' ALDICARB, ALDICARB SULFOXIDE
AND ALDICARB SULFONE -
1995
. V >
Drinking Water Health Advisory
Health and Ecological Criteria Division
Office of Science and Technology
Office of Water '
,U.S. Environmental Protection Agency
Washington, DC '20460
I. INTRODUCTION . '
0 The Health Advisory (HA) Program, sponsored by the Office of Water (OW),
provides information on the health effects, analytical methodology and
treatment technology that would be useful in dealing with the contamination of '
drinking water. Health Advisories describe nonregulatory concentrations of
drinking water contaminants at which adverse health effects would not be
anticipated to occur over specific exposure durations. 'Health Advisories
contain a margin of safety to protect sensitive members of .the population.
Health Advisories serve 'as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as^legally enforceable Federal standards. .The HAs are subject to
change as new information becomes available. - .
Health Advisories are developed for one-day, 'ten-day, longer-term
(approximately 7 years, or 10%.of individual's lifetime) and lifetime
exposures based on ,data describing noncarcinogenic endpoints of toxicity.
Health, Advisories do nob quantitatively incorporate any" potential carcinogenic
risk from such exposure. For those substances that are known or probable
Human ^carcinogens, according to the Agency classification scheme ('Group A or
B)> Lifetime HAs are not .recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates-by
" employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit >risk
is usually derived from the linear, multistage model with 95% upper.confidence
limits. This provides a low-dose estimate of cancer risk to humans that is
considered unlikely to pose a carcinogenic risk in excess of the stated
values. Excess cancer risk estimates may also be calculated using the one-
hit, Weibull, logit or probit'models. There is no current understanding of '
the- biological mechanisms involved in cancer to suggest that any one of these
models is able to predict risk more accurately than another. Because each
model is based on differing assumptions, the estimates that are derived can
differ by several orders of magnitude.: '.
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This Health Advisory (HA) is based on the revision of the 1987 drinking
water HA document: for these contaminants. The quantification of toxicological
effects in this HA is based on the available new information on these
chemicals up to 1994, including the November 1992 revised RfDs.
ii. GENERAL INFORMATION AND PROPERTIES
CAS Nos. Aldicarb - 116-06-3
Aldicarb sulf oxide - 1646-87-3 .
Aldicarb sulf one - .1646-88-4
Structural Formulas
1 - '
Aldicarb:
CH3 / .0
I
CH3 H
i ' - .
2-Methyl-2-(metnylthio)propiorialdenyde p-(methylcarbani6yi)oxinie
Aldicarb Sulf oxide:
O CH3 O ,
GH3 - ; H -
2-Methyl-2- (methylsulf InyDpropionaldehyde O- (methylcarbamoyl)oxime
Aldicarb Sulf one:
. ' V
O CH3 ,0
II ' II
CH3-S-C-CH = N~O- C -N-CH3
II. l ,
O CH3 H
2-methyl-2- (methyl sulf onyl) prop ionaldehyde 0- (methylcarbamoyl)oxinie
Synonyms - '
Aldicarb: Temik ' .
* Aldicarb sulf oxide: Temlk sulfide
Aldicarb sulf one: Aldoxicarb, Standak
Uses ; _ . ' '.-
Pesticide (insecticide, nenatocide, acaracide)
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1995
Properties (Registrant's unpublished data; FAO/WHO, 1980? Knaak- et al.. 1966;
Ruhr and Dorough, 1976; Lemley and Zhong, 1983; Martin and
Worthing, 1977) "
Chemical Formula
Molecular Weight
Physical State
Boiling Point (°C)
Melting Point (°C)
Density
Vapor Pressure (mm Hg>"
Specific Gravity
Water Solubility (g/L)
Log Octanol/
Water Part it ion
Coefficient ;
Taste Threshold (Water)
Odor Threshold (Water)
Odor Threshold (Air)
Aldicarb:
C7HI4O,N2S
190.. 3 "
White crystals
Decomposes
above 100 °C
100
0.05 (20°C)
1.195 (25°C).
0.6 (room temp.)
Aldicarb
" SuIfoxide ,
C7HMOjN2S
,206.06
.Crystalline
108-110
330
Aldicarb
Suifone
C7H,«04N2S ,
222.1
Crystalline
132-133
10 (20°C)
Odorless to light
sulfur smell
Occurrence
Hater
Aldicarb will be released to the environment from its
manufacture and use'as a systemic pesticide, acaricide,
nematocide (Howard, 1991; Budavari, 1989).
and
In' a data base that describes the extent of ground-rwater
contamination by aldicarb in the U.S., al'dicarb was detected
in- 19 of 25, States. A.total of 12 States reported levels
above 10 pg/L of which 10 had concentrations above 30 pg/L and
three had-concentrations'greater than 100 pg/L (Howard, 1991).
In the U.S. EPA's National Survey of Pesticides in Drinking -..
Water. Wells (National.Pesticide Survey},, aldicarb was .not
found in 566 community water system wells and 783 rural
domestic drinking water wells, with a minimum reporting limit'
of 0.71 pg/L. Based on the precision of the survey, U.S. EPA
estimates that the maximum number of wells that may contain
aldicarb-nationwide is 750 (0.8%) community water supply wells
and 83,100 (0.8%) rural domestic wells based on a 95% upper-
bound confidence level ((U-S. EPA, 1990).
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1995
Based on a review of the literature, Cohen et al. (1984) found
that typical aldicarb levels detected in well water from 13
States ranged from 1-50 /^g/L. ,
According to Miller et al . (1990), the California Department
of Food and Agriculture's well inventory data base reported
that aldicarb was undetected in 520 samples (456 wells) from <
25 California counties. Aldicarb' s degradation products,
aldicarb -sulf oxide and aldicarb sulfone, were detected in 7
wells, and >8 wells, respectively, out of 67 wells sampled in 14
counties. Concentrations ranged from 0.18-1.02 pg/L for
aldicarb sulfone and from 0.21-1.97 A*g/L for aldicarb
sulf oxide. .
Klaseus et. al. (1988) reported that in a cooperative survey
between the Minnesota Department of Health and the Minnesota
Department of Agriculture, aldicarb was found in 2 wells (5
samples) from 100 private wells and was undetected in '400
public wells sampled. Detections ranged from 0.50-30:6 pg/L
with a median of 9.0 /jg/L. The detection limit was 0.5
Jones and Beck (1984) reportedly found aldicarb in 10 of 39.
surface water samples and 3 of 53 ground-water samples from
'six, Florida citrus groves. . Concentrations ranged from
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1995
' Based on FDA Total Diet' Survey sampling results from the
period April 1982 to April 1985,., the daily dietary intake of
aldicarb for eight di'f ferent age-sex groups were calculated to
be as follows: Infants (6-11 months) "0.002. fjg/day, toddlers
(2 years) 0.006 /jg/day, females (14-16 years) 0.009 /^g/day, '
. males (14-16 years) 0.008 jjg/day, , females (25-30 years.) 0.008
fig/day, males (25-30 years) 0;011 (jg/day, females (60-65
years) 0^014 pg/day, "and males (60-65 years) 0.018 pg/day
(Gunderson, 1986).. . .
No. data were available concerning aldicarb 'levels in-air. '
However, -it is anticipated that .levels in ambient air may be
negligible due to, its low vapor .pressure.
Environmental Fate ,
* i -
,If released to soil, aldicarb is 'expected to be degraded both
biologically and chemically, being subject to oxidation and
hydrolysis. It is expected to be mobile in soil 'and has been' found to
be susceptible to leaching. Vaporization from soils will vary with
soil moisture, evaporating more rapidly from dry soils. (Howard, i991).
In a laboratory study by (Bull et al. ,' 1970 as cited in Howard, 1991),
8.2% and 16. .7% of aldicarb applied to wet and dry s'and (25°C),
respectively, was lost over a 24-hour period.'
- The adsorption coefficient (!(.) for aldicarb was measured in several
; studies with values ranging from 8.2-37 (Howard, 1991). Kenaga (1980)
estimated a similar value of 32. Based on these K^ values, aldicarb ,
should not adsorb significantly to soil. , '
In soils where oxidation and hydrolysis rates are slow compared to the
leaching rates, aldiqarb will be leached into ground water. - The
susceptibility of aldicarb to leaching is supported by monitoring
results whVich indicate the presence of aldicarb in the ground waters -
of many States (Howard, 1991; Cohen et al... 1984).
The hydrolysis of aldicarb in soil is catalyzed by both acids and
bases. The rate 'of hydrolysis was found to vary with pH in 'some
experiments with half-lives as low as 0.4-3.2 days (at-25°C) for 'a pH
range of 4.5-4.9 and as' much as 23 days (at 15°C) for a pH of 7.2. 'In
another study, however, rates varied only slightly in the pH range of
4-10 with half-lives found to be approximately 0.67 days {Howard,
' "
. Aldicarb is oxidized, in soil to trie .sulfoxide and sulfone by chemical
processes and is probably mediated biologically in some cases.' It has
been reported that 8-20% of (the aldicarb added to soil is oxidized
immediately to the sulfone, presumably by chemical oxidation, followed
. by slower oxidation rates. The overall oxidation halfrli'fe for
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1995
aldicarb in soil varies from 1.7-12 days (pH 1-10), but remains fairly
constant over the pH range of 4.4-10. The lowest oxidation half-lives
have been reported.for greenhouse soil, sandy loam, and Paimyrian soil,
ranging from less than 1 day to several days, while in clay loam and peaty
sand half-lives of about 1 .week were measured. In surface soils,
oxidation occurs more rapidly than in subsurface soils and fertilization
may.result in-increased oxidation rates (Howard, 1991).
\» Depending on the soil type, hydrolysis of aldicarb may 'occur at a
faster or slower rate than oxidation. Results from field studies have
found aldicarb-half-lives ranging from several days to several months.
In fields previously treated with aldicarb, degradation rates were
found to be more rapid (Howard, 1991). '
In water, aldicarb is not expected to adsorb ''significantly to bottom
sediments or suspended particles based on its low K^ value.
Experimental results indicate that it will be subject to hydrolysis
with rates varying with pH and temperature. At pH 7.5 or lower and
temperatures of,15°c or lower, aldicarb is relatively stable to
hydrolysis. The half-life .at pH 7.5 and 15°C is 1,90O days and 3,240
days at p!-J 5.5 and 15°C. The lowest measured hydrolysis half-life was
131 days at a pH of 4 and a temperature of 2O°C. Based on an
estimated Henry's Constant of 4.17xlO'9 atm-mj/mole, volatilization
from water should not be an important fats process. The
volatilization half-life for aldicarb in lake,and pond water was N
determined to be 5 days (Howard, 1991; Cohen et al.. 1984).,
Degradation of- aldicarb in ground water occurs at a slow rate. Under
aerobic conditions, it does not degrade unless a relatively high pH
exists (pH 8.5). In anaerobic studies, reported half-lives 'in ground
water were between 62-1,300 days at a pH range of 7-7-8.3.
