ALDICARB,  ALDICARB SULFOXIDE
                             AND ALDICARB SULFONE

                                     1995
                              ;
                        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 not quanLo.tatj.vely inc-orporate 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 sulfoxide - 1646-87-3
            Aldicarb sulfone — 1646-88-4


Structural Formulas


       Aldicarb:
                                 /

                                CH3            O
                                I               II
                       CH3-S - C -CH = N-O-C-N -CH3
                                I                   I
                                CH3               H



             2-Methyl-2-(methylthio)propionaldehyde 0-(methylcarbamoyl)oxime


      Aldicarb  Sulfoxide:



                             O  CH3            O                   ,

                       CH3-S-C-CH = N-0-C-N-CH3

                                CH3                H


            2-Methyl-2- (methylsulfinyl)propionaldehyde  O- (methylcarbamoyl)oxime


      Aldicarb Sulfone:



                            O   CH3            O
                             II               II
                       CH3-S - C -CH =N-O-C-N -CH3
                             II.                I
                            O   CH3               H


            2-methyl-2- (methylsulfonyl)propionaldehyde  O- (methylcarbamoyl)oxiine


   Synonyms


     •    Aldicarb:   Temik


     •    Aldicarb  sulfoxide:   Temlk sulfide


     •    Aldicarb  sulfone:   Aldoxicarb, Standak


   Uses


     • '  Pesticide  (insecticide, nematocide,  acaracide)

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Properties  (Registrant's unpublished data; FAO/WHO, 1980; Knaak et al. .'  1966;
            Kuhr 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 Partition
  Coefficient
Taste Threshold (Water)
Odor Threshold (Water)
Odor Threshold (Air)
                             Aldicarb
C7H,4O;N,S
190.3
White crystals
Decomposes
above 100°C
100

0.05 (20°C)
1.195 (25°C)
0.6 (room temp.)
 Aldicarb
 Sulfoxide

C7H1403N2S
206.06
Crystalline
108-110
330
  Aldicarb
  Sulfone

C7H,<0
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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 p/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 sulfoxide 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 p
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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 different age-sex groups were calculated to
        be as follows:   Infants (6-11 months) 0.002 'pg/day, toddlers
        (2 years) 0.006 jug/day, females (14-16 years) 0.009 /jg/day,
        males (14-16 years) 0.008 pg/day,  females (25-30 ye^rs) 0.008
        /^g/day,  males (25-30 years) 0.011 pg/day, females  (60-65
        years) 0.014 jjg/day, and males (60-65 years) 0.018 ^g/day
        (Gunderson,  1986).
    Air

    •   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

  • 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, 1991).
    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 sand (25°C),
    respectively,  was lost over a 24-hour period.

  • The adsorption coefficient (K^.) 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, aldicarb will be leached into ground water.  The
    susceptibility of aldicarb to leaching is supported by monitoring
    results which 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,
    1991).

  • Aldicarb is oxidized in soil to the 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 half-life  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 Palmyrian 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  3,24O
  days at pH 5.5 and 15°C.   The  lowest  measured hydrolysis  half-life was
  131 days at a pH of 4 and a temperature of 20°C.   Based on  an
  estimated Henry's Constant of 4.17xlO'9 atm-m3/mole, volatilization
  from water should not be an important fate process.  The
  volatilization half-life for aldicarb in lake and pond water was
  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
  biodegradation in natural waters were found.
                                                                     v
• 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 not 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 bioconcentration 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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III.  PHARMACOKINETICS

Aldicarb;

Absorption

  • 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 (Kuhr and
    Dorough, 1976; Martin and Worthing,  1977; West and 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

  • 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
    0.12 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).

  • In rats 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 1:1 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
    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 C02 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).

Aldicarb 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 raits resulted in 80-90%
    excretion of the radiolabel in the urine and 2-5% excretion in the feces
    within the first 24 hours (Andrawes et al., 1967).

  • Dermal absorption of aldicarb sulfoxide by laboratory animals is highly
    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.

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.

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                                                                        1995
Distribution

  • 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 distributio'n 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 with microsomes, with or without NADPH2
    (reduced nicotinamide adenine dinucleotide phosphate),  was found to
    partially destroy the sulfone derivative (Oonnithan and Casida, 1967).

