820K88114
August, 1987
DRAFT
METHOMYL
Health Advisory
Office of Drinking Water
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
understating of the biological mechanisms involved in cancer to suggest th t
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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Methomyl
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 16752-77-5
Structural Formula
0
CH,-C=N-0-C-N-CH3
S-CH, H
S-Methyl-N[(methylcarbamoyl)oxy]-thioacetimidate
Synonyms
Dupont Insecticide 1179; Dupont 1179; Insecticide 1,179; Insecticide
1179; IN 1179, Lannate; Mesomile; Nudrin; SD 14999; WL 18236 (Meister,
1983).
Uses
0 Methomyl is a carbamate insecticide used to control a broad spectrum
of insects in agricultural and ornamental crops (Meister, 1983).
Properties (Meister, 1983; Windholz et al., 1983; Cohen, 1984; CHEMLAB, 1985;
and TDB, 1985)
Chemical Formula
Molecular Weight
Physical State (25°C)
Boiling Point
Melting Point
Density (24°C)
Vapor Pressure (25°C)
Specific Gravity
Water Solubility (25°C)
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
C5H10°2N2S
162.20
White crystalline solid
78 to 79°C
U29
5 x 10~5 mm Hg
10,000 mg/L
-3.56
Occurrence
Methomyl has been found in 2 of 446 surface water samples analyzed
and in 25 of 1,023 ground water samples (STORET, 1987). Samples were
collected at 110 surface water locations and 1,000 ground water
locations, and methomyl was found in California, Georgia and Texas.
The 85th percentile of all non-zero samples was 2 ug/L in surface
water and 10 ug/L in ground water sources. The maximum concentration
found in surface water was 2 ug/L and in ground water it was 10 ug/L.
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Methomyl August, 1987
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Environmental Fate
8 In laboratory and greenhouse studies, methomyl was more rapidly
degraded in a sandy loam and a California soil than in silt loam
soils, with 21, 31, and 44 to 48% of the applied methomyl remaining in
the respective soils 42-45 days after treatment. The major degra-
dation product was carbon dioxide, which accounted for 23 to 47% of
the applied methomyl after 42 to 45 days. A minor degradation product,
S-methyl-N-hydroxy-thioacetimidate (a possible hydrolysis product),
was also found. Methomyl half-lives were less than 30 days in sandy loam
soil, less than 42 days in California soil, and approximately 45 days
in muck and silt loam soils. In a sterilized Flanagan silt loam
soil, 89% of the methomyl remained 45 days after application, indicating
that methomyl degradation in soil is primarily a microbial process
(Harvey, 1977a,b).
0 The nitrogen-fixing ability of some bacteria was severely reduced
(by as much as 85%) when methomyl was applied at 20 to 160 ppm (Huang,
1978).
0 In another study, methomyl (18 ppm) had no effect on fungal and
bacterial population or on carbon dioxide production in .either silt
loam or fine sand soils (Peeples, 1977).
0 No methomyl residues were detected in a muck soil 7 to 32 days after
treatment (E.I. DuPont de Nemours and Co., 1971).
0 The environmental fate of methomyl has also been the subject of
several undated, unpublished reports (Harvey, undated a,b; Harvey
and Pease; Han).
III. PHARMACOKINETICS
Absorption
0 Single oral doses of 1-14C-methomyl (purity not specified) were ad-
ministered via gavage to female CD rats as a suspension in 1% aqueous
methylcellulose. Ninety-five percent of the dose could be accounted
for in excretory products or tissue residues, indicating virtual
complete absorption from the gastrointestinal tract (Andrawes et al,
1976).
0 Baron (1971) reported that in rats given a single oral dose of 5 mg/kg
of 1-14C-labeled methomyl (purity not specified), approximately 2% of
the original label was excreted in the feces after 3 days, indicating
essentially complete gastrointestinal absorption.
Distribution
0 Baron (1971) fed a single oral dose of 1-14c-labeled methomyl (5 mg/kg,
purity not specified) to rats and analyzed 13 major tissues for residues
at 1 and 3 days after dosing. Only 10% of the label was present in
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Methomyl August, 1987
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tissues 24 hours after dosing, with no evidence of accumulation at
any site. By this time, over 40% of the label had been excreted via
the lung. At 3 days after dosing, tissue residues were essentially
unchanged from day 1, suggesting incorporation of label into tissue
components.