Experimental results have shown that aldicarb sulfoxide" is reduced to
aldicarb in ground water under aerobic conditions and under anaerobic
conditions when glucose is added (Howard, 1991) . No .studies on
biodegradatiori in natural waters were found.
Aldicarb has been shown to photolyze when irradiated at,254 nanometers
in acetonitrile. No information was found, however, concerning
photolysis of aldicarb in the environment (Howard, 1991).
In the atmosphere, aldicarb may be- partially adsorbed onto
particulates in air based on a relatively low vapor .pressure of IxlO"4
mm Hg. Aldicarb, which is riot adsorbed onto air particulates,'will be
susceptible to vapor phase reactions with hydroxyl radicals, with an
estimated .half^life of 0.24 days (Howard, 1991),
Aldicarb is not expected.to bioconcentrate on aquatic organisms based
on reported bioconcentratiori factors (BCF) of 42 and 4. Kenaga (1980)
calculated the BCF to be 4 from the water solubility of aldicarb,
while Garten and Trabalka (1983 as cited in Howard, 1991) measured a
BCF 'of 42 in a microcosm study for a single species of fish.
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. 1995
III. PHARMACOKINETICS '-'. ' '-, ^ . '.
Aldicarb; . . . . '
Absorption ' ... . ' N
1
Aldicarb is readily and almost completely absorbed through the gut in a
variety of mammalian and non-mammalian species (Knaak et al.. 1966;
>Andrawes et al... 1967; Dorough and Ivie, 1968; Dorough et al.. 1970; Hicks
et al.. 1972; Cambon et al., 1979). . .
Dermal absorption of aldicarb has been demonstrated in rabbits (Ruhr and
Dorough, 1976; Martin and Worthing/ 1977; West arid Carpenter, 1966) and
rats, "(Gaines, 1969) and would be expected to occur in unprotected humans.
in manufacturing and field application settings. West and Carpenter
"(1966) have shown that dermal .absorption of aldicarb by,, rabbits is
facilitated by the use of oil or an organic solvent as the application
;. vehicle. .- ' . <
Distribution .-."'
1 ' . ' " . :
Aldicarb was distributed widely in the tissues of Holstein cows when
administered in feed at 0.6 or 1.2 ppm (Dorouqh et al.', 1970).- Highest
residues were found in the liver.- When aldicarb was administered at
O.12 ppm in this study, residues were detected only in the liver.
Aldicarb residues have also been found in cow's milk (Dorough and Ivie.,
1968) . /' - '
' - . .'..' i " .
In fats administered aldicarb orally, -residues were found in -all 13 tissue
, types analyzed. Hepatic residue levels were similar to"those of many
other tissues (Andrawes et al.. 1967). , '. -
Aldicarb (in a 1:T molar ratio of the parent compound to the sulfone)
administered orally to laying hens in a single dose for 21 consecutive
days resulted in.patterns of distribution that were similar for both
^ exposure durations. The liver and kidneys were the ,main target organs
{Hicks et al.. 1972). Residues also were present in both the yolks and
whites of the eggs laid by these hens. ' ' .
Metabolism . . ','.."
The metabolism of aldicarb involves both hydrolysis of.the carbamate ester
and oxidation of the sulfur to the 'sulfoxide, and sulfone derivatives. All
three of these compounds are active'cholinesterase (ChE) inhibitors
(Andrawes et al.-, 1967;. Bull et al.. 1967).
Metabolic end products of aldicarb detected in both the milk and'urine of
1 a cow included the', sulfoxides and sulfones of .the parent,'compound. An
oxime and a nitrile, as well as. a number of unknown metabolites,, were also
detected (Dorough and Ivie, 1968).- ' '
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Excretion . '
Elimination of aldicarb and its metabolites occurs primarily via the
"urine, as demonstrated in rats (Knaak et 'al., 1966), cows (Dorough and
Ivie, 1968) and chickens (Hicks et al... 1972).
* Excretion of aldicarb as CO2 via the lungs has been demonstrated to be a
minor route in rats (Knaak et al.. 1966).
Excretion of aldicarb is relatively rapid with reported 24-hour
elimination values in rats and cows of approximately 80 to 90% of the
administered dose {Knaak et'al.. 1966; Dorough and Ivie, 1968).
ftldicarb Sulfoxide;
Absorption
Aldicarb sulfoxide is readily and almost completely absorbed through the
gut in a variety of mammalian and non-mammalian species* (Knaak' et al..
1966; Andrawes et al.. "1967; Dorough and Ivie, 1968; Dorough et al.. 1970;
Hicks et al.. 1972; Cambon et al., 1979). Administration of. oral doses of
radiolabeled aldicarb .sulfoxide to female rats resulted in 80-90%
excretion of the jradiolabel in the urine and 2-5% excretion in the feces
.within the first 24 hours (Andrawes et al., 1967).'
'. - i
Dermal absorption of aldicarb sulfoxide by laboratory animals is h£ghly
dependent on the methodology employed, particularly the application
vehicle. Studies by West and Carpenter (1966). have shown'that aldicarb
and its metabolites are absorbed when' applied to the skin of' rabbits;
however, the rate'and extent of absorption- vary, greatly. Aldicarb
sulfoxide which is considerably more water soluble than aldicarb, the -
parent compound, is not well absorbed'into the skin' from aqueous
solutions. . ' , -
r-
Distribution
Information regarding the distribution of aldicarb sulfoxide is limited to
studies in which tissue levels of the aldicarb and its metabolites were
measured following administration of the parent compound (Cambon et al..
1979; Andrawes et al.. 1967; Hicks et al.. 1972). These studies have
provided information on the general distribution pattern of radioactive
label with no indication that any particular tissue or group of tissues
was selectively sequestering aldicarb,sulfoxide.
' 8
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Distribution .,'.'' ;
r *
* \ ,
Information on distribution patterns of aldicarb sulfone is limited to
studies in which tissue levels .of aldicarb and its metabolites were
measured following administration of the parent compound (Cambon et al..
; 1979; Andrawes et al.. 1967; Hicks et al.. 1972). As stated previously,
these'studies have provided information on the distribution pattern of the
radioactive label .with no indication that any particular tissue or group
of tissues was selectively sequestering'.aldicarb sulfone. As previously
described, when aldicarb and/or aldicarb sulfone was orally administered
. to hens in either a single dose.or for 21 consecutive days, the pattern of
distribution was similar for either duration of exposure. Liver and
kidney were .found, to contain .the' highest level of residues (Hicks' et- al.,
1972). . . '
Metabolism - .. '
. Incubation of aldicarb sulfone withmicrpsomes, with or without NADPH,
(reduced nicotinamide adehine dinucleotide phosphate), was found to
partially destroy the sulfone derivative (Oonnithan and Gasida, 1967)..
Excretion ' . '
' V / " ''.''''-.'
/ ' . i
Aldicarb'sulfone is eliminated primarily through the urine.as demonstrated
in rats (Knaak et al.. 1966), cows (Dorough and Ivie,-1968) and chickens
(Hicks et al.. 1972).
IV. HEALTH EFFECTS '". . ..-.-,
i * ' ' "
Humans ... .
ffldicarb; -. ' ' ' ' ' ' . '. '
I
V
Short-term Exposure f
' ' ' ' I-
In two related incidents in 1978 and 1979, ingestion of cucumbers
presumed to contain aldicarb at about 7 to 11 .ppm resulted in
complaints of,diarrhea, abdominal pain, vomiting,'nausea, excessive
perspiration, .dyspnea, muscle fasciculation, blurred vision,
. , headaches, convulsions and/or temporary loss of limb function in a
total of fourteen residents of -a Nebraska town (CDC, 1979; Goes'
x et al., 1980). Symptoms occurred 15 minutes to 2.25 hours after food
consumption'and continued for approximately 4 to 12 hours.
' *'' ' ,
Goldman et al. (1990a,b) reviewed information available on four
outbreaks of food poisoning allegedly involving aldicarb-cpntaminated
cucumbers of watermelon, in California between 1985 and 1988. Dosage
"estimates for 28 of over 1000 reported cases were derived from average
, body weights by age arid sex (from standard tables),- self reported
symptoms and estimated consumption, and analyzed aldicarb sulfoxide
residues from watermelons. .Estimates for 13 additional cases were
* ' , k .
' * v- ' ' *
s .. ' 10 ' - - , . ' '
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provided by Hirsch et al. (1987) also based on estimates of body
weights and consumption, and residues (in cucumbers) of total aldicarb
believed to be primarily the -sulfoxide. This total population (N -
41) had a median of 0.01 mg/kg (for total aldicarb), a first quartile
of 0.06 mg/kg and a third guartile of 0.029 mg/kg. The dosage range
later calculated by Sette (1990) was 0.002-0.086 mg/kg for the Goldman
study. The studies have some limitations since the description of the
cases (self-reported) was limited in terms of onset, duration, and
severity and many of the symptoms (nausea, vomiting, and diarrhea) are
nonspecific. However, the cases analyzed .by Goldman (1990a,b) were
defined as. onset within 2 hours of ingestion which would be related to
the expected peak of cholinesterase inhibition. The analytical ,,
methodology to determine aldicarb sulfone residues was valid although
the limit of. detection of 0.2 pptri (Goldman et al. 1990b) was somewhat
higher than in other reports. As a result, some mi'sclassif ication
errors may have occurred. The use of sex and age averages for body
weights and self-reported food consumption values are also subject to
estimation errors (both underestimates and overestimates).
Nevertheless the dosage estimates are regareded as reasonable general
estimates of effects. The LOAEL.is 0.01 mg/kg; for the most sensitive
population the LOAEL' may be lower (O.002 mg/kg).
Industrial' exposure by a man bagging aldicarb for 1 day resulted in
nausea, dizziness, depression,* weakness, tightness of chest muscles,'
and decreases in plasma and red blood cell ChE activity (Sexton,
1966). The symptoms lasted more than 6 hours, but the subject
returned to work the following day without symptoms.
A California farm worker was found dead from chest injuries about
2 hours after he had begun loading aldicarb (formulated as Temik 15G)
into a hopper. A residue analysis .of his remains indicated that
aldicarb, aldicarb sulfoxide,and aldicarb sulfone were present in
samples of his blood, liver, kidney and skin (hand, abdomen and
thigh). The skin of the hand had the highest concentration of
aldicarb (0.492 ppm), while the kidney had the greatest concentrations
of the sulfoxide and sulfone metabolites (0.261 and 0.422 ppm,
respectively). Little or none of the parent- compound was found in the
blood, liver'or kidney (Lee and Ransdell, 1984). The results of the
toxicological analysis suggest that pesticide intoxication played at
least a contributory role in his death.
