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PESTICIDE RESIDUES IN FOOD - 1982


Sponsored jointly by FAO and WHO






EVALUATIONS 1982




Data and recommendations of the joint meeting
of the FAO Panel of Experts on Pesticide Residues
in Food and the Environment and the
WHO Expert Group on Pesticide Residues
Rome, 23 November - 2 December 1982

Food and Agriculture Organization of the United Nations
Rome 1983


ALDICARB

CH
3
O H
' " /
CH
3
SCCH = NOCN
' \
CH
3
CH
3


Explanation

Aldicarb was reviewed by the JMPR in 1979 (FAO/WHO 1980)
1/
. An
ADI of 0-0.001 mg/kg body weight was established, based on the
no-effect level of 0.125 mg/kg bw observed in a short-term feeding
study on rats. Further desirable information was noted at that time.

Additional data on aldicarb metabolites have become available,
primarily on aldicarb sulphone, which is one of the two major terminal
residues. The other major metabolite is aldicarb sulphoxide. The data
consist of acute, subchronic and chronic studies, with additional
information and observations in humans, as well as a water inclusion
study in rats.

The data considered in support of the ADI established by the 1970
JMPR are re-evaluated in this monograph addendum in light of the
additional data received, and a rationale is provided for revising the
previously recommended ADI.

EVALUATION FOR ACCEPTABLE DAILY INTAKE

TOXICOLOGICAL STUDIES

Special Study on Reproduction

Rat - aldicarb sulphone

Aldicarb sulphone (99.76% pure) was administered to rats
(10 males and 20 females/group) at dosage levels of 0, 0.6, 2.4 and
9.6 mg/kg/day in their diet for approximately 100 days. Rats were then
mated to initiate a three generation, one litter per generation,
reproduction study. Fertility, gestation survival (4, 14 and 21 days)
and lactation indices were determined, as well as body weights and
food consumption. Male rats fed 9.6 mg/kg exhibited reduced body
weights. There were no differences from the control with regard to
fertility, gestation survival or viability indices. Marginal effects




1/
See Annex 2 for WHO and FAO documentation.

on the lactation index were noted. It was determined that aldicarb
sulphone, at levels up to and including 9.6 mg/kg, was without adverse
effects on reproduction under the conditions of this study (Woodside
et al 1977a).

Special Study on Teratogenicity

Rat - aldicarb sulphone

The aldicarb sulphone reproduction study conducted by Woodside
et al (1977a) incorporated a teratology bioassay. The animals were
divided into four groups and orally dosed with either 0, 0.6, 2.4 or
9.6 mg/kg at one of the following time intervals of gestation: 0-20
days, 6-15 days, or 7-9 days. All animals were sacrificed before
parturition (day 20) and the foetuses examined for skeletal and
visceral changes. Resorption sites, number and condition of pups and
litter weights were recorded. The pregnancy rate was unaffected by
treatment, except that resorption sites per female were slightly
increased in 9.6 mg/kg-treated females for the 6-15 day treatment
interval. No increase in resorption was seen at the same dosage level
for days 0-20. Anomalies were essentially non-existent and there was
no indication of terata produced under the conditions of the study at
levels up to and including 9.6 mg/kg.

Special Study for Carcinogenicity

Mice - aldicarb sulphone

Groups of Charles River CD-1 mice (50/sex/group) were
administered 0, 0.15, 0.6, 2.4 and 9.6 mg/kg aldicarb sulphone in the
feed for 18 months. Mice were housed two per cage in the first year
and singly thereafter. Observations were made routinely throughout and
included mortality, food consumption and body weight determinations.
Gross and microscopic examination were performed on all mice. Body
weight changes were sporadic and exhibited no trends. Histologic
changes were not statistically different from controls at any dose
level for either sex. Based on these criteria, aldicarb sulphone did
not affect tumour incidence or produce any pathological alteration in
this strain of mouse (Woodside et al 1977b).