8 Baron (1971) reported that feeding methomyl to a lactating cow at
levels of 0.2 or 20 ppm in the diet (duration not specified) resulted
in very low residues (less than 0.02 ppm) in the milk, meat, fat,
liver and kidney.
Metabolism
0 According to Baron (1971), in 72 hours approximately 15 to 23% of a
5-mg/kg oral dose of I-14C-labeled methomyl in rats could be accounted
for as carbon dioxide, 33% as another metabolite in expired air, and 25%
as metabolites in the urine.
0 Harvey (1974) reported that in the rat, 1-14C-labeled methomyl (dose
and purity not specified) was metabolized to carbon dioxide (25%) or
acetonitrile (50%) within 72 hours.
0 Andrawes et al. (1976) reported that single oral doses of 4 mg/kg
were rapidly metabolized in the rat. In exhaled air, carbon dioxide
and acetonitrile were the major metabolites. In 24-hour urine samples,
polar metabolites (80%) and acetonitrile (18%), both free and conjugated,
were found with free methomyl, methy(o), the oxime and the sulfoxide
oxime detected at low levels.
0 Dorough (1977), in a series of studies with 14C-labeled isomeric forms
of methomyl, confirmed the report by Harvey (1974) of the excretion of
labeled carbon dioxide and acetonitrile in the expired air of treated
rats. In addition, nearly complete (79 to 84%) hydrolysis of the
ester linkage was apparent within 6 hours, prior to the major
formation of carbon dioxide and acetonitrile from methomyl. The
author suggested the following pathway: partial isomerization of
methomyl is followed by hydrolysis of the two isomeric forms to yield
two isomeric oximes that then break down to carbon dioxide and
acetonitrile at different rates. No additional metabolites were
identified.
Excretion
Baron (1971) stated that within 72 hours after receiving a single
oral dose of 1-14C-labeled methomyl, rats excreted 15 to 23% as
carbon dioxide, 33% as other metabolites in the expired air and
approximately 16 to 27% as methomyl and metabolites in the urine.
Harvey (1974) reported that 75% of an oral dose of 1-1 "^-labeled
methomyl (dose and purity not specified) was excreted by rats within
72 hours, 50% as acetonitrile and 25% as carbon dioxide in the expired
air. In contrast to other carbamates, sulfur-containing metabolites
were not found in the urine.
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Andrawes et al. (1976) reported that single oral doses (4 mg/kg) of
1-14c-labeled methomyl were rapidly excreted, with 32% of the dose
recovered in urine, 19% in feces and 40% in exhaled air after 4 days.
IV. HEALTH EFFECTS
Humans
Short-term Exposure
8 Liddle et al. (1979) reported a case of methomyl poisoning in Jamaica,
W.I., involving five men who had eaten a meal that included unleavened
bread. Methomyl was discovered in an unlabeled plastic bag in a tin
can, and had evidently been used as salt in preparation of the bread.
Approximately 3 hours after the meal, the men were found critically
ill, frothing at the mouth, twitching and trembling. Three were dead
on arrival at the hospital. One of the two survivors showed generalized
twitching and spasms, fasciculation, and respiratory impairment
thought to be due to severe bronchiospasms. The other patient walked
unaided and appeared generally normal. Both patients were given
atropine intravenously, and the symptomatic patient recovered within
2 hours after treatment. Methomyl was confirmed in the stomach
contents of each of the men who died, and analysis of the bread
indicated that it contained 1.1% methomyl. It was stated that two of
the victims had eaten about 75 to 100 g of bread each, or 0.82 to
1.1 g of methomyl. From these data it may be calculated that a dose
of 12 to 15 mg/kg body weight can be fatal in humans.
0 Araki et al. (1982) reported a case of a 31-year old woman who
committed suicide, giving methomyl in drinks to herself and her two
children. The 9-year-old elder son survived. In autopsies performed
on the mother and the 6-year-old son, the mucous membranes of the
stomach were blackish-brown, markedly edematous and congested. The
lungs were heavy and congested. On the basis of measured stomach
contents and tissue levels, it was estimated that the total doses
taken were 2.75 g (55 mg/kg) by the mother and 0.26 g (13 mg/kg) by
the child.
