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Aldicarb
CASRN 116-06-3
Contents
0003
Aldicarb; CASRN 116-06-3
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Aldicarb
File On-Line 01/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 11/01/1993
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 03/01/1991
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Aldicarb
CASRN -- 116-06-3
Primary Synonym -- Temik
Last Revised -- 11/01/1993
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ---------
Sweating as clinical NOAEL: 0.01 mg/kg-day 10 1 1E-3
sign of AChe inhibition mg/kg-day
LOAEL: 0.025 mg/kg-day
Acute Human Oral
Exposure Study
Rhone-Poulenc, 1992
Clinical signs and NOAEL: None
symptoms of
acetylcholinesterase LOAEL: (FEL) 0.1 mg/kg-day
inhibition including
sweating, pinpoint
pupils, leg weakness,
and other effects
Acute Human Oral
Exposure Study
Union Carbide, 1971
Nausea, diarrhea, and NOAEL: None
other signs and
symptoms LOAEL: (FEL) 0.01 mg/kg-day
Acute Human Oral
Poisoning Episodes
Goldman et al., 1990a,b;
Hirsch et al., 1987
*Conversion Factors and Assumptions -- Oral doses administered in 200 ml
orange juice ingested over 15 minutes with a light breakfast (study 1). Oral
doses administered neat in 100 ml water. Dose administered affected 4 out of
4 exposed men. (study 2). Oral doses estimated based on self reports of
amount of commodities consumed, measured residue levels in commodities, and
average body weights for given age and sex. Level listed is median of 41
cases (study 3).
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
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. HED Doc. No. 0010459.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Union Carbide Corporation. 1971. R. Haines, J.B. Dernehl, and J.B. Block,
supervising physicians. Ingestion of Aldicarb by Human Volunteers: A
Controlled Study of the Effects of Aldicarb on Man. ALD-03-77-2215. February
11, 1971. MRID No. 00101911. HED Doc. No. 010450. Available from EPA.
Write to FOI, EPA, Washington, DC 20460.
Goldman, L.R., M. Beller and R.J. Jackson. 1990a. Aldicarb food poisonings
in California, 1985-1988: Toxicity estimates for humans. Arch. Environ.
Health. 45(3): 141-147. HED Doc. No. 010451, 010455, 010458. Available from
EPA. Write to FOI, EPA, Washington, DC 20460.
Goldman L.R., D.F. Smith, R.R. Neutra, et al. 1990b. Pesticide Food
Poisoning from Contaminated Watermelons in California, 1985. Archives of
Environmental Health. 45(4): 229-236.
Hirsch, G.H., B.T. Mori, G.B. Morgan, P.R. Bennett, and B.C. Williams. 1987.
Report of Illnesses Caused by Aldicarb-Contaminated Cucumbers. Food Additives
and Contaminants. 5(2): 155-60. HED Doc. No. 010455, 010458. Available from
EPA. Write to FOI, EPA, Washington, DC 20460.
The double blind, placebo controlled study included 38 men and 9 women,
with 6 men and 5 women receiving both a dose and a placebo exposure (Rhone-
Poulenc Ag Company, 1992). Men were exposed to doses of 0, 0.01, 0.025, 0.05,
0.06, or 0.075 mg/kg of aldicarb, while women received 0, 0.025, or 0.05
mg/kg. Subjects were given a light breakfast on the day of the study,
including a drink of orange juice containing one of the doses of aldicarb or
the placebo to be consumed over 15-30 minutes of the breakfast period.
Subjects remained generally seated or recumbent for the first 4 hours after
dosing. A number of biological parameters known to be affected by
cholinesterase inhibitors were monitored before dosing, hourly for the first 6
hours after dosing, and at 24 hours after dosing. These measures included
recording of signs and symptoms (e.g., sweating), measurements of pulse and
blood pressure, evaluation of pulmonary functions (FEV-1 and FVC), saliva and
urine output, pupil diameter measurements, and measurement of plasma and red
blood cell cholinesterase activity. All study subjects were evaluated with
respect to the above consequences after dosing with aldicarb or placebo.
Emphasis was placed on the first 6 hours after exposure, because it is known
that the effects and cholinesterase inhibition caused by aldicarb are acute
and readily reversible. The major endpoints seen in the study and discussed
as potentially treatment-related were effects on red blood cell and plasma
cholinesterases, sweating, light-headedness, headaches, salivation, and supine
diastolic blood pressure.
Aldicarb treatment of both males and females resulted in statistically
significant inhibition of both red blood cell and plasma cholinesterase at all
dose levels. Peak effects were noted at 1 hour after the dose, and the degree
and duration of effect increased with increasing doses. One male in the 0.075
mg/kg group who had mistakenly received 0.06 mg/kg, developed diffuse and
profuse sweating that began within 2 hours and abated within 6 hours of
dosing. Two other treated males, one given 0.05 mg/kg and another given 0.025
mg/kg, developed localized and mild sweating with onset within the first 2
hours of dosing and abated within 6 hours of dosing. One male given 0.075
mg/kg reported that he was light-headed within 1 hour of dosing. Three men in
the 0.01 mg/kg group reported headaches, two with onset within 6 hours of
dosing, and one within 8 hours. This long time between dosing and onset is
beyond the peak of cholinesterase inhibition and the other effects seen here
and in both the Union Carbide study and the poisoning episodes. None of the
females developed any clinical signs or symptoms consistent with
cholinesterase inhibition or treatment.
