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DISCLAIMER '
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute1 endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and - Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfO, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the Hfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-|* (U.S. EPA, 1980), Is provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and cardno-
genlclty are derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification Is required 1n the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxlclty and carclno-
gerilclty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer based RQs are defined 1n U.S.
EPA, 1984 and 1986a, respectively.
111
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EXECUTIVE SUMHARY
Methomyl 1s a colorless, crystalline compound with a sulfurous odor
(Hartley and K1dd, 1985). It 1s used as a broad-spectrum Insecticide on
vegetables, soybeans, cotton, other field crops, certain fruits and
ornamental plants (Melster, 1987). The only current U.S. manufacturer of
methomyl 1s DuPont (SRI, 1987). Production of methomyl 1n 1983 was
estimated to be—4.5-7.5 million pounds. Methyl Isocyanate Is used as a
chemical Intermediate In the manufacture of methomyl (Martin and Worthing,
1977).
The dominant environmental fate process for methomyl 1n air Is expected
to be vapor-phase photooxldatlon with hydroxyl radicals. In an average
ambient atmosphere, the methomyl-hydroxyl radical reaction half-life was
estimated to be 6 hours (Atkinson, 1987). If released to environmental
waters, methomyl may be degraded by blodegradatlon, hydrolysis and photoly-
sis. B1odegradat1on may be the most Important transformation process 1n
water based upon the dominance of blodegradatlon 1n soil. Aqueous hydroly-
sis occurs, but at a relatively slow rate. Hydrolysis half-lives of 54, 38
and 20 weeks were experimentally determined at respective pH values of 6, 7
and 8 at 25°C (Chapman and Cole, 1982). Exposure to sunlight has been
reported to accelerate the decomposition of methomyl In aqueous solution
(Worthing and Walker, 1983). Blodegradatlon 1s the dominant fate process 1n
soil (Harvey and Pease, 1973; Johnson and Cox, 1985; Fung and Uren, 1977;
Heywood, 1975; Aly et al., 1979). Field studies 1n Delaware, Florida and
North Carolina found that at least 98.2% of soil-applied methomyl had
disappeared after a 1-month exposure (Harvey and Pease, 1973). Although
methomyl may adsorb weakly to moderately In soil (Lelstra et al., 1984;
1v
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Kenaga, 1980), leaching may not become Important since the compound may
degrade faster than significant leaching can occur. Leaching was not
significant during field and runoff studies (Harvey and Pease, 1973).
Methomyl 1s released primarily and directly to the environment from Us
application as air Insecticide. An analysis of food products collected
between 1980 and 1983 by U.S. FDA laboratories detected me thorny! In a
variety of vegetable and fruit samples at concentrations ranging from
<0.01-0.41 ppm (Krause, 1985). With the possible exception of data from the
U.S. EPA STORET Data Base (U.S. EPA, 1988), environmental monitoring data
for methomy1 are limited.
Channel catfish, I., punctatus. were among the most sensitive fish
species to any formulation of methorny! on an acute basis. The 96-hour
LC5_ for this species exposed to a 24% liquid formulation was 0.30 mg/a
(Mayer and Ellersleck, 1986). Results from one test with blueglll sunflsh,
L_. macrochlrus. produced the highest LC5Q (least toxic) among fish
(96-hour LC5Q = 7.7 ppm), although the majority of test results with this
species ranged from 0.43-2.8 mg/a (Mayer and Ellersleck, 1986). Salmo
clarkl demonstrated tolerance almost as high as that of the blueglll
(96-hour LCcQ = 6.8 mg/a). There was little evidence that water
chemistry significantly affected the toxldty of methomyl to fish.
Aquatic Invertebrates expressed greater sensitivity to exposure to
methomyl than fish. Water flea, D. maqna. were among the most sensitive to
methomyl on an acute basis (48-hour EC50 = 8.8 ppb). Copepods, Acartla
jtorisa., scud, G. pseudollmnaeus. and fiddler crabs were among the least
sensitive Invertebrates, with 96-hour LC5Qs of 0.41, 1.05 and 2.38 mg/a,
respectively (Kaplan and Sherman, 1977; Roberts et al., 1982; Mayer and
Ellersleck, 1986).
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Algae were very tolerant to exposure to methomyl compared with fish and
Invertebrates. The 96-hour EC5Qs with respect to growth for A. falcatus.
S. quadrlcauda and £. trlcornutum were 4.5, 67 and 82.0 mg/i, respec-
tively. Growth 1n £. fragile was Inhibited only at concentrations >225 ppm.
Methomyl appears to be absorbed rapidly and completely from the gastro-
intestinal tract of rats (Huhtanen and Dorough, 1976). At 24-72 hours after
gavage treatment with 14C-methomyl, -10% of the administered radioactivity
can be recovered from the body (Harvey et al., 1973). The largest amounts
are located In the eviscerated carcass, hide, gastrointestinal tract, blood
and liver. Metabolism of syn-methomyl, the Isomer used In Insecticide
formulations, begins with partial 1somer1zat1on to the ant1-Isomer, followed
by rapid hydrolysis of the ester linkage to liberate the carbonyl moiety and
form the corresponding syn- and ant1-ox1mes (Huhtanen and Dorough, 1976).
The carbonyl carbon Is rapidly and nearly completely expired as carbon
dioxide. The syn- and ant1-ox1mes undergo Beckmann rearrangement to form
more slowly metabolized Intermediates 1n the production of carbon dioxide
and acetonltrlle, respectively. The carbon dioxide and acetonUMle thus
formed are expired rapidly. Together, respiratory excretion accounts for
-31-36% of the dose of radioactivity. Urinary metabolites, which account
for -25-35% of the administered radioactivity, may consist primarily of the
oxlmes and acetonltrlle.
Methomyl was not carcinogenic In rat feeding studies (Kaplan and
Sherman, 1977) or mice feeding studies (Hazelton Laboratories, 1981) and was
negative 1n a transplacental hamster fetal cell . transformation assay
(Quarles et al., 1979). Results of mutagenlclty tests were largely negative
1n microorganisms (Simmon et al., 1976, 1977; Blevlns et al., 1977a; Waters
et al., 1980, 1982; Morlya et al., 1983; Klopman et al., 1985; Garrett et
v1
-------
al., 1986), but were mixed In Drosophlla (Waters et al., 1980, 1982;
Valencia, 1981; Hemavarthy and Krlshnamurthy, 1987a) and various mammalian
systems (Simmon et al., 1977; Blevlns et al., 1977b; Waters et al., 1980,
1982; Wojdechowskl and Kaur, 1980; Wojdechowskl et al., 1982; Debuyst and
Van Larebeke, 1983; Garrett et al., 1986; Hemavarthy and Krlshnamurthy,
1987b). NHrosomethomyl, however, was positive In cell transformation
(Quarles et al., 1979) and mutagenldty tests (Blevlns et al., 1977a,b;
Seller, 1977) and Induced forestomach tumors 1n rats treated by gavage
(LlJInsky and Schmahl, 1978).
The acute tox1c1ty of methomy1 appears to be equivalent among most
laboratory species; however, the mouse Is noticeably more sensitive than the
rat or dog. Single-dose oral LD5_ values ranged from 8.5-40 mg/kg (Kaplan
and Sherman, 1977; Fahmy et al., 1978; Antal et al., 1979; Dashlell and
Kennedy, 1984; Galnes and Under, 1986). Gender and age appear to have no
effect on toxic potency. Doses of 12-15 mg/kg have been fatal to humans
(Uddle et al., 1979; Arakl et al., 1982). Deaths are preceded by
chol1nerg1c signs (Kaplan and Sherman, 1977). Other effects attributed to
methomy1 Include altered pancreatic (Bedo and deleszky, 1980) and liver
enzyme activities (Iverson, 1977; El-Sewedy et al., 1982), effects on the
erythrocyte and hematopolesls (Nakamura et al., 1977; N1sh1da et al., 1980),
and sldn sens1t1zat1on (Kambe et al., 1976; Matsushita and Aoyama, 1979).
Methomyl has not been associated with neurotoxldty 1n hens (Kaplan and
Sherman, 1977; U.S. EPA, 1986b).
A number of subchronlc and chronic dietary studies have been performed
using rats, dogs and mice. In the subchronlc studies, 400 ppm (10 mg/kg/
day, the highest level tested) was considered a NOAEL In dogs (Kaplan and
Sherman, 1977), and 50 ppm (2.5 mg/kg/day) (Kapland and Sherman, 1977), 100
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ppm (5 mg/kg/day) (Bedo and deleszky, I960) and 3 mg/kg/day (Homan et al.,
1978) were considered NOAELs 1n- three studies using rats. At higher dosages
rats showed body weight gain depression, decreased erythrocyte counts and
Increased erythropolesls, depressed erythrocyte or brain chollnesterase
activities, minor • serum or liver biochemical alterations, and elevated
relative kidney weights. In a chronic rat study with dietary levels of
50-400 ppm (Kaplan and Sherman, 1977), 100 ppm (5 mg/kg/day) was a NOAEL,
and depressed growth rate, reduced blood hemoglobin concentration, Increased
splenic erythropolesls and mild kidney lesions were observed at higher
levels. In dogs chronically exposed to 50-1000 ppm, 100 ppm (2.5 mg/kg/day)
was a NOAEL, and anemia and mild lesions of the kidney, liver, spleen and
bone marrow were observed at higher levels (Kaplan and Sherman, 1977).
Mortality preceded by chollnergic signs was observed at 1000 ppm (25 mg/kg/
day). Increased mortality was observed In all groups of mice chronically
exposed to diets containing 50-800 ppm (Hazelton Laboratories, 1981). The
50 ppm level (6.5 mg/kg/day) was judged a LOAEL associated with reduced
longevity.
Methomy1 has been tested for developmental toxlclty In rabbits at
dosages up to 16 mg/kg/day (Kaplan and Sherman, 1977; Feussner et al., 1983)
and 1n rats fed diets containing <400 ppm (U.S. EPA, 1986b) with no evidence
of teratogenldty. No effects on reproduction were observed 1n a
3-generat1on study where rats were fed diets containing up to 100 ppm
(Kaplan and Sherman, 1977).
Me thorny! was classified In EPA Group 0, not classifiable as to human
carc1nogen1c1ty, because of no human data and Inadequate animal data. Data
were Insufficient for estimation of cancer potency factors for either oral
or Inhalation exposure. Data were also Insufficient for estimation of RfDs
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for subchronlc or chronic Inhalation exposure. An RfD of 0.025 mg/kg/day (2
mg/clay for a 70 kg human) was calculated for chronic oral exposure to
methomyl from the NOAEL of 2.5 mg/kg/day In the chronic dog study by Kaplan
and Sherman (1977). The chronic oral RfD was adopted as the subchronlc oral
RfD. A chronic -toxldty-based RQ of 100 was derived from the effect of
reduced survival of male mice 1n a chronic dietary study (Hazelton
Laboratories, 1981). Data were Insufficient to derive an RQ based on
carclnogenldty.
1x
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.2. WATER 4
2.2.1. Hydrolysis 4
2.2.2. Oxidation 5
2.2.3. Photolysis 5
2.2.4. MUroblal Degradation 5
2.2.5. Volatilization 5
2.2.6. Adsorption. 5
2.2.7. B1oconcentrat1on 6
2.3. SOIL 6
2.3.1. Degradation 6
2.3.2. Adsorption/Leaching 7
2.4. SUMMARY 8
3. EXPOSURE 9
3.1. HATER 9
3.2. FOOD 9
3.3. INHALATION 10
3.4. DERMAL 10
3.5. SUMMARY 10
4. AQUATIC TOXICITY 11
4.1. ACUTE TOXICITY 11
4.2. CHRONIC EFFECTS 22
4.3. PLANT EFFECTS 22
4.4. SUMMARY. . 23
5. PHARMACOKINETCS - 24
5.1. ABSORPTION 24
5.2. DISTRIBUTION 24
5.3. METABOLISM 25
5.4. EXCRETION 29
5.5. SUMMARY 30
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TABLE OF CONTENTS (cont.)
Page
6. EFFECTS 31
6.1. " SYSTEMIC TOXICITY 31
6.1.1.- - Inhalation Exposure 31
6.1.2. Oral Exposure 33
6.1.3. Other Relevant Information 38
6.2. CARCINOGENICITY 42
6.2.1. Inhalation 42
6.2.2. Oral 42
6.2.3. Other Relevant Information 43
6.3. MUTAGENICITY 44
6.4. TERATOGENICITY 47
6.5. OTHER REPRODUCTIVE EFFECTS 48
6.6. SUMMARY " 48
7. EXISTING GUIDELINES AND STANDARDS 51
7.1. HUMAN 51
7.2. AQUATIC 51
8. RISK ASSESSMENT 52
8.1. CARCINOGENICITY. . 52
8.1.1. Inhalation. ..... 52
8.1.2. Oral 52
8.1.3. Other Routes 52
8.1.4. Weight of Evidence 52
8.1.5. Quantitative Risk Estimates 53
8.2. SYSTEMIC TOXICITY. 53
8.2.1. Inhalation Exposure 53
8.2.2. Oral Exposure 53
9. REPORTABLE QUANTITIES 56
9.1. BASED ON SYSTEMIC TOXICITY 56
9.2. BASED ON CARCINOGENICITY 58
10. REFERENCES 61
APPENDIX A: LITERATURE SEARCHED 78
APPENDIX B: SUMMARY TABLE FOR METHOMYL 81
x1
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LIST OF TABLES
No. Title Page
4-1 Median Lethal and Effective Concentrations for Fish Exposed
to Methomyl (Lannate) 12
4-2 Medial Lethal and Effective Concentrations for Aquatic
Invertebrates Exposed to Methomyl (Lannate) 19
6-1 Acute Oral Toxldty of Methomyl 39
6-2 Genotoxldty Testing of Methomyl 45
9-1 Dietary Toxldty of Methomyl: Data Considered for
Derivation of Composite Score 57
9-2 Methomyl: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 59
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LIST OF ABBREVIATIONS
AChE
BCF
BHA
CAS
CS
DNA
dpm
DUEL
EC50
HA
Koc
Kow
LC50
LD50
LEL
LOAEL
MED
MTO
NOAEL
NOEL
ppb
ppm
RFO
RQ
RVd
«ve
SNARL
TLM
TLV
TWA
UV
Acetylchollnesterase
Bloconcentratlon factor
Butylated hydroxyanlllne
Chemical Abstract Service
Composite score
Deox1r1bonucle1c acid
Disintegrations per minute
Drinking water effect level
Median effective concentration
Health advisory
Soil sorptlon. coefficient
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
Dose lethal to SOX of recipients
Lowest effect level
Lowest-observed-adverse-effect level
M11mum effective dose
Maximum tolerated dose
No-observed-adverse-effect level
No-observed-effect level
Parts per billion
Parts per million
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Suggested no-adverse-reponse level
Median threshold limit
Threshold limit value
Time-weighted average
Ultraviolet
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1. INTRODUCTION
1.1, STRUCTURE AND CAS NUMBER
Methomyl Is a common chemical name for the compound currently referenced
by the Chemical Abstracts Service as ethan1m1doth1o1c add, N-(((methyl-
am1no)carbonyl)oxy~}-, methyl ester. It 1s also known by the synonyms
S-methyl N-(methylcarbamoyloxy)th1oacet1m1date, methyl N-[[(methylam1no)-
carbonyl]oxy]ethan1m1doth1oate and 2-methylth1oprop1onaldehyde 0-methyl-
carbamoyloxlme (Hartley and K1dd, 1985). Methomyl 1s marketed by E.I.
DuPont de Nemours and Co. under the trade names Lannate and Nudrln and by
Crystal Chemical Inter-America Co. under the trade name Lanox (Melster,
1987). The structure, molecular weight, empirical formula and CAS Registry
number for methomyl are as follows:
CH3
CH3
0 H
\ II I
C=N-0-C-N-CH3
Molecular weight: 162.21
Empirical formula: C^-N^S
CAS Registry number: 16752-77-5
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Methomyl 1s a colorless, crystalline compound with a sulfurous odor
(Hartley and K1dd, 1985). The commercial product 1s a mixture of the syn-
and ant1-1somers of methomyl with the syn-lsomer predominating (Worthing and
Walker, 1983). At 25°C, methomyl 1s soluble In water (58 g/kg), acetone
(720 g/kg), ethanol (420 g/kg), methanol (1000 g/kg) and toluene (30 g/kg)
(Worthing and Walker, 1983). Selected physical properties are listed below:
Melting point: 78-79°C.
Water solubility 58 g/kg
at 25°C:
Worthing and Walker, 1983
Worthing and Walker, 1983
0121d
-1-
06/08/88
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Vapor, pressure 0.00005 mm Hg Worthing and Walker, 1983
at 25°C:
Log Kow: 0.60 Hansch and Leo, 1985
A1r conversion 1 mg/m3 = 0.148 ppm
factors at 20°C: 1 ppm = 6.76 mg/m3
Aqueous solutions of methomy1 decompose slowly at room temperatures.
The decomposition can be accelerated with aeration, exposure to sunlight,
alkalinity or higher temperatures (Worthing and Walker, 1983).
1.3. PRODUCTION DATA
Methomyl Is currently manufactured 1n the United States by the
Agr1chem1cals Dept. of E.I. DuPont de Nemours and Company, Inc. 1n La Porte,
Texas (SRI, 1987). Production of methomyl 1s accomplished by reacting
methyl Isocyanate with methyl N-hydroxyth1oacet1m1date (Martin and Worthing,
1977).