Union Carbide Corporation (1971) conducted a study using human
volunteers (4 males/dosage level) who received aldicarb (99.2% a.i.)
in a single dose (administered in 100 mL of distilled water) at 0.025,
0.05 or 0.10 mg/kg. Each man's own blood ChE levels (based on blood
samples taken ,one hour prior to dosing) served as the control for
post-dosing ChE activity. Blood ChE activity was'decreased in every
test subject at 1 and 2 hours post-exposure, with individual decreases
ranging from 20 to 80% in the high-dosage group, 37 to 67% in the
0.05 mg/kg group and 30 to 57% in the 0.025 mg/kg group. There were
no clear dose-related trends in ChE inhibition. Recovery was almost
. complete (75%) by 6 hours after dosing, with more complete recovery
' 11
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1995
seen in the lower dose groups. All subjects that received 0.10 mg/kg
showed clinical effects within 1 to 2 hours with the most common
complaints being leg weakness, constriction of the. pupils, sweating,
salivation, slurred speech; nausea, and malaise. One subject at
0.05 mg/kg had a runny nose .and another at 0.025 mg/kg had a "panic
attack." The relationship of either of these observations to the
aldicarb dosing is not clear. A Lowest-Observed-Adverse-Effect -Level
(LOAEL) of 0.025 mg/kg can be identified from this study for
inhibition,of blood ChE. .
x' ' . '
Rhone-poulenc (1992) conducted a double-blind placebo controlled oral
dosing study with aldicarb (99.0% a.i.)including 38 men and 9 women.
Subjects received a light breakfast and single doses of orange juice
containing aldicarb to be consumed over a. period of 15-30 minutes.
The doses of aldicarb were 0.01, 0.025, 0.050, and 0.075 mg/kg body ',
weight in groups of 8 males (only 4 males at the highest dose) and
0.025 and 0.050 mg/kg body weight in groups of 4 females; 16 control
males and 6control females .were included. Subjects remained seated
or supine for the first 4 hours after dosing. Subjects were observed
and signs and symptoms (e.g., sweating) were recorded hourly for the
.first 6 hours and at 24 hours. Supine diastolic blood pressure, ECG
and pulse rate, pulmonary functions (PEV-1 and PVC), saliva and urine
output, and .pupil diameter were measured at pretest', hourly for 6
hours and at 24 hours. Red blood cell and plasma cholinesterase
activities were determined at pretest, 1, 2, 3, 4, 5/ and 6 hours.
Hematology and clinical chemistry parameters were evaluated at
screening, pretest, and at'24 hours. Erythrocyte and plasma
cholinesterase activities were depressed at all dose levels with peak
depressions occurring at 1 hour and the degree and duration of the '
effect increased with increasing doses. Inhibition of ChE activities
was greater in females than in males but lasted longer in males. At 1
hour post-dosing, red blood cell AChE was depressed 3.8%, 12%, 29%,
and 38% compared to pretest activity in males receiving 0.01, 0'.025,
0.050, or 0.075 mg/kg and were depressed 20% and 36%'in females'at
0.025 or.0.050 mg/kg aldicarb, respectively. One hour after- dosing,
mean plasma cholinesterase activity was depressed 13%, 35%, 55%, and
70% in males at 0.010, 0.025, 0.050, or 0.075: mg/kg and depressed 49%
and '68% in females at 0.025 or 0.050 mg/kg, respectively. One male in
the 0.075 mg/kg group who had mistakenly received 0.06 mg/kg developed
diffuse and profuse sweating that began at' about 2 hours and abated
within "6' hours of dosing; no other males in the O.O7S mg/kg-group >
experienced sweating. Two other treated males, one given 0.05 mg/kg
and,another given 0.025 mg/kg, experienced localized and mild sweating
with onset at 2*'hours and abatement within 6 hours. One male
receiving O;075 mg/kg reported that he was light-headed Within an hour
of dosing and 2 men in the 0.01 mg/kg-group reported headaches within
6 hours of dosing. None of the females developed any clinical signs
or, symptoms consistent with cholinesterase inhibition. U.S. EPAN
(1992d) .assessed the sweating in the male receiving 0.06 mg/kg to be-
definitely compound related and the mild sweating in other .males to be
a possible effect of treatment. A small decrease in supine diastolic
blood pressure, 'in general greater in the high-dose males .and females
.''' , 12- . - ' ' .
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1995
than in other groups, was observed but, was -hot clearly related to
dosing. Females at 0,05 mg/kg showed a higher saliva output than
controls which was marginally significant.' No consistent treatment-
related effects on EGG or pulse rate were seen and no effects on
clinical laboratory parameters or on lung function tests or pupil
diameters were observed in treated groups. The NOAEL is considered to
' be 0.01 mg/kg,! and the LOABL is 0.025 mg/kg aldicarb based .on sweating
observed in treated males.
\ '
Immunolooical Effects .
Fiore et ai. (1986) and Mirkin et al. (1990) investigated the effects
of exposure to aldicarb in drinking water on.immunological parameters
in women living in the same country in Wisconsin. Appropriate
controls had no detectable.levels of aldicarb in their drinking water.
Data in the first study and the followup study indicated
immunomodulatory effects on T- cell subsets, but no obvious adverse
effects^ ' ' .
In, the'Piore et al. (1986) study, the approximate aldicarb dose in 23
exposed subjects, was O.O05 to 0.803 pg/kg/day. [The mean adicarb
ingestion level as reanalyzed by Mirkin et al. (1990) was 0.087
pg/kg/day]. Several in vivo and in vitro immunological tests did not
reveal any differences between exposed and non-exposed groups (levels
of various immunoglobulins, differential leukocyte counts, antibody
titers after immunization with tetanus booster in vitro
antigenic/mitogenic stimulation assays, and lymphocyte proliferation
.assays). An increase in the T-8 cell population was observed.
In the Mirkin et al. (1990) followup, the aldicarb dose in 5 exposed
subjects was 0.001-0.066 pg/kg/day. An increase in blood levels of
IgG but not IgA or IgM was seen and the total numbers of CD2+ and CDS*
lymphocytes (same as T-8 cells) was increased. The CD 8-K population
of Ts cells was 90% higher than in nonexposed women and there was a '
significant correlation between the level of aldicarb ingestion and
1 the elevated parameters. The elevation of the T cell subset was not
accompanied by any clinical signs in either study. Immunological
hazards' due-to aldicarb are not considered to have been demonstrated
in these studies (U.S. EPA, 1993)
Aldicarb Sulfoxide; . , , .
Aldicarb sulfoxide has been identified as residues in watermelons and
cucumbers that were implicated in human food poisoning incidents (Goldman
et al. (1990a,b). '
Aldicarb Sulfone:
No information was located regarding human health effects resulting from
direct exposure to aldicarb sulfone. ' '
13
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Animals
Aldicarb;
Short-term Exposure '.''.
. ' "N
». NAS (1977) stated that the acute toxicity of aldicarb is probably one
of the greatest of any widely used pesticide. ,
Reported oral LD^ values for aldicarb administered to rats in corn or
peanut oil. range from about 0.65 to 1 mg/kg (Weiden et-'al.. 1965-;
Gaines, 1969).. Females appear to be. more sensitive than-males. The
oral LDM in mice is>0.3 to 0.5 mg/kg (Black et al.. 1973). -
Oral LDjg values .for aldicarb were higher when using a vehicle other
than corn or peanut oil. Weil (1973) reported an oral U>n".of
7.07 mg/kg/day in rats' administered aldicarb as dry granules.
carpenter.and Smyth .(1965) reported an LD^ of 6.2 mg/kg in rats,
administered.aldicarb-in drinking water.
The principal toxic effect of aldicarb in rats has 'been shown to be
' ' ChE inhibition (Weil.and Carpenter, 1963; Nycum and Carpenter, 1968;
Weil, '1969) . . " . .
Feeding studies of. short duration (7 to 15 days) have demonstrated
statistically significant decreases in ChE activity in rats at
aldicarb dosage levels of 1 mg/kg/day (the approximate LDX in rats)
(Nycum and Carpenter, 1970) and at 2.5 mg/kg/day.in chickens
(Schlinke, 1970). The latter dosage also resulted in some lethality
in test animals. . . »
. Hazleton Laboratories (1987a) conducted a two-week, range-^f inding
study, in which beagle dogs- (one/sex/dosage group)'were administered
"aldicarb (99.5% a.i.) in their diet at-. O. 0.1, 6.3, 1,, 3 or ,10 ppm
(corresponding to dosage levels of approximately .0, 0.003, 0.008,
0.029, 0.08M/0:114F, and'0.269M/0.294F).. The only, effects reported
were inhibition of plasma and erythrocyte ChE at. about, 3 ppm and
above,* corresponding to a LOAEL of 0.08-0.114-mg/kg/day. The study
design and data presentation are not sufficient to clearly identify a
.No-Observed-Adverse-Effect Level (NOAEL) for this study.
' '. Hazleton' Laboratories (1991) conducted a 5-week study in dogs
(6/sex/dosage group) that received aldicarb (99.7% a.i.) in their diet
at 0, 0.35, 0.7, or 2.0 ppm (corresponding to dosage levels of >
approximately 0.01, 0.02, or 0.57 mg/kg/day). .Blood cholinesterase
(ChE) activities were determined 2 hours after the 2-hour feeding
period; brain-cholinesterase. activity, was analyzed. No effect on ChE
activity was observed in dosed females. In 1/6 males receiving 0.7
ppm, a marginal inhibition of plasma ChE was observed when compared to
the pretest value (inhibition was defined as greater than 20%
depression compared to the zeroTday value); no effect-on red blood
' . ' 14 ..
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1995
cell '(RBC) ChE activity was seen at 0.7 ppm. In the 2 ppm group of
males, a mean reduction of 30% in plasma ChE activity was observed at
both 2 weeks (6/6 dogs) and 5 weeks (4/6 dogs). RBC ChE activity was
affected,in 1/6 dogs at 2 weeks and 3/6 dogs at 5 weeks (mean
reduction 30%). The LOAEL for ChE inhibition in males is 2 ppra (0.057
mg/kg/day) and the NOAEL is 0.7 ppm (0.02 mg/kg/day)1 Effects on gut
motility were not considered related to dosing (U.S. EPA, 1991b).'
Long-term Exposure ' -
' .