Long-term Exposure
0 Morse and Baker (1979) reported on a survey of the health of workers
in a plant that manufactured methomyl. The plant had also manufactured
propanil, an herbicide manufactured from 3,4-dichloroaniline. The
plant employed 111 workers in seven job categories. A complete work
history, symptoms or history of poisoning, personal habits, and
sources of other chemical exposure were obtained. Blood samples were
collected from 100 of.the 111 workers (96% males). Blood chemistries,
blood counts, and cholinesterase (ChE) determinations were carried
out. A routine urinalysis was also performed. Average employment at
the plant was 2 years. Packaging workers had the highest rate of
"methomyl" symptoms: small pupils (46%), nausea and vomiting (46%),
blurred vision (46%) and increased salivation (27%). Biomedical
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Methomyl August, 1987
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examination did not demonstrate significant effects, and acetylcholin-
esterase findings were normal. Other effects, such as chloracne,
were reported but were considered related to propanil exposure.
Animals
Short-term Exposure
0 The acute oral LDgQ reported for methomyl in the fasted male and female
rat ranged from 17 to 25 mg/kg (Bedo and Cieleszky, 1980; Dashiell
and Kennedy, 1984; Kaplan and Sherman, 1977). The oral LD^Q in the
nonfasted rat was 40 mg/kg (Dashiell and Kennedy, 1984). Clinical signs
in rats included chewing motions, profuse salivation, lacrimation,
bulging eyes, fasciculations and tremors characteristic of ChE inhibition,
0 The acute oral I>D$Q for methomyl in the mouse ranged from 27 to
55 mg/kg (Boulton et al., 1971; El-Sebae et al., 1979; Natoff and
Reiff, 1973).
0 The oral LDjg in hens was 28 mg/kg and in Japanese quail, 34 mg/kg.
(Kaplan and Sherman, 1977).
e The 4-hour inhalation ££50 of methomyl in rats was 300 mg/m^. Animals
showed the typical signs of ChE inhibition, including salivation,
lacrimation and tremors (ACGIH, 1984).
0 Bedo and Cieleszky (1980) administered single oral doses of methomyl
(purity not specified) by gavage to stock colony rats at dose levels
of 0, 2, 3 or 10 mg/kg. The high dose (10 mg/kg) produced typical
tremors in rats, and brain ChE levels were d.ecreased. Mixed-function
oxidase, glucose-6-phosphatase activity, glycogen, and vitamin A
levels in the liver were unaffected. Apparently, dose levels of 2 or
3 mg/kg did not produce these effects.
0 Woodside et al. (1978) fed methomyl (purity not specified) in the diet
to male and female Wistar rats for 7 days at dose levels of 0, 5.0,
17 or 41 mg/kg/day in males and 0, 6.3, 15 or 39 mg/kg/day in females.
Body weight gain was depressed at doses of 17 and 41 mg/kg/day in the
males and at 15 and 39 mg/kg/day in the females. Liver and kidney
weight were also depressed at 41 mg/kg/day in the male rat and at
15 and 39 mg/kg/day in the female rat. No effects were noted at the
lowest doses. This study did not mention clinical signs of toxicity,
and no measurements of plasma or brain ChE activity were reported.
The No-Observed-Adverse-Effect-Level (NOAEL) identified in this
study is 5.0 mg/kg/day.
0 Bedo and Cieleszky (1980) fed methomyl (purity not specified) in the
diet at levels of 0, 100, 400 or 800 ppm to young adult male and female
stock colony rats for 10 days. Assuming that 1 ppm in the diet of
rats is equivalent to 0.05 mg/kg/day (Lehman, 1959), these doses
correspond to 0, 5, 20 or 40 mg/kg/day. Brain ChE inhibition could
not be detected at any dietary level. The only findings were increased
mixed-function oxidase activity in the livers of female rats at 400
and 800 ppm. This study identified a NOAEL of 800 ppm (40 mg/kg/day).