Special Study on Neurotoxicity

Hen - aldicarb sulphone

Adult white Leghorn hens (40 each) were intubated to receive
250 mg/kg bw aldicarb sulphone suspended in maize oil. Two other
groups, each with 10 hens, received either TOCP (500 mg/kg) or maize
oil alone, and served as positive and negative control groups
respectively. The birds received single oral doses, 21 days apart, in
a typical acute delayed neurotoxicity evaluation. The hens were

observed every third day for 42 days. There were no neurological
effects other than acute cholinergic signs of poisoning in the TOCP
dosed group. No histological examination was performed, owing to the
lack of demonstrated neurotoxic signs. Aldicarb sulphone did not cause
delayed neurotoxic reactions under the conditions of the study (Babish
and Salerno 1977).

Special Study on Sensitization

Skin sensitization to aldicarb sulphone (UC 21865, technical) or
a 75% WP formulation was evaluated in albino guinea pigs (Hartley
Strain) using a modified Landsteiner technique. Neither substance was
determined to be a sensitizer under the conditions of this study
(Conroy and Carpenter 1977).

Acute Toxicity

The acute toxicity of aldicarb, aldicarb metabolites and of
aldicarb formulations to several animal species is summarized in
Table 1.

Aldicarb is very highly toxic to mammals by oral exposure. In all
species tested, the acute oral toxicity of aldicarb and its
formulations are similar. The oral toxicity of the formulations is
basically that associated with ingestion of the active toxicant; the
lower acute oral toxicity of aldicarb formulations reflects the
reduced concentrations of aldicarb as formulated in the granular
material. The toxicity of aldicarb when injected intraperitoneally or
intravenously is substantially similar to the toxicity via the oral
route, suggesting rapid absorption into the body.

Aldicarb is also highly toxic by dermal exposure; it readily
penetrates the skin, especially moist skin. In contrast, the dermal
toxicity of TEMIK
R
formulations is extremely low, reflecting the
greatly reduced availability of aldicarb from the formulations.
Moistening the Temik
R
formulation on the skin during dermal exposure
similarly enhances penetration of aldicarb; granular Temik
R

formulations are more toxic in contact with moist skin than with dry
skin.

The oral toxicities of aldicarb and its principal metabolite,
aldicarb sulphoxide, are similar, while the oral toxicity of aldicarb
sulphone is approximately 4% that of aldicarb. The other aldicarb
metabolites are considerably less toxic than these.

Table 1. Acute Toxicity of Aldicarb and Its Metabolites in Animals


"


Table 1 (con't)





Table 1 (con't)




1/
TSX is a mixture of Temik (5.5%), Terrachlor fungicide (9.5%) and
Terrazole fungicide (2.3%).
Short-Term Studies

Mice - aldicarb sulphone

Groups of Charles River, CD-1 mice (5/sex/group) were fed
aldicarb sulphone in the diet at levels of 0, 0.15, 0.6, 2.4, 9.6 and
38.4 mg/kg for seven days. Body weights were determined on three
separate days. Mice were observed daily for signs of toxicity or
abnormality. Selected organ weights (liver and kidneys) were measured
and their absolute and relative organ weights determined. It was
concluded that only the highest dose produced statistically
significant body weight decrease. There were no dose-related or
statistically significant organ weight changes. Cholinesterase values
were not determined (Weil and Carpenter 1974b).

Rat - aldicarb

Groups of CFE rats (10 per sex per group) were fed aldicarb in
their diet for 93 days at dosage levels of 0, 0.02, 0.1 and 0.5 mg/kg
body weight. One rat per level was killed for cholinesterase (plasma,
RBC and brain) determinations at 1 or 2, 4 and 29 days of dosing. Body
weights, diet consumption and selected organ weights (liver and
kidney) were determined, and histopathological examination of lung,
liver, kidney and trachea were done. Mortality was increased for the
highest dose levels, statistically at the 0.5 mg/kg bw dose level.
Body weight and food consumption were also decreased at the highest
level. Relative liver and kidney weights were not affected at any dose
level in comparison to control. Histopathology of the selected organs
was unremarkable and there were no compound-related effects noted.
There were no consistent dose-related effects on the cholinesterase
determinations, except for plasma cholinesterase depression in both
sexes after 30 days at the highest level. There was no indication of
how soon after feeding the ChE determinations were performed, which
could account for the sporadic results, together with the small number
of animals sampled at each interval (Weil and Carpenter 1963).