Females given 0.05 mg/kg showed higher saliva output than controls, with
marginal statistical significance. Observed changes in blood pressure were
generally small in magnitude, limited to supine diastolic pressure, and
statistically significant in some, but not other analyses. There were no
treatment-related changes in standing or supine pulse, pupil size, or urine
volume in either males or females. As expected, there were no changes in
hematology and clinical chemistry parameters.
There were statistically significant increases in FVC in men at the 0.01
and 0.075 mg/kg doses, but these were not considered to be treatment-related
based on a one way analysis of variance and on the observation that the
statistically significant findings were likely a result of a drop in control
values during the session.
A number of questions arose during the review of this study that made it
more difficult to fully interpret the results. Some of these were related to
incomplete reporting by the study authors. Others are simply limitations in
the design and conduct of the study.
The paucity of clearly and statistically significant chemical-related
effects other than inhibition of plasma and red blood cell cholinesterase
activity, and the limitations noted, make a definitive judgment of toxic and
non-toxic doses difficult. Effects noted tended not to demonstrate
statistical significance, dose-response or dose effect relationships, or
correspondence between males and females. Diffuse and profuse sweating in
one man given 0.06 mg/kg was the most clearcut sign of toxicity; the
appearance of localized sweating in one man at 0.05 and another at 0.025 mg/kg
suggests some dose-related response, especially in light of the Union Carbide
(1971) study, where all males receiving 0.1 mg/kg showed sweating. Some other
effects consistent with cholinesterase inhibition were noted in the range of
0.025-0.075 mg/kg.
In conclusion, the NOAEL for this study was considered to be 0.01 mg/kg-
day and the LOAEL is 0.025 mg/kg-day, based on the sweating seen in males.
This NOAEL serves as the operational basis for the RfD derivation.
In another human study (Union Carbide Corporation, 1971), 12 adult male
volunteers were weighed and assigned to different treatment groups based on
nearly equal average weights. None of the subjects had known exposure to
aldicarb or other cholinesterase inhibitors for a week prior to the study.
Subjects were divided into three test groups (4/group) and administered
aldicarb at 0.025, 0.05, or 0.1 mg/kg. A stock solution of 1 mg/ml of
aldicarb was prepared by dissolving 0.2 g of analytical grade aldicarb in 200
ml of distilled water. Dosages were prepared by diluting the appropriate
amount of aldicarb solution into 100 ml of distilled water, which was then
ingested in one draft. Subjects were given their doses between 9:00 and 9:15
a.m. and engaged in normal business activities except during blood and urine
sampling and clinical observations. Liquids were provided ad libitum during
the post-exposure period. Observations were reported 1, 2, 3, 4, and 6 hours
following the dose. These observations included measurement of pulse, blood
pressure, observation of pupil size, and subjects' complaints.
All three groups experienced significant cholinesterase inhibition in
whole blood, with the peak inhibition between 1-2 hours and almost complete
recovery in 6 hours. The 0.1 mg/kg dose elicited clinical signs in all four
subjects, predominantly sweating and leg weakness, while most subjects given
the two lower doses had no signs or symptoms. At 0.025 mg/kg, one subject
reported apprehension. The method of analysis of cholinesterase in blood was
valid and appropriate for this carbamate. The range of cholinesterase
inhibition at this dose(0.025 mg/kg) was 30-57%.
Therefore, an FEL of 0.1 mg/kg-day can be established for this study based
on clinical signs and symptoms of acetylcholinesterase inhibition including
sweating, pinpoint pupils, leg weakness, and other effects.
Dosage estimates for 28 cases of alleged aldicarb poisoning were derived
from average body weights by age and sex (from standard tables), self-reported
symptoms and estimated consumption, and aldicarb sulfoxide residues from
watermelons and cucumbers (Goldman et al., 1990a). Estimates for 13
additional cases were provided by Hirsch et al. (1987), also based on
estimates of body weights and consumption, and measurements of residues of
total aldicarb, believed to be primarily 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 description of cases
used for estimates was limited in terms of onset, duration, and severity, and
many of the reported symptoms of cholinesterase inhibition, (i.e., nausea,
vomiting, and diarrhea) are nonspecific. The analytical methodology 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 due to these factors (i.e., some false positives and false negatives),
may have occurred among the over 1000 reported cases of illness. Further, the
use of sex and age averages for body weights and self-reported food
consumption values are also subject to estimation errors, but these are
expected to include both under and overestimates. Nevertheless, these effects
were consistent with the expected syndrome, the analytical techniques were
considered valid and these dosage estimates are regarded as reasonable general
estimates of effects.