Excretion
                             «
  • 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                                     v

Humans

Aldicarb:

    Short-term Exposure

    •   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
        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-contaminated
        cucumbers or watermelon in California between 1985 and 1988.  Dosage
        estimates for 28 of over 1000 reported cases were derived from average
        body weights by age and sex (from standard tables), self reported   ,
        symptoms and estimated consumption, and analyzed aldicarb sulfoxide
        residues from watermelons.  Estimates for 13 additional cases were

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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 quartile 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 ppm (Goldman et al. 1990b) was somewhat
higher than in other reports.  As a result, some misclassification
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 (0.002 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 iasted 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

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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.

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 6 control 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, EGG
and pulse rate,  pulmonary functions (FEV-1 and FVC), 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 0.075 mg/kg-group
experienced sweating.  Two other treated males, one given 0.05 mg/kg
and atvother given 0.025 mg/kg, experienced localized and mild sweating
with onset at 2 hours and abatement within 6 hours.  One male
receiving 0.075 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. EPA
(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

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                                                                        1995
        than in other groups, was observed but was not 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 ECG 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 LOAEL is 0.025 mg/kg aldicarb based on sweating
        observed in treated males.

    Immunoloqical Effects

        Fiore et al.  (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 Fiore et al. (1986) study, the approximate aldicarb dose in 23
        exposed subjects was 0.005 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 CD8+-
        lymphocytes (same as T-8 cells),was increased.  The CD 8-1- population
        of T cells was 90% higher than .in nonexposed women and there was a
        significant correlation between the level of aldicarb ingestion and
        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.

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Animals

Aldicarb;

    Short-term Exposure

    •   MAS (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 LDs, in mice is 0.3 to 0.5 mg/kg (Black et al.. 1973).

    •   Oral LDjo values for aldicarb  were higher when using a vehicle other
        than corn or peanut oil.  Weil (1973) reported an oral LD^ of
        7.07 mg/kg/day in rats administered aldicarb as dry granules.
        Carpenter and Smyth (1965) reported an LDy, 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 LDjo 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-finding
        study in which beagle dogs (one/sex/dosage group) were administered
        aldicarb (99.5% a.i.)  in their diet at O.. 0.1,  0.3, 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 zero-day 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 S weeks (mean
    reduction 30%).  The'LOAEL for ChE inhibition in males is 2 ppm (0.057
    ing/kg/day) and the NOAEL is 0.7 ppm (0.02 mg/kg/day).  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 (5 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 ia no adverse effects in rats (Weil, 1975).

Dermal/Ocular Effects

•   Dermal LDj,, values (24-hour) were 2.5 mg/kg for female rats, 3 mg/kg
    for* male rats (Games, 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 0.294 mg/kg/day.  No adverse effects were reported.

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                                                                    1995
Immunoloqical 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-day 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-forming 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
    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,  O.OO2,  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  106 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 levels 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

                                  16

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                                                                    1995
    0,0.00032, 0.0031 and O.O33 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-
    lyrophocytes to lyse  P815 (H-2d)  mastocytoma tumor cells.   No
    differences were seen in the percentages or absolute numbers of spleen
    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 a
    3-generation study (Weil and Carpenter 1966c).  However, based on a
    decreased body weight of F, 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.  F0 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 F,,, Flb,  and
    F2a pups.  The parental systemic LOAEL was 0.7-0.9 mg/kg/day based on
    decreased body weights and the NOAEL is O.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-
    0.9 mg/kg/day.

Developmental Effects

•   No developmental effects have been demonstrated to result from the
    administration of aldicarb to rabbits (IRDC, 1983) or rats (Weil and
    Carpenter 1964; Tyl and Neeper-Bradley, 1988).

•   IRDC (1983) evaluated the developmental effects of aldicarb  (99.5%
    a.i.) administered by gavage to Dutch-Belted rabbits (16/dosage group)
    at O, 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

                                  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-related 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
NOAEL for systemic and developmental effects was equal to or greater
than 1 mg/kg/day.

Tyl and Neeper-Bradley (1988) investigated the developmental toxicity
of aldicarb (99.5% a.i.) administered by gavage 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 fetuses,  mean body weight was decreased at the
high dose.  Increases in the incidence of ecchymosis (small
hemorrhages of the skin) of the trunk were 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. the incidence (on a litter
basis) was within the range of  laboratory historical controls (U.S.
EPA, 1991a).  The NOAEL for this study is, therefore, 0.125 mg/kg/day,
and the LOAEL for effects on maternal weight gain and ecchymosis of
the fetus is 0.25" mg/kg/day.

No adverse effects on milk production were observed in studies of
lactating cows  (Dorough and Ivie, 1968; Dorough et al., 1970).

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.