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0 Kaplan and Sherman (1977) administered methomyl (90% pure) to six
male Charles River-Cesarian Derived (ChR-CD) rats at 0 or 5.1 mg/kg/day,
five times a week for 2 weeks. Following treatment, survival, clinical
signs, ChE activity and histopathology were evaluated. All rats
survived the dosing period. Clinical signs in treated rats included
chewing motions, profuse salivation, lacrimation, bulging eyes,
fasciculations and tremors characteristic of ChE inhibition. The
authors reported that the signs became less pronounced after the
first week of dosing, indicating some degree of adaptation. Plasma
ChE was comparable to control levels, and no compound-related histo-
pathologic effects were reported. A Lowest-Observed-Adverse-Effect-
Level (LOAEL) of 5.1 mg/kg/day was identified from this study.
Dermal/Ocular Effects
0 Kaplan and Sherman (1977) applied a 52.8% aqueous suspension of
methomyl to the clipped, intact skin of six adult male albino rabbits
and covered the area with an occlusive patch for a 24-hour period.
The lethal dose was found to be greater than 5,000 mg/kg, the maximum
feasible dose.
0 McAlack (1973) reported a 10-day subacute exposure of rabbit skin to
methomyl. Male albino rabbits, six per dosage group, were treated
with 0, 50 or 100 mg/kg/day for 10 days. The compound was diluted in
water (29% solution), placed on the skin and covered with an occlusive
covering for 6 hours per day. No signs of ChE inhibition were noted
in any of the animals.
0 Ten rabbits survived 15 daily doses of 200 mg/kg/day of methomyl
applied to intact skin. When the same dose of methomyl was applied
to abraded skin, rabbits showed labored respiration, nasal discharge,
salivation, excessive mastication, tremors, poor coordination, hyper-
sensitivity and abdominal hypertonia. These effects occurred within
1 hour after dosing in most animals. One animal died after the first
dose, and another died after the eighth application. These deaths
appeared to be compound-related (Kaplan and Sherman, 1977).
Long-term Exposure
0 Kaplan and Sherman (1977) reported a 90-day feeding study in
ChR-CD rats (10/sex/group) given food containing methomyl (90% purity)
at dietary levels of 0, 10, 50, 125 or 250 ppm active ingredient (a.i.).
Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day
(Lehman, 1959), this corresponds to doses of about 0, 0.5, 2.5, 6.2 or
12.5 mg/kg/day. After 6 weeks, the 125-ppm dose was increased to 500
ppm (25 mg/kg/day) for the remainder of the study. Clinical signs,
biochemical analyses (including plasma ChE) and urinalyses were not
abnormal. In a few cases, lower hemoglobin valves were observed at one
month in females receiving 50 ppm (2.5 ug/kg/day) and at two months
in males receiving 250 ppm. At three months, the red cell count of
female rats at 250 ppm was somewhat lower than controls, but still
within normal limits. These findings were consistent with moderate
increases of erythroid components observed histologically in the bone
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marrow. Microscopic examination of all other tissues showed no
consistent abnormalities. Based on these observations, this study
identified a NOAEL of 50 ppm (2.5 mg/kg/day) and a LOAEL of 250 ppm
(12.5 mg/kg/day).
0 In a 90-day study using dogs, Kaplan and Sherman (1977) fed methomyl
(90% pure) to four males and four females, 11 to 13 months of age,
at dietary levels of 0, 50, 100 or 400 ppm a.i. Assuming that 1 ppm
in the diet of dogs is equivalent to 0.025 mg/kg/day (Lehman, 1959),
this corresponds to doses of about 0, 1.25, 2.5 or 10 mg/kg/day.
Hematological, biochemical and urine analyses were conducted at least
three times on each dog prior to the study and then at 1, 2 and 3
months during the exposure period. Body weight was monitored weekly.
At necropsy, organ weights were recorded, and over 30 tissues were
prepared for histopathologic examination. No effects attributable to
methomyl were found during or at the conclusion of the study. Based
on these data, a NOAEL of 10 mg/kg/day was identified.
0 Homan et al. (1978) reported a 13-week dietary study of methomyl
(purity not specified) in F-344 rats. Dose levels were reported
to be 0, 1, 3, 10.2, or 30.2 mg/kg/day for male rats, and 0, 1, 3, 9.9
or 29.8 mg/kg/day for female rats. There were no deaths or clinical
signs of toxicity. The body weight gain of females (but not males)
was significantly depressed at all dose levels from day 28 until
completion of the study. Kidney weight to body weight ratios were
significantly increased in female rats at the two highest dose levels.