In conclusion, an FEL of 0.01 mg/kg-day can be established from these
three studies based on nausea, diarrhea, and other signs and symptoms.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- An uncertainty factor of 10 is proposed based on the NOAEL in the Rhone-
Poulenc human study to account for variation in sensitivity among persons in
the population. Several considerations went into the choice of this
uncertainty factor. Based on a relatively complete data base for systemic
toxicity, effects from repeated exposures have not been seen in laboratory
animals at levels comparable to those seen in humans exposed acutely, and so
would not support a lower RfD. While human data on the adverse consequences
of repeated aldicarb exposure is lacking, available evidence both in
experimental animals and in humans exposed to aldicarb suggest that
neurobehavioral effects are short lived with no accumulation of effects over
time. Thus, the doses producing effects following repeated daily exposure are
comparable to those following a single dose. Also, comparable degrees of
cholinesterase inhibition are seen from the same dose levels, whether
delivered in one acute dose or following subchronic or chronic dosing
(Hazelton et al., 1988; Rhone-Poulenc, 1992). Since aldicarb does not appear
to produce neurobehavioral effects at doses below those producing inhibition
of cholinesterase, an acute human experimental study is expected to reasonably
evaluate the potential neurobehavioral consequences of repeated human
exposure. Compared with the controlled studies, the human poisoning episodes
document effects in a group of individuals probably self-selected as a
sensitive population and more heterogeneous than the healthy adults chosen for
the controlled studies. The dosage estimates from these reports, however,
were derived from estimates of the body weights of the people involved, based
on tables of average weights for a given age and sex. They also were derived
from self-reported estimates of the amount consumed. Thus, while these dosage
estimates are based on reasonable estimates of body weight and amount of
watermelon consumed for each population sample, they are not as precise as
those derived in the controlled studies, where each subject was weighed and
received a known dose. It is more reasonable to examine the distribution of
estimated doses over which effects were reported, rather than to regard each
individual estimate as precise. All the estimates for the 41 cases from the
poisoning episodes are subsumed within this RfD. The proposed RfD provides
for a margin of exposure of 10 from that recorded in the controlled studies or
from the median poisoning estimate. It also subsumes the entire range over
which effects have been reported in the poisoning episodes which empirically
define, to some extent, the sensitivity of a more sensitive heterogenous
population.
MF -- None
___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD)
There is a rich data base bearing on the toxicity of aldicarb. The
compound is a potent cholinesterase inhibitor that rapidly induces adverse
effects that are rapidly reversed. Chronic toxicity in laboratory animals is
manifest at doses comparable to those that produce acute toxicity.
Essentially all hazards from aldicarb exposure are associated with
cholinesterase inhibition (ChEI). Both human and laboratory animal data can
be used to determine levels of aldicarb exposure that are probably not
associated with significant risk. An overall view of the data indicates that
various species show toxic effects at similar doses. Because of the
availability of human studies, it is logical to place primary reliance on
these studies in determining the RfD.
These four studies of humans provide the best information on the toxic
effects of aldicarb: the recent experiment conducted on behalf of Rhone-
Poulenc (1992), the Haines experimental study conducted by Union Carbide
(1971), and the evaluations of some pesticide misuse poisoning incidents
developed by Goldman and Hirsch (Goldman et al., 1990a,b; Hirsch et al.,
1987). In developing the RfD, primary emphasis has been placed upon the
Rhone-Poulenc study. The Union Carbide study provides some correlative
evidence of a frank effect level and sweating, while the poisoning incidents
provides important general estimates of potential population sensitivity. The
weight of the evidence from all of the available human data cited here were
considered critical in the estimation of this reference dose. Each of these
sources has limitations that raise concerns about sole reliance on any one as
a basis for this estimate. However, it was considered equally important to
consider use of all of the available evidence to estimate potential risks.
The Union Carbide study (1971) helps define a dose (0.1 mg/kg) that is
clearly associated with adverse effects in humans. At least three of four
subjects showed sweating, pupillary constriction, muscle weakness, and
increased salivation, while fewer demonstrated slurred speech, malaise,
nausea, gastrointestinal cramping, and vomiting. No confirmation of these
signs was noted in groups receiving 0.05 or 0.025 mg/kg of aldicarb.
Significant reductions in blood cholinesterase activity, which returned to
normal within a few hours, was noted in all dosed individuals.
In the Rhone-Poulenc study (1992), where groups received doses of aldicarb
between 0.01 and 0.075 mg/kg, there were less obvious indications of toxicity.
Some male subjects manifested sweating, headache, or light-headedness that
could have been due to aldicarb exposure. Only the sweating was a
manifestation in common with the subjects in the Union Carbide study. The
most obvious sign in the new study was the finding of diffuse and profuse
sweating in one male who had received 0.06 mg/kg of aldicarb; the other two
cases were males demonstrating localized sweating of the palms with or without
sweating of the soles (0.05 and 0.025 mg/kg, respectively). One of the
control males also developed sweating of the palms and forehead. Diffuse body
sweating is a well characterized cholinergic sign, whereas localized sweating
is mediated by sympathetic fibers that synapse at cholinergic ganglia and
communicate with the sweat glands of the palms and soles by norepinephrine.
Cholinesterase inhibition at the ganglia may sensitize these neurons to other
potential stimuli, like emotional factors. At 0.1 mg/kg, all four of the
treated males in the Union Carbide study demonstrated sweating, and two of
them had sweating localized to the palms and forehead. As in the Union
Carbide study (1971), dosed subjects in the Rhone-Poulenc study (1992) showed
depressions in blood cholinesterase that generally began to recover within a
few hours.
