820K88107
August, 1987
CARBARYL
Health Advisory
Office of Drinking Hater
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology 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 an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurate!' 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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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 63-25-2
Chemical Structure Q U
II I
0-C-N-CH,
1-Naphthalenol methylcarbamate
Synonyms
Arilate; Bereema NMC50; Caprolin; Sevin; Vioxan (Meister, 1983).
Uses
0 Contact insecticide used for the control of pests on more than 100
different crops, forests, lawns, ornamentals, shade trees and rangeland
(Meister, 1983).
Properties (Windholz et al., 1983; CHEMLAB, 1985)
Chemical Formula C12H11°2N
Molecular Weight 201.22
Physical State (25»C) White crystals
Boiling Point
Melting Point 142«C
Density
Vapor Pressure (25*C) <4 x 10-5 nun Hg
Water Solubility (30°C) 120 mg/L
Log Octanol/Water Partition 0.14
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor -
Occurrence
Carbaryl has been found in 61 of 522 surface water samples analyzed
and in 28 of 1,125 ground water samples (STORET, 1987). Samples were
collected at 138 surface water locations and 1,100 ground water
locations, and Carbaryl was found in 8 states. The 85th percentile
of all nonzero samples was 260 ug/L in surface water and 10 ug/L in
ground water sources. The maximum concentration found was 180,000
ug/L in surface water and 10 ug/L in ground water.
Environmental Pate
14c-Carbaryl (purity unspecified) at 10 ppm was relatively stable
to hydrolysis in buffered solutions at pH 3 and 6. It hydrolized at
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pH 9 with a half-life of 3 to 5 hours when incubated at 25*C (Khasawinah
and Holsing, 1977a). At 35«C, 14C-carbaryl was stable at pH 3, and
hydrolyzed with a half-life of >28 days and 30 to 60 minutes at pH 6 and
9, respectively. 1-Naphthol was the major degradate formed.
1*C-Carbaryl (purity unspecified) at 5 ppm photodegraded slowly in
0.1 M phosphate buffer solutions, with 4.39 to 4.49 ppm remaining as
parent compound after 18 days of irradiation (Khasawinah and Holsing,
1977b). In a 2* acetone solution, 14C-carbaryl accounted for 3.63 to
3.65 ppm after 18 days. 1-Naphthol and several unidentified compounds
were found at <0.07 ppm.
0 Under aerobic conditions, 14C-carbaryl (>99% pure) at 1 ppm degraded
with a half-life of 7 to 14 days in a sandy loam soil maintained at 15
or 23 to 25°C, and 14 to 28 days in a clay loam soil maintained at
23 to 25°C (Khasawinah and Holsing, 1978). Degradation was slightly
slower in sterile soils (half-lives of 14 to 56 days). The majority
of the applied radioactivity was bound to the soil or had been evolved
as 14CO2 by the end of the test period (112 days). No degradates were
found.
0 Under aerobic conditions, 14C-carbaryl (>99% pure) at 1 ppm degraded
with a half-life of 84 to 112 days in a flooded sandy loam soil (Khasa-
winah and Holsing, 1976). At 168 days after treatment, 14C-carbaryl
accounted for 42% of the applied radioactivity in the soil and water
layer. 4-Hydroxy carbaryl was found at <0.3% of the applied radio-
activity in soil samples taken after 112 days. Approximately 20% of
the total radioactivity was soil-bound at 112 days.
III. PHARMACOKINETICS
Absorption
Comer et al. (1975) reported the results of tests conducted in factory
workers exposed to carbaryl during the formulation of 4 and 5% carbaryl
dust. Carbaryl exposure via the skin was measured by attachment of a
special gauze pad to various parts of the body, and inhaled carbaryl
was measured by the use of special filter pads in face masks. Calcu-
lated exposures, were 73.90 and 1.10 mg/hour for the dermal and respiratory
routes, respectively. The total exposure was 75 mg/hour, or 600 mg/day.
Absorption levels were determined by estimation of the carbaryl
metabolite 1-naphthol in urine. It was determined that during an
8-hour workday the total absorption of carbaryl would be 5.6 mg.
This is about 0.9% of the total exposure, and the authors interpreted
this to mean that dermal absorption was not complete.
0 Feldman and Maibach (1974) applied 4 ug/cm2 of 14C-labeled carbaryl
(position of label not specified) dissolved in acetone to one or both
forearms of apparently healthy male volunteers. The area of application
was left unwashed and unprotected for 24 hours. Based on the .excretion
rate, it was determined that 73.9% of the applied carbaryl was absorbed
through the skin.