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                                                                        1995
    Mutaqenicltv

    •   Aldicarb has not been conclusively demonstrated to be mutagenic in
        Ames assays or in a dominant lethal mutagenicity test in rats
        (Ercegovich and Hashed, 1973; Weil and Carpenter, 1974; Godek et al.,
        1980).

    Carcinogenicitv

    •   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 O.005,
        O.O25, 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 al., 1979).

Aldicarb Sulfoxide:

    Short-term Exposure

    •   Oral LD,,, 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; Weil, 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

                                      19

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                                                                    1995
    activity, body weight changes, relative liver and kidney weights and
    mortality.  Male rats treated with 0.8 rag/kg/flay 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 mg/kg/day has been determined for a 1:1 mixture of
    aldicarb products (siilfone and 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, 0.0074, 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
    0, 0.125, 0:25, 0.5 or 1.0 mg/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 dosage 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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                                                                    1995
    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 (O.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 sulfoxide-sulfone
    mixture.

Dermal/Ocular Effects

•   No information has been located on dermal or ocular effects resulting
    from 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 aldicarb sulfoxide.

Mutaqenicity

•   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 and 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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                                                                        1995
    Carcinogenicitv

    •   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 aldicarb 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 thyroid; 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

    •   Aldicarb sulfone is considerably less toxic via the oral route of
        exposure in rats than is aldicarb or aldicarb sulfoxide.  An oral LD^
        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, in rabbits,  acute dermal LDj,, values of 20 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 LD^ 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).

    •   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 irata (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.O 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 the highest dose (20 mg/kg/day), there
        was a significant decrease in body weight and in 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.

                                      22

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                                                                    1995
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 tody 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, 0.6,  1.8 or
    5.4 mg/kg/day was also conducted by Weil and Carpenter (1968b).  Early
    in the study body weight was slightly 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 not fed for up to 24
    hours prior to cholinesterase determinations, 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 O, 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 interlobular fibrosis.  The LOAEL for
                                  23

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                                                                    1995
    systemic toxicity based on brain ChE decrease is 25 ppm (0.58
    mg/kg/day),  and the NOAEL is S ppm (0.11 mg/kg/day).

•   In a 2-year study, Weil and Carpenter (1972) maintained rats
    (20/sex/dosage 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. (1975) did not find aldicarb sulfone to be a primary eye
    irritant in rabbits or a primary dermal irritant in rats.

•   Aldicarb sulfone was not a dermal sensitizer in guinea pigs (Conroy
    and Carpenter, 1977).

Reproductive Effects

•   Aldicarb sulfone  (a.i. 99.76% and O.24% sulfoxide) was administered to
    Harlan-Wistar rats for 3 generations (one litter/generation) at
    dietary levels to provide an intake of 0, 0.6, 2.4 or 9.6 mg/kg/day
    Woodside et al. 1977).-  Males at 9.6 mg/kg/day had reduced body
    weights and both sexes at this dose had cholinesterase activity
    inhibition.   Reduced pup survival and marginal effects on lactation
  -. were observed at the 9.6 mg/kg/day-dose.  The LOAELs for reproductive
    effects and systemic toxicity are 9.6 mg/kg/day and the NOAELs are
    2.4 mg/kg/day.        '

Developmental Effects

•   In a separate study, Woodside et al {19"77) administered aldicarb
    sulfone (a.i. 99.76% and 0.24% sulfoxide) by oral gavage to female
    Wistar rats at levels of 0, 0.6, 2.4, or 9.6 mg/kg/day.  Different
    groups were dosed from gestation days 1-12, 7-9, or 6-15.  Diarrhea
    was observed in females at 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
    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.

Mutaqenicity

•   Aldxcarb sulfone was not mutagenic in Salmonella typhimurium strains
    TA98, TA100, TA1535, TA1537 or'TA1538 with or without 59 at levels
    between 50 and 10,000 pg/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 50, 250, or 500 j/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.

    Carcinoqenicity

    •   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,
longerrterm  (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:
wnere:
        NOAEL = No-Observed-Adverse-Effect Level  (the exposure dose  in mg/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).

        UF(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).

                                      25

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                                                                        1995
   The available data suggest that the appearance of cholinergic symptoms
 indicative of ChE inhibition is the most sensitive indicator of the effects of
 exposure to aldicarb 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.  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, 0.025,  0.050, or 0.075 mg/kg aldicarb
 over a period of 15-30 minutes and females received 0, 0.025, or 0.050 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 diastolic 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, O.O5 or 0.10 mg/kg dissolved in
100 mL of distilled water.  Each man's own blood ChE 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 O.O25 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 to 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-Poulenc 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 phronic 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 all 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. (199O)  on 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 Rhone-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 Rhone-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 0.01 mg/kg/day.  Therefore, the
Lifetime HA of 7 jjg/L  will be used as the One-day HA for aldicarb.