In 1971, an estimated 2 million pounds of methomyl was produced 1n the
United States (Ouellette and King, 1977). Current production volumes are
not available, but production volumes for 1983 can be approximated. It has
been estimated that 10% of methyl Isocyanate production Is used to manu-
facture methomyl and that 15-26 million pounds of methyl Isocyanate was
produced In 1983 (U.S. EPA, 1986b). Using these figures, production of
methomyl 1n 1983 can be roughly estimated to have been 4.5-7.5 million
pounds.
1.4. USE DATA
Methomyl 1s used as a broadspectrum Insecticide on vegetables, soybeans,
cotton, other field crops, certain fruits and ornamental plants (Melster,
1987). According to statistics compiled by the U.S. Dept. of Agriculture,
the quantities of methomyl applied to major field and forage crops 1n the
United States 1n 1971, 1976 and 1982 totaled 0.3, 2.5 and 1.7 million
0121d -2- 07/14/88
-------
pounds, respectively (USDA, 1983). In 1982, the major crops receiving
1nsect1c1dal applications of methomyl were soybeans, cotton, peanuts and
tobacco (USOA, 1983).
1.5. SUMMARY
Methomyl 1s a "colorless, crystalline compound with a sulfurous odor
(Hartley and Kldd, 1985). It 1s used as a broadspectrum Insecticide on
vegetables, soybeans, cotton, other field crops, certain fruits and
ornamental plants (Melster, 1987). The only current U.S. manufacturer of
methomyl 1s DuPont (SRI, 1987). Production of methomyl 1n 1983 was
estimated to be -4.5-7.5 million pounds. Methyl Isocyanate 1s used as a
chemical Intermediate In the manufacture of methomyl (Martin and Worthing,
1977).
0121d -3- . 06/08/88
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Organic compounds having vapor pressures >0.0001 mm Hg should exist
almost entirely 1n the vapor phase 1n the ambient atmosphere, while com-
pounds having vapor pressures
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2.2.2. Oxidation. Pertinent data regarding the oxidation of methomyl 1n
water were not located 1n the available literature dted 1n Appendix A.
2.2.3. Photolysis. Methomyl absorbs UV light at environmental wave-
lengths (Chen et a!., 1984), which Indicates a potential for direct photoly-
sis 1n sunlight. "The photodegradatlve half-life for a thin film of methomyl
applied to a glass slide and exposed to laboratory UV light of environment-
ally significant wavelengths (>295 nm) was 48.41 hours (Chen et al., 1984).
Extrapolation of these data to predict environmental photolysis rates 1s not
possible without additional experimental data; however, 1t does Indicate
that photolysis may be a viable mechanism by which methomyl may be degraded
In the environment. When a dilute aqueous solution of methomyl 1s Irradi-
ated with UV light at 254 nm, acetonHMle, dimethyl dlsulflde, acetone,
N-ethyl1denemethylam1ne and carbon dioxide are produced (Freeman and Ndlp,
1984).
The decomposition rate of methomyl 1n aqueous solution has been reported
to accelerate with exposure to sunlight (Worthing and Walker, 1983).
2.2.4. Mlcroblal Degradation. Based upon the soil mlcroblal degradation
data presented In Section 2.3.1., methomyl may be susceptible to significant
blodegradatlon 1n natural water because It has been shown to be degraded
primarily by blodegradatlon 1n soil.
2.2.5. Volatilization. Based upon a water solubility of 58 g/kg and a
vapor pressure of 0.00005 mm Hg at 25°C (Worthing and Walker, 1983), the
Henry's Law constant for methomyl can be estimated to be 1.84xlO~10
atm-mVmol, which Indicates that volatilization from environmental waters
1s not significant (Thomas, 1982).
2.2.6. Adsorption. Based upon the soil adsorption data presented 1n
Section 2.3.2., methomyl 1s not expected to partition significantly from the
water column to sediments or to suspended organic material.
0121d .5- . 06/08/88
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2.2.7. B1oconcentrat1on. The BCF of an organic chemical can be estimated
from the following recommended regression-derived equations (Bysshe, 1982):
log BCF = 0.76 log KQW - 0.23 (2-1)
log BCF = 2.791 - 0.564 log WS (1n ppm) (2-2)
For methomyl, the' BCF values calculated from Equations 2-1 and 2-2 are 1.7
and 1.3, respectively, based on a log K of 0.60 (Hansch and Leo, 1985)
and a water solubility of 58,000 ppm (Worthing and Walker, 1983). Kenaga
(1980) estimated the BCF for methomyl to be 8, based on an experimental
K of 160. These calculated BCF values suggest that environmental
oc
bloconcentratlon 1s not significant.
2.3. SOIL
2.3.1. Degradation. Harvey and Pease (1973) conducted soil degradation
studies of 14C radlolabeled methomyl under both laboratory and field
conditions. In the laboratory, 31-48% of applied methomyl remained 1n three
different soil types after a 42-day exposure period. The primary degrada-
tion product was C0_, which the authors attributed to mlcroblal degrada-
tion. A small amount of methomyl's hydrolysis product (S-methyl N-hydroxy-
th1oacet1m1date) also remained 1n the soils In addition to polar residues.
Under field conditions In Delaware, only 1.8% of applied radlolabeled
methomyl remained 1n the soil after a 1-month exposure. Approximately 71%
of the applied radioactivity was lost from the soil, presumably as CO-.
After 1 year, methomyl and Us hydrolysis product completely disappeared
from the soil. Similar field results were obtained from Florida and North
Carolina. Johnson and Cox (1985) found methomyl degradation In soils from
Georgia, Texas and California to be consistent with the results reported by
Harvey and Pease (1973).
0121d -6- ; 06/08/88
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Fung and Uren (1977) examined the degradation of methomyl 1n two tobacco
growing soils using perfuslon studies. Mlcroblal degradation was determined
to be the major transformation process based on dissipation results from
sterile (using sodium azlde) vs. nonsteMle soil. In both tobacco growing
soils, mlcroblal • degradation occurred after a lag period of 7-14 days;
however, no lag period was observed when these soils were previously exposed
to methomyl. Other authors have also determined that mlcroblal degradation
Is the primary path by which methomyl Is degraded 1n soil (Heywood, 1975;
Aly et al., 1979). Lelstra et al. (1984) found the degradation half-life of
methomyl 1n three greenhouse soils to range from 3-14 days.
In a compilation of foliage persistence data, methomyl has been reported
to have plant persistence half-lives ranging from 0.4-8.5 days with respect
to cotton, mint and Bermuda grass (Willis and McDowell, 1987).
2.3.2. Adsorption/Leaching. Harvey and Pease (1973) applied 14C radio-
labeled methomyl to field soils 1n Delaware, Florida and North Carolina, and
monitored the radioactivity at depths <15 Inches. After 1-12 months 1n
Delaware, 3 months In Florida and 5 months In North Carolina, the percent of
applied radioactivity at depths below 7 Inches was a maximum of 0.2%. The
remaining radioactivity was found predominantly 1n the upper 3 Inches of the
soils. Under farm use conditions, methomyl did not transport laterally Into
untreated areas with runoff water to any significant degree (Harvey and
Pease, -1973).
Lelstra et al. (1984) observed weak to moderate adsorption of methomyl
to three greenhouse soils, and Kenaga (1980) reported an experimental K
value of 160 for methomyl, which Is Indicative of moderate soil mobility.
These results suggest that significant leaching of methomyl 1n soil 1s
possible; however, under conditions where rapid degradation 1s occurring [as
0121d -7- 07/14/88
-------
was the case In the Harvey and Pease (T973) field study], leaching may not
be Important since the compound Is degrading faster than It Is leaching.
2.4. SUMMARY
The dominant environmental fate process for methomyl 1n air 1s expected
to be vapor-phase • photooxldatlon with hydroxyl radicals. In an average
ambient atmosphere, the methomyl-hydroxyl radical reaction half-life was
estimated to be 6 hours (Atkinson, 1987). If .released to environmental
waters, methomyl may be degraded by blodegradatlon, hydrolysis and photoly-
sis. Blodegradatlon may be the most Important transformation process In
water based upon the dominance of blodegradatlon 1n soil. Aqueous hydroly-
sis occurs, but at a relatively slow rate. Hydrolysis half-lives of 54, 38
and 20 weeks were experimentally determined at respective pH values of 6, 7
and 8 at 25°C (Chapman and Cole, 1982). Exposure to sunlight has been
reported to accelerate the decomposition of methomyl 1n aqueous solution
(Worthing and Walker, 1983). Blodegradatlon 1s the dominant fate process 1n
soil (Harvey and Pease, 1973; Johnson and Cox, 1985; Fung and Uren, 1977;
Heywood, 1975; Aly et al., 1979). Field studies 1n Delaware, Florida and
North Carolina found that at least 98.2% of soil-applied methomyl had
disappeared after a 1-month exposure (Harvey and Pease, 1973). Although
methomyl may adsorb weakly to moderately 1n soil (Lelstra et al., 1984;
Kenaga, 1980), leaching may not become Important since the compound may
degrade faster than significant leaching can occur. Leaching was not
significant during field and runoff studies (Harvey and Pease, 1973).
0121d -8- . 06/08/88
-------
3. EXPOSURE
As an Insecticide, methomyl 1s applied to plants and son by spraying
(CPP, 1987). Release to the environment occurs directly from Its applica-
tion as an Insecticide. Environmental releases resulting from Us manufac-
ture or formulation Into 1nsect1c1dal products are expected to be minor 1n
relation to the quantities released by Insecticide applications. At
present, some or all applications of methomyl may be classified by the U.S.
EPA as Restricted Use Pesticides (Melster, 1987). Improper disposal of
methomyl wastes Is a violation of Federal law (CPP, 1987).
3.1. HATER
The gross analysis of the water monitoring data from the U.S. EPA STORET
Data Base cites 1837 reporting stations for methomyl with a minimum, maximum
and mean concentration of 0.0, 500.0 and 7.2 ppb, respectively (U.S. EPA,
1988).
Methomyl was not detected (analytical detection limit not reported) In
any groundwater during a monitoring survey conducted In the early 1980s of
1174 community wells and 617 private wells In Wisconsin (KM 11 and Sonzognl,
1986). Methomyl was not detected (analytical detection limit of 1.0 ppb) In
water samples collected from 91 farm wells 1n southern Ontario 1n 1984
(Frank et al., 1987).
3.2. FOOD
Krause (1985) reported the results of an analysis of food products for
residues of carbamate pesticides conducted by the U.S. FDA laboratories.
Between 1980 and 1983, 39 different fresh crops, dehydrated apples, crackers
and wines were analyzed for methomyl. Methomyl was detected In 15 of 319
food samples analyzed at the following concentrations (by weight): cabbage,
0121d -9- 07/14/88
-------
0.02-0.41 ppm; cantaloupe, 0.02 ppm; cucumber, 0.04 ppm; grapes, 0.01-0.04
ppm; lettuce, 0.12 ppm; romalne, 0.02 ppm; squash, 0.06 ppm; potatoes, <0.01
ppm. One market basket from the U.S. FDA's Total Diet Program for 1983
contained 0.07 ppm methomyl 1n boiled collards and 0.067 ppm methomyl 1n raw
strawberries (Krau'se, 1985).
3.3. INHALATION
The average concentration of methomyl In the ambient air of a storage
room of a commercial pest control building was 13.7 ng/m3 over a 3-hour
monitoring period (Yeboah and Kllgore, 1984).
3.4. DERMAL
Pertinent monitoring data regarding dermal exposure were not located In
the available literature dted 1n Appendix A.
3.5. SUMMARY
Methomyl 1s released primarily and directly to the environment from Us
application as an Insecticide. An analysis of food products collected
between 1980 and 1983 by U.S. FDA laboratories detected methomyl 1n a
variety of vegetable and fruit samples at concentrations ranging from
<0.01-0.41 ppm (Krause, 1985). With the possible exception of data from the
U.S. EPA STORET Data Base (U.S. EPA, 1988), environmental monitoring data
for methomyl are limited.
0121d -10- . 06/08/88
-------
4. AQUATIC 'TOXICITY
4.1. ACUTE TOXICITY
The results of an extensive series of studies 1n which fish were exposed
to methomyl 1n a variety of formulations for <96 hours are reported 1n Table
4-1. Most of the- studies were reported by Mayer and Ellersleck (1986) and
were published previously by Johnson and Flnley (1980). The 96-hour LC5_s
for channel catfish, Ictalurus punctatus. exposed to methomyl In three
different formulations In tests conducted at three temperatures ranged from
0.30-0.76 mg/l. Catfish yolk-sac fry were less sensitive than sw1m-up fry
or flngerllngs (1.8 mg/l). Temperature appeared to have a minimal effect
on the toxldty of methomyl to blueglll sunflsh, Lepomls macrochlrus. The
96-hour LCggS at 12 and 22°C were 2.0 and 0.86 mg/i, respectively.
Schneider (1979) reported the highest LC5Q for bluegllls exposed to
methomyl (7.7 ppm); the lowest LC5Q for bluegllls In a 96-hour test was
0.37 mg/8, (Mayer and Ellersleck, 1986). The results of all other acute
studies with fish were comparable to those reported for channel catfish and
blueglll sunflsh. Rainbow trout, Sal mo galrdneM. eggs were the least
sensitive fish stage among studies reported. The 96-hour LC5Q for eyed
eggs was 32 mg/l (Mayer and Ellersleck, 1986).
Hashimoto and Fukaml (1969) assessed the toxldty of Lannate (methomyl)
to carp, Cyprlnus carplo Llnne, by three routes of exposure: oral, topical
and contact. Oral exposure was achieved by adding pesticide to powdered
fish feed that was mixed with distilled water to form a paste. The paste
was molded Into a small pellet and offered to the test fish. Mortality was
determined 48 hours after feeding. Topical application of pesticide was
achieved by applying solutions directly onto the gill lamella of anaesthe-
tized fish. The anaesthetic was a 0.1X aqueous solution of MS-222 SANDOZ
0121d -11- . 08/24/88
-------
1ABLE 4-1
Median Lethal and Effective Concentrations for Fish Exposed to Methoayl (Lannate)
rw
Q.
1
rvi
i
V
o
o»
>*
o
CO
v*
CO
CO
Median Response Concentration
Species
Cyprlnodon
varlegatus
Ictalurus
punctatus
Channel catfish
Ictalurus
punctatus
Channel catfish
Ictalurus
punctatus
Channel catfish
Ictalurus
punctatus
Channel catfish
(flngerllng)
Ictalurus
punctatus
Channel catfish
(swla-up fry)
Ictalurus
punctatus
Channel catfish
(yolk-sac fry)
Channel catfish
(species not
specified)
Cyprlnus carplo
Carp
Chemical
24X Lannate
In aethanol
95X technical
aatertal
24X liquid
29X liquid
24X liquid
24X liquid
'
24X liquid
nethoayl
lest
Method
S
S
S
S
S
S
S
S
24-Hour
(95X
NR
0.72 ag/t
(0.535-0.967)
0.45 ag/t
(0.30-0.65)
0.46 ag/t
(0.225-0.938)
0.76 ag/t
(0.635-0.909)
0.56 ag/t
(0.445-0.705)
2.4 ag/t
(2.0-2.9)
0.92 ag/t
48-Hour 96-Hour
confidence Halts)
NR 0.96 ag/t
(0.82-1.26)
NR 0.53 ag/t
(0.375-0.748)
NR 0.30 ag/t
(0.20-0.43)
NR 0.32 ag/t
(0.275-0.371)
NR 0.76 ag/t
(0.635-0.909)
NR <0.56 ag/t
NR 1.8 ag/t
(1.3-2.4)
NR NR
Comments
LC50. teap. = 22*C.
salinity = 10V»
IC50. teap. = 22*C.
pH = 7.4. hardness =
LC50. teap. * 22«C.
pH <= 7.4. hardness =
LC50. teap. = 17-C.
pH = 7.4. hardness •
LC50. teap. <• 22*C.
pH = 7.4. hardness «
LC50. teap. = 25-C.
pH = 7.4. hardness =
LC50. teap. = 25'C.
pH = 7.4. hardness =
LC50. teap. = 26«C
i
•
40 ng/t
40 ng/t
44 ag/t
40 ng/t
40 ng/t
40 ng/t
Reference
Roberts et
1982
Mayer and
Ellersleck,
Mayer and
E Hers leek,
Mayer and
Ellersleck.
Mayer and
Ellersleck,
Mayer and
Ellersleck.
Mayer and
Ellersleck,
Carter and
al..
1986
1986
1986
1986
.
1986
1986
Graves. 1973
Lannate
S
3.16 ag/t
(2.76-3.62)
2.96 ag/t NR
(2.54-3.54)
UH. teap . 22-25«C;
reported as ag/t of
results
active
El-Refal et
1976
al..
Ingredient; fish size = 1.75 g
Cyprlnus carplo
Carp
Lannate
S
1.55 ag/t
(1.02-2.35)
1.21 ng/t NR
(0.8-1.85)
11H, teap . 22-25'C;
reported as ng/t of
results
active
El-Refal et
1976
al.,
Ingredient; fish size = 31.5 g
-------
TABLE 4-1 (cant.)
_i Median Response Concentration
M
0.