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Carbaryl August, 1987
Houston et al. (1974) reported that 1*C-carbamyl-labeled carbaryl
administered by gavage to male rats at doses of 0.5 ag/kg (given as
0.5 aL of 0.5% propylene glycol in water) rapidly appeared in the
systemic circulation. Within a few ainutes, the plasma level was
50 ng/mL. A maximum level of 150 ng/mL was reached in less than
10 minutes and steadily declined to 20 ng/mL at 120 minutes. Only
4.6% of the dose was excreted in the feces, indicating that at least
95.3% had been absorbed.
* Falzon et al. (1983) administered single doses of 20 mg/kg of 14C-
carbaryl (in olive oil) to six female rats by gavage. After 24
hours, 5.8% of the label was recovered in the feces, indicating that
about 94.2% had been absorbed.
Distribution
0 The distribution of 14c-carbonyl-labeled carbaryl in male and female
rats after administration of 1.5 mg/kg by stomach tube was examined
in eight body tissues (Krishna and Casida, 1965). The amounts
detected (umol/kg) in males and females, respectively, were: cecum,
0.17 and 0.60; esophagus, 0.05 and 0.05; large intestine, 0.02 and
0.03; small intestine, 0.06 and 0.08; kidney, 0.06 and 0.07; liver,
0.11 and 0.112; spleen, 0.05 and 0.08; and stomach, 0.07 and 0.14.
Falzon et al. (1983) administered single oral doses of 20 mg/kg of
1*C-carbaryl to female Wistar rats by gavage. The amounts detected
24 hours after administration were 0.11% in the brain, 3.87% in the
digestive tract and 13.31% in the carcass.
Metabolism
0 Human tissues obtained by either biopsy or autopsy were incubated
using an in vitro organ-maintenance technique with 14c-(N-methyD-
labeled carbaryl (Chin et al., 1974). The following tissues were
examined: for males lung, liver and kidney; for females liver,
placenta, vaginal mucosa, uterus and uterine tumor (leiomyoma).
Hepatic tissues metabolized carbaryl by hydrolysis and/or demethylaticm,
hydroxylation and oxidation followed by conjugation. The primary
hydrolytic product was 1-naphthol (42% by 24 hours at pH 7.8). The
kidney produced naphthyl glucuronide; the uterus, lung and placenta
produced naphthyl sulfate from carbaryl. The vaginal mucosa produced
glucuronide and sulfate conjugates, but only a slight amount of
conjugating activity (napthol sulfate) was found in the uterine
leiomyoma.
0 Houston et al. (1974) administered 14C-carbamyl-labeled carbaryl
(0.5 mg/kg) to male rats by gavage. Within 48 hours, 54.5% of the
label had been excreted in the urine as metabolites (not identified).
In addition, 32.9% was excreted as C02> This indicated that carbaryl
was extensively metabolized in rats.
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Excretion
Comer et al. (1975) studied the excretion of 1-naphthol in the urine
of workers who were exposed to carbaryl in a pesticide formulation
plant. The workers were exposed to carbaryl both dermally (73.9
mg/hour) and by inhalation (1.1 mg/hour). Analyses of urine samples
indicated that the excretion rate of 1-napthol varied from 0.004 to
3.4 mg/hour, with a mean value of 0.5 mg/hour. This corresponds to
an excretion rate of 0.7 mg carbaryl/hour. Following exposure to
carbaryl at the start of the workday, the urinary level of 1-naphthol
increased, reached its maximum level during the late afternoon and
evening hours, and then dropped to a lower level before the start of
the next day's workday.
Urinary excretion of topically applied radiolabeled carbaryl in
healthy Bale volunteers was measured by Feldman and Maibach (1974).
A total of 26.1% of the dose was recovered in the urine over a
5-day period.
Krishna and Casida (1965) administered single doses of 1.5 mg/kg of
1^C-carbonyl-labeled carbaryl orally to rats. Excretion of the label
for male and female animals, respectively, was as follows: expired
carbon dioxide, 26% and 26%; urine, 64.0% and 72.0%; and feces, 4.0%
and 4.0%.
Houston et al. (1974) administered 14c-carbamyl-labeled carbaryl
(0.5 mg/kg) by gavage to male rats. The label was almost completely
excreted within 48 hours, with the following distribution: expired
carbon dioxide, 32.9%; urine, 54.5%; and feces, 4.6%. Less than 1%
of the label in urine was unchanged carbaryl. About 6.0% of the
label remained in the body. Biliary excretion was examined by bile-
duct cannulation. Within 6 hours, 30 to 33% of the administered dose
was present in the bile; after 6 hours, the amount in the bile leveled
off.
IV. HEALTH EFFECTS
Humans
Vanderkar (1965) investigated the effects of large-scale carbaryl
spraying in a village in Nigeria. No quantitative estimates of
exposure were obtained, but plasma cholinesterase (ChE) activity was
decreased by about 15% in eight applicators (spraymen) and by an
average of 8% in 63 villagers.