Aldicarb Sulfoxide;

   The One-day HA for  a 10-kg child exposed to aldicarb sulfoxide is the same
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 /jg/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 sa^ie value as the Ten-day HA for aldicarb, 7 pg/L.
                                      28

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                                                                        1995
Longer-term Health Advisory

Aldi-carb:

   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 /jg/L as  calculated below:

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 ^g/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 and 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 (DWEL) 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 a&sumed 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 of Carcinogenic Potential section.

Aldicarb

   The Lifetime Health Advisory and RfD are based on the acute human study by
Rhone-Poulenc (1992) and as discussed above supported by the study of acute
human exposure by Haines (Union Carbide Corporation, 1971) and analysis of
data for human food poisonings (Golman et al., 1990a,b; Hirsch et al., 1987).
The 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).
         s
   Using a NOAEL of 0.01 mg/kg/day,' the Lifetime HA is derived as follows:

Step 1:  Determination of the Reference Dose (RfD)
                                                                              t
                    RfD =  (0.01 rng/kg/dav) = 0 001 mg/kg/day


where:

  0.01  mg/kg/day =
                  NOAEL,  based on sweating (a cholinergic sign)  in human
                  volunteers  (Rhone-Poulenc,  1992).

              10 =
                  uncertaint-y 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 = /O 001 mg/kg/day)  (70 kg) = 0.035 mg/L  (rounded to  35
                      (2 L./dciy)           '


where:

 0.001  mg/kg/day =
                  RfD

           70  kg =
                  assumed body weight of an adult.
                                      30

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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  \ig/L)


where:

      0.035 mg/L =
                  DWEL

             20% =
                  assumed contribution of drinking water to total exposure to
                  aldicarb and its metabolites.      -                 ,

Aldicarb Sulfoxide;

   The Lifetime HA  for aldicarb sulfoxide is the same as the ,Lifetijne HA for
aldicarb, 7 /jg/L.

Aldicarb Sulfone;

   The Lifetime HA  for aldicarb sulfone is the same as the Lifetime HA for
aldicarb, 7 /L/g/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-year 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 over
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)  = Q 001 mg/kg/day
                                       31

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                                                                        1995
where:

0.11 mg/kg/day =  NOAEL,  based  on  Brain  ChE  activity inhibition in dogs
                  (Hazleton  Laboratories,  1987b).

             100 =
                  uncertainty factor  (UF), chosen  in accordance with NAS/EPA
                  guidelines to account  for  interspecies and intraspecies
                  differences when a  NOAEL from an animal study is used.
                                                                       /

Step 2:  Determination of the Drinking Water Equivalent Level  (DWEL)

       DWEL = (0-001 mg/kg/day)   (70 kg) = 0.035  mg/L 
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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 and  Aldicarb Sulfone;

  •   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.
VI.  OTHER CRITERIA, GUIDANCE AND STANDARDS

Aldicarb:

  •   The FAO/WHO proposed ADIs for total aldicarb residues of 0-
      O.O01 mg/kg/day in  1979 and O-0.005 mg/kg/day in 1982 (FAO/WHO, 1979,
      1982).

  •   An MCLG of O.OO1 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).

Aldicarb Sulfoxide and Aldicarb Sulfone;

  •   An MCLG of 0.001 mg/L was established for aldicarb sulfoxide by EPA's
      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 also
      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.
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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-me'thyl carbamoyloximes and N-methylcarbamates in
      drinking water (U.S. EPA, 1984).   In this method, the water sample is
      filtered and a 400 pL aliquot is  injected into a reverse phase HPLC
      column.  Separation of compounds  is achieved using gradient elution
      chromatography.  After elution from the HPLC column, the compounds are
      hydrolyzed with sodium hydroxide.   The methylamine formed during
      hydrolysis is reacted with o-phthalaldehyde (OPA) to form a fluorescent
      derivative which is detected using a fluorescence detector (detection
      limit = 1.3 A/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
      mechanical ultrasonic homogenizer  are used to extract carbamates.  Water
      soluble and nonpolar material are  separated by liquid-liquid
      partitioning.  Estimated limits of quantitation are O.O1 ppm.

Aldicarb Sulfoxide:

  •   The analytical methodologies described above for aldicarb and its
      metabolites are the only known methodologies appropriate for aldicarb
      sulfoxide.