1
CO
1
o
o
CO
Species
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
>'tepoa1s
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Chemical
95X technical
aaterlal
95X technical
aaterlal
95X technical
aaterlal
9SX technical
aaterlal
95X technical
aaterlal
95X technical
aaterlal
95X technical
aaterlal
29X liquid
29X liquid
24X liquid
24X liquid
Test
Method
S
S
S
S
S
S
S
S
S
ET
S
24-Hour 48-Hour 96-Hour
(95X confidence Halts)
3.3 ag/t NR
(2.11-4.51)
0.93-1. 8 ag/t NR
1.0 ag/t NR
(0.825-1.21)
1.55 ag/t NR
(1.11-2.16)
1.2. 0.94 ag/t NR
0.92 ag/t NR
(0.67-1.26)
1.3 ag/t NR
(1.01-1.67)
2.4 ag/t NR
(1.572-3.663)
2.4 mg/t NR
(1.572-3.663)
NR NR
0.76-0.79 ag/t NR
2.0 ag/t
(1.43-2.80)
0.6-1.2 ag/t
0.86 ag/t
(0.644-1.15)
0.84 ag/t
(0.53-1.34)
0.94. 0.48 ag/t
0.62 ag/t
(0.37-1.04)
1.05 ag/t
(0.859-1.28)
0.67 ag/t
(0.428-1.048)
0.67 ag/t
(0.428-1.048)
2.8 ag/t
(2.5-3.2)
0.37-0.71 ag/t
"50
pH =
Comments
. teap. = 12-C.
7.4. hardness =
: Reference
40
LC50. temp. = 17»C.
pH * 7.4. hardness = 40
results from 3 studies
"50
pH =
"50
pH =
. teap. = 22-C.
7.4. hardness =
. teap. = 17*C.
7.4. hardness -
LC50. temp. « 17«C.
pH = 6.0. 6.5.
hardness - 40 ag/t
LC50. teap. = 17«C.
pH = 8.5. hardness =
"50
pH =
"50
pH =
"50
pH =
"50
pH =
"50
pH =
. teap. = 20*C.
7.2, hardness =
. teap. = 22"C.
7.4. hardness =
. teap. = 17«C.
7.4. hardness =
. teap. - 22-C.
7.4. hardness =
40
mg/t
rag/I.
mg/t
320 mg/t
40
40
40
44
mg/t
mg/t
mg/t
mg/t
272 mg/t
. teap. = 20-22*C.
7.2-7.4. hardness =
. Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck,
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck,
Mayer and
Filers leek.
1986
1986
1986
1986
1986
1986
1986
1986
1986
1986
1986
_ Blueglll sunflsh
CO
40 ag/t. results from
4 studies
-------
TABLE 4-1 (cont.)
2 ' Median Response Concentration
i\> Species
Q.
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
. aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
aacrochlrus
Blueglll sunflsh
Lepoals
, aacrochlrus
— • Blueglll sunflsh
Blueglll sunflsh
(species not
specified)
Menldla aenldla
Mlcropterus
salmoldes
Largeaouth bass
Mlcropterus
salmoldes
Largeaouth bass
Plmephales
ooromelas
Fathead alnnow
g> Plmephales
\ promelas
Chemical
24X liquid
24X liquid
24X liquid
90X active
Ingredient In
wettable powder
24X liquid
methomyl
24X Lannate In
aethanol
95X technical
material
24X liquid
99X technical
material
24X liquid
Test
Method
S
S
S
S
S
S
S
S
S
S
S
24-Hour 48-Hour 96-Hour
(95X confidence limits)
>3.2 mg/t
2.5 mg/t
(1.69-3.3)
0.48 ag/t
(0.37-0.62)
2.35 ppa
12.0 ppa
NR
NR
1.25 mg/t
(0.956-1.63)
0.76 ag/t
(0.589-0.979)
3.8 ag/t
(2.6-5.6)
2.0 mg/t
(1.5-2.7)
NR
NR
NR
2.15 ppa
9.10 ppm
NR
NR
NR
NR
NR
NR
1.8 ag/t
(1.2-2.7)
1.2 ag/t
(0.924-1.56)
0.43 ag/t
(0.31-0.59)
2.15 ppa
7.70 ppa
2 ag/t
0.34 ag/t
(0.29-0.39)
1.25 ag/t
(0.971-1.61)
0.76 ag/t
(0.589-0.979)
2.8 ag/t
(1.8-4.3)
1.8 ag/t
(1.2-2.7)
Comments
I
LC50. teap. = 12-C.
pH = 7.4. hardness = 40 mg/t
LC50. teap. = 17-C.
pH - 7.4. hardness - 40 ag/t
LC50. temp. = 27 -C.
pH = 7.4. hardness = 40 ag/t
LC50. teap. « 18-C
LC50. teap. = 18'C
LC50. teap. * 23*C
LC50. teap. = 22'C,
salinity = 10V—
LC50. teap. = 22-C.
pH = 7.2. hardness = 40 mg/t
IC50. teap. » 22«C.
pH = 7.2. hardness = 40 mg/t
LC50. teap. = 17«C.
pH = 7.4. hardness = 45 mg/t
LCS0. temp. = 12*C.
pH = 7.2. hardness = 40 mg/t
Reference
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Schneider,
. 1986
. 1986
. 1986
1979
Schenlder. 1979
Carter and
Graves, 1973
Roberts et
1982
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer -and
Ellersleck
Mayer and
Ellersleck
al..
. 1986
. 1986
, 1986
. 1986
CO
CO
-------
TABLE 4-1 (cont.)
0
•J
PO
o.
Median Response Concentration
Species
Chemical
Test
Method
24 -Hour
48-Hour 96-Hour
Comments
Reference
(9SX confidence 1 tails)
i
en
0
c*
0
00
>x
CD
00
Ploephales
promelas
Fathead minnow
Salop dark!
Cutthroat trout
Saloo galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
Salao qalrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
Salgg galrdnerl
Rainbow trout
>*Sa1ao galrdnerl
Rainbow trout
Salao qalrdnerl
Rainbow trout
29X liquid
95X technical
material
95X technical
material
95X technical
material
95X technical
material
95X technical
material
95X technical
material
95X technical
material
29X liquid
24X liquid
24X liquid
24X liquid
24X liquid
S
S
S
S
S
S
S
S
S
FT
S
NR
S
2.8 og/l
(2.0-3.9)
>3.f> og/t
2.8 og/ft
(1.98-3.96)
2.1 og/l
(1.6-2.8)
1.45 mg/l
(0.93-2.26)
4.0 mg/l
(2.92-5.47)
1.3 mg/l
(0.96-1.75)
2.00-4.2 mg/l
1.8 mg/l
(1.32-2.45)
>2.5 og/l
1.8-5.0 og/l
3.8. 3.9,
3.0 og/l
2.7 og/l
(2.08-3.51)
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
1.5 mg/l
(0.9-2.5)
6.8 og/l
(2.18-7.53)
1.4 og/l
(0.95-2.0)
1.5 mg/l
(1.1-2.0)
1.2 mg/l
(0.78-1.86)
2.0 mg/l
(1.43-2.79)
0.86 ag/l
(0.59-1.26)
1.05-1.7 ag/l
1.2 ag/l
(0.76-1.88)
>2.5 ag/l
1.2-2.3 ag/l
1.4. 1.4. 1.5
mg/l
1.4 og/l
(1.1-1.79)
i
LC50. temp. = 12*C.
pH = 7.2. hardness = 46 rog/i
LC50. teop. = 10-C.
pH «= 7.4. hardness = 162 bg/l
LC50. teop. = 12'C,
pH = 7.4. hardness = 320 og/l
LC50. teap. = 12-C.
pH - 6.5, hardness = 40 mg/l
LC50. teap. = 12-C.
pH «= 8.5. hardness = 40 og/l
LC50. test temp. = 7'C.
pH = 7.4. hardness - 40 og/l
LC50. test teap. = 17*C.
pH = 7.4. hardness = 40 mg/l
LC50. test teap. <= 12*C.
pH " 7.2-7.5. hardness = 40 og/l,
results from 4 studies
IC50, teap. = 12-C.
pH = 7.4. hardness = 40 og/l
LC50. temp. = 12-C.
pH = 7.4. hardness = 272 og/l
LC50. test teap. » 10-12*C.
pH = 7.2. hardness = 40 og/l.
results froo 5 studies
LC5Q values after 1. 3. 7 days
of degradation, respectively
LC50. temp. = 17'C.
pH - 7.2. hardness = 40 og/l
Mayer and
E Her sleek.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck,
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck,
Mayer and
Ellersleck.
1986
1986
1986
1986
1986
1986
1986
1986
1986
1986
1986
1986
1986
-------
TABLE 4-1 (cont.)
0
_j
o.
i
o*
1
06/08/
Median Response Concentration
Species
Salmo galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
Salao galrdnerl
Rainbow trout
(eyed egg)
Salao galrdnerl
Rainbow trout
(swim-up fry)
Salao galrdnerl
Rainbow trout
(yolk-sac fry)
Salmo salar
Atlantic salaon
Salao salar
Atlantic salaon
Salao salar
Atlantic salaon
Salmo salar
Atlantic salaon
Salvellnus
"Font anil Is
Brook trout
Salvellnus
fontanllls
Brook trout
Chemical
90X active
Ingredient In
wettable powder
90X active
Ingredient In
wettable powder
24X liquid
24X liquid
24X liquid
95X technical
material
99X technical
material
99X technical
material
24X liquid
99X technical
aaterlal
24X liquid
Test
Method
S
S
S
S
S
S
S
S
S
S
S
24-Hour 48-Hour
(95X confidence
3.1 ppa 2.7 ppa
2.95 ppn 2.95 ppn
>10 ag/t NR
1.5 ag/t NR
(1.2-1.9)
>10 ag/t NR
0.8 ag/t NR
(0.7-0.92)
1.63-1.72 ag/t NR
0.82, 0.94 ag/l NR
1.6. 1.5 ag/t NR
2.25, 1.75 ag/t NR
NR NR
96-Hour
Halts)
2.38 ppa
2.60 ppa
32 ag/t
(18-55)
1.3 ag/t
(0.96-1.6)
3.2 ag/t
(2.3-4.5)
0.56 ag/t
(0.46-0.69)
1.0-1. 22 ag/t
0.64. 0.70 ag/t
1.4. 1.2 ag/l
2.2. 1.5 ag/t
1.22 ag/t
(0.86-1.73)
Comments
LC50. teap. = 12°C
tC50. leap. = 12«C
LC50. teap. = 10-C.
pH = 7.2. hardness = 40
LC50. teap. . 12«C.
pH = 7.4. hardness = 40
LC50. teap. = 12'C.
pH = 7.2. hardness = 40
LC50, test temp. = 17"C.
pH = 7.5, hardness = 40
LC50, teap. = 12'C,
pH = 7.5. hardness = 40
results from 5 studies
• 1
mg/t
ng/t
ng/t
mg/t
ng/t,
LC50. teap. . 12'C. pH = 6.0.
6.5. respectively, hardness =
40 ag/t. results from 2 studies
IC50. teap. = 12'C.
pH = 7.5. hardness = 40
results from 2 studies
LC50, teap. = 12'C.
pH = 7.5. hardness = 40
results from 2 studies
tC50. teap. = 12°C.
pH = 7.5. hardness = 40
ng/t.
ng/l.
ng/t
Reference
Schneider,
Schneider,
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
Mayer and
Ellersleck
1979
1979
. 1986
. 1986
. 1986
. 1986
. 1986
. 1986
. 1986
. 1986
. 1986
CO
CO
-------
TABLE 4-1 (cont.)
o
— ' Species Chemical
Median Response Concentration
Test
Method 24 -Hour
48 -Hour 96 -Hour
Comments
Reference
(95X confidence Units)
Tllapla nllotlca Lannate
Tllapla
Tllapla nllotlca Lannate
Ttlapla
S 1.0S4 ng/t
(0.983-1.13)
S 1.301 mg/t.
(0.855-1.980)
0.916 ng/t MR
(0.848-0.989)
0.884 ng/t MR
(0.570-1.37)
TLH. te«p.
reported as
Ingredient;
TLH. teap.
reported as
Ingredient;
= 22-25-C; results
ng/t of active
fish size = 1.5 g
= 22-25-C; results
mg/t. of active
fish size = 13.8 g
El-Refal et al..
1976
El-Refal et al..
1976
FT « Flowthrough; LCjQ = nedlan lethal concentration; NR = not reported; S = static
o
oo
CO
CO
-------
(methanesulphonate of meta-am1nobenzo1c add ethylester). F1sh were
observed for 48 hours after the application of pesticide. Contact exposure
was achieved by holding fish 1n 10 I of test solution at 20-22°C. The
duration of exposure was not specified. Hashimoto and Fukaml (1969)
reported LD5Qs for all treatments Including the contact studies by
assuming that all of the pesticide In the test solutions was "completely
accepted by the test fishes." They reported an oral L05Q of 4.2 mg/flsh,
a topical LD5Q of 0.036 mg/f1sh and a contact LD5Q of 2.0 mg/flsh. F1sh
were an average of 6.0 cm In total length and 2.5 g 1n weight.
Carter (1971) reported a 24-hour IC™ of 0.92 ppm for channel catfish,
Ictalurus punctatus. exposed to methomyl. Other than fish size (mean =
8.54 g), experimental conditions were not reported. Kaplan and Sherman
(1977) reported the results of acute studies with blueglll sunflsh, rainbow
trout and goldfish. The 96-hour LC5Qs were 0.875, 3.4 and >0.10,
respectively.
The results of studies In which aquatic Invertebrates were exposed to
methomyl for acute periods are presented 1n Table 4-2. Most of the studies
were reported by Mayer and Ellersleck (1986) and were published previously
by Johnson and Flnley (1980). In general, aquatic Invertebrates, mainly
crustaceans and Insects, demonstrated greater sensitivity to acute exposures
to methomyl than fish, although the toxldty was not dependent on water
chemistry. The 96-hour LC5Qs generated with copepods and shrimp ranged
from 0.29-0.41 and 0.03-0.064 mg/l, respectively, and were not signifi-
cantly affected by differences 1n salinity (Roberts et al., 1982). The
48-hour ECcg levels with Daphnla maqna were 0.0076 and 0.0088 mg/8.
despite differences 1n water hardness or methomyl formulation (Mayer and
0121d -18- . 06/08/88
-------
TABLE 4-2
Median Lethal and Effective Concentrations for Aquatic Invertebrates Exposed to Nethonyl (Lannate)
INJ : —
°- Median Response Concentration
i
i
o
0
CD
CD
CD
Species
Acartla tonsa
Copepod
Eurytemora afflnls
Copepod
Mysldopsis bah la
Mysld shrlap
Neomysts aaerlcana
Mysld shrimp
White River crawfish
(species not specified)
Daphnta aagna
Water flea
Daphnta aagna
Water flea
Gaaaarus
pseudollanaeus
Scud
Gaaaarus
pseudollanaeus
Scud
^Gajnarus
pseudol Imnaeus
Scud
Gaaaarus
pseudollanaeus
Scud
Chemical
24X Lannate
In aethanol
24X Lannate
in aethanol
24X Lannate
In nethanol
24X Lannate
In methanol
methomyl
95X technical
material
24X liquid
24X liquid
24X liquid
24X liquid
24X liquid
Test
Method 24-Hour 48-Hour 96-Hour
(95X confidence Halts)
S NR NR
S NR NR
S NR NR
S NR NR
S NR NR
S 0.012 ag/t 0.0088 ag/t
(0.0073-0.02) (0.0041-0.019)
S NR 0.0076 mg/t
(0.0048-0.0121)
FT >2.5 ag/t NR
NR NR 1.05. 0.075.
0.034 ag/t
S NR 1.05 ag/t
(0.424-2.60)
S >1 mg/t NR
0.41 ag/l
(0.26-0.62)
0.29 ag/t
(0.09-0.50)
0.050. 0.064
•9/t
0.034. 0.030
ag/t
1.0 ag/l
NR
NR
1.05 ag/l
(0.839-1.315)
NR
NR
0.72 ag/t
(0.572-0,907)
Comments
i
LC50. temp. = 22°C.
salinity = 10°/*«
LC50. temp. = 22'C.
salinity = 10V»
LCso. temp. = 22»C,
salinity = 20V. o.
results from 2 studies
LCjo. temp. = 22"C,
salinity = 20V-«.
results from 2 studies
LC50. temp. = 26°C
EC50. temp. = 21eC. pH =
7.4. hardness = 272 ag/t
ECjQ, temp. = 20*C. pH =
7.2. hardness = 40 mg/t
LCso. temp. = 12*C. pH =
7.4. hardness = 274 mg/t
LC50. temp. = 12-C, pH =
7.2. hardness = 40 mg/t;
values represent LCjo
after 1. 3 and 7 days of
degradation of active
metabolites In liquid
LC50. temp. = 12-C. pH =
7.2. hardness = 40 mg/t
LCc0. temp. = 17*C. pH =
7.4. hardness = 40 mg/l
Reference
Roberts et
1982
Roberts et
1982
Roberts et
1982
Roberts et
1982
al..
al..
al..
al..
Carter and
Graves. 1973
Mayer and
Ellersteck.
Mayer and
Ellersleck.
Mayer and
Ellersleck,
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
1986
1986
1986
1986
1986
1986
-------
TABLE 4-2 (cent.)