Wills et al. (1968) studied the subchronic toxicity of carbaryl in
human volunteers. Groups of five or six men were given daily oral
doses of 0, 0.06 or 0.13 mg/kg/day for 6 weeks. At the lower dose,
no significant effects were detected on kidney function, electroen-
cephalogram, hematology, blood chemistry, urinalysis or plasma and
red blood cell ChE activity. At the higher dose, the only detectable
effect was a slight increase in the urinary ratio of amino acid
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nitrogen to creatinine. This was interpreted to suggest a slight
decrease in resorption of amino acids in the kidney. This effect
was fully reversible. Based on these observations, a No-Observed-
Adverse-Effect-Level (NOAEL) of 0.06 mg/kg/day was identified.
Animals
Short-term Exposure
Carpenter et al. (1961) investigated the acute oral toxicity of
carbaryl in several species. Cats were found to be most sensitive
(2/2 deaths at 250 mg/kg). Guinea pigs, rats and rabbits were less
sensitive, with calculated 1*050 values of 280, 510 and 710 mg/kg,
respectively. No deaths were reported in dogs administered doses up
to 795 mg/kg/day.
The acute oral toxicity of carbaryl in male Sprague-Dawley rats was
studied by Rittenhouse et al. (1972). Carbaryl (99.9* active)
dissolved in acetone and propylene glycol (10% v/v) was administered
in a single dose at four dose levels to six animals per level.
Animals were observed for 14 days following treatment. Dose levels
were 439, 658, 986 or 1,481 mg/kg. Mortalities observed at these
levels were 0/6, 0/6, 4/6 and 5/6 rats, respectively. Most deaths
occurred, in the first 24 hours. The 1*050 was calculated to be
988 mg/kg. Animals at all dose levels exhibited symptoms of ChE
inhibition, but ChE activity was not measured. No other parameters
were reported.
Carpenter et al. (1961) fed single oral doses of carbaryl in capsules
to female mongrel dogs as follows: 250 mg/kg (one animal), 375 mg/kg
(four animals) or 500 mg/kg (one animal). Signs of overstimulation
of the parasympathetic nervous system were observed at the two higher
doses, but not at 250 mg/kg. These signs included: increased
respiration, lacrimation, salivation, urination, defecation, muscular
twitching, constriction of pupils, poor coordination and vomiting.
Plasma ChE was not affected at 375 mg/kg, but a transient decrease
(24 to 33%) was observed in erythrocyte ChE at this dose. After 1
day, the appearance of the animals was normal and no adverse CNS
effects were noted. Based on the absence of visible external effects
or inhibition of ChE, this study identified a NOAEL of 250 mg/kg.
0 Carpenter et al. (1961) also administered single oral doses of carbaryl
(560 mg/kg, by gavage in corn oil) to three groups of rats (seven to
nine per group). Groups were sacrificed after 0.5, 4 or 24 hours,
and ChE activity was measured in plasma, erythrocytes and brain.
Plasma ChE was slightly lower (7 to 14%) than control, but this was
not statistically significant. In erythrocytes, ChE was inhibited
42% after 0.5 hours, but this returned to near normal (86% of control)
within 24 hours. Brain ChE activity was inhibited 30% after 0.5 hours,
and this returned toward normal (91% of control) by 24 hours.
Neil et al. (1968) fed carbaryl in the diet for 1 week to Harlan-
Wistar albino rats (42-days old) at concentrations yielding ingested
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doses of 0, 10, 50, 250 or 500 mgfkq/day. Body weight gain was
decreased in animals exposed to 50 mg/kg/day or higher. At 10
ChE activity was not significantly affected in plasma, red blood
cells or brain. At 50 mg/kg/day/ plasma ChE was decreased 15 to 17%
and red blood cell ChE was decreased 26 to 47% (males and females,
respectively). At higher doses, larger decreases in plasma and red
blood cell ChE were seen, and brain ChE was also decreased (23 to 25%
at 250 mg/kg/day and 33 to 58% at 500 mg/kg/day). After 1 day on
control diet, these effects on ChE were entirely reversed. Based on
these data, a NOAEL of 10 mg/kg/day and a Lowest-Observed-Adverse-
Effect-Level (LOAEL) of 50 mg/kg/day were identified in rats.
Dermal Exposure
0 Carpenter et al. (1961) applied 0.01 mL of 10% carbaryl in acetone
(a dose of 1 mg) to the clipped skin of the belly of five rabbits.
No irritation was detected.
0 Gaines (1960) applied a series of doses of carbaryl dissolved in
xylene to the skin of Sherman rats. The dermal LD5Q value was greater
than 4,000 mg/kg for both males and females.