Aldicarb Sulfone;

  •   The analytical methodologies described above for aldicarb and its
      metabolites are the only known methodologies appropriate for aldicarb
      sulfone.
VIII.  TREATMENT TECHNOLOGIES

Aldicarb;

  •   Techniques which have been used to remove aldicarb from water are carbon7
      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 HF-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/min.  Water spiked with 200 ppb or l,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 mg 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 20O 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 A
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                                                                        1995
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Bull, D.L., D.A. Lindquist and J.R.  Coppedge.   1967.  Metabolism of 2-methyl-
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Cambon, C. , C. Declume and R.  Derache.  1979.   Effect of  the insecticidal
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                                                                          %
Carpenter, C.P. and H.F.  Smyth.   1965.  Recapitulation  of pharmacodynamic and
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                                      36

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                                                                        1995
DePass, L.R., E.V. Weaver and E.J. Mirro.  1985.  Aldicarb sulfoxide/aldicarb
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Dorough, H.W,. and G.W. Ivie.  1968.  Temik-S35 metabolism in a lactating cow.
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Godek, E.G., M.C. Dolak, R.W. Naismith and R.J. Matthews.  1980.  Ames
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Goes, E.H., E.P. Savage, G. Gibbons, M. Aaronson, S.A. Ford and H.W. Wheeler.
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Goldman, L.R., M. Seller and R.J. Jackson.  1990a.  Aldicarb  food poisonings
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Goldman, L.R., D.F. Smith, R.R. Neutra et al.  1990b.  Pesticide food
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                                                                        1995
Gunderson, E.L.  1986.  Food and Drug Administration, Div. of Contaminants
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Hazleton Laboratories.  1991.  Subchronic toxicity study in dogs with aldicarb
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Hazleton Laboratories.  1988.  One-year chronic oral toxicity study in beagle
dogs with aldicarb technical.  Rhone-Poulenc Ag Company.  Unpublished report.

Hazleton Laboratories.  1987a.  Two-week dose range-finding oral toxicity
study in beagle dogs with aldicarb technical.  Union Carbide Agricultural
Products Company.  Unpublished report.

Hazleton Laboratories.  1987b.  One-year feeding study in dogs with aldicarb
sulfone technical.  Union Carbide Agricultural Products Company.  Unpublished
report.

Hicks, B.W., H.W. Dorough and H.M. Mehendale.  1972.  Metabolism of aldicarb
pesticide in laying hens.  J. Agric.  Food Chem. 20(1):151-156.

Hirsch, G.H.,  B.T. Mori,  G.B. Morgan, P.R. Bennett and B.C. Welliams.  1987.
Reported illnesses caused by aldicarb contaminated cucumbers.  Food Additives
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Howard, P.H.  1991.  Handbook of Environmental Fates and Exposure Data for
Organic Chemicals.  Volume III:   Pesticides.  Chelsea,  Michigan:  Lewis
Publishers'.   pp. 76-84.                    v

IRDC.  1983.  International Research and Development Corporation.  Teratology
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Jones, R.L., R.C. Beck.   1984.  Monitoring aldicarb residue*, in florida soil
and water.  Environ. Toxicol. Chem. 3(1):9-20.

Kenaga, E.E.  1980.  Predicted bioconcentration factors and soil sorption
coefficients of pesticides and other chemicals.  Ecotox. Env. Safety 4:26-38.

Klaseus, T.G.,  G.C. Buzicky and B.C.  Schneider.  1988.   Pesticides and
Groundwater:  Surveys of  Selected Minnesota Wells.  Prepared for the
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Knaak, J.B., M.J. Tallant and L.J. Sullivan.  1966.  The metabolism of
2-methyl-2-(methylthio)propionaldehyde O-(methyl carbamoyl) oxime in the rat.
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Krause, R.T.  1985a.  Liquid chromatographic determination of N-methyl-
carbamate insecticides and metabolites in crops.  I.  Collaborative study.
J. Assoc. Off.  Anal. Chem. 68(4):726-733.

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                                                                        1995
Krause, R.T.  1985b.  Liquid chromatographic determination of N-methyl-
carbamate insecticides and metabolites in crops.  II.  Analytical
characteristics and residue findings.  J. Assoc. Off. Anal. Chem.
68(4):734-741.

Krill, R.M. and W.C. Sonzogni.  1986.  Chemical contamination of Wisconsin's
groundwater.  Bur. Water Supply, Wisconsin Dep. Nat. Resourc., Madison, WI.
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Ruhr, R.J. and H.W. Dorough.  1976.  Carbamate insecticides:  Chemistry,
biochemistry, and toxicology.  Cleveland, OH:  CRC Press, Inc., pp. 2-6,
103-112, 187-190, 211-213, 219-220.