O
I
Median Response Concentration
Species
Saaaarus
pseudollanaeus
Scud
Chlronoaus plumosus
Nidges
Chlronoaus pluaosus
Nidges
Isogenus sp.
Stonefly
Isogenus sp.
Stonefly
Pteronarcella badla
Stonefly
Pteronarcella badla
Stonefly
Chealcal Test
Method
99X technical S
aaterlal
24X liquid S
95X technical S
material
9SX technical S
material
24X liquid S
95X technical S
material
24X liquid S
24-Hour 48-Hour 96-Hour
(95X confidence Halts)
>.«/.
0.105 ag/l
(0.071-0.156)
NR
0.49 ag/l
(0.368-0.653)
0.066 ag/l
(0.046-0.095)
0.168 ag/l
(0.125-0.226)
0.067 ag/l
(0.056-0.080)
NR
0.032 ag/l
(0.013-0.080)
0.088 ag/l
(0.060-0.129)
NR
NR
NR
NR
0.92 ag/l
(0.68-1.24)
NR
NR
0.343 ag/l
(0.268-0.440)
0.029 ag/l
(0.021-0.041)
0.069 ag/l
(0.044-0.108)
0.060 ag/l
(0.045-0.080)
Comments
"!?•
5ci!'
"50.
7.4.
£?•
icl?'
icl?'
£?•
temp. =
hardness
temp. =
hardness
temp. =
hardness
teap. =
hardness
temp. =
hardness
teap. =
hardness
temp. =
hardness
17
20
22
T
T
T
s
T
•c
40
i
, PH =
mg/l
•C.'pH=
272 rag/l
°C
40
C.
42
C.
42
c.
40
C.
40
. PH =
mg/l
pH =
mg/l
pH =
mg/l
pH =
mg/l
pH =
Reference
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
Mayer and
Ellersleck.
1986
1986
1986
1986
1986
1986
1986
£650 « Median effective concentration; FT » flowthrough; LCjQ = aedlan lethal concentration; NR = not reported; S - static
o
CO
^K
CO
CO
-------
Ellersleck, 1986). The 96-hour LCcns obtained with' scud, Gammarus pseudo-
3U ___^^__
Hmnaeus. ranged from 0.72-1.05 mg/j, despite differences 1n water hardness
and methomyl formulation (Mayer and Ellersleck, 1986). The toxldty of
methomy1 to aquatic Insect larvae, however, was significantly affected by
formulation. The' 95% technical material was more than twice as toxic to
midges than the 24% liquid, and 10-fold more toxic to a stonefly Isoqenus
sp; however, these same formulations did not differ 1n their toxldty to
another stonefly genus, Pteronarcella badla. after 96 hours (Mayer and
Ellersleck, 1986).
Kaplan and Sherman (1977) reported the results of acute studies with
grass shrimp, pink shrimp, mud crab and fiddler crab. The 96-hour LC5Qs
for these organisms were 0.049, 0.019, 0.41 and 2.38, respectively.
N1sh1uch1 and Yoshlda (1972) exposed four species of snail to methomyl at
22°C for 48 hours, and reported TL s of 6.6, 12, 25 and 18 ppm for the
snails, Indoplanorbls exustus. Sem1.sulcosp1ra Hbertlna. C1panqopalud1na
ma 1'I eat a and Physa acuta. respectively, exposed to methomyl as a wettable
powder. The Investigators also reported that I., exustus and S. Hbertlna
experienced a loosening of body muscle at 1.2 and 0.60 ppm methomyl after 48
hours of exposure at 22°C.
Slmonet et al. (1978) used the negative phototaxls response of first
Instar larval mosquitoes, Aedes aeqyptl. to estimate an EC5Q for exposure
to methomyl. Groups of 25 larvae were placed Into stacking dishes contain-
ing 100 ma of test solution for 8 hours. Photomlgratlon tests were run In
a multi-unit apparatus consisting of four glass chambers (4x4x4.7 cm) with a
moveable gate; the maximum migration distance was 30 cm. The EC5Q was
defined as the concentration of methomyl reducing migration 1n 50% of the
0121d -21- . 06/08/88
-------
test larvae as compared with the controls. The 8-hour EC5Q (and. 95%
confidence limits) was 0.39 mg/8. (0.85-1.70). Strlckman (1985) exposed
second Instar larvae of the mosquito, Hyeomyla smithll, to methomyl 1n 30
ma of aged tap water 1n 7-day static tests. There were no mortalities at
1 ppm, but 100% mortality after 7 days at 5 ppm. The Investigators noted
delayed development of larvae at 1 ppm.
4.2. CHRONIC EFFECTS
Carter (1971) reported an EC5Q (Inhibition) of 0.016 ppm for channel
catfish exposed to methomyl 1n a static test conducted In 5000 l pools.
Brain AChE, Inhibited 80-90%, recovered to 80% of normal activity In 6-10
days following treatment for fish that were left 1n the treatment pools.
Carter (1971) also reported that scol1os1s, a lateral curvature of the
spine, usually with localized hemorrhaglng, was produced In channel catfish
by methomyl at sublethal concentrations.
4.3. PLANT EFFECTS
Khalll and Hostafa (1986) exposed the freshwater blue-green algae,
Phorm1d1um fragile, to methomyl to assess effects on growth and physiologi-
cal behavior. Algal cultures (6-7 days old) were exposed to methomyl 1n 100
mi of experimental medium for 7 days at 28-30°C. Concentrations <225 ppm
did not produce any significant effects on the growth of P. fragile. Growth
(blomass yield) was reduced significantly at concentrations ranging from
225-900 ppm. Exposure to methomyl at concentrations >225 ppm also produced
reductions 1n the levels of chlorophyll a, carotenes and carbohydrate
contents. Ibrahim (1984) determined the EC5Qs for exposure of the chloro-
phytes, Anklstrodesmus falcatus and Scenedesmus guadrlcauda. and the diatom,
Phaeodactylum trlcornutum. to methomyl (Lannate). The 96-hour ECcls,
0121d -22- 07/14/88
-------
defined as the calculated concentration of Lanhate that would Inhibit growth
by 50% as compared with control growth, were 4.5, 67.0 and 82.0,
respectively.
4.4. SUMMARY
Channel catfish, l_. punctatus. were among the most sensitive fish
species to any formulation of methomyl on an acute basis. The 96-hour
LCcQ for this species exposed to a 24% liquid formulation was 0.30 mg/a.
(Mayer and Ellersleck, 1986). Results from one test with blueglll sunflsh,
L. macrochlrus. produced the highest 1C., among fish (96-hour LC5Q =7.7
ppm), although the majority of test results with this species ranged from
0.43-2.8 mg/i (Mayer and Ellersleck, 1986). Salmo clarkl demonstrated
tolerance almost as high as that of the blueglll (96-hour LC5Q = 6.8
mg/i). There was IHtle evidence that water chemistry affected the
toxIcHy of methomyl to fish.
Aquatic Invertebrates expressed greater sensitivity to exposure to
methomyl than fish. Water flea, D. maqna. were among the most sensitive to
methomyl on an acute basis (48-hour EC™ = 8.8 ppb). Copepods, Acartla
tonsa. scud, G. pseudollmnaeus. and fiddler crabs were among the least
sensitive Invertebrates, with 96-hour LC5Qs of 0.41, 1.05 and 2.38 mg/l,
respectively (Kaplan and Sherman, 1977; Roberts et al., 1982; Mayer and
Ellersleck, 1986).
Algae were very tolerant to exposure to methomyl compared with fish and
Invertebrates. The 96-hour EC5Qs with respect to growth for A. falcatus.
£. quadrlcauda and P_. trlcornutum were 4.5, 67 and 82.0 mg/i, respec-
tively. Growth 1n £. fragile was Inhibited only at concentrations >225 ppm.
0121d -23- 07/14/88
-------
5. PHARHACOKINETICS
5.1. ABSORPTION
Metabolism studies with orally administered [14C=0]-and [14C=N]-
methomyl provide excretion data from which Information regarding gastro-
intestinal absorption can be Inferred. The most useful Information comes
from studies using the [14C=0] label, because metabolism and excretion of
the [C=0] moiety 1s more rapid than metabolism and excretion of the [C=N]
moiety.
Huhtanen and Dorough (1976) administered single oral 1-2 million dpm
doses of syn-[14C=0]-methomyl 1n corn oil to two male and two female
Cox-SO rats and measured the radioactivity excreted 1n urine, feces and
expired carbon dioxide at various times during 24 hours. Fecal radioactiv-
ity accounted for only 0.2% of the administered dose In both sexes. Urinary
radioactivity accounted for 4.8-4.9% and expired radioactive carbon dioxide
for 83.0 and 87.7% of the dose 1n males and females, respectively. Total
recovery was 88.0% 1n males and 92.8% In females. Radlolabeled carbon
dioxide appeared within the first hour of treatment; Us excretion was
nearly complete within 10 hours. These data suggest that methomyl Is
rapidly and nearly completely absorbed from the gastrointestinal tract of
rats. U.S. EPA (1987a) mentioned an unpublished study from the OPP CBI
files (Andrawes et al., 1976) and a paper presented at an International
symposium on pesticide terminal residues (Baron, 1971), both of which
suggest that gastrointestinal absorption In rats Is nearly complete.
Data were not located regarding the absorption of Inhaled methomyl.
5.2. DISTRIBUTION
Harvey et al. (1973) administered a 1.2 mg (5.0-5.5 mg/kg) dose of
[14C=N]-methomyl 1n peanut oil by gavage to two rats that had been main-
tained on a diet containing 200 ppm cold methomyl for 8 days. Radioactivity
0121d -24- . 06/08/88
-------
was measured 1n expired air, urine, feces, several Individual organs and
tissues and the eviscerated carcass upon sacrifice at 72 or 24 hours.
Collectively, the organs and eviscerated carcass contained 10 and 9% of the
administered dose of radioactivity after 72 and 24 hours, respectively.
Radioactivity was expressed as yCl per organ rather than 1n terms of
concentration, obscuring tissue affinities for methomyl or Its radioactive
metabolites. The largest amounts of radioactivity were located In the
carcass, hide, gastrointestinal tract, blood and liver, -0.2, 0.14, 0.014,
0.084 and 0.04 yd, respectively. Amounts In other organs ranged from
0.000-0.014 yd. The amount of radioactivity In the blood was greater
after 72 hours (0.084 yC1) than after 24 hours (0.034 yC1).
In rats treated with a single oral 5 mg/kg dose of [14C=N]-methomyl, a
total of 10X of the dose of radioactivity was recovered from tissues upon
sacrifice at 24 hours (Baron, 1971). No tissue site demonstrated a tendency
to accumulate radioactivity. Tissue levels were nearly Identical In rats
sacrificed 3 days after .treatment, suggesting that the radlolabel had been
Incorporated Into tissue components.
5.3. METABOLISM
Huhtanen and Dorough (1976) and Oorough (1977) reported extensively on
the metabolism of orally-administered radlolabeled 1-2 million dpm doses of
methomyl 1n corn oil 1n male and female Cox-SD rats, and proposed the
metabolic scheme presented 1n Figure 5-1 and discussed below. Methomyl
exists 1n two geometric forms, syn-methomyl and ant 1-methomyl; the syn-
Isorner 1s the more stable and 1s the form present 1n Insecticide formula-
tions. Following absorption, syn-methomyl undergoes partial 1somer1zat1on
to the anti-form. Hydrolysis of the ester linkage liberates the carbonyl-
contalnlng moiety and the corresponding syn- and ant1-ox1mes. The carbonyl
0121d -25- . 06/08/88
r
-------
CM3
CH
I
$-CH3
FIGURE 5-1
§? Proposed Metabolic Pathway for Hethonyl In Rats
o
\ Source: Huhtanen and Dorough,, 1976
CO
oo
-------
carbon Is metabolized rapidly to carbon dioxide, which Is eliminated 1n the
expired air. The oxlmes are partially excreted In the urine; the remaining
syn- and ant 1-oxlmes undergo Beckmann rearrangement to form Intermediates
that are further metabolized to carbon dioxide and acetonltrlle, respec-
tively. These Intermediates may be metabolized slowly, as Indicated by the
continued expiration of labeled carbon dioxide and acetonltrlle for at least
3 days after a single dose of labeled methomy1.
The pathways proposed above were supported by the results of several
experiments. When [14C=0]-syn-methomyl was given to rats, 83-88% of the
administered radioactivity was recovered as 14C-carbon dioxide within 24
hour, Indicating that hydrolysis of the ester linkage with formation of
carbon dioxide and the oxlme 1s rapid and nearly complete. Further support
for extensive hydrolysis of the ester linkage comes from the observation
that <5% of the administered dose of radioactivity from [14C=N]-syn-
methomyl was recovered 1n the urine as an Intact carbamate compound.
Administration of either Isomer of [14C=N]-methomyl resulted 1n
recovery of14C-carbon dioxide within 2 hours. 14C-AcetonHr11e was
recovered within 2 hours when the ant1-1somer was given, but not before 6
hours when the syn-1somer was given. The Investigators theorized that the
delay between administration of syn-methomyl and recovery of 14C-aceto-
nltrlle represented the time required for 1somer1zat1on of the syn- to the
ant1-1somer, because oral administration of [14C=N]-ant1-methomyl or
l4C-aceton1tr1le resulted 1n prompt recovery of l4C-aceton1tr1le from
expired air. When the ant1-1somer was given 14C-carbon dioxide, excretion
was rapid but essentially complete by 14 hours, suggesting that Its source
was actually syn-methomyl, which contaminated the ant1-Isomer up to a level
of 20%. Administration of a purified ant1-1somer preparation (5% syn-form)
0121d -27- . 06/08/88
-------
resulted In substantially less expiration of 14C-carbon dioxide, suggesting
that the syn-lsomer was the source of the carbon dioxide and that the
ant1-1somer does not 1somer1ze to any extent in vivo. Experiments with
[4C=N]-syn and antl-methomyl oxlme confirmed their conversion to
14C-carbon dioxide -and l4C-aceton1tr1le, respectively.
Although the radioactive urinary metabolites were not Identified
precisely, Huhtanen and Dorough (1976) speculated that they consisted of the
oxlme and a highly volatile fraction, possibly acetonltMle. In a briefly
reported unpublished study 1n rats, urinary excretory products Included
unchanged methomyl, free and conjugated acetonltrlle, the oxlme and the
sulflde oxlme and unidentified polar metabolites (Andrawes et al., 1976).
In a similar study In rats, Harvey et al. (1973) established that urinary
excretion products did not Include unmetabollzed methomyl, N-hydroxyth1o-
acetlmldate, or sulfoxldatlon products or their glucuronlde conjugates. In.
vitro studies with hepatic flavlne adenlne dlnucleotlde-dependent mono-
oxygenase (Hajjar and Hodgson, 1980, 1982) confirmed that methomyl was not a
substrate for sulfoxldatlon, which occurs commonly with thloether-containing
carbamate Insecticides.
There 1s considerable Interest 1n the ability of pesticides containing
secondary amlne groups to undergo nltrosatlon In the acid environment of the
stomach to form N-nltroso derivatives, several of which (Including nltroso-
methomyl) have been shown to*be carcinogenic In gavage studies using rats
(L1J1nsky and Schmael, 1978). Although methomyl has been nltrosated 1n the
laboratory (Lljlnsky and Schmahl, 1978; IARC, 1983), nltrosatlon did not
occur In one experiment under simulated stomach conditions using nitrite-
containing cured meats Incubated at pH 2 (Han, 1975). Additional studies of
the 1n vivo nltrosatlon of methomyl are 1n progress (NTIS, 1988).
0121d -28- 07/14/88
-------
5.4. EXCRETION
Huhtanen and Dorough (1976) orally administered radlolabeled syn- or
antl-methomyl to rats and measured expired 14C-carbon dioxide and aceto-
nltrlle and urinary radioactivity over a 24-hour period as described above.
When [14C=0]-syn-methomyl was given, total recovery of radioactivity was
>88% (>83.0% as expired carbon dioxide, <5% as urinary metabolites and 0.2%
1n the feces), suggesting that excretion of the metabolites of the carbonyl-
contalnlng moiety was rapid and complete. When [14C=N]-methomyl was
given, 24-hour recovery of respiratory radioactivity ranged from 31-36% and
urinary radioactivity ranged from 25-35% of the administered dose. For
syn-methomyl, carbon dioxide accounted for 19.5 and acetonltrlle for 11.3%
of the dose of radioactivity. For the ant1-1somer, carbon dioxide accounted
for 7.6 and acetonltrlle for 27.9% of the dose of radioactivity. Respira-
tory excretion continued for at least 3 days following treatment. The
Investigators concluded that the extended period of excretion observed with
[14C=N] methomyl compared with [14C=0] methomyl resulted from persis-
tence of the carbon dioxide and acetonltrlle precursors formed from the
ox1 me rather than delay In the excretion of carbon dioxide and acetonltrlle
themselves.
Similar observations were reported by Harvey et al. (1973), who adminis-
tered [14C=N]-methomyl orally to rats at 3.6-5.5 mg/kg/day and measured
excretion of radioactivity as expired carbon dioxide and acetonltrlle,
urinary metabolites and fecal metabolites for 24-72 hours. Expired carbon
dioxide ranged from 15-23%, acetonltrlle accounted for -33%, urinary metabo-
lites for 16-24% and fecal radioactivity for <2% of the dose.