0 Carpenter et al. (1961) detected a weak skin sensitization reaction
in 4 of 16 male albino guinea pigs given eight intracutaneous injec-
tions of 0.1 mL of 0.1% carbaryl (0.1 mg/dose). The challenge dose
(not specified) was given 3 weeks later, and examinations for sensiti-
zation reaction were performed 24 and 48 hours thereafter.
e Carpenter et al. (1961) applied carbaryl to the eyes of rabbits and
evaluated corneal injury. Technical carbaryl (98% pure) applied as
a 10% suspension in propylene glycol caused mild injury in 1/5 eyes.
A 25% aqueous suspension caused no injury, and 50 mg of powder caused
only traces of corneal necrosis.
Long-term Exposure
0 Wistar rats (five/sex, 45-«Jays old) were fed carbaryl (as Compound
7744; purity not specified) in the diet for 90 days at levels of
0.0037, 0.011, 0.033 or 0.10% (Weil, 1956). Assuming that 1 ppm in
the diet of young rats is equivalent to approximately 0.10 mg/kg/day
(Lehman, 1959), this corresponds to doses of about 3.7, 11, 33 or 100
mgA9/day. The author stated that there were no significant changes
in appetite or weight gain when compared to the control; micropathology
revealed no changes in lung, liver or kidney tissue at any dose level.
It was concluded that for these end points the effect level for
toxicity is higher than 0.10%, which is equivalent to a NOAEL of
about 100 mgAg/day (the highest dose tested).
0 Carbaryl was administered to male rats by gavage at a level of
200 mgAg, 3 days a week for 90 days (Dikshith et al., 1976). This
corresponds to an average dose of 86 mg/kg/day. The control animals
received vehicle (peanut oil) on a similar schedule. There were no
overt .toxicological signs in these rats, and no marked biological
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changes were seen in testes, liver and brain (enzymatic determinations)
except for ChE activity, which was inhibited 34% in blood (p <0.001 )
and 11% in brain (p <0.05). No significant histological changes were
noted in testes, epididymis, liver or kidney. Based on ChE inhibition,
the LOAEL for this study was identified as 86 mg/kg/day.
0 Carpenter et al. (1961) fed carbaryl to male and female Basenji-Cocker
dogs (four or five per dose) for 1 year. Dietary levels were about
0, 24, 95 or 41 4 ppm, which were adjusted to supply ingested doses of
0, 0.45, 1.8 or 7.2 mg/kg/day. No compound-related effects were
detected on mortality, body weight, hematocrit, hemoglobin, leukocyte
count, blood chemistry, plasma or erythrocyte ChE activity, or liver
and kidney weights. Microscopic examination of tissues revealed dif-
fuse cloudy swelling of renal nephrons and focal debris in glomeruli
of dogs fed the higher dose. These conditions were also observed in
controls, but less frequently, and the authors judged they were not
early stages of toxic degeneration. One dog at the low dose displayed
a transient hind leg weakness after 189 days. This disappeared within
3 weeks, although dosing was continued throughout. Subsequent micro-
scopic examination revealed no differences between this dog and
others. A NQAEL of 7.2 mg/kg/day (the highest dose tested) was
identified.
0 Shering (1963) administered carbaryl (5.0 mg/kg/day) by gavage to 25
male and 25 female rats, 5 days per week for 18 months. No effects
were observed on weight gain, organ weights, urinalysis, hematology
or histologic appearance of tissues. The authors concluded that 5.0
was a NOAEL in rats.
0 Carpenter et al. (1961) studied the toxicity of carbaryl in a 2-year
feeding study in rats. Groups of 20 male and 20 female CF-N rats
(60-days old) were maintained on a diet containing 0, 50, 100, 200
or 400 ppm dry Sevin. Based on measured food consumption and body
weights, the authors reported the doses to be equivalent to 0, 2.0,
4.0, 7.9 or 15.6 mg/kg/day in males, and 0, 2.4, 4.6, 9.6 or 19.8
ng/kg/day in females. No adverse effects were detected on life span,
food consumption, body weight gain, liver and kidney weights, cataract
formation or hematocrit. Histological examination after 1 year
revealed mild changes in the kidney, characterized by cloudy swelling
of the nephrons. This was statistically significant (p <0.004) at
the high dose. Cloudy swelling of hepatic chords was also observed
at the high dose, and this was significant after 2 years (p <0.002).
No histological changes were detectable at the lower doses. Based on
these observations, a NOAEL of 7.9 mg/kg/day for males and 9.6 mg/kg/day
for females was identified.