The relative drop in supine diastolic blood pressure during the first
hour post-dosing in the Rhone-Poulenc (1992) study was significantly greater
in the male 0.075 mg/kg group than in the controls when an unweighted analysis
was performed but not when a weighted analysis was performed. Females in the
0.025 mg/kg group showed a decrease in the relative diastolic pressure at 1
hour post-dosing, which was significant in a weighted analysis but not in an
unweighted analysis. Higher-dosed females (0.05 mg/kg) showed no significant
differences. In contrast, the mean supine diastolic pressure of the male 0.05
mg/kg group in the Rhone-Poulenc (1992) study was statistically significantly
higher than that in the placebo group. There were no differences in the
supine systolic pressures or the standing blood pressures in treated males and
females. Also of interest is the absence of blood pressure changes in the
males in the Union Carbide (1971) study who received doses of 0.025, 0.05, or
0.1 mg/kg of aldicarb.
As would be expected from ChEI, salivation was statistically
significantly increased in the 0.05 mg/kg female dose group (highest dose
tested in females) as compared with controls in the Rhone-Poulenc study. In
contrast, males in the 0.01 and 0.05 mg/kg groups and the male who received
0.06 mg/kg showed a significant decrease in salivation; males receiving 0.075
mg/kg showed no difference from the placebo group. Increased salivation was
noted in 3 of the 4 treated males in the Union Carbide study that received 0.1
mg/kg aldicarb, but not in those receiving 0.025 or 0.05 mg/kg. Headache was
reported by three males in the 0.01 mg/kg dose group in the Rhone-Poulenc
study (1992), but this symptom was not declared among males in any of the
other groups or in any of the females. Headache was not reported in the males
in the Union Carbide study.
In sum, there is very good information that 0.1 mg/kg of aldicarb is toxic
to humans and produces multiple effects including such things as sweating,
muscular weakness, and pinpoint pupils. Diffuse or localized sweating was
noted in 4 of 4 subjects at 0.1 mg/kg and in one subject each who had received
the 0.06, 0.05, and 0.025 mg/kg doses; no sweating was reported at 0.01 mg/kg.
Other indications of a potential cholinergic response in these studies are
less reliable: they occur at some doses but not at doses higher or doses
lower; there is a failure across sexes to confirm the presence of effects or
there is an opposite effect; there is no statistical significance and there is
no dose response. These limitations apply to the evaluation of all the
effects in these studies.
A reasoned course is to place major emphasis on sweating, the only sign
of cholinergic response that was noted in both experimental studies.
Therefore based on sweating, a LOAEL of 0.025 mg/kg and a NOAEL of 0.010 mg/kg
were identified. These considerations include the bulk of other potential
effects such as headaches that were noted in the Rhone-Poulenc study.
Recognizing that these judgments are based upon a limited number of
observations in humans, an uncertainty factor of 10 is included to account for
potential human variability. The estimates of potential exposure from five
pesticide misuse poisoning incidents (Goldman et al., 1990a,b; Hirsch et al.,
1987) were all higher than the proposed RfD. Based upon all of the data on
humans from these sources, exposure to 0.001 mg/kg of aldicarb, the present
RfD, is expected to be without significant adverse effect.
Two other general comments related to the population sensitivity and the
nature and extent of effects should be noted. First, the broad range of
exposure levels over which effects in humans have been seen in these studies
(0.002-0.1 mg/kg) suggests that some portion of population sensitivity is
accounted for in the data. Second, the effects seen are acute, relatively
small in magnitude in many cases, and of relatively low incidence at all but
the highest dose levels.
Other Data Reviewed:
1) 1-Year Feeding - dog: Core grade supplementary (Rhone-Poulenc, 1988a;
Rhone-Poulenc, 1991a).
Groups of beagle dogs (5/sex/dose) were administered Aldicarb, technical
grade, in the diet for 52 weeks at doses of 0, 0.028, 0.054, 0.132, and 0.231
mg/kg-day for males and 0, 0.027, 0.055, 0.131, and 0.251 mg/kg-day for
females. It was initially concluded that the lowest dose tested, 1 ppm (0.028
mg/kg-day) was a LOAEL for plasma cholinesterase inhibition in males and that
the next higher dose level (0.055 mg/kg) and above produced signs consistent
with cholinesterase inhibition, including diarrhea and mucoid and/or soft
stool. According to the study report, group brain cholinesterase was
significantly inhibited only at the highest dose in males compared with
controls. A NOAEL for ChE inhibition in the study was not established.
Review of an addendum submitted by the registrant(Rhone-Poulenc, 1991a) which
provided additional pre-exposure data on clinical signs seen in the 1-year dog
study, and after extensive statistical analyses by EPA, it was concluded that
the available data and evaluations on clinical signs in dogs of diarrhea and
soft and mucoid stool were insufficient to support the conclusion that this
was an effect of treatment.
2) Subchronic Feeding - dog: (Rhone-Poulenc, 1991b).
This study established a clear NOAEL for plasma cholinesterase between
0.35 and 0.7 ppm in the diet (0.012-0.025 mg/kg) for dogs fed these levels in
the diet for 5 weeks. No clinical signs were noted as effects of treatment.