0121d -29- . 06/08/88
-------
5.5. SUMMARY
Methomyl appears to be absorbed rapidly and completely from the gastro-
intestinal tract of rats (Huhtanen and Dorough, 1976). At 24-72 hours after
gavage treatment with 14C-methomyl, -10% of the administered radioactivity
can be recovered "from the body (Harvey et al., 1973). The largest amounts
are located 1n the eviscerated carcass, hide, gastrointestinal tract, blood
and liver. Metabolism of syn-methomyl, the Isomer used 1n Insecticide
formulations, begins with partial 1somer1zat1on to the ant1-1somer, followed
by rapid hydrolysis of the ester linkage to liberate the carbonyl moiety and
form the corresponding syn- and ant1-ox1mes (Huhtanen and Dorough, 1976).
The carbonyl carbon 1s expired rapidly and nearly completely as carbon
dioxide. The syn- and ant1-ox1mes undergo Beckmann rearrangement to form
more slowly metabolized Intermediates 1n the production of carbon dioxide
and acetonltrlle, respectively. The carbon dioxide and acetonUrlle thus
formed are expired rapidly. Together, respiratory excretion accounts for
-31-36X of the dose of radioactivity. Urinary metabolites, which account
for -25-3554 of the administered radioactivity, may consist primarily of the
oxlmes and acetonltrlle.
0121d -30- . 06/08/88
-------
6. EFFECTS
6.1. SYSTEHIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC — In the only repeated exposure Inhalation study
located, Ta'naka et al. (1987) exposed groups of 10 young adult male Wlstar
rats In an Inhalation chamber to a dust generated from a formulation of
methomy1. Exposures were 4 hours/day, 5 days/week for 3 months. Concentra-
tion of dust was 0 or 14.8+4.2 mg/m3. The formulation contained 45%
methomyl; Identity of the Inerts present was not reported. Presumably, the
concentration of methomyl In the chamber atmosphere was 14.8 mg/m3 x 0.45,
or 6.7 mg/m3. The mass median aerodynamic diameter was estimated at
4.4 p. with a standard deviation of 2.9 M. Body weights of exposed rats
were slightly below those of controls from week 4 to termination of the
study, but the differences were not statistically significant. There were
no effects on absolute or relative weights of lung, liver, kidney or spleen
compared with controls. H1stopatholog1c examination, limited to the organs
listed above as well as the upper respiratory tract, the brain and organs of
sight and hearing, revealed focal hemorrhages In the lungs of three exposed
rats and scattered foam cell aggregations In the lungs of three exposed and
one control rats, but the Investigators concluded that these effects were
not related to methomyl exposure. Exposure had no significant effect on the
concentration of I1p1ds, or the fatty add content of Uplds 1n lung tissue.
Plasma choilnesterase activity determined at sacrifice was depressed 1n
exposed rats compared with controls, but the extent of depression was not
greater than that measured In rats following only one 4-hour Inhalation
exposure at 9.9 mg/m3. Erythrocyte choilnesterase activity was not
depressed.
0121d -31- . 07/14/88
-------
.6.1.1.2. CHRONIC — Pertinent data regarding the toxldty In labora-
tory animals of chronic Inhalation exposure to methomyl were not located 1n
the available literature cited in Appendix A. Morse et al. (1979) performed
a health effects study In August, 1976, on 101 workers In a methomyl produc-
tion and packaging -plant. Until June, 1976, the plant had also produced the
herbicide propanll from 3,4-d1chloroan1l1ne, so that exposure to a mixture
of chemicals was likely. Workers were divided by job category as follows:
packaging (n=ll), production (n=28), safety, laboratory (safety and labora-
tory together, n=15), maintenance, other (maintenance and other together,
n=31) and office (n=16). According to Morse et al. (1979), a separate OSHA
Investigation revealed that highest atmospheric levels of methomyl were
located In the packaging area, but concentrations were not reported. The
Investigators stated that differences 1n demographics between the job
category groups were minor. Average length of employment was 24 months.
Data on health effects were obtained from a questionnaire, hospital records
and a complete physical examination Including hematology, urlnalysls, plasma
and erythrocyte chollnesterase activity and vibratory sensation tested with
a tuning fork. Symptoms of methomyl toxldty recorded were mlosls, nausea.
vomiting, blurred vision, muscle weakness, fatigue and Increased salivation.
Expressed 1n terms of the mean number of methomyl symptoms/worker, the
greatest Incidence of symptoms was observed In packaging (2.55) followed by
production (1.11), maintenance (0.78), safety (0.60), office (0.25), labora-
tory (0.20) and other (0.13). There were no measurable effects on urlnaly-
sls, hematology, acetyl chollnesterase activities of plasma or erythrocytes
or sensitivity to vibration. The Incidence of methomyl-related health
effects decreased after cleaning procedures were Improved In the packaging
area (Morse et al., 1979).
0121d -32- 06/08/88
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6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC — Kaplan and Sherman (1977) summarized the
results of 3-month dietary studies with methomyl (>90% purity) 1n rats and
dogs. Groups of 10 male and 10 female ChR-CD rats were fed diets containing
methomyl at 0, 10, 50, 125 or 250 ppm for 90 days. The 125 ppm dietary
concentration was Increased to 500 ppm after 6 weeks. There were no effects
on general appearance or behavior and no mortality. Body weight gain
depression accompanied by a depression 1n food consumption was observed 1n
males at 250 ppm and In both sexes at 500 ppm. There were no effects on
urlnalysls, or on plasma or erythrocyte chollnesterase activities measured
at 2 months 1n five rats/sex In the group Initiated at 125 ppm and Increased
to 500 ppm, or measured at termination In five rats/sex from the 250 and 500
ppm groups compared with controls. Hematologlc examination revealed slight
depressions 1n blood hemoglobin concentrations In 50 ppm females at 1 month
and In 250 ppm males at 2 months. Depressed erythrocyte counts compared
with controls were observed 1n 250 ppm females, although values were within
normal limits. There were no effects on organ weights or hlstopathologlc
appearance of the tissues (>20) examined, with the exception of moderately
Increased hematopolesls 1n the bone marrow 1n unspecified treated groups.
U.S. EPA (1987a) considered 50 ppm a NOAEL and 250 ppm a LOAEL for rats In
this study.
In the dog study, groups of one male and one female beagle dog were fed
diets containing 0, 50, 100 or 400 ppm methomyl for 92-101 days (Kaplan and
Sherman, 1977). There were no effects on food Intake, body weights, general
appearance, hematology, urlnalysls, unspecified biochemical parameters,
organ weights or the hlstopathologlc examination of >30 tissues. U.S. EPA
(1987a) considered the 400 ppm level a NOAEL for dogs In this study.
0121d -33- 07/14/88
-------
U.S. EPA (1987a) summarized a 13-week unpublished dietary study where
F-344 rats were fed methomyl of unspecified purity (Roman et al., 1978).
Dosage levels were estimated at 0, 1, 3, 10.2 and 30.2 mg/kg/day for the
males and 0, 1, 3, 9.9 and 29.8 mg/kg/day for the females. There were no
effects on survival or clinical appearance. Body weight gain was depressed
significantly In all treated groups of females at >4 weeks. The magnitude
of the weight gain depression was not reported, and It 1s not known whether
the effect occurred In a dose-related fashion. Effects on body weight gain
were not observed 1n males. Organ weight determinations of 7 organs and
hlstopathologlc examinations of >30 tissues from representative control and
high-dose animals revealed elevated relative kidney weights In females at
9.9 and 29.8 mg/kg/day, but no hlstopathologlc effects at any level.
Erythrocyte chollnesterase activities were depressed In both sexes In the
high-dose groups, but there was no effect on plasma or brain chollnesterase
activities. Despite the effects on body weight gain In treated female rats,
U.S. EPA (1987a) judged 3 mg/kg/day a NOAEL and 9.9 mg/kg/day a LOAEL 1n
this study.
Antal et al. (1979) fed a semi-synthetic diet containing 90% methomyl at
0 or 200 ppm to groups of 10 male and 10 female Lean R/Amsterdam albino
rats, a strain that resists excessive weight gain, for 12 weeks. There were
no effects on food or water consumption or growth. The Investigators
estimated the Ingested dosage at 1.08 mg/100 g (10.8 mg/kg/day) 1n treated
males and 1.29 mg/100 g (12.9 mg/kg/day) 1n treated females. There were no
effects on hematocrlt or fasting blood glucose. Treated males had elevated
relative spleen weights and treated females had elevated relative kidney
weights compared with controls, but there were no hlstopathologlc effects
(examination limited to liver, kidney, adrenal, heart and spleen). Elevated
0121d -34- 07/14/88
-------
liver trlglycerlde content and reduced liver free fatty acid content was
observed 1n treated males, but there were no effects on liver glycogen
content. Reduced hepatic glucose-6-phosphate dehydrogenase activities were
observed 1n treated rats of both sexes, but there were no effects on
glucose-6-phosphafase or two drug metabolizing enzyme activities. Acetyl-
chollnesterase activities, measured only In the brain, were depressed In
treated rats of both sexes.
Male and female rats (strain and groups sizes not reported) were fed
diets containing 100 or 200 ppm 90% methomyl for 3 months (Bedo and
deleszky, 1980). There were no effects on body weights, food or water
consumption, oral glucose tolerance or hexobarbHal sleeping time. Compared
with controls, females at 200 ppm had significantly decreased brain cholln-
esterase activity and elevated serum I1p1d and cholesterol levels, although
the cholesterol levels were within the normal range, and slightly decreased
liver glucose-6-phosphatase activity. Other effects attributed.to exposure
to methomyl, but of uncertain toxlcologlc significance, Included slightly
altered activities of two drug-metabolizing enzymes and vitamin A content 1n
the liver and altered activities of pancreatic enzymes. The Investigators
stated that histology was normal and concluded that 100 ppm was a no-effect
level 1n this study.
6.1.2.2. CHRONIC — Kaplan and Sherman (1977) briefly summarized the
results of chronic dietary studies with methomyl (>90% pure) In rats and
dogs. Six groups of 35 male and 35 female ChR-CD rats were fed diets
containing 0, 0, 50, 100, 200 or 400 ppm for 22 months. Mortality was not
affected by exposure to methomyl. The authors noted that early In the
study, methomyl 1ngest1on at 400 ppm was ~60 mg/kg/day, >3 times the
reported oral LD5Q, without any deaths. They theorized that when rats
0121d -35- . 06/08/88
-------
Ingested methomyl gradually 1n the diet, they were able to metabolize the
pesticide at a rate sufficient to prevent death. Body weights of 400 ppm
males were significantly less than controls for the first 52 weeks of the
study. This trend was also observed 1n males at 200 ppm and 1n females at
400 ppm, but was -not statistically significant. Food consumption 1n males
at 200 and 400 ppm was reduced significantly for the first 26 weeks of the
study. There were no effects on urlnalysls, biochemistry or hematology,
with the exception of a dose-related reduction 1n blood hemoglobin concen-
tration 1n female rats at 18 and 22 months, particularly evident at >200 ppm
(statistical analysis not reported). Specific data were not reported for
effects on plasma, erythrocyte or brain chollnesterase activities measured
at 12 months and at termination. Elevated relative testlcular weight
unaccompanied by hlstopathologlc alteration was observed at 400 ppm. Rats
of both sexes at 400 ppm had mild kidney lesions (protein accumulation,
tubular dilatation and hypertrophy and vacuollzatlon of tubular epithelium)
and females at 200 and 400 ppm had Increased hematopolesls 1n the spleen.
In this study, 100 ppm was considered a NOEL and 200 ppm a LOAEL for
methomyl 1n rats (U.S. EPA, 1987a).
The dog study was performed with groups of four male and four female
young adult beagles fed diets containing methomyl at 0, 50, 100, 400 or 1000
ppm for 24 months (Kaplan and Sherman, 1977). Mortality attributed to
exposure to methomyl claimed two females at 1000 ppm: one after 8 weeks of
exposure and the other (her replacement) after 18 days of exposure. The
latter death was preceded by convulsive seizures and coma. Chollnerglc
signs occurred 1n two males at 1000 ppm, but no deaths occurred. There were
no effects on appetite, body weights, urlnalysls or biochemistry Including
chollnesterase activity 1n plasma and erythrocytes measured 1n controls and
0121d -36- 08/24/88
-------
high-dose dogs at 9 weeks and In high-dose dogs only at 13 weeks. A slight
to moderate anemia was observed 1n five high-dose dogs at 3 months that
persisted 1n one male throughout the study. There were no effects on organ
weights. Hlstopathologlc lesions observed 1n the kidneys Included Increased
pigmentation In the proximal convoluted tubule 1n males at 400 ppm and 1n
females at 1000 ppm. Tubular epithelial cells exhibited slight swelling In
both sexes at 1000 ppm only. Increased hematopolesls In the spleen was
observed In both sexes at 1000 ppm; pigment deposition In the spleen was
observed 1n both sexes at 400 ppm. A minimal to slight Increase 1n bile
duct proliferation In the liver and a slight Increase In bone marrow
activity was observed 1n both sexes at 1000 ppm. The 100 ppm dietary level
was a NOAEL and 400 ppm was a LOAEL 1n this study.
U.S. EPA (1986c) mentioned a 1981 2-year dietary study with methomyl In
rats 1n which 100 ppm (5 mg/kg/day) was a NOEL and 400 ppm was an LEL
associated with growth retardation and Inhibited chollnesterase activities.
No further Information was provided and the study was not discussed In the
methomyl Registration Standard (U.S. EPA, 1981) or the recent Health
Advisory (U.S. EPA, 1987a).
Hazelton Laboratories (1981) fed diets containing 0, 50, 100 or 800 ppm
methomyl of unspecified purity to groups of 80 male and 80 female CD-I mice
for 104 weeks. Significantly reduced survival 1n mice of both sexes at week
26 at 800 ppm led to reducing dietary concentration to 400 ppm at week 28
and to 200 ppm at week 39. Also at week 39, the 100 ppm diet was reduced to
75 ppm. Survival was reduced 1n all treated groups of males at termination,
although there were no hlstopathologlc lesions attributed to exposure to
methomyl. The lowest dietary level of 50 ppm was considered a LOAEL based
on decreased survival In males (U.S. EPA, 1987a).
012'ld -37- . 06/08/88
-------
6.1.3. Other Relevant Information. Acute oral toxldty data for me thorny!
1n several species are presented 1n Table 6-1. Oral LD50. dietary LC™,
approximate lethal dose and minimum lethal dose values (the last two
criteria are equivalent) suggest that mice are moderately more sensitive
than other laboratory species to the acute oral toxldty of methomyl.
Gender and age appear to have little Impact on the lethal potency of
methomyl. Methomyl appears to be sightly more toxic 1n fasted than In
normally fed rats. Exposing mice to dietary BHA for 4 days before Intuba-
tion with methomyl reduced the toxldty of methomyl (Jao and Hsu, 1981).
BHA possibly Induced drug-metabolizing enzyme activities, as suggested by
the observation of decreased pentobarbltal sleeping time.
Mortality was preceded by signs of acute chollnergic poisoning (Kaplan
and Sherman, 1977; Dashlell and Kennedy, 1984) 1n rats at doses as low as
5.1 mg/kg (Kaplan and Sherman, 1977). Kaplan and Sherman (1977) reported
that decedents exhibited no hlstopathologlc signs attributed to exposure.
In an abstract, however, H1gash1hara (1987) reported biochemical evidence of
Impaired liver and kidney function and hlstopathologlc lesions In the lungs
of rats treated orally with 5 mg/kg, and hlstopathologlc lesions of the
liver and kidney at 15 mg/kg. In a 2-week study In which six male rats were
treated by gavage with 5.1 mg/kg/day on 5 days/week, the Intensity of the
chollnergic signs decreased during the second week of treatment (Kaplan and
Sherman, 1977). There were no deaths, no hlstopathologlc lesions and no
effects on plasma chollnesterase activities at 4 hours or 14 days after the
last treatment.
Studies of accidental and suicidal deaths In humans poisoned orally with
methomyl suggest that doses of 12-15 mg/kg are fatal (Arakl et al., 1982;
0121d -38- 07/14/88
-------
1
CO
TABLE 6-1
Acute Oral Toxlclty of Hethoayl
Spec les/Stra In/Sex
Rat/ChR-CD/H
Rat/ChR-CD/F
Rat/NR/NR
Rat/Sheraan/N.F
Rat/Sheraan/F
Rat/Crl-CD/H
Rat/Wlstar/N.F
Rat/ChR-CD/H
Nouse/SwIss/NR
House/Swlss/F
Guinea plg/NR/N
dog/Beagle/M
Honkey/rhesus/N.F
Purity/Vehicle
90X/peanut oil
90X/peanut oil
NR/NR
technical/peanut oil
technical/peanut oil
99X/corn oil
99*X/corn oil
99»X/corn oil
NR/corn oil -diet
90X/peanut oil
purified/corn oil
NR/water
90X/peanut oil
90X/capsule
90X water
Concentration
or Dosage
17 ag/kg
23.5 ag/kg
37 ag/kg
25 ag/kg
27 ag/kg
25 ag/kg
40 ag/kg
26 ag/kg
5000 ppa In diet
for 5 days
5.1 ag/kg
10 ag/kg
8.5 ag/kg
15 ag/kg
30 ag/kg
40 ag/kg
Effect
LDjo In fasted rats
LDjo In fasted rats
LOjo In fed rats
LDso In adult rats
1050 In weanling rats
LOso In fasted rats
1050 In fed rats
approxtaate lethal dose,
fed rats
LC5Q for growing rats
chollnerglc signs
LD5Q
LDjQ
alnlaua lethal dose
alnlaua lethal dose
alnlaua lethal dose
Reference
Kaplan and Shernan, 1977;
Antal et al., 1979
Kaplan and Sheraan, 1977
Antal et al.. 1979
Antal et al.. 1979
Galnes and Under, 1986
Galnes and Under. 1986
Dashlell and Kennedy. 1984
Oashlell and Kennedy. 1984
Kennedy et al.. 1986
NcCann et al.. 1981
Kaplan and Shernan, 1977
Fahmy et al.. 1978
El-Sewedy et al.. 1982
Kaplan and Sheraan. 1977
Kaplan and Shernan, 1977
Kaplan and Shernan, 1977
NR = Not reported
o
00
CO
CO
-------
Llddle et al.-, 1979). Symptoms reported were those of classic chollnerglc
toxldty. Survivors of accidental poisoning responded to atroplne (Llddle
et al., 1979).
