observed in plants, i.e., mecarboxon, diethoate, or
    diethoxon. At least 13 and 19% of the radiolabelled products found in
    the urine of male and female rats, respectively, were found to be
    conjugated. HPLC analysis of non-hydrolysed urine showed some
    quantitative but no qualitative differences in the pattern of
    radiolabelled metabolites between male and female rats and confirmed
    the presence in both sexes of at least 1 conjugated metabolite
    (Hall et al., 1984).

    Goats

         The absorption, biotransformation, and excretion of
    14C-mecarbam (98% pure, radiolabelled on the carbamoyl group) after
    a single oral dose of 10 mg/kg b.w. were studied in 3 lactating goats
    1 to 3 years old. Within 96 hours after dosing a mean of 86% of the
    administered radioactivity was recovered in urine (79%), faeces
    (4.5%), milk (1.3%), and cage washings (1.5%). The majority (82%) of
    the administered radioactivity was eliminated within 24 hours, mostly
    in the urine (77%). The absorption of radioactivity was rapid in the 3
    animals, with peak plasma levels of 1.7, 1,4, and 1.5 g equivalents
    of 14C-mecarbam/ml being reached at 0.25, 0.5, and 1.0 hours
    post-dose, respectively. The elimination rate was exponential, with
    the half-life ranging from 5.1 to 7.4 hours. Tissue residues measured
    at 96 hours were not detectable in the blood, fat, heart, plasma, or
    spleen, and they were low in the liver, kidneys, and muscle. A total

    of 0.07% of the administered dose was found in the liver. After TLC
    analysis of plasma, milk, and urine extracts, at least 6 radiolabelled
    products in plasma and 3 in milk and urine were found that were more
    polar than either the parent compound or any of its metabolites in
    plants, i.e. mecarboxon, diethoate, and diethoxon. None of the 6
    radiolabelled products found in urine was likely to be a conjugate
    since the pattern was essentially unchanged following hydrolysis with
    -glucuronidase and/or aryl sulfatase (Cresswell & Hopkins, 1986).

    Metabolism

         The urinary metabolites of orally administered 14C-mecarbam
    (98% pure) in rats and goats were characterised by TLC and mass
    spectrometry analysis. No evidence was obtained in either species for
    the presence in urine of either unchanged mecarbam or its plant
    metabolites, mecarboxon, diethoate, and diethoxon. Rat urine contained
    6 major metabolites, each accounting for more than 10% of the
    radioactivity. The major metabolite (22%) was identified as a
    phosphorothioate (a product of oxidative desulfuration) containing
    both the P=O moiety and the 14C-carbamoyl group. Another metabolite
    (10%) was identified as a phosphorodithioate, possibly (S-methylcar-
    bamoyl-N-hydroxymethyl)-O,O-diethyl phosphorodithioate. The remaining
    metabolites were products of esterase hydrolysis of the S-C bond,
    resulting in the separation of the phosphorous and carbamoyl moieties.
    Only 3 metabolites were found in goat urine. The major product (78%)
    was identified as the same phosphorodithioate compound present in rat
    urine. There was little evidence of oxidative desulfuration or
    esterase hydrolysis of 14C-mecarbam in the goat (Hall et al.,
    1986).

    Toxicological Studies

    Special studies on delayed neurotoxicity

    Chickens

         Four treatment groups and 1 negative control group of 10 hens
    each (hybrid brown laying strain, 12 - 13 months old) were treated
    with single oral doses of 175 or 0 mg/kg b.w. mecarbam (97% pure, 7%
    w/v in corn oil) at a dose volume of 2.5 mg/kg b.w. The dose level of
    175 mg/kg b.w. was selected on the basis of the results of a
    preliminary study which showed the LD50 for mecarbam in these hens
    to be 171 mg/kg b.w. All birds dosed with mecarbam were given
    10 mg/kg b.w. atropine sulfate immediately prior to dosing. An
    additional group of 10 positive control hens were given single oral

    doses of 500 mg/kg b.w. TOCP. Due to good survival after the first
    dose, the animals of only 2 test groups and those of the negative
    control (corn oil) group were re-administered the same dose level on
    day 22 from the first dose. These animals were sacrificed 21 days
    after the second dose, whereas the hens of the remaining 2 test groups
    and the positive control hens were sacrificed 21 days after the first
    dose.