Levels of red blood cell cholinesterase inhibition may have been
underestimated, however.
3) 2-Year Feeding - rat: Core grade supplementary (Union Carbide, 1966c).
Four groups of rats (20/sex/dose) were maintained on diets containing 0,
0.005, 0.025, 0.05, or 0.1 mg/kg-day of aldicarb for 2 years. Based upon
measurements of food consumption; mortality and lifespan; incidence of
infection; liver and kidney weights as percentage of body weight; body weight
gain; hematology; incidence of neoplasms; incidence of pathological lesions;
and brain, plasma, and erythrocyte cholinesterase levels, the animals were
found not to differ significantly from controls for any of these parameters.
Therefore, the NOAEL for systemic toxicity is greater than or equal to 0.1
mg/kg-day.
4) 2-Year Feeding (carcinogenicity) - rat: Core grade minimum (Union Carbide,
1972).
Groups of 20 Greenacres laboratory controlled flora rats of each sex were
fed 0 or 0.3 mg/kg-day of aldicarb in the diet for 2 years. There were no
differences from controls in mortality, growth, hematological characteristics,
or other histological abnormalities. The NOAEL for systemic toxicity is
therefore greater than or equal to 0.3 mg/kg-day.
5) 3-Generation Reproduction - rat: Core grade minimum (Union Carbide,
1974a).
Rats were fed aldicarb at dose levels of 0, 0.2, 0.3, or 0.7 mg/kg-day for
90 to 100 days and mated to produce the respective F1, F2, and F3 generations.
All animals were maintained continuously on diets containing aldicarb. The F3
animals were histologically examined either at weaning or at 90 days of age.
No reproductive effects were noted at any dose tested. Decreased body weight
of F2 pups was observed at 0.7 mg/kg-day. Therefore, the NOAEL and LOAEL for
fetotoxicity are 0.3 and 0.7 mg/kg-day, respectively.
6) 2-Generation Reproduction - rat: core grade minimum (Rhone Poulenc,
1991c).
Twenty-six males and females/dose were administered aldicarb at dose
levels of 0, 0.1, 0.4, 0.7-9, and 1.4-1.7 mg/kg-day for 70 days prior to
mating and then bred to obtain the F1A litters. These progeny were raised
until weaning (day 21). The F0 rats were then bred producing the F1B litters.
Aldicarb had no adverse effects on reproductive capacity during either mating.
At 1.4-1.7 mg/kg-day dose, there were decrease pup weights and reduced pup
viability observed at lactation day 4. At 0.7-0.9 mg/kg-day, in parents
decreased body weights and decreased RBC and plasma cholinesterase levels were
seen. The NOEL for parental systemic toxicity was 0.4 mg/kg-day and the
fetotoxic NOEL was 0.7-0.9 mg/kg-day.
7) Developmental toxicity - rat: Core grade minimum (Union Carbide, 1966a).
Pregnant rats were administered aldicarb in the diet at dose levels of 0,
0.04, 0.2, and 1 mg/kg-day. The rats were further divided into three groups:
Group 1 rats were fed aldicarb in the diet throughout pregnancy or until the
pups were weaned; Group 2 rats were administered aldicarb from the day the
vaginal plug first appeared through the seventh day; and Group 3 received
aldicarb from days 5 through 15 of gestation. No congenital malformations
were reported for any of the treated groups, and body weights of both the
mothers and pups were normal. No significant effects were observed on
fertility, gestation, viability of offspring, or lactation. Therefore, the
NOAEL for systemic and developmental effects is equal to or greater than 1
mg/kg-day (HDT).
8) Developmental toxicity - rat: Core grade minimum (Rhone-Poulenc, 1988b).
Groups of CD rats were admistered aldicarb by gavage at dose levels of 0,
0.125, 0.25 and 0.5 mg/kg-day. Effects on pregnant dams were found at 0.25
and 0.5 mg/kg-day and consisted of decreased body weight gain and food
consumption. There were some maternal deaths at 0.5 mg/kg-day. The NOEL for
maternal toxicity was 0.125 mg/kg-day. In offspring, at the 0.5 mg/kg-day
dose level, there were significant increases in the dilation of the lateral
ventricles of the brain, poor ossification of the sixth sternebra, and
significant decreases in fetal body weight. In addition, ecchymosis (small
hemorrhages) of the trunk were significantly increased (p<0.05) at the 0.25
and 0.5 mg/kg-day dose levels. The incidence of this finding at the low-dose
group was not statistically significant and was within the historical control
range. The NOEL for developmental effects was 0.125 mg/kg-day.
9) Developmental toxicity - rabbit: Core grade guideline (Union Carbide,
1983).