Lee, M.H. and J.F. Ransdell.  1984.  A farmworker death due to pesticide
toxicity:  A case report.  J. Toxicol. Environ. Health 14:239-246.

Lemley, A.T. and W.Z. Zhong.  1983.  Kinetics of aqueous base and acid
hydrolysis of aldicarb, aldicarb sulfoxide and aldicarb sulfone.  J. Environ.
Sci. Health 818:189-206.

Martin, H. and C.R. Worthing, eds.  1977.  Pesticide manual.  British Crop
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Miller, C., M. Pepple, J. Troiano, D. Weaver and W. Kimaru.  199O.  Sampling
for Pesticide Residues in California Well Water.  1990 Update.  Well Inventory
Data Base.  California Department of Food and Agriculture, Sacramento,
California.  December 1.

Mirro, E.J., L.R. DePass and F.R. Frank.  1982.  Aldicarb sulfone:  Aldicarb
sulfoxide twenty-nine-day water inclusion study in rats.  Carnegie-Mellon
Institute Report No. 45-18.

Mirkin, I.R., H.A. Anderson, L. Hanrahan, R. Hong, R. Golubjacnikov and
D. Belluck.  1990.  Changes in T-lymphocyte distribution associated with  •
ingestion of aldicarb-contaminated drinking water:  A follow-up study.
Environ. Res. 51:35-50.

Myers, R.C., C.S. Weil, N.I. Condra, et al.  1975.  Temik Sulfone-75% WP
(UC 21865-75%).  Range finding toxicity studies:  Special report 38-87.
(Unpublished study received January 18, 1977 under 1016-EX-37; prepared by
Carnegie-Mellon University, Carnegie-Mellon Institute of Research, Chemical
Hygiene Fellowship, submitted by Union Carbide Corporation, Arlington, VA.
CDL-.228975-B

MAS.  1977.  National Academy of Sciences.  Drinking water and health.
Vol. 1.  Washington, DC:  National Academy Press, pp.19-63.

NCI.  1979.  National Cancer Institute.  Bioassay of aldicarb for possible
carcinogenicity.  NCI-CG-TR-136.  U.S. Department of Health, Education  and
Welfare, U.S. Public Health Service, National  Institutes of Health.

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                                                                         1995
Nycum, J.S. and C. Carpenter.  1970.  Summary with respect to Guideline
PR70-15.  Mellon  Institute Report No. 31-48.  EPA Pesticide Petition
No. 9F0798.

Nycum, J.S. and C. Carpenter.  1968.  Toxicity studies on Temik  and related
carbamates.  Mellon Institute.  Unpublished Report No. 31-48.

Olson, L.J., B.J. Erickson, R.D. Hinsdill, J.A. Wyman, W.P. Porter,
L.K. Benning, R.C. Bidgood and E.V. Nordheim.  1987.  Aldicarb
immunomodulation  in mice:  An inverse dose-response to parts per billion
levels in drinking water.  Arch. Environ. Contam. Toxicol. 16:433-439.

Oonnithan, E.S. and J.E. Casida.  1967.  Oxidation of methyl- and dimethyl
carbamate insecticide chemicals by microsomal enzymes and anticholinesterase
activity of the metabolites.  J. Agric. Food Chem. 16:29-44.

Pozzani, U.C. and C.P. Carpenter.  1968.  Sensitizing potential  in guinea pigs
as determined by  a modified Lansteiner test.  Mellon Institute Report No.
31-143.  EPA Pesticide Petition No. 9F0798.

Quarles, J.M., M.W. Sega/ C.K. Schenley and W. Lijinsky.  1979.
Transformation of hamster fetal cells by nitrosated pesticides in a
transplacental assay.  Cancer Res. 39:4526-4533.

Rhone-Poulenc.  1991.  Two-generation reproduction study in rats with
aldicarb.  Hazleton Report No. 656-157 by J.K. Lemen. (MRID No.  421484)
Available from EPA, write to FOI, EPA Washington, DC 20460.

Rhone-Poulenc Ag Company.  1992.  A safety and tolerability study of aldicarb
at various dose levels in healthy male and female volunteers.  Inveresk
Clinical Research Report No. 7786 (MRID No. 423730-01). Available from EPA,
write to FOI, EPA Washington, DC 20460.

Schlinke, J.C.  1970.  Toxicologic effects of five'soil nematocides in
chickens.  J. Am. Vet. Med. Assoc. 31:119-121.