Red blood cell ChE activity was elevated at the high dose levels, but
plasma and brain ChE levels were normal at all dose levels. Histo-
pathological examination of 31 tissues from representative high-dose
and control animals revealed no significant effects. Weights of
brain, liver, kidney, spleen, heart, adrenals and testes were not
altered. This study identified a NOAEL of 3 mg/kg/day and a LOAEL of
9.9 mg/kg/day.
0 Bedo and Cieleszky (1980) reported a 90-day feeding study of methomyl
in male and female rats receiving dietary levels of 100 or 200 ppm.
Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day
(Lehman, 1959), this corresponds to doses of 5 or 10 mg/kg/day. At
200 ppm, the female rats showed decreased brain ChE activity, decreased
liver vitamin A content and elevated total serum lipids. This study
identified a NOAPL of 100 ppm (5 mg/kg/day).
0 Kaplan and Sherman (1977) reported a 22-month dietary feeding study
in which Charles River-CD male and female rats were fed methomyl
(90 or 100% pure) at dietary levels of 0, 50, 100, 200 or 400 ppm
a.i. Assuming that 1 ppm in the diet of rats is equivalent to
0.05 mg/kg/day (Lehman, 1959), this corresponds to doses of about 0,
2.5, 5, 10 or 20 mg/kg/day. Mortality data were not reported. At
autopsy, 9 of 13 males and 21 of 23 females at the 400-ppm level had
kidney tubular hypertrophy and vacuolization of epithelial cells of
the proximal convoluted tubules. Compound-related histological
alterations were also seen in the spleens of female rats at the
200-ppm dose level. No effects were seen on ChE levels in plasma or
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red blood cells. This study identified a LOAEL of 200 ppm
(10 mg/kg/day) and a NOAEL of 100 ppm (5 mg/kg/day).
0 Kaplan and Sherman (1977) performed a 2-year feeding study in beagle
dogs (four/sex/dose). Methomyl (90 or 100% pure) was supplied at
dietary levels of 0, 50, 100, 400 or 1,000 ppm a.i. Assuming that
1 ppm in the diet of dogs is equivalent to 0.025 mg/kg/day (Lehman,
1959), this corresponds to doses of about 1.25, 2.5, 10 or 25 mg/kg/day.
Hematological, biochemical (including plasma- and red-blood-cell ChE
activity) and urinanalyses were conducted once on each dog prior to
the start of the study, at 3, 6, 12, 18 months during the exposure
period and at 24-month sacrifice. At 1 year, one male and one female
per dose group were sacrificed for histopathological examination.
One female dog at the 1,000-ppm dose level died after 8 weeks ,in the
study, and a replacement dog died after 18 days. Death was preceded
by convulsive seizures and coma. These deaths appear to be compound-
related. Two male dogs in the 1,000-ppm dose group showed clinical
signs during week 13, including tremors, salivation, incoordination
and circling movements. Hematological studies revealed slight-to-
moderate anemia in five dogs (1,000-ppm dose group) at 3 months,
which persisted in one dog to sacrifice. No compound-related signs
or effects were noted with respect to appetite, body weight changes,
biochemical studies (including ChE) and urinanalyses. Dose-related
histopathological changes were seen in kidney and spleen of animals
receiving 400 and 1,000 ppm. Changes were also seen in livers and
bone marrow of animals receiving 1,000 ppm. Pigment deposition was
noted in the epithelial cells of the proximal convoluted tubules of
the kidney in males at 400 and 1,000 ppm and in females at 1,000 ppm.
A minimal-to-slight increase in bile duct proliferation and a slight
increase in bone marrow activity was seen in animals receiving
1,000 ppm. The authors concluded that histological results indicated
a NOAEL of 100 ppm (2.5 mg/kg/day). Minimal histopathological changes
seen in the kidneys and spleen of animals receiving 400 ppm (10 mg/kg/day),
identified this level as the LOAEL.