In a 1-year feeding study conducted by Hazleton Laboratories (1988),
beagle dogs (5/sex/dose) were administered aldicarb (99.7% a.i.) in
their diets at 0, 1, 2, 5, or 10 ppm (corresponding to^doses of
approximately 0.028, 0.054, 0.132, and 0.231 mg/kg/day for males and
0.027,- 0.055, 0.132, and 0;251 mg/kg/day in females). Significant"
decreases in plasma cholinesterase (ChE) activity were seen in males
at all treatment levels throughout the duration of the study.. In
females, transitory decreases in plasma ChE activity were seen at 2
ppm and above. Red blood cell ChE activity was transiently decreased
in males (5 ppm) and females (S ppm and 10 ppm), but the activity was
comparable to controls at the 52-week test period. Brain ChE activity
was decreased only in males at 10 ppm. An increased incidence of soft
stool and mucoid stool in treated male dogs was reported. However,
considering the predose incidence rates and variations in groups, this
was not considered evidence of a treatment related effect. The data
are flawed because of differences in reporting clinical signs, failure
to compare incidence for individual dogs at pretest with that, during
dosing and inappropriate timing of observations to' detect cholinergic
effects expected to occur within 2 hours of dosing (U.S. EPA, 1992a).
Dogs were checked for clinical signs only once daily. Therefore, a
NOAEL cannot be determined. ,The,LOAEL for effects ,on ChE activity was
0.028 mg/kg/day.
Aldicarb administered for 2 years in the diets of rats or dogs at .
dosage levels up to 0.1 mg/kg/day resulted in no significant increases
in adverse effects based on a variety of toxicologic end points (Weil
and Carpenter, 1965, 1966a). In another 2-year study, levels of up to
0.3 mg/kg/day resulted in no adverse effects in rats '{Weil, 1975).'
Dermal/Ocular Effects .
Dermal LDW values (24-hour) were 2.5 mg/kg for female rats, 3 .mg/kg
for male rats (Gaines,. 1969) and 5 mg/kg for rabbits (Weiden et _al..
1965). -
The results of dermal sensitization tests'in guinea pigs were also
reported to be negative (Pozzani and Carpenter, 1968). No other
details are available.
Hazleton Laboratories (1987a) conducted ophthalmologic examinations of
beagle dogs-exposed to aldicarb (technical) in their diet at dosage
levels of 0.003 to O.294 mg/kg/day. No adverse effects were reported.
15
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1995
Immunoldaical.Effects .
Olson et al._ (1987) conducted a series of four experiments to '
determine the effects of very low concentrations of aldicarb in -.
drinking water on certain immune parameters in two outbred strains of
mice. In a 14-rday study, Swiss-Webster mice (5/group) received
aldicarb at 0, 10.,, 100 or 1,000 ppg in drinking water (corresponding
to daily dosages of approximately 0, 0.0013, 0.013 and
0.. 13 mg/kg/day). On day 10, mice were challenged with an injection of
sheep*" erythrocytes (SRBCs),-In plaque-lorming cell (PFC) assays to
determine the number of specific anti-SRBC antibody secreting plasma
cells, an'inverse dose-response relationship was seen with the most
dramatic and only statistically significant decrease occurring in the .
1 low .dosage, group (10 ppb). The number of PFCs per 106 spleen .
lymphocytes was also decreased only in the 10 ppb group.
In another experiment- in this series, CF-1 mice (10/group) were given
drinking water, with aldicarb at ,0, 1, 10, 100 or 1;000 ppb
(corresponding to approximately 0, 0.0002,'0.002, 0.02 and
0.2 mg/kg/day) .for 44 days with SRBC challenge at 30 days (Olson
et.al.. 1987). Significant decreases in the number, of PFCs per spleen
and per 10* spleen lymphocytes were seen only at-,the lowest level of
exposure (1 ppb). Again, an .inverse dose-response relationship was
evident. .Analysis of plasma hemolysin titers (antibodies produced in
response to SRBCs) also showed an inverse dose-response relationship
with the 1 ppb group having the lowest,titer (62% of the control
__value) ' , ' :
Similar'results were reported for two additional 34-day experiments
using Swiss-Webster and CF-1 mice (each with 10 mice/dosage group)' at
the same drinking water concentrations and estimated dosage levels 'as
for the 44-day study described above (Olson et al.. 1987). In
addition, the study using CF-1 mice also measured chemiluminescence
,(CHLM), which is considered to be a correlate of phagocytic killing
capability because it measures the respiratory hurst in the phagocytic
cell when phagocytosis occurs. CHLM measurements on peripheral blood
.cells indicated nonsignificant reductions of the CHLM response, at the
three -lower dosages and a 16% enhancement over the controls at the
highest level (1,000 ppb). The CHLM measurements in the peritoneal
exudate cells' (PECs) showed .a clear and'Significant inverse dose-
response with inhibition of'this parameter to 63% of the control level
at' 1 ppb to 87% elevation over the control level at- 1,000 ppb.
Although the significance of the inverse dose-response relationship
for any of these experiments is not understood, these studies provide
evidence that immunomodulatory effects can occur, in two strains of
mice at extremely low level's of aldicarb in. drinking water as low as
0.0013 mg/kg/day for '10 days for Swiss Webster mice and as low as
0.0002 mg/kg/day for '30 days in Swiss Webster,and CF-1 mice.
Thomas et al. (1990) did not'observe adverse effects on the immune
systems of B6C3F, mice exposed to aldicarb in drinking water-at 0, 1',
10 or 100 ppb- for ;34 days (corresponding to dosage .levels of.-
''.'.'' V ' ' 16 - '. ' '.'-
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1995
0>0.00032, 0.0031 and 0.033 mg/kg/day). Following aldicarb exposure,
no effects were observed "on the ability of splenic natural killer
cells to lyse YAC-1 lymphoma cells and the ability of sensitized T-
lymphocytes to lyse P815 (H-2d) mastocytoma tumor cells. No
differences were seen in the percentages or absolute numbers of spleen
1 lymphocyte subpopulations of T-cells, T-suppressor cells, T-helper
cells or B-cells. The NOAEL for these effects was 0.033 mg/kg/day.
Reproductive Effects
No reproductive effects have been demonstrated to result from the
'administration of aldicarb to rats at levels up to 0.7 mg/kg/day in at
3-generation study (Weil and Carpenter 1966c). However, based on a
decreased body weight of F2 pups in 'this study, a fetotoxic LOAEL was
identified as 0.7 mg/kg/day, and the NOAEL is 0.3 mg/kg/day.
A two generation reproduction study in rats was conducted at dietary
levels that provided 0. 0.1. 0.4. 0.7-0.9, or 1.4-1.7 mg (aldicarb,
(99.7% a.i.)/kg/day (Rhone-Poulenc, 1991). Males and females
(26/sex/group) were fed treated diets for 70 days prior to mating and
continuously throughout the study. P,j females were bred twice; the
second mating was 2 weeks after weaning the Fla pups. The F,
generations were similarly mated to produce 2 litters. Aldicarb had
no apparent effect at-any mating based on precoital interval,
pregnancy rate, gestational index and length, and there was a lack of
,. abnormalities in delivery. Body weight gains were decreased during
the growth phase for F0/males,at 1.4-1.7 mg/kg/day; and for F0and F,
females, weight gains were decreased during growth, gestation, and
lactation at the two highest doses. Plasma and erythrocyte
cholinesterase activities were decreased 21%-30% in both males and
females receiving 1.4-1.7 mg/kg/day. The pup viability index at day 4
was .decreased at the highest dose for both the first and second
"litters in both'generation. At 1.4-1.7 mg/kg/day, body weights were
significantly lower than, controls during lactation in the Fu, F|k, and
F2. Pups- The parental systemic LOAEL was 0.-7-0.9 mg/kg/day based en
decreased body weights and the NOAEL is 0.4 mg/kg/day. The
reproductive LOAEL is 1.4-1.7 mg/kg/day based on decreased pup wights
and decreased pup viability-at day 4 of lactation; the NOAEL is 0.7-
O.9 mg/kg/day; '
.'
Developmental Effects
-No developmental effects have been demonstrated to result from the
administration of aldicarb' to rabbits (1RDC, 1983) or rats (Weil and
Carpenter 1964; Tyl and Neeper-Bradley, 1988).
j
IRDC (1983) evaluated the developmental effects of aldicarb (99.5%
a.i.) administered by.gavage to Dutch-Belted rabbits (16/dosage group)
"at 0, 0.1, .0.25 or 0.5 mg/kg/day on gestation days 7 through 27. At
the two higher dosage levels, body weight was decreased and pale .. '
kidneys and hydroceles on the oviducts were seen. The numbers of
implantations and viable fetuses per dam were reduced in all treatment
i - /
17
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1995
groups! However, these decreases (only significant at the lowest
dose) were not considered-compound related and were due to ,the
unusually large number of corpora'lutea/dam and the.low rate of
preimplantation loss in the control group; historical data supported
this conclusion (U.S. EPA, 1992e). No compound-re'lated effects' were
seen on mean fetal .body weight, sex ratio'or incidence of visceral or
skeletal malformations.. The LOAEL for this study is 0.1 mg/kg/day for
fetal.viability and implantation loss. The NOAEL for this study
(maternal toxicity) is 0.1 mg/kg/day. ' ,
Weil and Carpenter (1964) fed aldicarb (99.7% a.i.) to pregnant rats
either from gestation days 1-7, 5-15, or throughout'pregnancy and
weaning at dietary levels to provide an intake of 0, 0.04, 0.2, or
1 mg/kg/day. No congenital malformations were reported for any group.
Maternal and fetal ,body weights were not affected .and there were no
effects on implantation, gestation, lactation, or pup viability. The
NOASL for systemic and developmental.effects was equal to or greater
than/I mg/kg/day. , .
s
Tyl and Neeper-Bradley (1988) investigated the developmental toxicity
of ;aldicarb (99.5% a.i.} administered by gayage to rats ,(25/dosage
group) at 0, 0.125, 0;25 or 0.5 mg/kg/day on gestation days 6 through
15. Three dams in the high dosage group died on day 7 of gestation
and others in this group developed hypoactivity, tremors, urine
stains, audible respiration, lacrimation, nasal and ocular crusting
and loose feces. Significant .reductions in body weight gain and
decreased levels of food consumption were observed at the two higher
dosage levels! In the'.fetuseg, mean, body weight'was decreased at the
high dose. .Increases in the incidence of ecchymosis (small
hemorrhages of the skin) of the trunk we're seen at the mid and high
doses.' Also at the-"high'dose, there' was an increased'incidence of
lateral ventricle dilation with tissue depression and poor' '
ossification, of the sixth sternebra. Although fetuses at the 0.125
mg/kg/day dose displayed some-ecchymosis. V.he incidence (on a litter
basis) was within the range of laboratory historical.controls (U.Si
EPA, 1991a). The NOAEL for this study is, therefore, 0.125 mg/kg/day,
and the LOAEjL, for effects on maternal weight gain and ecchymosis of
the fetus is 0.25 mg/kg/day. . . . ' . . -
No adverse effects on milk;prdduction were observed in studies of
lactating .cows (Dorough and Iv.ie, 1968; Dorough et al. . .19701.