Methorny! has been shown to be acutely toxic to rats exposed by
Inhalation. Kaplan and Sherman (1977) reported a 4-hour LC5Q of 76.8 ppm
(510 mg/m3) using a mist created from an aqueous solution. Plasma cholln-
esterase Inhibition was observed In rats exposed for 4 hours to a dust of a
formulation containing 45% methorny! (Ta'naka et al., 1987). The exposure
concentration of methomyl was estimated at 4.5 mg/m3.
Galnes and Under (1986) reported that the dermal LD5Q for methomyl 1n
rats was >2400 mg/kg. For rabbits, the dermal LD5Q was determined to be
>5000 mg/kg (Kaplan and Sherman, 1977). Kaplan and Sherman (1977) reported
that methomyl was mildly Irritating to the skin and eyes of guinea pigs, but
was not a sensitizing agent when administered topically or Intradermally.
Brief abstracts of Japanese studies, however, reported that methomyl-sensl-
tlzed guinea pigs cross-reacted with blnomyl (Matsushita and Aoyama, 1979,
1980). Humans occupatlonally exposed to methomyl responded positively to
the patch test (Kambe et al., 1976) and cross-reacted to the pesticide
blnomyl (Matsushita and Aoyama, 1979).
In other experiments In which animals were acutely exposed to methomyl
by various routes, Increased activities of pancreatic digestive enzymes 1n
rats (Bedo and deleszky. 1980), decreased hepatic kynurenlne hydrolase and
kynurenlne amlnotransferase activities In mice (El-Sewedy et al., 1982) and
decreased hepatic carboxylesterase and amldase activities In rats (Iverson,
1977) were reported. Nakamura et al. (1977) and Nlshlda et al. (1980)
reported hematologlc changes Including Increased numbers of retlculocytes
and punctate basophlUc erythrocytes and decreased erythrocyte resistance to
0121d -40- . 06/08/88
9
-------
osmotic pressure 1n rabbits (and possibly other species) exposed to methomyl
or other pesticides by 1ntraper1toneal Injection. Similar changes In the
blood were observed 1n farmers who used pesticides. A single Intraperlto-
neal dose of methomyl of 8.3 mg/kg had no effect on Immune function In mice
as evaluated by humoral response to sheep erythrocytes or to mouse hepatitis
virus 3 (Fournler et al., 1986).
Methomyl did not cause evidence of delayed neurotoxldty 1n Red-Rock
Cross hens treated orally with 28 mg/kg and held for 22 days (Kaplan and
Sherman, 1977). Without providing any additional data, U.S. EPA (1986c)
stated that methomyl was not a neurotoxln In hens at dosages up to 200
mg/kg/day.
Bracy et al. (1979) Investigated the effect of dietary exposure to
methomyl, ethanol or the combination of chemicals on plasma and erythrocyte
chollnesterase activity and three parameters of behavior In male Sprague-
Dawley rats. The test substances were mixed 1n corn syrup, which was used to
coat pellets of standard laboratory rat diet. The corn syrup contained 200
ppm methomyT, but data were not provided that permitted estimation of the
Ingested dosage. Control diet was prepared using corn syrup alone. Sucrose
was added to the control and methomyl diets to equalize caloric Intake.
Response to handling and open-field activity was recorded on exposure days
4, 7, 10 and 13. A mouse-killing test was performed on exposure day 13.
The rats were sacrificed for measurement of erythrocyte chollnesterase
activity on day 14. Plasma and erythrocyte chollnesterase activity 1n
methomyl-treated rats was depressed to ~25X of that of controls. Cholln-
esterase activity In ethanol and methomyl-ethanol rats was depressed only to
-50% of that of controls. None of the treatments had any effect on the
parameters of behavior evaluated.
0121d -41- . 06/08/88
-------
Selmed-Antal et al. (1980) Investigated the effects of methomy1 alone
at 200 ppm In the diet or with caffeine at 30 mg% or ethanol at 10% 1n the
drinking water 1n rats exposed for 12 weeks. Compared with methorny! alone,
methomyl and ethanol markedly depressed the growth rate of rats of both
sexes and methomyV and caffeine depressed the growth rate of female rats.
The combination of methomyl and caffeine elevated the relative weights of
the kidney, liver, spleen and heart .In female rats and of the adrenals 1n
rats of both sexes. Methomyl and ethanol elevated fasting glucose levels In
females, and liver trlglycerlde and free fatty add levels In males.
Ethanol was considered to have exacerbated the disruption of I1p1d metabo-
lism observed with methomyl alone (Antal et al., 1979). Altered hepatic
enzyme activities were observed 1n female rats treated with methomyl and
caffeine. Ethanol In combination with methomyl depressed brain chollnes-
terase activities 1n male rats beyond the slight depression observed with
methomyl alone.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carcinogenic potential
of Inhalation exposure to methomyl were not located 1n the available
literature cited In Appendix A.
6.2.2. Oral. Kaplan and Sherman (1977) reported a 22-month study In
which rats were fed diets containing 50-400 ppm methomyl (Section 6.1.2.2.).
There were no effects on survival, but growth was delayed In males at >200
ppm and 1n females at 400 ppm, and hlstopathologlc lesions were observed 1n
the kidneys of both sexes at 400 ppm and 1n the spleens of females at >200
ppm. The authors reported that the Incidence of neoplasms at 400 ppm was
similar to that observed 1n controls.
0121d -42- . 06/08/88
-------
Hazelton Laboratories (1981) fed CD-I mice diets containing methomyl at
50-800 ppm for 104 weeks (see Section 6.1.2.2..). Survival was reduced 1n
male mice, motivating a reduction 1n the dietary levels as the experiment
progressed. H1stopatholog1c examination revealed no compound-related
effects on the Incidence of tumors.
6.2.3. Other Relevant Information. Quarles et al. (1979) tested methomyl
for activity In the transplacental hamster fetal cell transformation assay.
In this test, a 1.0 mg/kg dose of methomyl 1n an unspecified solvent was
administered by IntraperUoneal Injection to hamsters on day 10 of gesta-
tion. Solvent controls and positive controls, known carcinogens represent-
ing several different classes of compounds, were also Included. On gesta-
tion day 13, cell suspensions were made of the decapitated, eviscerated
fetuses from which the limbs had been removed. Primary liquid cultures were
prepared from cells that were washed, trypslnlzed and suspended In a
complete medium. Subcultures were prepared and plated from the primary
culture every 4-6 days. Colonies were scored for plating efficiency and
transformations at the third, fifth, sixth or seventh, and tenth subcul-
tures. At the same time that subcultures were prepared for evaluation of
transformation, growth (cloning efficiency) 1n soft agar was also evaluated
as further Indication of cellular transformation. Cells, usually from the
sixth subculture, were Injected subcutaneously Into young adult nude mice,
which were observed for 6 months to 1 year for the appearance of Injection
site tumors.
Solvent controls yielded negative results 1n the cell transformation
test, the growth 1n soft agar test and the tumor1gen1dty 1n nude mice test.
012'ld -43- . 06/08/88
-------
Positive controls responded appropriately with positive results In one or
more of the above tests. Methomyl yielded negative results 1n all three
tests, and nltrosomethomyl yielded consistently positive results 1n all
three tests.
As mentioned "1-n Section 5.3., there 1s considerable Interest 1n the
ability of pesticides containing secondary amlne groups to undergo nltrosa-
tlon In the add environment of the stomach. L1j1nsky and Schmahl (1978)
reported that nltrosomethomyl Induced forestomach tumors In male and female
Sprague-Dawley rats, treated by gavage for 10 consecutive weeks with
once-weekly doses of 50 mg/kg.
6.3. MUTAGENICITY
Results of reverse mutation tests 1n five strains of Salmonella typhl-
murlum and Escher1ch1a coll WP2, differential toxlclty tests (DNA damage) 1n
E_. coll and Bacillus subtnis. and enhanced mltotlc recombination tests In
Saccharomyces cerevlslae D3 have been largely negative (Simmon et al., 1976,
1977; Waters et al., 1980, 1982; Klopman et al., 1985; Garrett et al., 1986;
MoHya et al., 1983; Blevlns et al., 1977a), as summarized In Table 6-2.
Positive results 1n the reverse mutation test 1n S. typhlmurlum (Njagl and
Gopalan, 1980) and 1n an unspecified test 1n S. cerevlslae (Guerzonl et al.,
1976) were reported, but these data were available only In abstract form and
1t was not possible to evaluate the studies and explain these apparent
contradictions. Minor discrepancies appeared 1n the reports by Simmon et
al. (1976, 1977), Waters et al. (1980, 1982), Klopman et al. (1985) and
Garrett et al. (1986), all of which appeared to summarize the results of
tests performed at Stanford Research Institute under contract to the U.S.
EPA. Not all reports Included S. typhlmurlum strain TA98 1n the Ames test,
some reported purity as technical grade and others as 99.0%, and most stated
0121d -44- . 06/08/88
-------
TABLE 6-2
Genotoxtclty Testing of Nethoayl
ISJ
£ Assay
Reverse Mutation
i
V
i
Differential
toxlclty
(DNA damage)
v-
§ Enhanced Ml t otic
>* recombination
o
00
00
CD :
Indicator/Organist Purity
Salmonella NR
typhlmurluM
S. typhlMurlua technical grade.
TA1535, TA1537. 99. OX
TA1538. TA100.
TA98
S. typhlMurluM NR
TA1535. TA1537.
TA1538. TA100,
TA98
S. tvphlmurlua technical grade
TA1535. TA1537.
TA1538. TA98.
TA100
Escherlchlae coll technical grade
UP2
i. coll UP2 NR
E. coll H3110. technical grade.
P3478 99. OX
Bacillus subtllls technical grade,
H17. N45 99. OX
Saccharomvces technical grade.
cerevlslae 03 99. OX
Application
NR
plate
Incorporation
plate
Incorporation
spot test and
plate Incorpo-
ration
plate
Incorporation
plate
Incorporation
spot test
spot test
plate
Incorporation
Concentration Activating
of Dose System
NR
6 concentrations » S-9
at 1-1000 ng/plate
>1 concentration » S-9
at <5 ag/plate
50 nM solution NR
6 concentrations «• S-9
at 1-1000 Vg/p1ate
>1 concentration * S-9
at <5 Mg/plate
1 mg/dlsh none
1 Mg/dtsh none
0.1-3X In aedla » S-9
Response Reference
i
» NJagl and Gopalan.
1980
Slmnon et al.. 1976.
1977; Haters et al..
1980. 1982; Klopman
et al.. 1985; Garrett
et al.. 1986
Horlya et al.. 1983
Blevlns et al.. 1977a
Haters et al.. 1980,
1982; Garrett et al..
1986; Simmon et al..
1977
Horlya et al.. 1983
Haters et al.. 1980.
1982; Garrett et al..
1986; Slimon et al..
1976. 1977; Klopman
et al.. 1985
Haters et al.. 1980.
1982; Garrett et al..
1986; Sloraon et al..
1976. 1977; Klopman
et al.. 1985
Haters et al.. 1980.
1982; Garrett et al..
1986; Slmnon et al..
1976. 1977
-------
TABLE 6-2 (cont.)
o
o.
i
06/08/88
Assay
NR
Sex-linked
recessive lethal
Chromosomal
translocatlon
Chromosome loss,
rearrangement and
non-disjunction
Nutation to
ouabaln resis-
tance
Sperm morphology
assay
Chromosomal
aberration
Induction of
sister chroma t Id
exchanges
Unscheduled DNA
synthesis
DNA strand
breaks
NR = Not reported;
Indicator /Organism Purity
S. cerevlslae NR
Orosophlla NR
melanogaster
0. melanoqaster technical grade
Canton-S wild type
0. melanoqaster 20X formulation
D. melanoqaster 20X formulation
D. melanogaster technical grade
Chinese hamster NR
V79 cells
Swiss mouse 20X formulation
Swiss mouse 20X formulation
human lymphocytes NR
human lung flbro- technical grade.
blast MI -38 cells 99. OX
human skin flbro- -95X
blast
NA = not applicable
Application
NR
NR
adult feeding
continuous
larval feeding
continuous
larval feeding
NR
cell culture
oral once dally
for 5 consecu-
tive days
oral once dally
for 5 consecu-
tive days
cell culture
cell culture
cell culture
Concentration
or Dose
50 ppm
NR
4 or 10 ppm
2-6 ppb In food
2-6 ppb In food
10 ppm
1.0. 5.0 and
10.0 mN
0. 20. 40 or 60
mg/kg total dose
0. 20. 40 or 60
mg/kg total dose
NR
10"' to 10'« N
10'* H
Activating
System
NR
NA
NA
NA
NA
NA
» Irradiated
fetal Syrian
hamster cells
NA
NA
± S-9
± S-9
none
Response Reference
«• Guerzonl et al.. 1976
Gopalan and NJagt.
1981
Haters et al.. 1980.
1982; Valencia. 1981
* Hemavarthy and
Krlshnamurthy. 1987a
Hemavarthy and
Krlshnamurthy. 1987a
Valencia. 1981
Uojclechowskt and
Kaur, 1980;
Hojctechowskt et al..
1982
+ Hemavarthy and
Krlshnamurthy. 1987b
<• Hemavarthy and
Krlshnamurthy. 1987b
f Debuyst and
Van Larebeke. 1983
Simmon et al.. 1977;
Haters et al.. 1980.
1982; Garret t et al..
1986
Blevtns et al.. 1977b
-------
that the metabolic activation system was derived from Aroclor 1254-treated
male Sprague-Dawley rats, while Simmon et al. (1977) stated that the activa-
tion system was derived from Aroclor-treated male mice.
Mixed results were reported 1n sex-linked recessive tests In DrosophUa
me'lanoqaster (Gopalan and Njagl, 1981; Hemavarthy and Krlshnamurthy, 1987a;
Waters et al., 1980, 1982) and In several mammalian test systems
(Woj dec hows k1 and Kaur, 1980; Wojdechowskl et al., 1982; Hemavarthy and
Krlshnamurthy, 1987a; Oebuyst and Van Larebeke, 1983; Simmon et al., 1977;
Waters et al., 1980, 1982; Garrett et al., 1986; Blevlns et al., 1977b).
NUroso derivatives of me thorny! caused mutations In S. typhlmurlum
(Blevlns et al., 1977a; Seller, 1977) and caused DNA strand breaks 1n human
skin flbroblasts (Blevlns et al., 1977b), whereas methomy1 Itself did not.
6.4. TERATOGENICITY
Kaplan and Sherman (1977) briefly described a teratogenlcHy study using
New Zealand white rabbits. Diets containing methorny! at 0. 50 or 100 ppm
were fed to pregnant rabbits on days 8-16 of gestation. Dams were sacri-
ficed on gestation day 29 or 30 or were allowed to deliver at term. Fetal
body weights, gross malformations and uterine resorptlon sites were evalu-
ated, and skeletal examination was performed on about one-third of the
fetuses. The Investigators reported no evidence of a teratogenlc response,
but did not mention maternal effects or effects on fetal body weights or
uterine resorptlons.
A second developmental toxldty study 1n rabbits (Feussner et al., 1983)
was reviewed briefly by U.S. EPA (1987a). Groups of five New Zealand white
rabbits were treated with 98.7% methomyl (route unspecified) on gestation
days 7-19 at dosages of 0, 2, 6 or 16 mg/kg/day. Maternal toxldty was
0121d -47- 07/14/88
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restricted to choHnerglc signs and death of one dam at 16 mg/kg/day. There
were no effects on embryo survival or the Incidence of soft tissue or
skeletal malformations.
U.S. EPA (1981, 1986c) mentioned a teratogenlcHy study where rats were
fed diets containing 0, 50, 100 or 400 ppm methomyl on days 6-15 of gesta-
tion. Maternal toxldty was reported at 400 ppm, but there was no evidence
of embryotoxldty or teratogenlcHy.
6.5. OTHER REPRODUCTIVE EFFECTS
Kaplan and Sherman (1977) briefly described a 3-generatlon reproduction
study where groups of 10 male and 20 female ChR-CD rats were fed diets
containing methomyl at 0, 50 or 100 ppm. Hating commenced after 3 months of
feeding. Two Utters were delivered In each generation. Several Indexes of
reproduction and lactation were calculated and hlstopathologlc examination
was performed on 10 male and 10 female weanlings from the F-. Utters of
controls and both test groups. There were no effects on reproduction or
lactation and no gross or hlstopathologlc lesions 1n F3b weanlings that
were associated with exposure to methomyl.