8 Hazelton Laboratories (1981) reported a 2-year study of methomyl
(purity not specified) in mice. Male and female CD-1 mice (80/sex/dose)
were fed methomyl in the diet at dose levels of 0, 50, 100, or 800 ppm
for 104 weeks. Assuming 1 ppm in the diet to be equivalent
to 0.15 mg/kg/day (Lehman, 1959), this corresponds to doses of about
0, 7.5, 15 or 120 mg/kg/day. Survival was significantly reduced (no
details provided) in both males and females at the 800-ppm dose level by
week 26. The 800 ppm dose level was reduced to 400 ppm (1.0 mg/kg/day)
at week 28 and then further reduced to 200 ppm (30 mg/kg/day) at week
39. At week 39, the 100 ppm was decreased to 75 ppm (11.2 mg/kg/day).
Survival was depressed in all groups of treated males at 104 weeks.
No compound-related histopathological changes were noted in tissues
of animals necropsied at 104 weeks. A LOAEL of 50 ppm (7.5 mg/kg/day;
the lowest dose tested) may be identified based on decreased survival.
Reproductive Effects
0 Male and female weanling Charles River-CD rats were fed methomyl
(90% pure) at dietary levels of 0, 50, or 100 ppm a.i.. for 3 months.
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Methomyl August, 1987
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Assuming that 1 ppm in the diet of weanling rats is equivalent to
0.05 mg/kg/day (Lehman, 1959), these doses correspond to about 0, 2.5
or 5 mg/kg/day. Ten males and twenty females from each group were
bred and continued on the diet through three generations. No adverse
effects were reported on reproduction or lactation., and no pathologic
changes were found in the weanling pups of the F-^ generation (Kaplan
and Sherman, 1977). A NOAEL of 5 mg/kg/day was identified from the
highest dose tested.
Developmental Effects
0 New Zealand White rabbits, five per group, were dosed with 0, 2, 6 or
16 mg/kg of methomyl (98.7% pure) on days 7 through 19 of gestation.
One animal died at the 16 mg/kg dose level, exhibiting characteristic
signs of ChE inhibition, including tremors, excitability, salivation
and convulsions. No adverse effects were observed at any dose level
on embryo viability or on the frequency of soft-tissue or skeletal
malformations (Feussner et al., 1983). This study identified a
maternal NOAEL of 6 mg/kg and a teratogenic NOAEL of 16 mg/kg/day,
the highest dose tested.
0 Kaplan and Sherman (1977) fed methomyl (90% pure) to pregnant New
Zealand White rabbits on days 8 to 16 of gestation at dietary levels
of 0, 50 or 100 ppm active ingredient. Assuming that 1 ppm in the
diet of rabbits is equivalant to 0.03 mg/kg/day (Lehman, 1959), this
corresponds to doses of about 0, 1.5 or 3 mg/kg/day. One-third of
the fetuses were stained with Alizarin Red S and cleared for skeletal
examination. Since no soft tissue or skeletal abnormalities were
observed at any dose level tested, a NOAEL of 3 mg/kg/day was identified.
Mutagenicity
0 Methomyl has been reported to be negative in the Ames test utilizing
Salmonella typhimurium strains TA 98, TA 1OO, TA 1535, TA 1537, and
TA 1538 without metabolic activation (Blevins et al., 1977; Moriya
et al., 1983). Waters et al. (1980) reported methomyl as negative
with and without metabolic activation in strains TA 10O, TA 1535,
TA 1537 and TA 1538.
Carcinogenicity
0 Kaplan and Sherman (1977) fed ChR-CD rats (35/sex/dose) methomyl (90%
pure) in the diet at levels of 0, 50, 100, 200 or 400 ppm active
ingredient for 22 months. Assuming that 1 ppm in the diet of rats is
equivalent to 0.05 mg/kg/day (Lehman, 1959), these doses correspond
to about 0, 2.5, 5, 10 or 20 mg/kg/day. Gross and histological
examination revealed no increased tumor incidence in either male or
female rats.
0 Hazelton Laboratories (1981) reported the results of a 2-year study
of methomyl (purity not specified) in CD-1 mice (80/sex/dose). Initial
dose levels were 0, 50, 100, or 800 ppm. Assuming that 1 ppm in the
diet of mice is equivalent to 0.15 mg/kg/day (Lehman, 1959), these
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Methomyl August, 1987
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doses correspond to 0, 7.5, 15 or 120 mg/kg/day. Because of early
mortality, the 800-ppm dose was reduced to 400 ppm (60 mg/kg/day)
at week 28, and then to 200 ppm (30 mg/kg/day) at week 39. At week
29, the 100-ppm dose was reduced to 75 ppm (11.2 mg/kg/day). Histo-
logical examination at necropsy did not reveal any treatment-related
effects on tumor incidence.