Reproductive Effects
Weil et al. (1972) investigated the reproductive effects of carbaryl
. in female rats exposed either by gavage or by feeding. Doses of 0.,
2.5 and 10 mg/kg/day ingested from the diet for three generations
resulted in no statistically significant, dose-related effects on fer-
tility, gestation, lactation or pup viability. Doses of 100 mg/kg/day
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given by gavage (5 days/week, beginning at 5 weeks of age) resulted
in maternal Mortality, reduced fertility and signs of ChE inhibition.
These signs were not seen in animals ingesting doses of up to 200
from the diet.
0 Murray et al. (1979) assessed the reproductive effects of carbaryl
(99%) in rabbits (New Zealand White). Pregnant females were given
either 150 or 200 mg/kg/day by gavage from days 6 through 18 of
gestation. The incidence of pregnancy was not significantly affected
at either dose level. On days 6 through 11, carbaryl -treated rabbits
gained significantly less weight than the controls (p <0.05 at the
high dose); this effect was less pronounced at the lower dose. There
was no statistically significant effect of carbaryl at either dose
level on the average number of live fetuses/litter or on the frequency
of resorptions. A marginal increase (p <0.08) in the incidence of
resorptions was observed at the higher dose level. A statistically
significant decrease in fetal body weight was noted at 150 mg/kg/day
but not 200 mg/kg/day. Based on both maternal and fetal toxicity,
the LOAEL for reproductive effects in rabbits was identified as
150 mg/kg/day.
Murray et al. (1979) studied the reproductive effects of carbaryl
(99% active ingredient) in female CF-1 mice. Carbaryl was admini-
stered by gavage at 100 or 150 mg/kg/day, or by feeding in the diet
at 5,660 ppm (calculated by the authors to be equivalent to 1,166
mg/kg/day). At the gavage dose of 150 mg/kg/day, the mice gained
less weight and exhibited significant maternal toxicity, including
salivation, ataxia and lethargy, and 10/37 females died during the
experimental period. At 100 mg/kg/day by gavage, a single maternal
death occurred, but weight gain was normal and no other evidence of
maternal toxicity was observed. No maternal deaths or signs of ChE
inhibition were seen among the mice supplied carbaryl in the diet
(1,166 mgA9/day), although there was a significant (p <0.05) decrease
in body weight gain on days 10 through 15. The incidence of pregnancy,
the average number of live fetuses/ litter and the incidence of resorp-
tions were not altered by carbaryl for either route of administration.
Mean fetal body weight and length were significantly (p <0.05) lower
than control values among litters given carbaryl in the diet, but was
not affected among those given carbaryl by gavage. Based on maternal
reproductive effects, the NQAEL in mice was identified as 100 mg/kg/day,
0 In an investigation using Sprague-Oawley rats, carbaryl was admini-
stered by gavage at levels of 1 , 1 0 or 1 00 mg/kg/day for 3 months
prior to and throughout gestation (Lechner and Abdel-Rahman, 1984).
Carbaryl of formulation grade (purity not specified) was administered
in corn oil. Dams were sacrificed on day 20 for examination. Animals
receiving 100 mg/kg/day showed a significant decrease in weight gain
during the gestational period, occurring primarily in the third week
(days 15 to 20). There was also a slight decrease in the number of
implantation sites and live fetuses per dam after treatment at this
dose level. Fetal weights and body length for all three doses were
within the range of control values. There were no overt signs of
maternal toxicity that suggested ChE inhibition. Based on maternal
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weight gain and number of implantations, the NOAEL in this study was
identified as 10 mg/kg/day.
Golbs et al. (1975) orally administered carbaryl to Wistar rats at
doses of 200 or 350 mg/kg on days 5, 7 and 9, or on days 11, 13 and
15 of the gestation period. In one group of rats, 200 mg/kg was admin-
istered on days 5, 7, 9, 11, 13 and 15. Doses of 350 mg/kg given during
late gestation (days 11 to 15) delayed fetal development, whereas the
same dose given at the earlier interval (days 5 to 9) resulted in
loss of fertilized ova and more pronounced retardation in development
of individual fetuses. Similar results were produced by the 200-mg/kg
dose given on alternate days from day 5 through day 15. It was
concluded that carbaryl produces dose-dependent effects on intrauterine
development in rats. Based on this study, a LOAEL of 200 mg/kg (100
ng/kg/day) was identified.