Rat - aldicarb sulphoxide: aldicarb sulphone (1:1)

Wistar rats (10 males and 10 females per group) were administered
aldicarb sulphoxide and aldicarb sulphone in a 1:1 ratio, in the
drinking water, ad libitum, for 29 days. Nominal dose levels were 0,
0.075, 0.3, 1.2, 4.8 and 19.2 ppm. Body weight, food and water
consumption, and clinical haematology parameters were measured weekly.
Plasma and red blood cell cholinesterase levels were determined after
8, 15 and 29 days of treatment. Brain cholinesterase was measured at
termination. Animals were continuously exposed to the test substances
in water until blood samples were taken or sacrifice was performed,
Cholinesterase activity in blood and brain was analysed by a
modification of an automated procedure described by Humiston and
Wright (1965), which is an adaptation of the method described by

Ellman et al (1961). Preliminary in vitro enzyme inhibition
kinetic studies verify the methodology as acceptable for defining
reversible carbamate-induced cholinesterase inhibition in rats.
Significant depression of plasma, RBC and brain cholinesterase, in
both sexes, occurred at the highest dose level. Sporadic differences
in plasma and RBC cholinesterase values, which occurred in males only,
were inconsistently depressed and within the range of biological
variability. The data demonstrate that a level of 4.8 ppm of aldicarb
sulphoxide: aldicarb sulphone in water is without effect on
cholinesterase (plasma, RBC, brain) in either sex. Based on the actual
concentrations being approximately 80% of the nominal values, the no-
effect level is roughly 3.84 ppm or 0.384 mg/kg (in water). Food and
water consumption values together with body weight gains were
significantly decreased in both sexes at the high dose level when
compared to controls. There were no such differences at any of the
other dose levels. There was no mortality (Mirro et al 1982).

Rabbit - aldicarb sulphone (dermal)

Aldicarb sulphone (technical and 75 WP) were administered to
the unabraded, but closely clipped, ventral surface of rabbits
(6 males/group, 5 days/week for 19 applications) at dosages of
4.8 mg/kg bw for 75 WP and 3.5, 7.0 and 14.0 mg/kg bw for technical
aldicarb sulphone. No mortality, skin irritation or cholinesterase
depression were observed. However, rabbits were removed from treatment
19 hours prior to ChE analysis, which could account for the lack of
response (ChE depression) considering the rapid reversibility of ChE
inhibition for aldicarb and its ChE-inhibiting metabolites. Body
weight was significantly depressed in the high dose level rabbits.
There were no reported treatment-related effects on organ weights or
organ-to-body weight ratios (liver, kidney, brain). Necropsy findings
were unremarkable (Weil et al 1977).

Observations in Humans

Fifteen male volunteers participated in a study in Panama to
evaluate human exposure in a banana plantation where Temik-15G was
applied under natural conditions. Temperatures ranged from 75F (24C)
to 92F (32C) with 80 to 90% relative humidity. The workers used
three different types of hand-held applicators. Blood samples were
taken from all volunteers prior to initiating the test and immediately
following each 6-hour working period. Samples were obtained in the
field and analysed 1-2 hours later in the laboratory using the
Boehringer Mannheim method, a photometric test based on the method of
Ellman et al (1961). Urine samples were also collected. Only two
workers showed greater than 25% reduction in their blood
cholinesterase activity (29% and 50%). Spontaneous reversibility was
evident in both cases. The worker with 50% reduction showed 25%
recovery within three hours. Blood samples from the other worker
indicated 100% recovery 24 hours later. Results of blood analyses

indicated that cholinesterase activity was below the normal range
(population) in samples collected from six workers during the second
day of the study. Cholinesterase activity in all samples taken during
the first and third day of the study were within the normal range. No
clinical signs of aldicarb-induced intoxication were found, although
one individual presented symptoms of nausea, stomachache and headache
(Union Carbide 1979).