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 = JNOAEL or LOAEL) X (BW) „ mg/L ( ug/L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
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 information found in the available literature was suitable for deter-
mination of the One-day HA value for methomyl. It is, therefore, recommended
that the Drinking Water Equivalent Level (DWEL), adjusted for a child,
(0.25 mg/L) be used at this time as a conservative estimate of the One-day HA
value.
Ten-day Health Advisory
The health effects associated with acute and subchronic exposure to
methomyl are primarily associated with cholinesterase (ChE) inhibition.
Symptoms of ChE inhibition have been shown in rats at doses (via gavage) as
low as 5.1 mg/kg/day for 2 weeks (Kaplan and Sherman, 1977). Methomyl
incorporated into the diet may have less dramatic effects; no ChE effects
were observed in rats exposed subchronically to methomyl at dietary levels of
100 ppm (5 mg/kg/day)(Kaplan and Sherman, 1977; Bedo and Cieleszky, 1980).
•Animal studies may be misleading in assessment of human toxicity. No
controlled human studies have been performed, but human fatalities from
methomyl ingestion after a single exposure to an estimated dose of 12 mg/kg
in bread or 13 mg/kg in drinks have been reported (Liddle et al., 1979; Araki
et al., 1982).
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Methomyl August, 1987
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Because the timing and nature of administration can profoundly
affect the expression of methomyl toxicity, and little margin of safety
can be expected between doses that are fatal and those that cause little or
no acute toxicity, the available studies were judged to be inadequate for the
basis of the Ten-day HA value. Therefore, it is recommeded that the DWEL,
adjusted for a 10-kg child (0.25 mg/L), be used at this time as a conservative
estimate of the Ten-day HA value.
Longer-term Health Advisory
The onset of subchronic or chronic methomyl toxicity appears to occur at
doses similar to those that cause acute toxicity. Kidney toxicity (increased
kidney weight and hypertrophy) in acute, subchronic and chronic conditions
has been reported at doses of 15, 9.9 and 10 mg/kg/day, respectively (Woodside
et al., 1978; Homan et al., 1978; Kaplan and Sherman, 1977). Acute ChE
inhibition in rats exposed to methomyl via gavage has been reported to occur
at doses as low as 5.1 mg/kg/day, and human fatalities from methomyl ingestion
of approximately 12 mg/kg in bread and 13 mg/kg in drinks have been reported
(Liddle et al, 1979; Araki et al., 1982).
Little margin of safety can be expected between doses of methomyl that
are fatal and those that cause little or no longer-term toxicity. Therefore,
it is recommended that the DWEL adjusted for the child (0.25 mg/L) be used at
this time 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
(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 assumed body weight ^f 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 classifi-
cation scheme of carcinogenic potential (U.S. EPA, 1986), then caution should
be exercised in assessing the risks associated with lifetime exposure to this
chemical.
Chronic exposure to methomyl in the diet induces renal toxicity in rats
and dogs. Rats exposed to 900 ppm (20 mg/kg/day) for 22 months exhibited
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Methomyl August, 1987
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kidney tubular hypertrophy and vacuolation of the eptithelial cells, and
dogs exposed to 400 ppm (10 mg/kg/day) for 2 years exhibited swelling and
increased pigmentation of the epithelial cells of the proximal tubules
(Kaplan and Sherman, 1977). Effects on the kidney (increased weight) have
also been observed in rats exposed to 9.9 mg/kg/day in the diet for 13 weeks
(Homan et al., 1978). The NOAEL of 2.5 mg/kg/day identified from the dog
study is a conservative estimate of the NOAEL and serves as the basis for the
Lifetime HA.
In the Kaplan and Sherman (1977) study, beagle dogs (4/sex/dose) were
exposed to 50, 100, 400 or 1,000 ppm methomyl in the diet for 2 years (1.25,
2.5, 10 and 25 mg/kg/day). Dogs receiving 1.25 or 2.5 mg/kg/day showed no
evidence of toxic effects. Those receiving 10 mg/kg/day exhibited histopatho-
logical changes in the kidney and spleen. In addition to these effects,
animals receiving the highest dose also exhibited symptoms of central nervous
system (CNS) toxicity, as well as liver and bone marrow effects.