Collins et al. (1970) reported (abstract) the effects of carbaryl in
the diet on various reproductive parameters over three generations of
rats. Osborne-Mendel rats were fed 0, 2,000, 5,000 or 10,000 ppm
carbaryl in the diet. Assuming that 1 ppm in the diet of rats is
equivalent to 0.05 mg/kg/day (Lehman, 1959), these levels correspond
to doses of about 0, 100, 250 or 500 mg/kg/day. At 10,000 ppm, no
litters were produced after the first litter of the second generation;
decreases were observed in the fertility, viability, survival and
lactation indices in all litters at this dose. The survival index
also showed a decrease at the 5,000-ppm level. Dose-related decreases
were observed in the ratio of average number of animals weaned per
number of litters at both 5,000 and 10,000 ppm. At all three dose
levels there was a decrease in weanling weights. In rats, the LOAEL
was identified as 2,000 ppm (100 mg/kg/day).
0 Collins et al. (1970) reported (abstract) the effects of carbaryl in
a three-generation study in gerbils. Carbaryl was fed at dose levels
of 0, 2,000, 4,000, 6,000 or 10,000 ppm. Assuming that 1 ppm in the
diet of gerbils is equivalent to 0.05 mg/kg/day (Lehman, 1959), this
corresponds to doses of about 0, 100, 200, 300 or 500 mg/kg/day. No
second litters were produced in the third generation at 10,000 ppm.
Decreases in the viability index were observed at 6,000 and 10,000 ppm.
Dose-related decreases in the survival index were also observed.
The average number of animals weaned per litter was also decreased.
Based on these findings, a LOAEL of 6,000 ppm (300 mg/kg/day) and a
NOAEL of 4,000 ppm (200 mg/kg/day) were identified.
Developmental Effects
0 Weil et al. (1972) exposed pregnant Harlan-Wistar rats to carbaryl
in the diet on days 5 to 15 of gestation. Ingested doses were 0, 20,
100 or 500 mg/kg/day. Animals were sacrificed on days 19 to 21, and
fetuses were examined for soft-tissue and skeletal abnormalities. No
increased incidence of teratogenic anomalies was detected at any dose
level. Based on this information, a NOAEL of 500 mg/kg/day (the-
highest dose tested) was identified.
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Carbaryl August, 1987
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Murray et al. (1979) administered 200 mg/kg/day carbaryl to female
rabbits by gavage on days 6 to 18 of gestation. Fetuses were removed
and examined for developmental defects. There was a significantly
(p <0.05) higher incidence of omphalocele in fetuses from exposed
animals than in the controls. The anomalies occurred in litters from
does that showed the greatest weight losses during the experimental
period. No other anomalies were seen at this dose level. At
150 mg/kg/day, there were single cases of omphalocele, hemivertebrae
and conjoined nostrils with missing nasal septum, but no fetal alterations
occurred at an incidence significantly different from that of the
control group. Based on fetal defects, the LOAEL for the rabbit was
identified as 150 mg/kg/day.
0 Murray et al. (1979) studied the teratogenic effects of carbaryl
in CF-1 mice. Carbaryl was administered by gavage at 100 or
150 mg/k9/day» or by feeding in the diet at 5,660 ppm (calculated by
the authors to be equivalent to 1,166 mg/kg/day). No major malformations
were detected among the offspring of dams given carbaryl by either
route at incidences significantly different than concurrent or histo-
rical controls. Delayed ossification of skull bones and of sternebrae
occurred significantly more often among litters from dams given
carbaryl in the diet, but not in litters from gavage-administered
dams. Based on developmental observations in fetuses, the NOAEL in
this study was identified as 150 mg/kg/day.
0 Lechner and Abdel-Rahman (1984) administered carbaryl to Sprague-Dawley
rats by gavage for 3 months prior to and throughout gestation at doses
of 0, 1, 10 or 100 mg/kg/day. Dams were sacrificed on day 20, and
fetuses were examined for external, skeletal and visceral malforma-
tions. There were no statistically significant increases of serious
anomalies at any dose level. The authors concluded that in the rats
tested, carbaryl displayed no evidence of teratogenicity. On this
basis, a NOAEL of 100 mg/kg/day (the highest dose tested) was identified.
0 Benson et al. (1967) fed mice carbaryl in their diet (intake levels
of 10 or 30 mg/kg/day) during gestation. Some dams were allowed to
deliver naturally, and others were delivered by Cesarean section.
There were no differences between the offspring of the two treated
groups and the controls in sex ratio, incidence of anomalies or in
ossification. Based on this information, a NOAEL of 30 mg/kg/day
(the highest dose tested) was identified.
Mutagenicity
0 The effects of pesticides on scheduled and unscheduled DNA synthesis
of rat thymocytes and human lymphocytes were studied by Rocchi et al.
(1980). Carbaryl (99.2% pure) in the rat thymocyte culture inhibited
thymidine uptake 15, 22 and 99% at levels of 1, 10 and 100 ug/mL,
respectively. In the human lymphocytes, a dose of 50 ug/mL produced
62% inhibition on scheduled DNA synthesis, but had no effect on
unscheduled DNA synthesis.