Statistically significant inhibition of ChE activity has-.been
demonstrated in the liver, brain and blood of rat fetuses when their
mothers were administered aldicarb by gastric intubation on day 18 of
gestation (Cambon et al.. 1979). These changes were seen at doses of
0,. 001 mg/kg and above' and were manifested within 5 minutes of the
administration of 0.1 mg/kg. This study,. because of its design; does
not demonstrate any adverse developmental or- fetotoxic effects. It *
does demonstrate that aldicarb rapidly crosses the placenta and the
data "reflect a potential effect on ChE activity in the fetus.
' .'
18 ' -
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Mutagenicitv . . .
» Aldicarb has not been conclusively demonstrated to be mutagenic in
~Ames assays or in a dominant lethal mutageriicity test in rats.
(Ercegovich and Hashed, 1973; Weil and Carpenter, 1974; Godek et al.,
1980). - . ,
Care inoqen ic ity-
Aldicarb does not significantly increase the incidence of tumors in
,. mice or rats in feeding studies (Weil and Carpenter, 1965; NCI, ,1979).
Bioassays with aldicarb in.which rats and mice were fed either 2 or
6 ppm in the diet for 103 weeks, revealed no treatment-related tumors
(NCI, 1979). It was concluded that under the conditions of the
bioassay, technical grade (99+%) aldicarb was not carcinogenic to F344
rats or B6C3F, mice of either sex. A 2-year feeding study reported by
Weil and Carpenter {1965} also showed no statistically significant
-' increase in tumors over controls when rats were administered aldicarb
in the diet at concentrations equivalent to dosage levels of 0.005,
0.025, 0.05 or 0.1 mg/kg/day. However, the maximum tolerated dose
(MTD) was not reached in these studies. Weil (1975) similarly
reported no adverse effects in rats fed aldicarb at 0.3 mg/kg/day, for
2( years; however, data from this study are questionable because the
experimental protocol was not designed to assess the oncogenicity of
this chemical.
' In.a skin-painting study, Weil and Carpenter (1966b).found that
aldicarb was noncarcinogenic in male C3H/H3J mice under the conditions
, of the experiment. . . '
Intraperitoneally administered aldicarb did not exhibit transforming
or tumorigenic activity in a host-mediated assay using pregnant
hamsters and nude (athymic) mice (Quarles et a1., 1979).'
Aldicarb Sulfoxide;
Short-term 'Exposure . - '
Oral LD.JO values for aldicarb sulfoxide administered in corn oil to
male rats range from 0.45-1.1 mg/kg (Weil and Carpenter, 1970; Nycum
and Carpenter, 1968; West and Carpenter, . 1966) . ,
In rabbits, an acute dermal LD^ value of 20 mg/kg was determined for
aldicarb sulfoxide in aqueous solutions (West and Carpenter, 1966).
'The principal toxic effect of aldicarb sulfoxide (and the parent
compound, .aldicarb) in rats is ChE inhibition (Weil and Carpenter,
1963; Nycum and Carpenter, 1968;. Weii^ 1969).
Nycum and Carpenter (1970) fed rats (5/sex/dosage group) aldicarb
sulfoxide at. 0, 0.4 or" 0:8 mg/kg/day for 7 consecutive days.
Evaluation criteria included plasma, erythrocyte and brain ChE
%_ f
-19 '
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,
activity, body weight changes, relative liver and kidney weights and
. mortal-ity. Male rats treated with 0.8 mg/kg/day had statistically
significant decreases in erythrocyte ChE activity and in body weight.
No effects were seen in females or , males that .received 0.4 mg/kg/day;
this is identified as the NOAEL for this study. The'LOAEL was
0.8 mg/kg/day. .
A NOAEL of 0.12 rag/kg/day has been determined for a 1:1 mixture of
aldicarb products (sulf one arid sulfoxide) , based on data reported by
, Mirro et. al. (1982) and DePass et al. (1985) who administered these
compounds in the drinking water of young adult rats (10/sex/dosage
group) for. 29 days at a total concentration of 0, 0.075, 0.3, 1.2,
4.8, *or 19.2 ppm. Based on water consumption, the dosage levels were
approximately 0, 0;0074j 0.03, 0.12, 0.47 and 1.67 mg/kg/day for males
and 0, 0.0098, 0.035, 0.14, "0.54 and 1. 94, mg/kg/day for females. Body
weight and water consumption .were significantly reduced for males and
females at the high .dose level (19.2 ppm). Significant .decreases .in
plasma and erythrocyte ChE activity were seen at 4.8 ppm in males and
at 19.2 ppm in females. Female rats at 19.2 ppm also displayed
significant reductions in brain ChE activity. , '
Long-term Exposure
Aldicarb sulfoxide was administered at levels to provide an 'intake of .
O, 0.125, 0.25, 0.5 or 1.0 rag/kg/day in the diet_ to rats for 6 months
(15/sex/dosage group) for 6 months' (Weil and Carpenter, 1968a) . All
, animals were evaluated for relative ChE levels, liver and kidney
weights and body weights. Only ChE activity was significantly,
altered. , Plasma ChE activity was significantly inhibited in males and
females that received 0.5' and 1.0 mg/kg/day and' in males that received
0.125- and 0.25 mg/kg/day. The inhibition of plasma ChE -activity at
0.125 mg/kg/day -in males was noted at 3 months'but not' at .6 'months.
. Erythrocyte ChE activity was inhibited at doses of 0.25 mg/kg/day and
above- following 'both 3 and- 6 months of exposure in males and females.
Brain ChE activity was significantly lower in females fed. 1.0 and
0.5 mg/kg aldicarb sulfoxide for 6 months. A NOAEL of 0.125 mg/kg/day
and a LOAEL '.of. 0. 25. mg/kg/day can be identified from this study based
on brain ChE inhibition; ' ...;'-
In a second set of experiments' by 'Weil and Carpenter (1968a), used the
same dosage levels of aldicarb .sulfoxide as above for 3 months, groups
of rats (15/sex/dosage group) were either sacrificed. immediately after
the cessation of 'feeding or were placed on a control, diet for a 1-day
recovery period. Rapid recovery of inhibited ChE activity was
observed at all but the highest do-sage level. '
' "> . '
:' A' 3-month feeding study with' dogs that received aldicarb sulfoxide at
dosage levels of 0, 0.0625, 0,125, 0.25 or 0. 5 mg/kg/day was also
conducted by Weil and Carpenter (1968a). None of the dogs died and no
treatment-related effects were observed in body weight, organ weight,
20 '
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pathology or clinical chemistry. . The only effect observed was a
slight decrease in plasma ChE activity at 0.5 mg/kg. This decrease
was'seen only after 1 month and not at 3 months of exposure. A NOAEL
of 0.25 mg/kg/day and ,a LOAEL of 0.5 mg/kg/day can be identified from
this study. .
In a 2-year study, Weil and Carpenter (1972) maintained rats
(20/sex/dosage group) on diets containing aldicarb sulfoxide at 0.3 or
0.6 mg/kg/day or a 1:1 mixture of sulfoxide and sulfone (0.6 and
1.2 mg/kg/day). "A control group on a basal diet was also maintained
under identical conditions. Additional groups of'16 rats/sex/dosage
group were maintained in parallel for serial sacrifice to determine'
interim organ weights and histological effects. The only treatment-
related effect was reduced body weight and depression of plasma ChE
activity in male rats at the. high dose of the sulfpxide-sulfone
mixture.
s ' '
Dermal/Ocular Effects
No information has been located on dermal or ocular effects resulting
fronT exposure to aldicarb sulfoxide. . .
Reproductive Effects .
No reproductive studies on aldicarb sulfoxide have been located in the
- available literature. However, as with other effects, it is assumed
that the reproductive effects of this compound would be similar to
those of the parent compound.
Developmental Effects ' -
No studies of the developmental effects of aldicarb sulfoxide have
been located in the available literature. However, Wilkenson et al.
(1983) have- speculated that due to the increased polarity of this
compound, it would be less likely than aldicarb itself to cross the
placenta. Therefore, it would be conservative ,to assume that the
NOAEL identified for the developmental effects of the parent compound,
aldicarb, would also be a NOAEL for al'dicarb sulfoxide.
Mutaaenicity
" X .
No studies were located in the available literature,that assess -the
mutagenic potential, of aldicarb sulfoxide in somatic cells or germinal
-cells. Evaluations of the parent compound {aldicarb) have indicated
that it is nonmutagenic (Blevins et al.. 1977; Weil and Carpenter,
1974; Dunkel and Simmon, 1980; Ercegovich andi Rashid, 1973). As with
other effects, it is assumed that the mutagenic potential of aldicarb
sulfoxide would be similar to that of the parent compound.
21
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\Carcinoqenicitv ' ,
Neither aldicarb nor its sulfoxide metabolite significantly increase
. the incidence of tumors in mice or rats in feeding studies' (Weil and
Carpenter, 1965, 1972,* NCI, 1979). A 2-year feeding study reported by
Weil-and Carpenter (1972) did not result in a statistically
significant increase in -tumors in the exposed group over the control
group when rats were' fed aidicarb sulfoxide or a 1:1 mixture of .
aldicarb sulfoxide and sulfone at concentrations equivalent to '
dosage levels of 0.3 and 0.6 or 0.6 and 1.2 mg/kg/day, respectively.
The most frequent types of tumors in both controls and in treated rats
were adenomas,of the pituitary and>triyroid; however, the overall.
incidence rate and type of tumor was,similar in all groups. The
existing data base is considered inadequate to evaluate the potential
. for-human carcinogenicity by any of these compounds.
'Aldicarb Sulfone' .
Short-term Exposure . ' ,
i . . -
Aldicarb sulfone is considerably less toxic via the oral route of
,. exposure in rats than is aldicarb or aldicarb sulfoxide. An oral LDg,
of 20-25 mg/kg has been reported for the sulfone'in male rats (Weil
and Carpenter, 1970; Nycum and Carpenter, 1968;" West and Carpenter,
1966). However,i in rabbits, acute dermal LD^ values of 2O'mg/kg were
determined for both, aldicarb sulfoxide and aldicarb sulfone in aqueous
solutions (West and Carpenter,! 1966). Weil et al. (1974) reported
that the acute dermal, LDW for male rabbits was 194 mg/kg.
