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 µg 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
ß-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)