6.6. SUMMARY
Methomyl was not carcinogenic In feeding studies 1n rats (Kaplan and
Sherman, 1977) or mice (Hazelton Laboratories, 1981), and was negative 1n a
transplacental hamster fetal cell transformation assay (Quarles et a!.,
1979). Results of mutagenldty tests were largely negative In microorgan-
isms (Simmon et al., 1976, 1977; Blevlns et al.t 1977; Maters et al., 1980,
1982; Morlya et al., 1983; Klopman et al., 1985; Garrett et al., 1986), but
were mixed In DrosophUa (Waters et al., 1980, 1982; Valencia, 1981;
Hemavarthy and Krlshnamurthy, 1987a) and various mammalian systems (Simmon
et al., 1977; Blevlns et al., 1977b; Waters et al., 1980, 1982;
0121d -48- 07/14/88
-------
Wojclechowskl and Kaur, 1980; Wojdechowskl et al., 1982; Debuyst and Van
larebeke, 1983; Garrett et al., 1986; Hemavarthy and Krlshnamurthy, 1987b).
NHrosomethomyl, however, was positive 1n cell transformation (Quarles et
al., 1979) and mutagenldty tests (Blevlns et al., 1977a,b; Seller, 1977),
and Induced fore-stomach tumors 1n rats treated by gavage (L1j1nsky and
Schmahl, 1978).
The acute toxlclty of methomyl appears to be equivalent among most
laboratory species; except that the mouse 1s noticeably more sensitive than
the rat or dog. Single-dose oral LD5Q values ranged from 8.5-40 mg/kg
(Kaplan and Sherman, 1977; Fahmy et al., 1978; Antal et al., 1979; DashlelT
and Kennedy, 1984; Galnes and Under, 1986). Gender and age appear to have
no effect on toxic potency. Doses of 12-15 mg/kg have been fatal to humans
(Llddle et al., 1979; Arakl et al., 1982). Deaths are preceded by
cho11nerg1c signs (Kaplan and Sherman, 1977). Other effects attributed to
methomyl Include altered pancreatic (Bedo and deleszky, 1980) and liver
enzyme activities (Iverson, 1977; El-Sewedy et al., 1982), effects on the
erythrocyte and hematopolesls (Nakamura et al., 1977; Nlshlda et al., 1980),
and skin sensltlzatlon (Kambe et al., 1976; Matsushita and Aoyama, 1979)..
Methomyl has not been associated with neurotoxldty In hens (Kaplan and
Sherman, 1977; U.S. EPA, 1986c).
A number of subchronlc and chronic dietary studies have been performed
using rats, dogs and mice. In the subchronlc studies, 400 ppm (10 mg/kg/
day, the highest level tested) was considered a NOAEL In dogs (Kaplan and
Sherman, 1977), and 50 ppm (2.5 mg/kg/day) (Kaplan and Sherman, 1977), 100
ppm (5 mg/kg/day) (Bedo and deleszky, 1980) and 3 mg/kg/day (Homan et al.,
1978) were considered NOAELs 1n three studies 1n rats. At higher dosages,
rats showed body weight gain depression, decreased erythrocyte counts and
0121d -49- 07/14/88
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Increased erythropolesls, depressed erythrocyte or brain chollnesterase
activities, minor serum or liver biochemical alterations and elevated
relative kidney weights. In a chronic study where rats were dosed with
dietary levels of 50-400 ppm (Kaplan and Sherman, 1977), 100 ppm (5 mg/kg/
day) was a NOAEtj and depressed growth rate, reduced blood hemoglobin
concentration, Increased splenic erythropolesls and mild kidney lesions were
observed at higher levels. In dogs chronically exposed to 50-1000 ppm, 100
ppm (2.5 mg/kg/day) was a NOAEL, and anemia and mild lesions of the kidney,
liver, spleen and bone marrow were observed at higher levels (Kaplan and
Sherman, 1977). Mortality preceded by choHnerglc signs was observed at
1000 ppm (25 mg/kg/day). Increased mortality was observed 1n all groups of
mice chronically exposed to diets containing 50-800 ppm (Hazelton
Laboratories, 1981). The 50 ppm level (6.5 mg/kg/day) was judged a LOAEL
associated with reduced longevity.
Methomyl has been tested for developmental toxldty 1n rabbits at
dosages <16 mg/kg/day (Kaplan and Sherman, 1977; Feussner et al., 1983) and
1n rats fed diets containing <400 ppm (U.S. EPA, 1986c), with no evidence of
teratogenldty. No effects on reproduction were observed 1n a 3-generat1on
study In rats fed diets containing <100 ppm (Kaplan and Sherman, 1977).
0121d -50- 07/14/88
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
ACGIH (1987) recommends a TLV-TWA of 2.5 mg/m3 for methomyl. ACGIH
(1986) reported a 4-hour LC.- of 0.30 mg/l (300 mg/m3) for methomyl
mist 1n an unnamed- species and concluded that the factor of 120 between the
TLV and the LC5Q should be adequately protective. There are no NIOSH
criteria or OSHA standards for methomyl.
U.S. EPA (1982, 1985a, 1987b,c) established tolerances for methomyl on
or 1n raw agricultural commodities. For Items grown as food for humans,
allowed tolerances range from 0.1-7 ppm. For livestock feed, tolerances
range from 0.1-40 ppm. World Health Organization recommendations for
methomyl residues range from 0.02 ppm, considered at or near the limit of
detection, for meat and milk, to 5 ppm 1n various fruits and vegetables
(WHO, 1976a,b, 1977). Recommendations for livestock forages range from
0.1-10 ppm.
NAS (1983) derived a SNARL for methomyl of 0.175 mg/l, based on the
no-effect level of 2.5 mg/kg/day In the 2-year study In dogs described In
Section 6.1.2.2. (Kaplan and Sherman, 1977). Based on the NOEL of 2.5
mg/kg/day In the same study In dogs, U.S. EPA (1986c) derived an oral RfD of
2 ing/day. One-day, 10-day and longer-term HAs of 0.25 mg/l were based on
the DWEL for a child of 0.25 mg/l. A lifetime HA of 0.175 mg/l (175
ug/l) was also recommended.
U.S. EPA (1985b) listed an RQ for methomyl of 100.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of methomyl were not located 1n the available literature.
0121d -51- 07/14/88
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenlcUy of
Inhalation exposure to methomyl were not located In the available literature
dted 1n Append1x-A.
8.1.2. Oral. Kaplan and Sherman (1977) reported no Increased Incidence
of tumors In groups of 35 rats/sex fed diets containing methomyl at 50-400
ppm for 22 months. Although there were no effects on mortality, growth rate
was depressed at >200 ppm and lesions of the kidneys were observed at 400
ppm, suggesting that the MTD may have been reached. Hazelton Laboratories
(1981) reported no compound-related effect on the Incidence of tumors In
groups of 80 mice/sex fed diets containing 50-800 ppm methomyl for 104
weeks. Increased mortality was observed 1n all treated groups of males.
Because only a brief report was available, H 1s not known whether a suffi-
cient number of animals remained at risk for late developing tumors;
therefore, confidence 1n the negative results of this study Is low.
8.1.3. Other Routes. Methomyl was negative 1n the transplacental hamster
fetal cell transformation assay (Quarles et al., 1979).
8.1.4. Weight of Evidence. U.S. EPA (1987a) evaluated the weight of
evidence for the carclnogenlcUy of methomyl and characterized both human
and animal data as "Inadequate," resulting In classification In EPA Group D,
not classifiable as to human cardnogen1c1ty (U.S.EPA, 1986d). Because data
were not located regarding the cardnogenlcHy of methomyl In humans, human
evidence may more appropriately be characterized as "no data." The animal
data are best characterized as "Inadequate," because the complete studies
were not available for thorough review. Particularly In question 1s the
adequacy of the mouse study (Hazelton Laboratories, 1981), because 1t 1s not
0121d -52- 07/14/88
-------
known whether decreased survival resulted In Inadequate numbers of mice at
risk for late developing tumors, the most appropriate classification for
methomyl continues to be EPA Group D.
8.1.5. Quantitative Risk Estimates. The lack of Inhalation cancer data
and the negative-results of the oral studies 1n rats (Kaplan and Sherman,
1977) and mice (Hazelton Laboratories, 1981) preclude derivation of potency
factors for either route of exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. The only repeated exposure Inhalation study
located was a 13-week experiment In which rats were exposed to dust of a
formulation of methomyl containing 45% active Ingredient (Ta'naka et al.,
1987). The only effect attributed to methomyl was plasma chollnesterase
Inhibition. This study 1s not suitable for use In risk assessment because
of the large proportion of uncharacteMzed Inert substances 1n the test
material. Therefore, no subchronlc or chronic RfD 1s estimated for Inhala-
tion exposure to methomyl.
8.2.2. Oral Exposure. In the dietary studies discussed below, trans-
formed dosages expressed In mg/kg/day have been estimated from the dietary
concentrations expressed 1n ppm by multiplying the dietary concentrations by
reference food factors adopted by the Agency. In the absence of actual
Intake data, the Agency assumes dally food consumption by rats, dogs and
mice equivalent to 5, 2.5 and 13% of their body weights, respectively (U.S.
EPA, 1986e). For example, a dietary level of 50 ppm Is equivalent to 2.5
mg/kg/day In rats, 1.25 mg/kg/day In dogs and 6.5 mg/kg/day In mice.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- Subchronlc
dietary studies using rats Identify NOAELs of 50 ppm (2.5 mg/kg/day) (Kaplan
and Sherman, 1977) and 3 mg/kg/day (Homan et al., 1978). LOAELs Identified
0121d -53- 07/14/88
-------
1n different studies Include 12.5 mg/kg/day associated with reduced food
consumption, body weight gain and blood hemoglobin 1n males, and reduced
erythrocyte count 1n females (Kaplan and Sherman, 1977), and ~10 mg/kg/day
associated with elevated relative kidney weight In females (Homan et al.
1978) and elevated relative spleen and kidney weights, decreased brain
chollnesterase activity, and other biochemical effects of uncertain toxlco-
loglcal significance (Antal et al., 1979; Bedo and deleszky, 1980). The
NOAELs and LOAELs observed 1n subchronlc rat studies are virtually Iden-
tical to those observed In chronic studies (Section 8.2.2.2.), suggesting
that the thresholds for subchronlc and chronic exposure are very similar.
Adverse effects were not observed In dogs fed diets containing 400 ppm
(10 mg/kg/day) for 3 months, although mild kidney lesions were observed at
this dietary level In dogs exposed for 24 months (Kaplan and Sherman, 1977).
An RfD for subchronlc oral exposure to methomyl could be derived by
applying an uncertainty factor of 100 (10 for animal to human extrapolation
and 10 to provide additional protection for more sensitive Individuals) to
the NOAEL of 3 mg/kg/day 1n rats In the 13-week dietary study by Homan et
al. (1978). This would result In an RfO of 0.03 mg/kg/day, equivalent to 2
mg/day for a 70 kg human. Because the subchronlc and chronic thresholds of
methomyl are similar, an equally sound approach would be to adopt the RfD
for chronic oral exposure as the RfD for subchronlc oral exposure. The
latter approach 1s preferred, because the RfD for chronic oral exposure has
been verified by the Agency and Is available on IRIS (U.S. EPA, 1986c)
(Section 8.2.2.2.). Accordingly, the RfD for subchronlc exposure to methomyl
1s 0.025 mg/kg/day, equivalent to 2 mg/day for a 70 kg human, derived from
the Kaplan and Sherman (1977) 2-year dog study. Confidence 1n the critical
study 1s medium, but confidence In the data base and RfD are high, as
discussed 1n Section 8.2.2.2.
0121d -54- 07/14/88
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8.2.2.2. CHRONIC EXPOSURES — Chronic studies available 1n sufficient
detail to warrant consideration for derivation of an RfO for oral exposure
Include studies using rats (Kaplan and Sherman, 1977), dogs (Kaplan and
Sherman, 1977) and mice (Hazelton Laboratories, 1981). In rats exposed to
dietary levels of- 0, 50, 100, 200 or 400 ppm (0, 2.5, 5.0, 10 and 20 mg/kg/
day), 5.0 mg/kg/day was a NOAEL and 10 mg/kg/day was a LOAEL associated with
reduced blood hemoglobin concentration and Increased splenic hematopolesls
1n females. In dogs exposed to dietary levels of 0, 50, 100, 400 or 1000
ppm (0, 1.25, 2.5, 10 and 25 mg/kg/day), 2.5 mg/kg/day was a NOAEL and 10
mg/kg/day was a LOAEL associated with mild kidney lesions In males. In the
mouse study, the lowest dietary level, 50 ppm (6.5 mg/kg/day), was a LOAEL
associated with decreased survival In males.
In earlier analyses, the U.S. EPA (1986c, 1987a) conservatively chose
the dog NOAEL of 2.5 mg/kg/day (Kaplan and Sherman, 1977) as the basis for
derivation of an RfO. Application of an uncertainty factor of 100 resulted
1n an RfD of 0.025 mg/kg/day. Multiplication by 70 kg results In an RfD for
a 70 kg human of 1.75 mg/day, which may be rounded to 2 mg/day. The
previously derived oral RfD of 2 mg/day 1s adopted for the purposes of this
document. U.S. EPA (1986b) placed medium confidence 1n the critical study
and high confidence In the data base and RfD.
0121d -55- 07/14/88
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The systemic toxldty of methomyl discussed 1n Chapter 6 Includes one
repeated exposure Inhalation study using rats and several dietary studies
using rats, dogs and mice. In the Inhalation study, rats exposed to dust of
a formulation of methomyl containing 4554 active Ingredient for 13 weeks had
depressed plasma chollnesterase activity. This study Is not suitable for
derivation of a CS because of the large proportion of the test material that
consisted of unidentified Inerts.
Table 9-1 presents data from the dietary studies considered for deriva-
tion of CSs. Kaplan and Sherman (1977) reported a study In which rats were
fed diets containing 50-400 ppm methomyl for 22 months. Mild kidney lesions
were observed In rats of both sexes at 400 ppm (20 mg/kg/day), and reduced
blood hemoglobin concentration and Increased splenic hematopolesls were
observed In females at 200 ppm (10 mg/kg/day). Because an RV ranking of
5 Is appropriate for the effects observed at both dietary concentrations,
only the effects on females at 10 mg/kg/day 1n this study are presented In
Table 9-1. In subchronlc dietary studies using rats, Homan et al. (1978)
reported elevated relative kidney weight 1n females at -10 mg/kg/day and
depressed erythrocyte chollnesterase activities In both sexes at -30 mg/kg/
day. Antal et al. (1979) and Bedo and deleszky (1980) reported depressed
brain chollnesterase activities and other biochemical effects 1n rats at 200
ppm (10 mg/kg/day) 1n the diet. Because these effects occurred at dosages
>10 mg/kg/day associated with reduced blood hemoglobin and splenic effects
In the Kaplan and Sherman (1977) study and rate an RV ranking <5, they
are not Included In Table 9-1.
0121d -56- 07/14/88
-------
o
ro
o.
TABLE 9-1
Dietary Toxlctty of Hethomyl: Data Considered for Derivation of Composite Score
en
-j
r
Species/
Strain
Rat/ChR-CD
Dog/beagle
Nice/CD-I
No. at
Start/
Sex
35/f
4/N
80/N
Average
Body Height
(kg)
0.35*
12. 7d
0.03e
Purity Exposure
>90X 200 ppm diet
for 22 Months
>90X 400 ppm diet
for 24 aonths
NR SO pp» diet
for 104 weeks
Trans forMed
An low 1 Dose*
(ng/kg/day)
10
10
6.5
Trans forMed
Human Doseb
(Mg/kg/day)
1.7
5.7
0.49
Response
Reduced blood hemo-
globin concentrations.
Increased splenic
hematopotesls
Mild kidney lesions
Reduced survival
Reference
Kaplan and
Sherman. 1977
Kaplan and
Sherman. 1977
Hazelton
Laboratories.
1981
Calculated using reference food Intakes (U.S. EPA. 1986d) as described In Section 8.2.2.
^Calculated by Multiplying the animal transformed dose by the cube root of the ratio of animal to reference human body weight (70 kg).
Reference body weight for rats (U.S. EPA. 1986d)
^Reference body weight for dogs (U.S. EPA. 1986d)
'Reference body weight for mice (U.S. EPA. 1986d)
NR = Not reported
o
CO
•^
CD
00
-------
Kaplan and Sherman (1977) also reported a study In which dogs were fed
diets containing 50-1000 ppm methomyl. The highest dosage level (25
mg/kg/day) resulted In acute signs of chollnerglc toxldty and death of 2/5
females within 18 days to 8 weeks of Initial exposure. The acute nature of
these effects precl-udes the use of this dosage for dogs In derivation of a
CS for methomyl. The authors also reported Increased pigmentation In the
proximal convoluted tubules of male dogs (RV = 5) at 400 ppm (10
mg/kg/day). These data are presented 1n Table 9-1. No effects were
observed 1n dogs fed diets containing <400 ppm for 3 months (Kaplan and
Sherman, 1977).