The principal toxic effect of aldicarb sulfone in rats has been shown
to'be ChE inhibition (Weil and Carpenter, 1963; Nycum and Carpenter,
1968; Weil, 1969). > ' ' ,
i ' i i
f
Nycum and Carpenter (1970) fed aldicarb sulfone at 0, 0.4, 1.0, 2.5,
5.0 or 20.0 mg/kg/day for 7 consecutive days to rats (5/sex/dosage * '
group). Animals were evaluated on the'following criteria:, plasma,
erythrocyte and brain ChE activity, body weight changes, relative
liver "and kidney weight and-'mortality. No effects were observed in
male rats fed up to 2.5 mg/kg/day, while at 5.0 mg/kg/day, there was a
significant decrease; in plasma and erythrocyte ChE "activity. -In ' .
females, brain ChE activity'was significantly decreased at
2.5, mg/kg/day and above. - At the1 highest dose (20 mg/kg/day), there
was a significant decrease in body weight and i'n" plasma,''erythrocyte
and brain ChE activity for-all animals. No effects .were observed in
those animals given the lowest.dose.(0.4 mg/kg/day} (Nycum and
Carpenter, 1970,).
, As described previously, a NOAEL of 0.12 mg/kg/day has been determined
for a mixture of aldicarb oxidation products, based on data reported
,by Mirro et al. (1982) and DePass et al. (1985). who. administered
aldicarb sulfone and sulfoxide in-.a 1:1 ratio in the drinking-water of
rats, for 29 days. .
' / ' ' < . -V
\
. .' ' .22 .
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Long-term Exposure
In a series of experiments in rats, Weil and Carpenter (1968b)
.administered aldicarb sulfone (99.7% pure, 0.24 sulfoxide) at levels
of 0, 0.2, 0.6, 1.8, 5.4 or 16.2 mg/kg/day in the diet (15/sex/dosage
group) for 3 or 6 months. After 3 months, groups were sacrificed
immediately after feeding diet for a 1-day recovery period. All
animals were evaluated for relative ChE levels, liver and kidney
weights and body weights. A transient but significant ±>ody weight
reduction was seen at the highest dose (16.2 mg/kg/day) but not at the
lower dose levels. ChE (plasma, erythrocyte and brain) activity was
significantly inhibited in both sexes at, doses of 1.8 mg/kg/day and
above after both 3 and 6 months on, the diet. In all cases, the
greatest inhibition of"ChE activity'was seen in the plasma, followed
by erythrocytes and then brain. In the recovery period, ChE activity
returned to control levels in all groups, except those receiving the
highest dosage level. The NOAEL for brain ChE inhibition after 6
months of dietary exposure was 0.6 mg/kg/day.
A 3-month feeding study with dogs that received aldicarb sulfone
<99."76% a.i., 0.24% sulfoxide) at levels of 0, 0.2, O.6, 1.8 or
5.4 mg/kg/day was also conducted by Weil and carpenter. (1968b). Early
in the study body weight was sl-ightly reduced at 5.4 mg/kg/day. ^No
mortality was observed and no treatment-related effects were observed
in organ weight, pathology or clinical chemistry. After three months,
brain cholinesterase activity was reduced at doses above 0.2 mg/kg/day
(0.6, 1.8, or 5.4 mg/kg/day). Since animals were hot fed for up to 24
hours prior to cholinesterase-determination's, the values do not
.reflect peak ChE activity depression which is known to occur within 2
hours of dosing and is then partially or fully reversed. Red blood
cell ChE activity on the average was not significantly different from
controls in all dosed groups.- The LOAEL for systemic toxicity is 5.4
mg/kg/day based on weight decrement and the NOAEL is 1.8 mg/kg/day.
The NOAEL for depression of brain ChE activity is 0.2 mg/kg/day.
» Hazleton Laboratories (1987b) conducted a 1-year feeding study in
beagle dogs that were administered aldicarb sulfone (99% a.i.)in their
diets at 0, 5, 25 or 100 ppm (corresponding to 'dosage levels of
approximately 0, 0.11, 0.58-0.61 .and 2.21-2.30 mg/kg/day). Brain
cholinesterase (ChE)' activity at study .termination was significantly
. depressed in high-dose males (24%) and mid- and high-dose females
(19-23%) when compared,to controls.' Red blood cell cholinesterase
activity was also significantly depressed ,in high-dose groups of both
sexes (25-36%) and in mid-dose females (up to 22%). Plasma
. cholinesterase was inhibited 20-80% in dosed males and 40-72% in mid-
and high-dose females. At the lowest dose, no inhibition of plasma
ChE was observed in females, but a marginal .decrease (25%) was seen in
males. Decreased spleen weights were seen in mid- and high-dose
females and decreased thyroid/parathyroid weights in high-dose
.females. In high-dose males, livers had slight centrilobular venous
.thickening and hyalinization and interlbbular fibrosis. The LOAEL for
23
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1995
systemic toxicity based on brain ChE decrease is 25 ppm (O.58
mg/kg/day), and the NOAEL is 5^ ppm (0.11 mg/kg/day).
In a 2-year study, Weil and Carpenter (1972) maintained rats
(20/sex/dbsage group) on diets containing aldicarb sulfone (99.76%
a.i. and 0.24% sulfoxide) at 0.6 or 1.2 mg/kg/day. No treatment-
related effects were reported at either dosage level.
Dermal/Ocular"Effects * : " '
, Hazleton Laboratories (1987b) found no treatment-related ophthalmic,
abnormalities in dogs that .received aldicarb sulfone in their diet at...
levels corresponding'to 0.11 to 2.30 mg/kg/day for 1 year.
» Myers et al. the 9.6 mg/kg/day-dose. No developmental
effects :or anomalies were seen in pups. Wilkenson et al. (1983) noted
that because of the increased polarity of aldicarb sulfone. as compared.
t to the parent compound, this chemical would be less likely to cross
the placenta. Therefore, it would be conservative to assume that the
NOAEL identified for the developmental effects of the- parent compound,
aldicarb, would -also be a NOAEL' for aldicarb sulfone.
Mutaoenicity -
, /
Aldicarb sulfone was not mutageiiic in Salmonella'tvphimurium strains
TA98, TA100, TA1535, TA1537 or TA1538 with or-without 59 at Uevels'
between 50 and 10', 000">g/plate (Godek et al.. 1980). .Aldicarb sulfone
' '24
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1995
was not clastogenic nor did it cause chromosome aberrations in
cultured CHO cells activated with rat liver homogenate and tested at -
sulfone levels of SO, 250, or 500 //g/mL (Pharmacon, 1984).
Evaluations of the parent compound, aldicarb, have indicated that it
is nonmutagenic {Blevins et._al._, 1977; Weil and Carpenter, 1974;
Dunkel and Simmon, 1980; Ercegovich and Rashid, 1973).. As with other
effects, it is assumed that the mutagenic potential of aldicarb
sulfone would be similar to that of the parent compound.' .
Carcinoaenicity
Neither aldicarb nor its sulfone metabolite have been demonstrated to
significantly increase the incidence of tumors in mice or rats in
feeding studies (Weil and Carpenter, 1965, 1972; NCI, 1979). A 2-year
feeding study reported by Weil and Carpenter (1972) did not result in
a statistically significant increase in tumors over controls when rats
were fed aldicarb'sulfonate dosage levels equivalent to 0.3, 0.6 or
2.4 mg/kg/day. The most frequent types of tumors in both control and
treated rats were adenomas of the pituitary and thyroid. However, the
overall incidence rate and type of tumor was similar in all groups.
The overall data base is considered inadequate to evaluate the
potential for human carcinogenicity from aldicarb-sulfone.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (up to 7 years) and lifetime exposures if adequate data are
available that identify a sensitive noncarcinogenic end point of.toxicity. The
HAs for noncarcinogenic toxicants are derived using the following formula:
u, _ (NpAEL or LOAEL) (BW)
(UF) ( L/day)
mg/L {or pg/L)
where:
NOAEL = No-Observed-Adverse-Effect.Level (thei exposure dose in rag/kg
bw/day).
LOAEL - Lowest-Observed-Adverse-Effect Level (the exposure dose in
mg/kg bw/day). ' '
BW = assumed body weight of protected individual (10-kg for child
or 70-kg for adult).
UP(s) = uncertainty factors, based upon quality and nature of data
(10, 100, 1,000, or 10,000) in accordance with NAS/EPA
guidelines; '
_'L/day = assumed water consumption (1 L/day for child or 2 L/day for
adult) . '*_
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1995
The available data suggest that the .appearance of chollnergic symptoms
indicative of ChE inhibition is 'the most sensitive indicator of the effects of
exposure to al'dicarb and its metabolites. Because these' effects are rapidly
reversible, the, same NOAEL or LOAEL can be used as the basis for the
derivation'of acceptable levels of exposure over virtually any duration. In
addition, the Health Advisories values calculated in this document' are
appropriate for use in circumstances in which the sulfoxide and/or' sulfone may
be the, substance(s) present in a drinking water sample.1 By establishing
Health Advisories based upon data, from valid studies with the most potent of
the three substances, there is greater assurance that the guidance is
protective of human health. This approach has been employed because it may
not be possible to specifically characterize the residue present using some ''
analytical techniques. ' , , , . . " ,
. .. ' . " >,
The studies upon which the Health Advisories values and Reference Dose
^(RfD) for aldicarb are based are the acute experimental human study by Rhone-
Poulenc (1992), a similar study in humans by Haines(Union Carbide, 1971) and
analysis of data from human food poisoning incidences by-Goldman et al.
(1990a,b) and.Hirsch et al. (1987). The human studies are supported by the 1-
year study by Hazleton Laboratories (1988) in beagle dogs.
Aldicarb; , . , . ,
In the human study by Rhone-Poulenc (1992), groups of male subjects
received a single oral dose of 0, 0.01", 6.025,. O^OSO, or 0.075 mg/kg aldicarb
over a period of 15-3O minutes and females received 0, 0.025, or O.O50 mg/kg
similarly.' -A number of biological' parameters known 'to be affected by
cholinesterase inhibitors were monitored before dosing, hourly for 6 Hours,
and'at 24 hours.- The major endpoints that were considered treatment related-
were effects on plasma and erythrocyte cholinesterase activity at all' dose
levels in both sexes, sweating (profuse in one high-dose male receiving
0.06 mg/kg), light-headedness, headaches, salivation, and a slight decrease in
supine diastplic blood pressure. No important clinical signs or symptoms
consistent with cholinesterase inhibition developed in- females. One female at'
0.05 mg/kg (highest dose tested) had a higher 'saliva,output than controls that
was marginally significant. Sweating in the male that received 0.06 mg/kg
. developed at about 2 hours and abated 'by 6 hours; localized mild sweating was
experienced in one male.receiving 0.05 mg/kg and in one male receiving
0.025 mg/kg. Sweating was not observed in 3 other, males in the high-dose
group that received 0.075 mg/kg, but one male in this group reported 'light
headedness one hour after dosing. No consistent effects were seen on supine
or standing diastolic blood pressure; and there were no effects on EGG, pulse
rate, pupil diameter, or lung function test. RBC acetylcholinesterase
activity was depressed 12-38% in'males at doses between 0.025^0.075 mg/kg and
depressed 20% and 36% in females at doses of 0.025 or 0.050 mg/kg. Plasma
cholinesterase activity was depressed in a dose-related manner in dosed males
(13-70%) and depressed 49% and 68% in females, at 25 or 50 pg/kg.