Sette, W.F.  1990.  Aldicarb food poisonings in California - 1985-1988:
Toxicity estimates for humans.  Data evaluation report.  Sponsored by
Environmental Epidemiology and Toxicology Section, California Department of
Health Services, Emeryville, CA.

Sexton, W.F.  1966.  Report on aldicarb.  EPA Pesticide Petition No. 9F0798,
Section C.

Thomas, P., H. Ratajczak, D. Demetral, K. Hagen and R. Baron.  1990.  Aldicarb
immunotoxicity:   Functional analysis of cell-mediated immunity and
.quantitation of lymphocyte subpopulations.  Fundam. Appl. Toxicol. 15:221-230.

Tyl, R.W. and T.L. Neeper-Bradley.  1988.  Developmental toxicity evaluation
of aldicarb administered by gavage to CD (Sprague-Dawley) rats:   Rhone-Poulenc
Ag Company.  Unpublished Study No. 551, conducted by Bushy Run Research
Center, Export, PA.

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                                                                        1995
Union Carbide Corporation.   1971.  R. Haines, J.B. Dernehl and J.R. Block
supervising physicians.   Ingestion of aldicarb by .human volunteers:  A
controlled study of the effects of aldicarb on man.  ALD-03-77-2215. MRID No.
00101911. HED Doc. No. 010450. Available from EPA.

Union Carbide Corporation.   1979.  Union Carbide Agricultural Products
Company.  Temik   aldicarb pesticide.  Removal of residues from water.
Research and   Development Department.

U.S.D.A.  1990.  U.S. Department of Agriculture.  Code of Federal Regulations
40CFR 180.269.  p. 328.

U.S. EPA.  1992a.  Aldicarb:  Addendum to Hazleton Laboratories 1-year chronic
oral toxicity study in dogs  with aldicarb technical.  A memorandum from
William Sette, Ph.D. to Seppehr Haddad.

U.S. EPA.  1992b.  Aldicarb  and aldicarb sulfone 1992 RfD verification
document.

U.S. EPA.  1992c.  Aldicarb  sulfone 1992 RfD verification document.
                                                          f
U.S. EPA.  1992d.  Review of the 1992 Rhone-Poulenc human study.  ICR Project
No. 003237, Reviewer William Sette.  A memorandum to the ad hoc Joint
OPPT/OW/OR Review Group,  September 4, 1992.

U.S. EPA.  1992e.  RfD/Peer  review report of Aldicarb.  A memorandum from
George Ghali, Ph.D. to Dennis Edwards.  September 15, 1992.

U.S. EPA.  1992f.  SAP/SAB Peer review report of aldicarb and aldicarb sulfone
RfD.  November 1992.

U.S. EPA.  1991a.  Aldicarb  rat developmental toxicity study:  Analysis of
historical control incidence of ecchymosis:  Re-evaluation.   A memorandum from
William Burnum to William Sette, Ph.D.  October 3, .1991.

U.S. EPA.  199Ib.  Review of the final report on a 5-week dog study on dietary
treatment with aldicarb.  A  memorandum from Henry Spencer, Ph.D. to William
Sette, Ph.D.  HED Project No 01838/2038.

U.S. EPA.  1991c.  U.S. Environmental Protection Agency.  Fed. Reg.
56(126):30266-30281.  July 1.

U.S. EPA.  1990.  National Pesticide Survey:  Summary of Results of EPA's
National Survey of Pesticides in Drinking Water Wells.  PB91-126795.  U.S.
Environmental Protection  Agency, Office of Water and Office of Pesticides and
Toxic Substances.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.  Guidelines for
carcinogen risk assessment.  Fed. Reg. 51(185):33992-34003.   September 24.
                                      41

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                                                                        1995
U.S. EPA.  1984.   U.S. Environmental Protection Agency.  Method 531.
Measurement of N-methyl carbamoyloximes and N-methylcarbamates in drinking
water by direct aqueous injection HPLC with post column derivatization.
Environmental Monitoring and Support Laboratory, Cincinnati,^OH.

U.S. FDA.  1990.   Food and Drug Administration Pesticide Program:  Residues in
Food - 1989.  U.S. Food and Drug-Administration, Div. of Contaminants Chem. ,
Washington, D.C.   J. Assoc. Off Chem. 73(5):127A-146A.

Weiden, M.H.J., H.H. Morefield and L.K. Payne.  1965.  O-(Methyl carbamoyl)
oximes:  A new class of carbamate 'insecticides-acaricides.  J. Econ. Entomol.
58:154-155.