COMMENTS

Aldicarb, the active ingredient of the nematocide-insecticide
sold under the trade name TEMIK
R
, is rapidly absorbed and
metabolized by mammals to aldicarb sulphoxide, its major metabolite.
Aldicarb sulphoxide is more slowly degraded to aldicarb sulphone. All
metabolites of aldicarb, both oxidative and hydrolytic, are rapidly
and completely eliminated from the body, 80-90% being excreted within
24 hours, and leave no detectable residues by the fifth day. Data
demonstrate that they are not stored in body tissues.

The toxicological properties of aldicarb and its metabolites have
been assessed in several species of laboratory animals under a variety
of exposure conditions (acute, subchronic and chronic) and routes
(oral by gavage, diet and drinking water; dermal; inhalation and
injection). Aldicarb is extremely toxic acutely, with an oral LD
50
in
rats of approximately 1 mg/kg body weight. Aldicarb sulphoxide is a
more potent acetylcholinesterase inhibitor than aldicarb, and the
rapid conversion in animals to aldicarb sulphoxide is probably
responsible for the acute toxic reaction associated with aldicarb.
The acute toxicity of aldicarb sulphone is considerably less (LD
50
=
20-25 mg/kg) than either aldicarb or aldicarb sulphoxide.

Studies examining the acute and subchronic effects of aldicarb
administered orally to human volunteers and under a variety of actual
working conditions reveal the same pattern of acetylcholinesterase
depression and rapid recovery as that demonstrated in experimental
animals. Depressed cholinesterase levels return rapidly to normal and
symptoms, if any, subside immediately following removal from exposure
to aldicarb. There have been no lasting effects on the health of
volunteers exposed to aldicarb under natural or laboratory conditions.
The toxicological responses of humans to aldicarb and its metabolites,
under such conditions, do not differ from those of laboratory animals.

Aldicarb's inhibitory effect on acetylcholinesterase is rapidly
reversed following hydrolysis of the carbamylated enzyme to regenerate
active enzyme. In experimental animals and humans, spontaneous
recovery from sublethal doses of aldicarb occurs very rapidly (within
a few hours of exposure). The competition of acetylcholine and
aldicarb for the enzyme's active site, the instability of carbamylated
enzyme, together with the efficient metabolism and high aqueous

solubility of aldicarb, contribute to the spontaneous rapid recovery
of inhibited enzyme. The rate at which acetylcholinesterase activity
recovers makes it difficult to measure acetylcholinesterase inhibition
analytically in the laboratory, and rapid assays must be used under
carefully controls conditions.

Short-term and long-term studies with aldicarb and its sulphone
and sulphoxide metabolites have revealed no neurological,
carcinogenic, mutagenic or teratogenic effects, and no adverse effect
on reproduction. At a dietary dose of 0.25 mg/kg/day, a minimal
depression of blood cholinesterase was observed in rats. In dogs, a
no-effect level was noted at 0.25 mg/kg/day. Cholinesterase levels
(RBC and plasma) were apparently unaffected in this study, although
these were measured after a period that allowed the spontaneous
recovery of the enzyme. In a subchronic study where aldicarb
sulphoxide and sulphone were added to drinking water in a 1:1 ratio,
the no-effect level was observed to be 4.8 ppm, based on
cholinesterase depression. In a 6-month rat feeding study with the
sulphoxide metabolite, the no-effect level for cholinesterase
depression has been accepted as 0.125 mg/kg body weight, with no other
effects observed at higher doses.