Groups of pregnant Dutch Belted rabbits (16/group) were administered
aldicarb by gavage at dose levels of 0, 0.1, 0.25, and 0.5 mg/kg-day from days
7 through 27 of gestation. On the first day of dosing (day 7), 8
animals/group were misdosed with 3 ml/kg instead of 1 ml/kg. Consequently,
5/8 rabbits died in the 0.5 mg/kg-day group. Remaining misdosed animals in
all groups were sacrificed and replaced. Survival, other than noted above,
was comparable among all groups. General observations for toxic signs were
unremarkable, except for pale kidneys and hydroceles on the oviducts at doses
greater than or equal to 0.25 mg/kg-day. There were compound-related
decreases in body weight for dams at the two highest doses. Based on
decreased body weight, pale kidneys, and hydroceles on the oviducts, the NOEL
and LOEL for maternal toxicity are 0.25 and 0.5 mg/kg-day, respectively. The
number of viable fetuses/doe was significantly reduced in all treatment
groups, as was the total number of implantations/doe. Group mean post-
implantation loss was significantly reduced in all treatment groups, as was
the total number of implantations/doe. These observations (which were
statistically significant only at the lowest dose tested) were considered to
be due to the unusually large number of corpora lutea/dam and the low rate of
pre-implantation loss in the control group, both of which contributed to a
higher number of viable fetuses and implantations in the control group. The
historical control data supported this conclusion. Therefore, the NOEL for
fetotoxicity was 0.5 mg/kg-day, and the overall NOEL for developmental
toxicity is 0.25 mg/kg-day.
10) 2-Year Feeding - dog: Core grade minimum (Union Carbide, 1966b).
Four groups of dogs (3/sex/dose) were fed aldicarb in the diet at dose
levels of 0, 0.025, 0.05, and 0.1 mg/kg-day for 2 years. Based upon
observations of body weight changes, appetite, mortality, histopathology,
hematology, biochemistry, and terminal liver and kidney weights, there were no
statistically significant effects found at any dose tested. Therefore, the
NOAEL for systemic toxicity is greater than or equal to 0.1 mg/kg-day.
11) 3-Month Feeding - dog: Core grade minimum (Union Carbide, 1974b).
Dogs were fed aldicarb in the diet at dose levels of 0, 0.2, 0.3, and 0.7
mg/kg-day for 90 days. The only effects observed were the slightly decreased
weight of the testes and the slightly increased weight of the adrenal glands
in males at 0.7 mg/kg-day. Therefore, the NOAEL and LOAEL for systemic
toxicity are 0.3 and 0.7 mg/kg-day, respectively.
12) 14-Day Feeding - dog: Core grade supplementary (Union Carbide, 1987).
One dog/sex/dose received aldicarb in the diet at dose levels of 0, 0.1,
0.3, 1, 3, and 10 ppm (Male: 0, 0.003, 0.008, 0.029, 0.08, and 0.269 mg/kg-
day; Female: 0, 0.003, 0.008, 0.029, 0.114, and 0.294 mg/kg-day) for 2 weeks.
Treatment-related effects were observed for inhibition of red blood cell (RBC)
acetylcholinesterase (AChE) and plasma butyrlcholinesterase (BuChE) which
occurred at or about 3 ppm. Three weekly pre-dose determinations for both RBC
and plasma were utilized for comparison of an individual to its own baseline
cholinesterase levels. Serial measurements performed every 2 hours for the
first 8 hours post-dosing in Group 6 (10 ppm dose) clearly demonstrated
inhibition of RBC AChE to 45% of normal and plasma BuChE to 34% of normal.
Inhibition was not fully recovered at 8 hours. Based on plasma and RBC ChE
inhibition, the NOAEL and LOAEL for systemic toxicity are 1 (0.029 mg/kg-day)
and 3 ppm (Male: 0.08 mg/kg-day; Female: 0.114 mg/kg-day).
13) Immunotoxicity - humans: Fiore et al., 1988; Mirkin et al., 1990.
These two published studies suggest that data from women exposed to
aldicarb in their drinking water indicated immunomodulatory effects on T Cell
subsets. The second, followup study notes evidence of lymphocyte (CD8+ T-
cell increases) in peripheral blood without clinical signs in five women.
U.S. EPA, Office of Pesticide Programs reviews conclude that for a number of
methodological, statistical, and other reasons, that immunological hazards due
to Aldicarb have not been demonstrated in these studies.
Data Gap(s): The Agency is preparing a Data Call In for aldicarb that is
expected to call for further neurotoxicity studies, and a rat dominant lethal
study.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Medium
RfD -- Medium
The principal studies are given a medium to low confidence rating because
none establish a definitive state of the science NOAEL for adverse effects and
are limited in the ways described above. Their corroboration of one another
in some ways provide additional support. The data base consists of numerous
studies and is given a medium confidence rating for completion due to the lack
of definitive neurotoxicity studies for a chemical which is a potent
neurotoxicant. Confidence in the RfD can be considered medium.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation -- U.S. EPA, 1984, 1988, 1991
Agency Work Group Review -- 12/02/1985, 02/05/1986, 05/15/1986, 06/20/1990, 07/25/1990,
09/22/1992, 10/15/1992
Verification Date -- 10/15/1992
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Aldicarb
CASRN -- 116-06-3
Primary Synonym -- Temik
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Aldicarb
CASRN -- 116-06-3
Primary Synonym -- Temik
Last Revised -- 03/01/1991
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- D; not classifiable as to human carcinogenicity.