Using a NOAEL of 2.5 mg/kg/day, the Lifetime HA is calculated as
follows:
Step 1: Determination of the Reference Dose (RfD)
KfD = (2.5 mg/kg/day) = Q.025 mg/kg/day
(100)
where:
2.5 mg/kg/day = NOAEL, based on absence of effects on blood chemistry
(including ChE activity), hematology, urinalysis,
histopathology or body weight in dogs exposed 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*025 mg/kg/day) (70 kg) = Q.875 mg/L (875 ug/L)
(2 L/day)
where:
0.025 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of adult.
For the 10-kg child, the DWEL is calculated as follows:
DWEL = (0*025 mg/kg/day) (1Qkg) = 0.25 mg/L (250 ug/L)
child (1 L/day)
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Methomyl August, 1987
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where:
0.025 mg/kg/day - RfD
10 kg - assumed body weight of a child
1 L/day = assumed daily water consumption of child
Step 3: Determination of a Lifetime Health Advisory
Lifetime HA = (0.875 mg/L) (20%) - 0.175 mg/L (175 ug/L)
where:
0.875 mg/L = DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 Two-year carcinogenicity studies in rats and mice (Kaplan and Sherman,
1977; Hazelton Laboratories, 1981) have not revealed any evidence of
carcinogenici.ty.
0 The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of methomyl.
0 Applying the criteria described in EPA's final guidelines for assess-
ment of carcinogenic risk (U.S. EPA, 1986), methomyl is classified
in Group Ds not classifiable as to human carcinogenicity. This group
is used for agents with inadequate human and animal evidence of
carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The National Academy of Sciences (NAS, 1983) has a Suggested-No-Adverse-
Response-Level (SNARL) of 0.175 mg/L, which was calculated using an
uncertainty factor of 100 and a NOAEL of 2.5 mg/kg/day identified in
the 2-year dog study by Kaplan and Sherman (1977).
0 Residue tolerances have been established for methomyl in or on raw
agricultural commodities (U.S. EPA, 1985). These tolerances are
based on an ADI value of 0.025 mg/kg/day, based on a NOAEL of
2.5 mg/kg/day in dogs and an uncertainty factor of 100. Residues
range from 0.1 (negligible) to 40 ppm.
0 The World Health Organization identified a Temporary ADI of 0.01
ing/kg/day (Vettorazzi and Van den Hurk, 1985).
0 ACGIH (1984) has adopted a threshold limit value (TLV) of 0.2 mg/m3
as a time-weighted average exposure for an 8-hour day.
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Wethomyl August, 1987
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VII. ANALYTICAL METHODS
0 Analysis of methomyl is by a high-performance liquid chromatographic
(HPLC) procedure used for the determination of N-methyl carbamoyloximes
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. Compounds are separated by gradient
elution chromatography. After elution from the HPLC column, the
compounds are hydrolyzed with sodium hydroxide. The methyl amine
formed during hydrolysis is reacted with o-phthalaldehyde to form a
fluorescent derivative that is detected using a fluorescence detector.
The method detection limit for methomyl has been estimated to be
approximately 0.7 ug/L.
VIII. TREATMENT TECHNOLOGIES
Available data indicate that granular-activated carbon (GAC) adsorption
will remove methomyl from water. Whittaker (1980) experimentally
determined adsorption isotherms for methomyl solutions on GAC.
0 Whittaker (1980) reported the results of GAC columns operating under
benchscale conditions. At a flow rate of 0.8 gpm/sq ft and empty
bed contact time of 6 minutes, methomyl breakthrough (when effluent
concentration equals 10% of influent concentration) occurred after
124 bed volumes (BV). When a bi-solute methomyl-metribuzin solution
was passed over the same column, methomyl breakthrough occurred after
55 BV.
Treatment technologies for the removal of methomyl from water are
available and have been reported to be effective (Whittaker, 1980).
However, 'the selection of individual or combinations of technologies
must be based on a case-by-case technical evaluation, and an assessment
of the economics involved.
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Methomyl August, 1987
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•Confidential Business Information submitted to the Office of Pesticide
Programs.
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