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Carbaryl August, 1987
i *
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Carcinogenicity
* Carpenter et al. (1961) fed carbaryl to groups of CF-N rats
(20/sex/dose) for 2 years. Concentrations in the diet were 0, 50,
100, 200 or 400 ppm, reported by the authors to be equal to doses of
0, 2.0, 4.0, 7.9 or 15.6 ag/kg/day in Bales and 0, 2.4, 4.6, 9.6 or
19.8 mg/kg/day in females. Based on gross and histological examina-
tion of tissues, no increased frequency of any tumor type was detected.
The total number of tumors seen at each of the five concentrations
tested was 10, 12, 8, 9, 12 and 11, respectively.
* Shering (1963) dosed 25 male and 25 female rats by gavage with
5.0 mg/kg/day carbaryl for 18 months. Based on histological examination
of tissues, no effects of carbaryl on tumor frequency were detected.
Carbaryl (30 mg/kg/day) was administered by gavage to mongrel rats
daily for 22 months (Andrianova and Alekseev, 1969). At the termi-
nation of the study, 46 of the original 48 controls survived and one
animal had a malignant tumor. In the treated rats, 12 of the original
60 survived to 22 months, and 4 of these had malignancies (25%). It
was concluded that carbaryl was carcinogenic in this investigation.
0 Zabezhinski (1970) studied the carcinogenic!ty of beta-Sevin (the
2-napthol analog of carbaryl, often an impurity in technical Sevin).
Mice and rats (CC57W) were fed beta-Sevin in the diet five times per
week for their lifetime. Mice were fed 10 mg for 24 months and rats
25 mg for 33 months. On the assumption that this refers to mgAg/day
(translation does not use that designation), the average daily
consumption would be 7 mg/kg/day for mice, and 17 mg/kg/day for rats.
At the end of the experiment, 31% (8/26) of the surviving mice had
malignancies. The author noted that some of the tumor types were
occasionally observed in control mice, but at a much lower frequency.
Of the original 50 rats, several died due to nephrosis and other ail-
ments that were attributed to the carbaryl. Of the 16 rats surviving
to the end of the study, 4 had malignancies. No malignancies were
observed in the controls. It was concluded that beta-Sevin had a
weak carcinogenic effect in mice and rats.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (approximately 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:
HA - (NOAEL or LOAEL) x (BW) = ng/L ( ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL - No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
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Carbaryl August, 1987
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BW - assumed body weight of a child (10 kg) or
an adult (70 kg).
UF « uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
_ L/day » assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
No data were found in the available literature that were suitable for
determination of the One-day HA value. It is recommended that the Ten-day HA
value for a 10-kg child (1.0 mg/L, calculated below) be used at this time as
a conservative estimate of the One-day HA value.
Ten-day Health Advisory
The study by Weil et al. (1968) has been selected to serve as the basis
for determination of the Ten-day HA for the 10-kg child. This study identified
a NOAEL of 10 mg/kg/day in rats fed carbaryl in the diet for 7 days, based on
inhibition of ChE in plasma and red blood cells.
The Ten-day HA for a 10-kg child is calculated as follows:
Ten-day HA - (10 mg/kg/day) (10 kg) . uo mg/L (1 000 ug/L)
(100K1 L/day)
where:
10 mgAg/day » NOAEL, based on absence of effects on ChE in rats
exposed to carbaryl in the diet for 7 days.
10 kg » assumed body weight of a child.
100 - uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day « assumed daily water consumption of a child.
Longer-term Health Advisory
No data were found in the available literature that were suitable for
the determination of a Longer-term HA value. It is, therefore, recommended
that the DWEL, adjusted for a 10-kg child (1.0 mg/L) be used as a conservative
estimate of the Longer-term HA value.
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 noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three-step process. Step 1 determines the Reference Dose
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Carbaryl August, 1987
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(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate 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 assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The 2-year feeding study in rats by Carpenter et al. (1961) has been
selected to serve as the basis for determination of the Lifetime HA for
carbaryl. This study identified a NOAEL of 9.6 mg/kg/day, based on absence
of effects on mortality, body weight, organ weight, hematology, cataract
frequency or histopathology. This value is supported by a 1-year feeding
study in dogs, which identified a NOAEL of 7.2 mg/kg/day (Carpenter et al.,
1961), and an 18-month oral study in rats, which identified a NOAEL of 5.0
mg/kg/day (Shering, 1963); however, these latter studies were not selected
because exposure was less-than-lifetime.
Using the NOAEL of 9.6 mg/kg/day, the Lifetime HA for carbaryl is calcu-
lated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD « (9.6 mg/kg/day) . 0., mg/kg/day
(100)
where:
9.6 mg/kg/day - NOAEL, based on absence of adverse effects in rats
fed carbaryl in the diet for 2 years.