Basis -- Aldicarb was not found to induce statistically significant increases
in tumor incidence in mice or rats in feeding studies or mice in a skin
painting study. In the feeding studies there were, however, significant
trends in pituitary tumors in female rats and fibrosarcomas in the male
mouse. This evidence, together with the fact that less than maximum
tolerated doses were used, indicates that the available assays are inadequate
to assess the carcinogenic potential of aldicarb.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Inadequate. The NCI (1979) conducted a bioassay of aldicarb for possible
carcinogenic effects in rats and mice. Fifty male and 50 female F344 rats
and the same numbers of male and female B6C3F1 mice were administered doses
of 2 or 6 ppm in the diet for 103 weeks. The animals were then observed for
an additional 0 to 2 weeks before terminal sacrifice. Matched controls were
composed of 25 untreated rats and 25 untreated mice of each sex. There was a
dose-related trend in incidence of pituitary adenomas or carcinomas in the
female rats for which the Cochran-Armitage test was statistically significant
but the Fisher exact test was not significant. There were occurrences of
pancreatic islet-cell adenomas in both treated male and female rats. The
incidences were not statistically significant but were nonetheless regarded
as compound-related by NCI since there were no pancreatic tumors in the
concurrent controls. A dose-related trend in incidence of fibrosarcoma or
sarcoma of the subcutaneous tissue was observed in treated male mice for
which the Cochran-Armitage test was statistically significant. The Fisher
exact test, however was not significant. NCI acknowledged that maximum
tolerated doses were not achieved in this study, and it was concluded that
none of the tumors could be clearly attributed to the administration of
aldicarb.
In a 2-year feeding study, Weil and Carpenter (1965) administered 0.005,
0.025, 0.05 or 0.1 mg aldicarb/kg/day in the diet (0.1, 0.5, 1.0 or 2.0 ppm,
assuming food consumption of 5% of body weight per day) to an unspecified
strain of rats. The tumor incidences were not significantly greater than
those of the control animals. Weil and Carpenter (1972) reported similar
results in Greenacres Laboratory Controlled Flora rats fed 0.3 mg/kg/day (6
ppm) for 2 years. No adverse effects were observed due to the aldicarb
administration.
Weil (1973) conducted a skin painting study using male C3H/HEJ mice.
Female mice were not used for the study due to the high incidence of
spontaneous mammary tumors. Mice were administered the aldicarb in the form
of applications of 0.125% concentration to hair-free skin on the backs of the
animals twice a week for up to 28 months or until death. When compared to
controls (positive control group painted with cholanthrene), aldicarb was
determined to be noncarcinogenic under the conditions of the experiment.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Ercegovich and Rashid (1973) found aldicarb to be weakly mutagenic in
five strains of Salmonella typhimurium in the absence of liver microsomal
enzymes.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1987
The 1987 Drinking Water Criteria Document for Aldicarb has received Agency
peer and administrative review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 08/05/1987, 08/26/1987
Verification Date -- 08/26/1987
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Aldicarb
CASRN -- 116-06-3
Primary Synonym -- Temik
Last Revised -- 11/01/1993
__VI.A. ORAL RfD REFERENCES
Fiore M.C., H.A. Anderson, R. Hong, et al. 1986. Chronic Exposure to
Aldicarb Contaminated Groundwater and Human Immune Function. Environ. Res.
41: 633-645.
Goldman L.R., M. Beller, and R.J. Jackson. 1990a. Aldicarb Food Poisonings
in California, 1985-1988: Toxicity Estimates for Humans. Arch. Environ.
Health. 45(3): 141-147.
Goldman L.R., D.F. Smith, R.R. Neutra, et al. 1990b. Pesticide Food
Poisoning from Contaminated Watermelons in California, 1985. Arch. Environ.
Health. 45(4): 229-236.
Hirsch G.H., B.T. Mori, G.B. Morgan, P.R. Bennett, and B.C. Williams. 1987.
Report of Illnesses Caused by Aldicarb-Contaminated Cucumbers. Food Add.
Contam. 5(2): 155-60.
Mirkin I.R., H.A. Anderson, L. Hanrahan, R. Hong, R. Golubjatnikov, 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.
Rhone-Poulenc Ag Company. 1988a. MRID No. 40695901; HED Doc Nos. 007058,
010449, 010456. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Rhone-Poulenc Ag Company. 1988b. MRID No. 41004501; HED Doc. Nos. 007254,
010453. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Rhone-Poulenc Ag Company. 1991a. MRID No. 42191501; HED Doc. No. 010456.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Rhone-Poulenc Ag Company. 1991b. MRID No. 41919901, 41956101; HED Doc. Nos.
008388, 010454. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Rhone-Poulenc Ag Company. 1991c. MRID No. 421484-01; HED Doc. No. 010457.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Rhone-Poulenc Ag Company. 1992. MRID No. 423730-01; HED Doc. No. 0010459.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Union Carbide Corporation. 1966a. MRID No. 00058631, 00085456; HED Doc. No.
004022. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Union Carbide Corporation. 1966b. MRID No. 00085458; HED Doc. No. 004022.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Union Carbide Corporation. 1966c. MRID No. 00085460; HED Doc. No. 004022.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Union Carbide Corporation. 1971. MRID No. 00101911; HED Doc. No. 010450.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Union Carbide Corporation. 1972. MRID No. 00029943; HED Doc No. 004022.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Union Carbide Corporation. 1974a. MRID No. 00044736, 00069918; HED Doc. No.