Cholinesterase activities reached peak depression at 1 hour and were'reversed
by 6 hours. The NOAEL was considered to be 0.01 mg/kg and the NOAEL
0.025 mg/kg'based on sweating in treated males. ' '
' In the Haines study (union Carbide, 1971)., male volunteers (4/dosage level)
, " '26
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1995
received aldicarb as a single dose of 0.025, 0,05 or 0.10 mg/kg dissolved in
100 mL of distilled water. Each man's own blood ChiE levels (based on blood
samples taken 1 hour prior to dosing) served as the control for post-dosing
ChE activity. Blood ChE activity was decreased in every test subject at 1 and
2 hours post-exposure, with decreases ranging from 20 to 80% at 0.1 mg/kg, 37
to 67% at 0.05 mg/kg and 30 to 57% at 0.025 mg/kg. . There were no clear dose-
related trends in ChE inhibition. Recovery was almost complete (75%) by
6 hours after dosing,, with more complete recovery in the lower dose groups.
All four subjects that received 0.10 mg/kg showed clinical effects with the
most common complaints being leg weakness, constriction of the pupils and
sweating. One subject in each of the two lower dosage groups had clinical
symptoms {a runny nose and anxiety) that were not clearly related to aldicarb
administration. The method of analysis of ChE, activity in blood was
considered valid and appropriate. Based on significant inhibition of whole
- blood ChE observed at all dose levels, the LOAEL for ,this study is 0.025 mg/kg
(the lowest dose tested). The range of ChE inhibition at this dose was 30 to
57%. A NOAEL was not established for this study.
In the-Goldman et al,. (1990a,b) studies, information was. reviewed on four
outbreaks of food poisoning involving aldicarb or aldicarb sulfoxide-
contaminated watermelons in California between 1985 and 1988. .An additional
study Hirsch et al., 1977) reported food poisonings from aldicarb contaminated
cucumbers. Dosages were estimated for.28 persons (Goldman et al., 1990a,b)
and 13 additional persons {Hirsch et al., 1977) who reported nausea, vomiting
and diarrhea (nonspecific symptoms of ChE inhibition). The median dosage for
.41 persons was 0.01 mg/kg (total aldicarb). .The range of dosages were later
recalculated by Sette (1990) as 0.002-0.086 mg/kg. Limitations in these
studies include the use of hypothetical rather than actual weights to1 estimate
dosage levels, self-classification'of symptoms, and the use of - analytical
methodology with a limit of detection of 0.2 ppm to measure aldicarb sulfoxide
(a higher limit than that used in other studies). Despite the limitations
discussed above, this study is viewed as presenting valid evidence of clinical
effects-at aldicarb levels as, low as 0'. 002 mg/kg in a sensitive human
population. The symptoms reported by individuals exposed to fruits and
vegetables with detectable aldicarb residues were consistent: with the syndrome
expected in cases of ChE inhibition. The analytical technique was a valid
method for estimating aldicarb residues in fresh produce and estimates of -
cucumber and watermelon consumption were plausible and displayed limited
variability. There was also a reasonable correlation of dosage estimates with
ChE inhibition symptoms. These dosage estimates are, accordingly, regarded as
acceptable approximations of aldicarb potency.
The critical study for\ deriving a reference dose (RfD) and Health
Advisories is the Rhone-Pouleric 1992,study. Although longer-term studies are
not available in human volunteers, both animal and human data support the
finding that neurobehavioral changes are short lived, and there is no
accumulation of effects over time.-. Using cholinesterase inhibition as a
biomarker of potential neurotoxic or behavioral effects in animal studies,
there is a comparable degree of cholinesterase ^inhibition at the same- doses in
acute, subchronic, and chronic studies and no neurotoxic signs are seen at
dose levels below those causing cholinesterase 'inhibition. Therefore, the^
27
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/
' 1995
. effects of an acute, human study are equivalent to those that'would be observed,
after repeated human exposure. The peak of cholinesterase inhibition in human
' studies occurs within 2 hours of dosing and inhibition- is reversed by 6 hours.
' The observed effects, of aldicarb "in animal studies are similarly rapidly
- reversed. The reversal is supported by pharmacokinetic studies demonstrating
rapid absorption, metabolism, and excretion of aldicarb'. >
In the. study"by Haines, blood cholinesterase activity inhibition was
- observed within 1-2 hours and- almost completely recovered by 6 hours in groups
of 4 males administered 0.025, 0.05, or 0.1 mg/kg of aldicarb as a single oral'
dose. . The highest dose elicited clinical signs in air four .subjects,
predominantly sweating and leg weakness, while-most subjects at the^two lower
doses had no signs or symptoms. This study helps define a dose (0.1 mg/kg)
that is clearly associated with adverse effects in humans; The study by' ,
Goldman et al. (1990) oh alleged aldicarb poisoning identified a median effect
dose of 0.01 mg/kg. The-range of doses causing clinical effects
(0.002-0.086 mg/kg) may reflect individual variation with the 0.002 mg/kg dose
applicable to the most sensitive population. However,, the estimated dose for
this population was much.less precise than the two controlled populations in
' the RhSne-Poulenc and Haines studies; the symptoms were non-specific for ChE;
^and blood cholinesterase levels were not measured., Both the Haines study and
,the Goldman 'study add weight of evidence to the Rhdne-Poulenc study.
Based on'the fact that the acute and chronic symptoms of, ChE inhibition are
the same, -the One-day and Ten-day HAs for aldicarb can be calculated from the ,
Rhone-Poulenc (1992) study with a NOAEL of O.01 mg/kg/day. Therefore, the
Lifetime HA of 7 pg/L will be used as the One-rday HA for aldicarb.
Aldicarb Sulfoxide; .. , ,
The One-day HA- for a 10kg child exposed to aldicarb. sulfoxide is the ^sarne
value as the One-day HA for aldicarb, 7 /jg/L.
Aldicarb .Sulfone; . '."'-.
Due to the data gaps in the toxicity profile of aldicarb-sulfone and due to
the absence of acute human data on the sulfone, the one-day HA for ,a 10-kg
.child exposed to aldicarb, 7 pg/L,- will also" be used for the sulfone.
. Ten-day Health Advisory.. ,
Aldicarb; - ' ' -
The Lifetime HA for the 10-kg child will be used as the'Ten-day HA (7 pg'/L)
for aldicarb.
Aldicarb Sulfoxide and Aldicarb Sulfone; ' . .
The Ten-day HA for.a 10-kg child exposed to aldicarb sulfoxide -or aldicarb
sulfone is the same value as the Ten-day HA for aldicarb, 7 £ig/L. ^ ,'-'
28
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1995
Longer-term Health Advisory . ,
Aldicarb; ' . " .
Since ,the chronic and acute effects of aldicarb are the same, the Longer-
term HA values for a 10-kg child and a 70-kg adult are the same as the
Lifetime HA of 7 fjg/L as calculated below:
i
Aldicarb Sulfoxide; . . '-..
The Longer-term HA values for aldicarb sulfoxide for the 10-kg child and
the 70-kg adult are the same as the Lifetime HA value of 7 pg/L for aldicarb .
sulfoxide. ' .
Aldicarb Sulfone; ,
The Longer-term HA values for aldicarb sulfone for the 10-kg child and the
70-kg adult are the same as the Lifetime HA value of 7 Aig/L for aldicarb
sulfone. .
Lifetime Health Advisory
-,
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water arid is considered protective of
noncarcinogenic adverse 'health effects over a lifetime exposure. The Lifetime
HA is derived in a three-step'process, step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an
.estimate of a daily exposure to the human population that is likely to be
without appreciable risk of deleterious effects over .a lifetime, and is
derived from the NOAEL (or LOAEL), identified from a chronic (or subchronic)
study, divided by an uncertainty factor(s). From the RfD, a .Drinking Water
Equivalent Level.(OWEL) can be determined (Step 2). A DWEL is a medium--
specific (i.e. , drinking water) lifetime exposure level, assuming 100%
exposure from, that medium, at which adverse, noncarcinogenic health effects
would not be expected to occur. The DWEL is -derived from the multiplication
of the RfD by the assumed body- weight of an adult and divided by the assumed
daily water consumption of an adult. The Lifetime HA is determined in Step 3 ,
by factoring in other sources of exposure, the relative source contribution
(RSC). The RSC'from drinking water is based on actual exposure data or, if
data are not available, a value of 20% is assumed. If the contaminant is
classified as a known, probable or possible carcinogen, according to the .
Agency's classification scheme of carcinogenic potential {U.S. EPA, 1986),
.then caution must be exercised in making a decision on how to deal with
possible lifetime, exposure to this substance. For human (A) or probable human
(B) carcinogens,.a Lifetime HA is not recommended. For possible human
carcinogens (C), an additional 10-fold safety factor is used to calculate the
Lifetime HA., The risk manager must balance this assessment of carcinogenic
potential and the quality of the data against the likelihood of occurrence and
significance of health effects related -to noncarcinogenic end points of
toxicity. To assist the risk manager in this process, drinking water
concentrations associated with estimated excess lifetime cancer risks over the
29
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1995
range of 1 in 10,000 to 1 in 1,000>000 for the 70-kg.adult drinking ,2 L of
water/day are provided in the Evaluation ofCarcinogenic Potential section.
Aldicarb . . ' , ' -.
: ' t -. i i ''. t
The Lifetime Health Advisory and RfD are,based on the acute human study by
Rh6ne-Poulenc (1992) and as discussed above supported by the study of acute
human exposure by Haines (Onion Carbide Corporation, 1971) and analysis of
data for: human food poisonings (Golman et al., 1990a,b; Hirsch et al., 1987).
- - xhe effects of aldicarb are readily reversible in humans and animals. A large
.data base in animals shows that a comparable inhibition of cholinesterase is
found at the same doses in acute, subchronic, and chronic studies and that
inhibition and recovery of cholinesterase activity parallels, the clinical
neurotoxic/neurobehavioral signs. Therefore,, it is concluded that the same
... NOAELs or LOAELs for neurotoxic-signs can be-used as the basis for-the
calculation of acceptable levels of exposure over .virtually any duration of
exposure. The RfD for Aldicarb has been verified by the Agency in October,
1992 and peer reviewed by'the SAP/SAB Committee in November, 1992 (U.S. EPA,
1992b). '- j >-
;i-'
Using a NOAEL of 0.01 mg/kg/day, the Lifetime HA is derived as follows:
'Step 1: Determination of the Reference Dose (RfD)
-.' RfD = (0-01 ing/kg/day) = 0-001 mg/kg/day
where:
0.01 mg/kg/day =
NOAEL, based on sweating (a cholinergic sign) in human
volunteers (Rh6ne-Poulenc, 1992).'