100 « uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL - (0.1 mg/kg/day) (70 kg) , 3>5 /L (3,500 ug/L)
(2 L/day)
where:
0.1 mgAg/day - RfD.
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Carbaryl August, 1987
-15-
70 kg - assumed body weight of an adult.
2 L/day - assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA - (3.5 mg/L) (20%) - 0.70 mg/L (700 ug/L)
where:
3.5 mg/L - DWEL.
20% « assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
8 The International Agency for Research on Cancer (IARC) (1976) has
classified carbaryl in Group 3; i.e., this chemical cannot be
classified as to its carcinogenicity for humans.
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986), carbaryl may be classified
in Group D: not classified. This category is for substances with
inadequate animal evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The U.S. EPA/Office of Research and Development determined an Acceptable
Daily Intake (ADI) of 0.096 mg/kg/day based on a rat chronic oral NOAEL
of 9.6 mg/kg/day (Carpenter, 1961) with an uncertainty factor of 100.
c The National Academy of Sciences (MAS) determined an ADI of 0.082
mgAg/day based on a rat chronic oral NOAEL of 8.2 mg/kg/day (Union
Carbide, 1958) and an uncertainty factor of 100.
0 The NAS has also determined a Suggested-No-Adverse-Response-Level
(SNARL) of 0.574 mg/L, based on an ADI of 0.082 mg/kg/day (70-kg adult
consuming 2 L/day and a 20% source contribution factor) (NAS, 1977).
0 The U.S. EPA has established residue tolerances for carbaryl in or
on raw agricultural commodities that range from 0.1 to 100 ppm (CFR,
1985).
VII. ANALYTICAL METHODS^
Analysis of carbaryl is by a high-performance liquid chromatographic
(HPLC) procedure used for the determination of N-methylcarbamoyloximes
and N-methylcarbamates in drinking water (U.S. EPA, 1984). In this
method, the water sample is filtered and a 400-uL aliquot is injected
into a reverse-phase HPLC column. Separation of compounds is achieved
using gradient elution chromatography. After elution from the HPLC
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Carbaryl August, 1987
-16-
column, the compounds are hydrolyzed with sodium hydroxide. The
ethyl amine formed during hydrolysis is reacted with o-phthalaldehyde
(OPA) to fora a fluorescent derivative that is detected using a
fluorescence detector. The method detection limit has been estimated
to be approximately 0.7 ug/L for carbaryl.
VIII. TREATMENT TECHNOLOGIES
Available data indicate that granular-activated carbon (GAG) adsorption,
ozonation and conventional treatment will remove carbaryl from water.
The percentage removal efficiency ranged from 43 to 99%.
0 Whittaker (1980) determined adsorption isotherms using GAC on laboratory*
prepared carbaryl in water solutions.
Pilot studies proved that GAC is 99% effective for carbaryl removal
(Whittaker et al., 1980 and 1982). Two columns, each packed with 37 kg
(80 Ibs) of two different GAC, were studied at an empty bed contact
time of 8 minutes and an optimum flow rate of 1 gpm.
0 Laboratory studies for both batch and flow-through columns were used
to examine carbaryl adsorption on two different GAC particle sizes
(Whittaker et al., 1982). Data were fitted to both Langmuir and
Freundlich isotherms; the monolayer capacity was calculated to be
800 moles carbaryl/gm and 1,250 moles carbaryl/gm for the 1.2 mm and
0.6 mm GAC, respectively.
0 Ozonation has been 99% effective in removing carbaryl and its
hydrolysis product, napthol, from aqueous solution (Shevchenko et al.,
1982). Carbaryl and napthol were not detected in the treated effluent
after the addition of 24.8 mg/L and 4.8 mg/L, of ozone respectively.
Before ozonation can be used to treat carbaryl contaminated drinking
water, however, the identity and toxicity of the resulting degradates
must be established.
0 Conventional water treatment by alum coagulation, 30-minute settling
period and filtration removed 56% of the carbaryl present (Whittaker
et al., 1982). Alum dosage of 100 mg/L plus the addition of 1 mg/L
of anionic polymer achieved this degree of removal of carbaryl from
wastewater.
0 A 3-day settling period without any chemical treatment yield a 50%
carbaryl concentration reduction (Holiday and Hardin, 1981).
0 Treatment technologies for the removal of carbaryl from water are
available and have been reported to be effective. However, selection
of individual or combinations of technologies to attempt carbaryl
removal from water must be based on a case-by-case technical evaluation,
and an assessment of the economics involved.
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Carbaryl August, 1987
}
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'Confidential Business Information submitted to the Office of Pesticide
Programs.
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