004022. Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Union Carbide Corporation. 1974b. MRID No. 00044737; HED Doc. No. 004022.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Union Carbide Agricultural Product Company, Inc. 1983. MRID No. 00131661,
00132668; HED Doc No. 003466, 010460. Available from EPA. Write to FOI, EPA,
Washington, DC 20460.
Union Carbide Agricultural Product Company, Inc. 1987. MRID No. 40166601;
HED Doc. No. 005925. Available from EPA. Write to FOI, EPA, Washington, DC
20460.
U.S. EPA. 1984. Requirements for Interim Registration of Pesticide Products
containing Aldicarb as the Active Ingredient. Office of Pesticides and Toxic
Substances, Washington DC. March 30. NTIS PB84-207653.
U.S. EPA. 1988. Aldicarb Special Review Technical Support Document. Office
of Pesticides and Toxic Substances, Washington DC. June. NTIS PB88-236856.
U.S. EPA. 1991. Drinking Water Criteria Document for Aldicarb. Office of
Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC.
__VI.B. INHALATION RfC REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Ercegovich, C.D. and K.A. Rashid. 1973. Mutagenesis induced in mutant
strains of Salmonella typhimurium by pesticides. Abstracts of papers. Am.
Chem. Soc. Abstract No. 43.
NCI (National Cancer Institute). 1979. Bioassay of aldicarb for possible
carcinogenicity. NCI Report No. 136. DHEW Publ. No. (NIH) 79-1391.
U.S. EPA. 1987. Drinking Water Criteria Document for Aldicarb. Prepared by
the Office of Health and Environmental Assessment, Cincinnati, OH, for the
Office of Drinking Water, Washington, DC. ECAO-CIN-420.
Weil, C.S. 1973. Miscellaneous toxicity studies. Mellon Institute Report
35-41. EPA Pesticide Petition No. 3F1414.
Weil, C.S. and C.P. Carpenter. 1965. Two-year feeding of Compound 21149 in
the diet of rats. Mellon Institute Report No. 28-123. EPA Pesticide Petition
No. 9F0798.
Weil, C.S. and C.P. Carpenter. 1972. Aldicarb (A), aldicarb sulfoxide (ASO),
aldicarb sulfone (ASO2) and a 1:1 mixture of ASO:ASO2. Two-year feeding in
the diet of rats. Mellon Institute Report No. 35-82. EPA Pesticide Petition
No. 9F0798.
_VII. REVISION HISTORY
Substance Name -- Aldicarb
CASRN -- 116-06-3
Primary Synonym -- Temik
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/01/1988 I.A.5. Confidence levels revised
03/01/1988 I.A.7. Primary contact changed
03/01/1988 III.A. Health Advisory added
08/22/1988 II. Carcinogen summary on-line
05/01/1989 I.A.5. Confidence statement revised
05/01/1989 I.A.7. Secondary contact changed
06/01/1989 II.D.2. Work group review date added
08/01/1989 VI. Bibliography on-line
07/01/1990 I.A. Oral RfD summary noted as pending change
08/01/1990 I.A. Withdrawn; new Oral RfD verified (in preparation)
08/01/1990 III.A.5. DWEL & Lifetime HA withdrawn (RfD withdrawn)
08/01/1990 VI.A. Oral RfD references withdrawn
03/01/1991 II.D.3. Secondary contact changed
07/01/1991 I.A. Oral RfD summary replaced; RfD changed
07/01/1991 III.A.5. DWEL and Lifetime HA replaced
07/01/1991 VI.A. Oral RfD references replaced
07/01/1991 III.A. Section III.A.1-4 replaced
08/01/1991 I.A. General edit
01/01/1992 IV. Regulatory actions updated
10/01/1992 I.A. Oral RfD summary noted as pending change
10/01/1992 I.A.6. Work group review date added
12/01/1992 I.A.6. Work group review date added
11/01/1993 I.A. Oral RfD summary replaced; new RfD
11/01/1993 III.A. Health Advisory withdrawn
11/01/1993 VI.A. Oral RfD references replaced
11/01/1993 VI.D. Health Advisory references withdrawn
01/01/1994 III.A. Message revised to include contact's name and number
VIII. SYNONYMS
Substance Name -- Aldicarb
CASRN -- 116-06-3
Primary Synonym -- Temik
Last Revised -- 01/31/1987
116-06-3
Aldecarb
Aldicarb
Ambush
Carbamyl
Carbanolate
ENT 27,093
2-Methyl-2-(Methylthio)Propanal, O-((Methylamino)Carbonyl) Oxime
2-Methyl-2-(Methylthio)Propionaldehyde O-(Methylcarbamoyl)Oxime
NCI-C08640
OMS 771
Propanal, 2-Methyl-2-(Methylthio)-, O-((Methylamino)Carbonyl)Oxime
Propionaldehyde, 2-Methyl-2-(Methylthio)-, O-(Methyl-carbamoyl)Oxime
Sulfone aldoxycarb
Temic
Temik
Temik 10 G
Temik G 10
Temik TSK
UC 21149
Union Carbide 21149
Union Carbide UC-21149
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0003.HTM
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