10
uncertainty factor (UF), chosen in accordance with NAS/EPA
guidelines for use of human data to account for variation in
sensitivity among persons in the population.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
' - DWEL = s< 0.001 mg/kg/day) (70kg) = Q35 mg/^ (roun
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1995
2 L/day
assumed daily water consumption of an adult.
Step 3: Determination of-the Lifetime HA
, Lifetime HA = (0.035 mg/L) (20%) - 0.007 mg/L "(rounded to 7 pgr/L)
where:
0.035 mg/L =
20%
DWEL
assumed contribution of drinking water to total exposure to
aldicarb and its metabolites.
Aldicarb Sulfoxide;
The Lifetime HA for aldicarb suIfoxide is the same as the .Lifetime HA for
aldicarb, 7 fjg/1,. '[
Aldicarb Sulfone: ."''
The Lifetime HA for aldicarb sulfone is the same as the Lifetime HA for
aldicarb, 7 .pg/L. However, this value is based on data from the one year dog
feeding- study by Hagleton (1987b) and further supported by the data base and
the human study (Rhone-Poulenc, 1992) for aldicarb.
In the Hazleton Laboratories (1987b) 1-yeair dietary study of aldicarb
sulfone in dogs, a NOAEL of 0.11 mg/kg/day was identified for cholinesterase
inhibition. At higher levels" (0.58 mg/kg/day and above), levels of plasma,
erythrocyte and. brain cholinesterase activity were inhibited. Although human
data were not available on aldicarb sulfone, and although data gaps were noted
for reproductive and developmental.effects, and there was the lack of an
adequate rat chronic study, the available information on the parent compound
is sufficient to support the data base.for this metabolite. Therefore, the
dog study was selected for calculation of the Lifetime HA. Aldicarb sulfoxide
has also been demonstrated to be rapidly degraded and eliminated in animal
studies (Andrawes et al.. 1967). Therefore, the same NOAEL or LOAEL can be
used as the basis for the calculation of acceptable levels of exposure ove'r
virtually any duration. The RfD for aldicarb sulfone has been verified by the
Agency in September, 1992 and peer reviewed by the SAP/SAB Committee in
November, 1992 {U.S. EPA, 1992c). . ,
Step 1: 'Determination of the Reference Dose (RfD) -
RfD = (0.11 mg/kg/day) - 0"-001 mg/kg/day . ".
31
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1995
where:
0.11 mg/kg/day
10O '
NOAEL, baaed on Brain ChE activity inhibition in dogs
(Hazleton Laboratories, 1987b). . . .
_
uncertainty factor (UF), chosen in accordance with" NAS/EPA
guidelines to account for interspecies . and intraspeci.es
differences when a NOAEL from an animal study is used.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0-001 ^/kg/day)' (70 kg) 0,Q35 mg/L (rounded to 35 ,,g/L)
(2 L/day) ' .
where: .
0.001 mg/kg/day =
v "' 70 kg
RfD .
assumed body weight of an adult. ' .
'2 L/day = . '
assumed daily water consumption of an adult.
- i
Step 3: Determination of the Lifetime HA ;
Lifetime HA = (0.035 mg/L) (20%) =0.007 mg/L (rounded to 7 (ig/L)
where:
.O.035 mg/L =
20%
DWEL
assumed contribution of drinking water, to total exposure to
aldicarb and its metabolites. ' "
Health advisory Values for Mixture of the Aldicarbs - .
i ,
Because the mechanism of neurotoxicity^ .of.aldicarb, aldicarb sulfoxide and
aldicarb sulfone is the same, the presence of these contaminants in mixture is
additive. Therefore, the HA values for the .mixture is also- 0.007mg/1.
Evaluation of Carcinogenic Potential
Aldicarb: ' ' ./''-.
) - - -
' *** Although^ aldicarb was honcarcinogenic under all conditions tested, the
'' - 32 .,',.'
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1995
MTD was not reached in the chronic feeding studies in rats (Weil and
Carpenter, 1965; NCI, 1979} or mice (NCI, 1979).
The International Agency for Research on Cancer (IARC) has not
classified aldicarb in terms of its carcinogenic potential.
Applying the criteria described in EPA'.s guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), aldicarb may be classified in
- , Group D: not classified. This category is for agents with inadequate
animal evidence of carcinogenicity.
Aldicarb Sulfoxide andAldicarb Sulfbne:
The carcinogenic potential for both aldicarb sulfoxide and aldicarb
sulfone has not been assessed.
Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), both aldicarb sulfoxide and aldicarb
sulfone may be classified in Group D: not classified. This category, is
for agents with inadequate, animal evidence of carcinogenicity.
.f' i
VI. OTHER CRITERIA, GUIDANCE AND -STANDARDS
Aldicarb: ' ,
The FAO/WHO proposed ADIs for total aldicarb residues of 0-
0.001 mg/kg/day in 1979 and 0-0.005 mg/kg/day in 1982 (FAO/WHO, 1979,
1982). :
' s
An MCLG of 0.001 mg/L was established for aldicarb by EPA's Office of
Water on July 1, 1991. Based on practical quantitation .limits (PLQs),-
an MCL of 0.003 mg/L has been set (U.S. EPA; 1991). 'in response to the
registrant's appeal of the MCL, this..regulation was stayed in May 1992 '
until additional new data were evaluated.
Tolerances for aldicarb residues in agricultural commodities ranging
from 0.002 to 1 ppm have'been set by USDA (USDA, 1990).
v
Aldicarb Sulfoxide and Aldicarb Sulfone;
' i '
An MCLG of 0.001 mg/L was established for aldicarb sulfoxide by EPA's J
Office of Water on July 1, 1991. Based on PLQs, an MCL of 0.004 mg/L
has been set. An MCLG of 0.002 mg/L was established for aldicarb
sulfone by EPA's Office of Water on July 1, 1991. This level has also1
been established as the MCL (U.S. EPA, 1991c). In response to the
registrant's appeal of these MCLs, this 'regulation was'stayed in May
1992 until additional new data were evaluated.
33
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1995
VI. ANALYTICAL METHODS -, .
Aldicarb; ...''
Analysis of aldicarb and its metabolites, the sulfoxide and sulfone, is .
by a high performance liquid chromatographic procedure used for,' the. .
determination of N-methyl carbamoyloximes arid N-methylcarbamates in
drinking water (U.S. EPA, 1984). .In this method, the water sample is
filtered and a'400 //L aliquot is injected into a reverse phase HPLC
column. Separation of compounds is achieved using gradient elution
chromatography. - After elutibn from the HPLC column, the compounds are
hydrolyzed with sodium hydroxide. The methylamine formed during1
hydrolysis is reacted with o-phthalaldehyde (OPA) to form a fluorescent
derivative which is detected using a fluorescence,detector (detection
limit = 1.3 ^g/L for aldicarb).
Krause (1985a,b). reported a liquid chromatographic (LC) multiresidue
method for determining residues of carbamate insecticides, including
aldicarb, its sulfoxide and'its sulfone. In this method, methanol and a
mechan'ical ultrasonic homogenizer are used,to extract carbamates. Water
soluble and nonpolar material are separated by liquid-liquid
partitioning. Estimated limits of quantitation are O.'Ol ppm.
v /
Aldicarb Sulfoxide;
The'analytical methodologies described above for aldicarb and its
metabolites are the only known methodologies appropriate for aldicarb
sulfoxide. . "
Aldicarb Sulf one;' "'.''''
The analytical methodologies .described above for aldicarb and its.
metabolites are the only known methodologies appropriate .for aldicarb
sulfone.
Will. TREATMENT TECHNOLOGIES
Aldicarb;
Techniques which have been used to removealdicarb from water are carbon
adsorption and filtration. Since aldicarb is converted to aldicarb
sulfoxide and sulfone, all three compounds must be considered when
evaluating the efficiency of any decontamination technique.
Granular activated carbon. (GAC) was used in two studies',of aldicarb
removal- from contaminated water (Union Carbide/ 1979; ESE, 1984). Both
studies utilized home water treatment units rather than large-scale
water treatment systems. Union Carbide tested the Hytest Model HP-1
water softener in which'the ion exchange ion was replaced .with 38.5 Ib
Filtrasorb 400 (Calgon GAC). The .unit was operated at a flow rate of
3 gal/miri. Water spiked with 200 ppb or 1,000 ppb of a mixture of
".'."'. / / 34 ' ' . .'''/.
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1995
aldicarb, aldicarb sulfoxide and aldicarb sulfone in a 10:45:45 ratio
was treated. Under these conditions, the total aldicarb residue level
was reduced by 99% to 1 ppb for the treatment of 13,500 gallons of water
with 200 ppb of residues and 41,500 gallons with' 1,000 ppb total
residues. No breakthrough of aldicarb occurred.' When the study was
terminated, the carbon had adsorbed 9 rag aldicarb residue.per gram.
This value can be compared with an equilibrium loading value of 21 mg
per gram of carbon at 16°c determined using 200 ppb aldicarb residues.
In the second study, ESE (1984) did a field study in Suffolk County, NY.
Nineteen units using type CW 12 x 40 mesh carbon were tested. After
38' months of use, breakthrough of aldicarb occurred to levels over
7 jug/L in eight units tested. The range of usage values can be
attributed to- the fact that the natural well samples contained a variety
of adsorbable substances in addition to aldicarb..
Chlorination also appears to offer the potential for aldicarb removal
(Union Carbide, 1979). The company reported that 1.0 ppm free chlorine
caused a shift in the ratio of aldicarb,' its sulfoxide and its sulfone
so that all residues were converted to the sulfoxide within 5 minutes of
chlorine.exposure. Normal conversion of aldicarb to aldicarb sulfone
did not appear to be affected. on standing, the sulfoxide and sulfone
decomposed. The. decomposition products were not identified.
Aeration or air stripping which is commonly used to remove synthetic
organic chemicals is not considered to be a good technique for the
removal of aldicarb (ESE, 1984). This is because aldicarb -has a low
Henry's Law Constant (2.32 x 10'4 atm) .
Aldicarb Sulfoxide:
Treatment technologies described above for aldicarb and its metabolites
are the only technologies known.to be appropriate for aldicarb -
sulfoxide. . .
Aldicarb Sulfone; .
' Treatment technologies described above for aldicarb and its metabolites
are the only technologies known to be appropriate for aldicarb sulfone.
, 35
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, 1995
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\. -
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- , - ' ( ' «
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42
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. \ '
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''
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'-~ ' ~\
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', '
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43
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