         Cholinergic signs of acute toxicity (subdued appearance,
    trembling, weakness, unsteadiness, and inability to stand) were
    observed in animals of all groups dosed with mecarbam. Mortality
    incidence after the first dose in the test, negative control, and
    positive control animals was 7/40, 1/10, and 3/10, respectively.
    Another test animal died after the second dose of mecarbam.
    Significant decreases in body weight and food consumption were
    observed during the 3-day period after the first and second doses in
    hens treated with mecarbam. No clinical signs of neurotoxicity
    (ataxia) were recorded, after the first or the second dose, in any of
    the test or negative control birds. Eight positive control animals
    developed delayed locomotor ataxia following the first dose of TOCP.
    Histopathological examination of the brain, spinal cord, and
    peripheral nerves of all birds except those which died within 2 days
    of dosing indicated no change in nervous tissue attributable to the
    administration of mecarbam. The authors of the study concluded that,
    under the conditions of the test, oral administration to hens of a
    single dose of mecarbam of 175 mg/kg b.w., followed by a second equal
    dose, did not produce any clinical signs or any significant
    histopathological changes indicative of delayed neurotoxicity
    (Roberts et al., 1986).

    COMMENTS

         Orally administered 14C-mecarbam was rapidly and almost
    completely absorbed and metabolized by rats, and rapidly eliminated in
    the urine. Little or no unchanged mecarbam and at least 10
    non-conjugated and 1 conjugated (possibly with sulfate) metabolites
    were found in the urine. Orally administered 14C-mecarbam was also
    rapidly absorbed, metabolized, and excreted by goats. At least 6
    non-conjugated metabolites were found in the urine.

         The metabolism of mecarbam appears to be different in rats than
    in lactating goats. In rats, hydrolysis, oxidative desulfuration, and
    degradation of the carbamoyl moiety were the major metabolic
    reactions. In goats, metabolism occurred mainly at the carbamoyl
    moiety. In both species O-de-ethylation was a minor pathway.

         A neurotoxicity study in hens indicated no clinical or
    histopathological evidence of neurotoxicity after 2 repeated
    administrations of mecarbam at single dose levels of approximately
    the LD50.

         On the basis of the results of the metabolism and delayed
    neurotoxicity studies an ADI was allocated.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Rat:    5 ppm in the diet, equivalent to 0.21 mg/kg b.w./day.
         Dog:    10 ppm in the diet, equal to 0.35 mg/kg b.w./day.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.002 mg/kg b.w.

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
    EVALUATION OF THE COMPOUND

         Observations in man.

    REFERENCES

    Cresswell, D.G. & Hopkins, R. 14C-Mecarbam: a study of absorption,
    1986      distribution, metabolism and excretion following oral
              administration to the goat. Unpublished report
              No. 4899-50/543 from Hazleton Laboratories Europe, Ltd.,
              Harrogate, U.K. Submitted to WHO by Dow Chemical Europe
              S.A., Horgen, Switzerland.

    Hall, B., Ward, C., & Hopkins, R. 14C-Mecarbam: metabolic fate in the
    1984      rat. Unpublished report No. 3778-50/147 from Hazleton
              Laboratories Europe, Ltd., Harrogate, U.K. Submitted to WHO
              by Dow Chemical Europe S.A., Horgen, Switzerland.

    Hall, B.E., Webborn, P., & Hopkins, R. The metabolism of 14C-mecarbam
    1986      in the rat and lactating goat. Unpublished report
              No. 5037-50/662 from Hazleton Laboratories Europe, Ltd.,
              Harrogate, U.K. Submitted to WHO by Dow Chemical Europe
              S.A., Horgen, Switzerland.

    Roberts, N.L., Phillips, C.N.K., Gopinath, C., Fish, C.J., & Begg, S.
    1986      Acute delayed neurotoxicity study with mecarbam in the
              domestic hen. Unpublished report No. DWC 464/86139 from
              Huntingdon Research Centre, Huntingdon, Cambridgeshire, UK
              Submitted to WHO by Dow Chemical Europe S.A., Horgen,
              Switzerland.
    





    See Also:
       Toxicological Abbreviations
       Mecarbam (ICSC)
       Mecarbam (Pesticide residues in food: 1980 evaluations)
       Mecarbam (Pesticide residues in food: 1983 evaluations)