These studies demonstrate that the method of administering the
dose to the animal can greatly modify the toxic properties of
aldicarb, as contrasted in the acute oral versus short- and long-term
dietary studies. Rats, mice and dogs have tolerated LD
50
doses
repeatedly administered from 7 days to 2 years, when incorporated in
their diet. Similarly, a 1:1 mixture of aldicarb sulphoxide and
aldicarb sulphone when administered in the drinking water to rats for
28 consecutive days at doses equivalent to the LD
50
for aldicarb
sulphoxide (e.g. 0.38 to 1.5 mg/kg bw) caused no deaths and only
moderate ChE depression at the high dose. Conversely, a single bolus
of aldicarb or aldicarb sulphoxide equivalent to the above doses, when
administered by gavage or intubation to laboratory animals, caused
death in less than 2 hours. This ability of all animals to survive
daily doses of aldicarb equivalent to single-dose LD
50
values
suggests the reduced bioavailability of aldicarb when administered in
the diet. Human volunteers tolerated single oral doses of aqueous
solutions of aldicarb (in doses of 0.025, 0.05 or 0.1 mg/kg) with only
mild depression of whole blood cholinesterase in all cases. Only the
persons receiving 0.1 mg/kg aldicarb presented symptoms of acute
cholinergic stress (i.e. nausea, sweating, pin-point pupils,
salivation). These data indicate that humans are no more sensitive to
aldicarb, aldicarb sulphoxide or aldicarb sulphone than laboratory
animals.

In the light of the data on aldicarb, the spontaneous recovery of
the carbamylated cholinesterase enzyme within a few hours and the
reduced bioavailability from dietary exposure, it is unlikely that
humans exposed to residues of aldicarb in food will suffer any

prolonged or significant cholinesterase depression, provided such
residues are from purposeful use in accordance with GAP (good
agricultural practice) and within established international limits
(MRLs). This is suggested by the no-effect levels determined from
reproduction, teratogenic, carcinogenic, neurotoxic, subchronic and
chronic dietary studies. ChE inhibition is transient and recovery is
rapid and spontaneous.

Accordingly, the Committee has revised the ADI to reflect more
accurately the concern for aldicarb residues that may be present in
foodstuffs.

TOXICOLOGICAL EVALUATION

Level Causing no Toxicological Effects

Rat: 2.5 ppm in the diet, equivalent to 0.125 mg/kg bw.

Dog: 0.25 mg/kg bw

Estimate of Acceptable Daily Intake for Man

0 - 0.005 mg/kg bw.

REFERENCES

Babish, J.G. and Salerno, A. Neurotoxicity evaluation of UC 21865
1977 in white Leghorn hens (Gallus domesticus). Report from
Food and Drug Research Laboratories submitted to the World
Health Organization by Union Carbide Corporation.
(Unpublished)

Conroy, W.J. and Carpenter, C.P. UC 21865 Technical and 75% WP
sensitization potential 1977 in guinea pigs as determined by
intradermal injection. Report from Carnegie-Mellon Institute
(No. 40-12) submitted to the World Health Organization by
Union Carbide Corporation. (Unpublished)

Ellmann, G.L. Courtney, K.D., Andres, V. Jr. and Featherstone, R.M.
1961 A new and rapid colorimetric determination of
acetylcholinesterase activity. Biochem. Pharmacol. 7:88.

Field, W.E. Acute dermal toxicity in rabbits. Report from CDC
1979a Research, Inc, (CDC-UC-009-79) submitted to the World Health
Organization by Union Carbide Corporation. (Unpublished)

1979b Acute dermal toxicity in rats. Report from CDC Research,
Inc. (CDC-UC-008-79) submitted to the World Health
Organization by Union Carbide Corporation. (Unpublished)

Humiston, C.G. and Wright, G.J. A new automated method for the
1965 determination of cholinesterase activity. Clin. Chem.
11:802.

Johnson, H.E. and Carpenter, C.P. Temik (technical grade compound
1966 21149). Comparative behavioural effect in rats. Report from
Mellon Institute (No. 29-89) submitted to the World Health
Organization by Union Carbide Corporation. (Unpublished)

Myers, R.C., Weil, C.W. and Carpenter, C.P. Temik, 10G: Acute 4-hour
1975a skin penetration of rats. Report from Mellon Institute (no.
38-40) submitted to the World Health Organization by Union
Carbide Corporation. (Unpublished)

Myers, R.C., Weil, C.S. and Cox, E.F. Temik 19G B.C. (coal); 10G and
1975b 15G (gypsum); 15G (corn cob). Comparative toxicity studies
via peroral, dermal and inhalation routes. Report from
Mellon Institute (no. 38-141) submitted to the World Health
Organization by Union Carbide Corporation. (Unpublished)