Weil, C.S.  1975.  Mellon Institute Report No. 35-72, Section C.  EPA
Pesticide Petition No. 3F1414.

Weil, C.S.  1973.  Aldicarb, seven-day inclusion in diet of dogs.  Carnegie-
Mellon Institute of Research,  Unpublished Report No..36-33.

Weil, C.S.  1969.  Purified and technical Temik.  Results of feeding in the
diets of rats for one week.  Mellon Institute, Unpublished Report No. 32-11.

Weil, C.S. and C.P. Carpenter.  1974.  Aldicarb.  Inclusion in the diet of
rats for three generations and a dominant lethal mutagenesis test.  Carnegie-
Mellon Institute of Research.   Unpublished Report No. 37-90.
     *

Weil, C.S. and C.P. Carpenter.  1972. ' Aldicarb (A), aldicarb sulfoxide (ASO),
aldicarb sulfone (ASO,)  and a  1:1  mixture  ASO:ASO:.  Two-year feeding in the
diets of rats.  Mellon Institute Report No. 35-82.  EPA Pesticide Program No.
9F0798.'

Weil, C.S. and C.P. Carpenter.  1970.  Temik and other materials.
Miscellaneous single dose peroral and parenteral LDj,, assays and some joint
action studies.  Mellon Institute Report No.  33-7.  Amendment to EPA Pesticide
Petition No. 9F0798.

Weil, C.S. and C.P. Carpenter.  1968a.  Temik sulfoxide.  Results of feeding
in the diet of rats for 6 months and dogs for 3 months.  Mellon Institute
Report No. 31-141.  EPA Pesticide Petition No. 9F0798.

Weil, C.S. and C.P. Carpenter.  1968b.  Temik sulfone.  Results of feeding in
the diet of rats for 6 months and dogs for 3 months.  Mellon Institute Report
No. 31-142.  EPA Pesticide Petition No. 9F0798.

Weil, C.S. and C.P. Carpenter.  1966a.  Two-year feeding of Compound 21149 in
the diet of dogs.  Mellon Institute.  Unpublished Report No. 29-5.

Weil, C.S. and C.P. Carpenter.  1966b.  Skin painting study in mice.  No
citation reference available.
                                      42

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                                                                        1995
Weil, C.S. and C.P. Carpenter.   1966c.  Results of a developmental toxicity
study in rats.  Mellon  Institute Report No. 37-90.  (MRID No. 0044736).

Weil, C.S. and C.P. Carpenter.   1965.  Two-year feeding of Compound 21149 in
the diet of rats.  Mellon  Institute.  Unpublished Report No. 28-123.
 /
Weil, C.S. and C.P. Carpenter.   1964.  Results of a three-generation
reproduction  study on rats fed  Compound 21149 in their diet.  Mellon Institute
Report No. 27-158.  EPA Pesticide  Petition No. 9F0798.

Weil, C.S. and C.P. Carpenter.   1963.  Results of- three months of inclusion of
Compound 21149 in the diet of rats.  Mellon Institute.  Unpublished Report
No. 26-47.

Weil, C.S., N.I. Condra, D.L. Geary Jr., et al.  1974.  UC 21865-Technical and
75% WP (1974): , Some range finding toxicity studies:  Special report 37-49.
(Unpublished  study received Jan. 18, 1977 under 1016-EX-37; prepared by
Carnegie Mellon University,  Division of Sponsored Research, Chemical Hygiene
Fellowship, submitted by Union  Carbide Corporation, Arlington, VA;
CDL:228152-C.

West and C.P. Carpenter.   1966.  Temik joint action with selected organic
phosphate and carbamate pesticides.  Mellon Institute Report No. 29-98.  EPA
Pesticide Petition No.  9F0798.

Wilkenson, C.F., G.C. Bajgish,  A.T. Lemley, et al.  1983.  A toxicological
evaluation of aldicarb  and its  metabolites in relation to the potential human
health impact of aldicarb  in Long  Island groundwater.  Report 1.  Prepared by
the Institute for Comparative and  Environmental Toxicology, Cornell
-University, Ithaca, NY.

Woodside, M.D., C.S. Weil, J.R.  Bernard, et al.  1977.  Aldicarb sulfone:
Inclusion in  the diet of rats for  three generations:  Dominant lethal
mutagenesis and teratology studies:  Project Report 40-1.  Unpublished study
received January 25, 1978  under 1016-79; prepared by Carnegie-Mellon
University, Institute of Research, Chemical Hygiene Fellowship, submitted by
Union Carbide Corporation, Arlington, VA.  CDL:096728-O.
                                       43

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