Mirro, E.J., DePass, L.R. and Frank, F.R. Twenty-nine day water
1982 inclusion study in rats. Report from Bushy Run Research
Laboratory (no. 45-181) submitted to the World Health
Organization by Union Carbide Corporation. (Unpublished)

Nycum, J.S. and Carpenter, C.P. Toxicity studies on Temik and
1968 related carbamates. Report from Mellon Institute (no. 31-48)
submitted to the World Health Organization by Union Carbide
Corporation. (Unpublished)

Union Carbide. Volunteer worker's exposure monitoring study
1979 (Panama). Report from Union Carbide Corporation submitted to
the World Health Organization by Union Carbide Corporation.
(Unpublished)

Weil, C.S. and Carpenter, C.P. Results of three months of inclusion
1963 of Compound 21149 in the diet of rats. Report from Mellon
Institute (No. 26-47) submitted to the World Health
Organization by Union Carbide Corporation. (Unpublished)

1968 Temik 10G-V (10.3% granular formulation of Compound 21149).
Acute and 14-day dermal application to rabbits. Report from
Mellon Institute (no. 31-137) submitted to the World Health
Organization by Union Carbide Corporation. (Unpublished)

1969 Four-hour wet skin contact test on rats. Report from Mellon
Institute (no. 32-64) submitted to the World Health
Organization by Union Carbide Corporation. (Unpublished)

Weil, C.S. and Carpenter, C.P. Comparative skin penetration toxicity
1970 of Temik 10GV and 15 other pesticide formulations as
marketed. Report from Mellon Institute (No. 33-15) submitted
to the World Health Organization by Union Carbide
Corporation. (Unpublished)

1971 Comparative skin penetration toxicity of Temik, Temik 10GV,
Temik 15GV, and 5 other pesticide formulations as marketed.
Report from Mellon Institute (No. 34-76) submitted to the
World Health Organization. (Unpublished)

1972 Miscellaneous toxicity studies. Report from Mellon Institute
(No. 35-41) submitted to the World Health Organization by
Union Carbide Corporation. (Unpublished)

1974a Temik aldicarb pesticide 10G and 15G. Range-finding toxicity
studies. Report from Mellon Institute (no. 37-39) submitted
to the World Health Organization by Union Carbide
Corporation. (Unpublished)

1974b UC 21865; results of feeding in the diet of mice for 7 days.
Report from Mellon Institute (No. 37-89) submitted to the
World Health Organization by Union Carbide Corporation.
(Unpublished)

Weil, C.S., Conroy, W.J., Condra, N.I. and Cox, E.F. Aldicarb
1977 sulphone UC 21865. 19-day rabbit skin inunction. Report from
Mellon Institute (No. 40-13) submitted to the World Health
Organization by Union Carbide Corporation. (Unpublished)

Woodside, M.D., Weil, C.S. and Cox, E.F. Inclusion in the diet of
1977a rats for three generations (aldicarb sulphone), dominant
lethal mutagenesis and teratology studies. Report from
Carnegie Mellon (no. 40-1) submitted to the World Health
Organization by Union Carbide Corporation. (Unpublished)

1977b Aldicarb sulphone; 18-month feeding in the diet of mice.
Report from Carnegie Mellon (No. 40-38) submitted to the
World Health Organization by Union Carbide Corporation.
(Unpublished)

Wolfe, G.W. and Bristol, K.L. Acute oral toxicity study in rats. Temik
1980 TSX. Report from Hazleton Laboratories America, Inc. (Report
400-631) submitted to the World Health Organization by Union
Carbide Corporation. (Unpublished)

Wolfe, G.W., Voelker, R.W. and Dauvin, E.M. Acute dermal toxicity
1980 studies in rabbits. Temik TSX. Report from Hazleton
Laboratories America, Inc., (Report 400-632) submitted to
the World Health Organization by Union Carbide Corporation.
(Unpublished)