Hazelton Laboratories (1981) fed mice diets containing methomyl at
50-800 ppm for 104 weeks. Reduced survival (RV = 10) was observed 1n all
treated groups of males, and this effect at 50 ppm (6.5 mg/kg/day) 1s
presented In Table 9-1. From the data presented 1n Table 9-1, 1t 1s clear
that the most severe effect, reduced survival, occurred at the lowest human
equivalent dosage, 0.49 mg/kg/day. Therefore, 1t 1s necessary to calculate
a CS only for this effect. The human equivalent dosage of 0.49 mg/kg/day 1s
multiplied by 70 to calculate a human MED of 34 mg/day for a 70 kg human,
which 1s equivalent to an RV. of 3.2. A CS of 32 corresponding to an RQ
of 100 1s calculated by multiplying the RV. of 3.2 by the RVg of 10.
This CS 1s presented 1n Table 9-2.
9.2. BASED ON CARCINOGENICITY
Carclnogenlclty data for methomyl consist of negative dietary studies
using rats (Kaplan and Sherman, 1977) and mice (Hazelton Laboratories, 1981)
and negative results In the transplacental hamster fetal cell transformation
assay (Quarles et al., 1979). U.S. EPA (1987a) assigned methomyl to EPA
Group D, not classifiable as to human cardnogen1c1ty, because the negative
0121d -58- 08/24/88
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TABLE 9-2
METHOMYL
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 34 mg/day
Effect: reduced survival
Reference: Hazelton Laboratories, 1981
RVd: 3.2
RVe: 10
Composite Score: 32
RQ: .100
^Equivalent human dose
0121d -59- 06/08/88
-------
studies for differing reasons were Inadequate and weakened the negative
observations. Because quantitative data are not available from which to
derive a potency factor, derivation of a cardnogen1c1ty-based RQ 1s
precluded.
0121d -60- • ' i 09/20/88
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10. REFERENCES
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Documentation of the Threshold Limit Values and Biological Exposure Indices,
5th ed. Cincinnati, OH. p. 363.
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Threshold Limit values and Biological Exposure Indices for 1987-1988.
Cincinnati, OH. p. 25.
Aly, M.I., N. Bakry, A.H. El-Seabe and H. Abu Elamayem. 1979. Carbaryl and
methomy1 degradation by soils and clay minerals. Alexandria J. Agrlc. Res.
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Andrawes, W.R., R.H. Bailey and G.C. Holslng. 1976. Metabolism of acetyl-
l-l4C-methomyl 1n the rat. Report No. 26946. Unpublished study. (Cited
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Antal, M., H. Bedo, G. Constantlnovlts, K. Nagy and J. Szepvolgyl. 1979.
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Arakl, M., K. Yonemltsu, T. Kambe, et al. 1982. Forensic toxlcologlcal
Investigations on fatal cases of carbamate pesticide methomyl (Lannate)
poisoning. Nippon Holgaku Zasshl. 36(4): 584-588. (CA 98:029105x)
0121d -61- . 06/08/88
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Atkinson, R. 1987. A structure-activity relationship for the estimation of
the rate constants for the gas-phase reactions of OH radicals with organic
compounds. Int. J. Chem. Klnet. 19: 799-828.
Baron, R.L. 197V. lexicological considerations of metabolism of carbamate
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Bedo, H. and V. deleszky. 1980. Nutritional toxicology 1n the evaluation
of pesticides. Blbl. Nutr. D1eta. 29: 20-31.
Blevlns, R.D., N. Lee and J.O. Regan. 1977a. MutagenlcHy screening of
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Blevlns, R.D., W. L1j1nsky and J.O. Regan. 1977b. Nltrosated methylcarba-
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Bracy, O.L., R.S. Doyle, M. Kennedy, S.H. McNally, J.D. Weed and B.M.
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Bysshe, S.E. 1982. B1oconcentrat1on factor 1n aquatic organisms. In:
Handbook of Chemical Property Estimation Methods, W.J. Lyman, W.F. Reehl and
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Carter, F.L. 1971. Ln vivo studies of brain acetylchollnesterase Inhibi-
tion by organophosphate carbamate Insecticide 1n fish. D1ss. Abstr. 32(5):
2772B-2773B.
Carter, F.L. and-J-.B. Graves. 1973. Measuring effects of Insecticides on
aquatic animals. La. Agr. 16(2): 14-15.
Chapman, R.A. and C.M. Cole. 1982. Observations on the Influence of water
and soil pH on the persistence of Insecticides. J. Environ. Sc1. Health.
817(5): 487-504.
Chen, Z.M., M.J. Zablk and R.A. LeavHt. 1984. Comparative study of thin
film photodegradatlon rates for 36 pesticides. Ind. Eng. Chem. Prod. Res.
Oev. 23: 5-11.
CPP (Chemical and Pharmaceuticals Press). 1987. Crop Protection Chemicals
Reference. Chemical and Pharmaceuticals Press with John Wiley and Sons,
Inc., New York. p. 451-453.
Dashlell, O.L. and G.L. Kennedy, Jr. 1984. The effects of fasting on the
acute oral toxldty of nine chemicals 1n the rat. J. Appl. Toxlcol. 4(6):
320-325.
Debuyst, B. and N. Van Larebeke. 1983. Induction of sister-chromatic!
exchanges 1n human lymphocytes by aldlcarb, thlofanox and methomyl. Mutat.
Res. 113: 242-243.
0121d -63- 07/14/88
-------
Dorough, H.W. 1977. Metabolism of carbamate Insecticides. NTIS PB26-66233.
(Cited In U.S. EPA, 1987a)
Elsenrelch, S.J., 8.B. Looney and O.J. Thornton. 1981. Airborne organic
contaminants 1n -the Great Lakes ecosystem. Environ. Sd. Technol. 15:
30-38.
El-Refa1, A., A. Fouad, A. Fahmy, M.F.A. Abdel-Lateef and A.K.E. Imam.
1976. Toxldty of three Insecticides to two species of fish. Int. Pest
Control. 18(6): 4-8.
El-Sewedy, S.M., M.A. Zahran, M.A. Zeldan, M.H. Mostafa and E.A.
El-Bass1oun1. 1982. Effect and mechanism of action of methomy1 and
cypermethrln Insecticides on kynurenlne metabolizing enzymes of mouse liver.
J. Environ. Sc1. [B]. 17(5): 527-539.
Fahmy, M.A.H., N.M. Mall1pud1 and T.R. Fukuto. 1978. Selective toxldty of
NtN'-th1od1carbamates. J. AgMe. Food Chem. 26(3): 550-557.
Feussner, E., M. Christian, G. Llghtkep, et al. 1983. Embryo-fetal
toxlclty and teratogenldty study of methomyl 1n the rabbit. Study No.
104-005. Unpublished study. MRIO 00131257. (Cited 1n U.S. EPA, 1987a)
Fournler, M., J. Bernler, D. FHpo and K. Krzystynlak. 1986. Evaluation of
pesticide effects on humoral response to sheep erythrocytes and mouse
hepatitis virus 3 by Immunosorbent analysis. Pestle. Blochem. Physio!.
26(3): 353-364.
0121d -64- 07/14/88
-------
Frank, R., B.O. Rlpley, H.E. Braun, B.S. Clegg, R. Johnston and T.J. O'Neill.
1987. Survey of farm wells for pesticides, residues, southern Ontario,
Canada, 1981-1982, 1984. Arch. Environ. Contam. Toxlcol. 16: 1-8.
Freeman, P.K. and E.M.N. Nd1p. 1984. Photochemistry of oxlme carbamates.
II. Phototransformatlon of methomyl. J. Agrlc. Food Chem. 32: 877-881.
Fung, K.K.H. and N.C. Uren. 1977. Mlcroblal transformation of S-methyl
N-[(methylcarbamoyl)oxy]th1oacet1m1date (methomyl) In soils. J. Agrlc. Food
Chem. 25: 966-969.
Galnes, T.B. and R.E. Under. 1986. Acute toxlclty of pesticides 1n adult
and weanling rats. Fund. Appl. Toxlcol. 7(2): 299-308.
Garrett, N.E., H.F. Stack and H.D. Waters. 1986. Evaluation of the genetic
activity profiles of 65 pesticides. Mutat. Res. 168(3): 301-325.
Gopalan, H.N.B. and G.D.E NjagV. 1981. Mutagenldty testing of pesticides.
Genetics. 97(51): 544.
Guerzonl, M.E., L. Del Cupolo and I. Pontl. 1976. Mutagenlc activity of
pesticides. R1v. Sd. Tecnol. Allmentl. Nutr. Urn. 6(3): 161-165. (CA
86:0124938)
Hajjar, N.P. and E. Hodgson. 1980. Flavin adenlne dlnucleotlde-dependent
monooxygenase: Its role In the sulfoxldatlon of pesticides In mammals.
Science. 209(4461): 1134-1136.
0121d -65- 07/14/88
-------
Hajjar, N.P. and E. Hodgson. 1982. Sulfoxldatlon of thloether-contalnlng
pesticides by the flavln-adenlne dlnucleotlde-dependent monooxygenase of pig
liver mlcrosomes. Blochem. Pharmacol. 31(5): 745-752.
Han, J.C-Y. 1975.' Absence of nltroso formation from (14-C)methomyl and
sodium nitrite under simulated stomach conditions. J. Agrlc Food Chem.
23(5): 892-896.
Hansch, C. and A.J. Leo. 1985. Medchem Project. Issue No. 26. Pomona
College, Claremont, CA.
Hartley, D. and H. K1dd. 1985. The Agrochemlcals Handbook. Unwln Brothers
Limited, Old Woklng, Surrey, England.
Harvey, J., Jr. and H.L. Pease. 1973. Decomposition of methomyl 1n soil.
J. Agrlc. Food Chem. 21: 784-786.
Harvey, J. Jr., A.G. Jellnek and H. Sherman. 1973. Metabolism of methomyl
1n the rat. J. Agrlc. Food Chem. 21(5): 769-775.
Hashimoto, Y. and J. Fukaml. 1969. Toxldty of orally and topically
applied pesticide Ingredients to carp, CypMnus carplo. Bochu-Kagaku.
34(2): 63-66.
Hazelton Laboratories. 1981. Final report: 104-week chronic toxldty and
cardnogenldty study 1n mice. Project No. 201-510. Unpublished study.
MRID 00048423. (Cited In U.S. EPA, 1987a)
0121d -66- . 06/08/88
-------
Hernavarthy, K.C. and N.B. KMshnamurthy. 1987a. Mutagenldty studies 1n
Drosophlla melanogaster with Lannate 20. Mutat. Res. 191(1): 41-43.
Hemavarthy, K.C. and N.B. Krlshnamurthy. 1987b. Evaluation of Lannate 20,
a carbamate pesticide 1n the germ cells of male mice. Environ. Res. 42(2):
362-365.
Heywood, D.L. 1975. Degradation of carbamate Insecticides In soil.
Environ. Qual. Saf. 4: 128-133. (CA 85:42181)
Hlgashlhara, E. 1987. Acute toxldty of the Insecticide met homy 1 1n rats.
Yamaguchl Igaku. 36(4): 233-251. (Jap.) (CA 107:192625e)
Homan, E.R., R.R. Maronpot and J.B. Reid. 1978. Methomyl: Inclusion In the
diet of rats for 13 weeks. Project Report 41-64. Unpublished study. MRIO
00044881. (Cited 1n U.S. EPA, 1987a)
Huhtanen, K. and H.U. Dorough. 1976. Isomer1zat1on and Beckmann rearrange-
ment reactions In the metabolism of methomyl In rats. Pestle. Blochem.
Physlol. 6(6): 571-583.
IARC (International Agency for Research on Cancer). 1983. General
Considerations on N-nUrosatable Pesticides. IARC Monograph. 30: 360-365.
Ibrahim, A. 1984. Effects of some pesticides on growth rate of the micro-
scopic algae Anklstrodesmus falcatus (Corda) Ralfs, Scenedesmus quadrlcauda
(Turp.) Breb. and Phaeodactylum tMcornutum (Bohlln). Aqua. 5: 303-306.
0121d -67- 07/14/88
5-
-------
Ive'rson, F. 1977. Inhibition and regeneration of rat liver enzymes
hydrolyzlng acetanlUde and 0-n1trophenyl butyrate. Bull. Environ. Contain.
Toxlcol. 18(4): 466-471.
Jao, L. and S. Hsu. 1981. Effects of BHT and BHA on the toxldty of Insec-
ticides. I. Effects of efficacies of chlorpyMfos, methomyl and Nembutal.
K'o Hsueh Fa Chan Yueh K'an. 9(5): 426-432. (Ch1.) (CA 95:074993j)
Johnson, D.B. and B.L. Cox. 1985. Aerobic soil metabolism and residue
uptake 1n plants of an organophosphorus carbamate Insecticide. J. Agrlc.
Food Chem. 33: 255-259.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of acute toxldty of
chemicals to fish and aquatic Invertebrates. U.S. Dept of Interior, F1sh
and Wildlife Service. Washington, DC. Res. Publ. No. 137. p. 1-8, 49.
Kambe, Y., T. Ide and M. Takeshlge. 1976. Investigation on allergy due to
pesticides by patch test II. Nippon Noson Igakkai Zasshl. 25(4): 628-629.
(Jap.) (Taken from PESTAB 77:1660)
Kaplan, A.M. and H. Sherman. 1977. Toxldty studies with methyl
N-[[(methylam1no) carbonyl](oxy] ethanlmldothloate. Toxlcol. Appl.
Pharmacol. 40(1): 1-17.
Kenaga, E.E. 1980. Predicted bloconcentratlon factors and soil sorptlon
coefficients of pesticides and other chemicals. Ecotoxlcol. Environ. Saf.
4: 26-38.
0121d -68- 07/14/88
-------
Kennedy, G.L., Jr., R.L. Ferenz and B.A. Purge. 1986. Estimation of acute
oral toxldty In rats by determination of the approximate lethal dose rather
than the LD5Q. J. Appl. Toxlcol. 6(3): 145-148.
Khalll, Z. and -I-.Y. Mostafa. 1986. Interactions of pesticides with
freshwater algae. 1. Effect of methomyl and Us possible degradation by
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Klopman, G., R. Contreras, H.S. Rosenkranz and H.D. Waters. 1985.
Structure-genotoxlc activity relationships of pesticides: Comparison of the
results from several short-term assays. Mutat. Res. 147(6): 343-356.
Krause, R.T. 1985. Liquid chromatographlc determination of N-methylcarba-
mate Insecticides and metabolites 1n crops. II. Analytical characteristics
and residue findings. J. Assoc. Off. Anal. Chem. 68: 734-741.
Kr1ll, R.M. and W.C. Sonzognl. 1986. Chemical monitoring of Wisconsin's
groundwater. J. Am. Water Works Assoc. 78: 70-75.
Lelstra, M., A. Oekker and A.M.M. Vanderburg. 1984. Computed and measured
leaching of the Insecticide methomyl from greenhouse soils Into water
courses. Water Air Soil Pollut. 23: 155-167.
Lemley, A.T., W.Z. Zhong, G.E. Janauer and R. Rossi. 1984. Investigation
of degradation rates of carbamate pesticides. Exploring a new detoxifica-
tion method. ACS Symp. Ser. 259(Treat. Disposal Pestle. Wastes): 245-259.
0121d -69- 07/14/88
-------
Llddle, J.A., R.D. Klmbrough, L.L. Needham, R.E. CUne and A.L. Smrek.
1979. A fatal episode of accidental methomyl poisoning. CHn. Toxlcol.
15(2): 159-167.
Lljlnsky, W., and" D. Schmahl. 1978. Carc1nogen1c1ty of N-n1troso deriva-
tives of N-methylcarbamate Insecticides 1n rats. Ecotoxlcol. Environ. Saf.
2(3-4): 413-419.
Martin, H. and C.R. Worthing, Ed. 1977. Pesticide Manual, 5th ed. British
Crop Protection Council Publications, Worcestershire, England, p. 349.
Matsushita, T. and K. Aoyama. 1979. Examination on cross sensitivity
between blnomyl and other major pesticides In hypersensitive contact
dermatitis. Nippon Noson Igakkal Zasshl. 28(3): 464-467. (Jap.) (Taken
from PESTAB 79:3072)
Matsushita, T. and K. Aoyama. 1980. Participation of cross reaction 1n
skin sensltlzatlon by pesticides. Nippon E1se1gaku Zasshl. 35(1): 171.
(Jap.) (Taken from PESTAB 80:1717)
Mayer, F.L. and M.R. Ellersleck. 1986. Manual of Acute Toxlclty: Interpre-
tation and Data Base for 410 Chemicals and 66 Species of Freshwater Animals.
U.S. Oept. of Interior, F1sh and Wildlife Service, Washington, DC. Res.
Publ. 160. p. 1-63, 296-299.
McCann, J.A., W. Teeters, D.J. Urban and N. Cook. 1981. A short-term
dietary toxlclty test on small mammals. ASTM Spec. Tech. Publ. 757(Av1an
Mamm. Wlldl. Toxlcol): 132-142.
0121d -70- . 06/08/88
-------
Melster, R.T. 1987. Farm Chemicals Handbook '87. Melster Publishing Co.,
Wllloughby, OH. p. C165.
Morlya, M., T. Ohta, K. Watanabe, T. Mlyazawa, K. Kato and Y. Shlrasu.
1983. Further mutagenldty studies on pesticides 1n bacterial reversion
assay systems. Mutat. Res. 116: 185-216.
Morse, O.L., E.L. Baker, Jr., R.D. K1mbrough and C.L. Wlsseman, III. 1979.
Propanll-chloracne and met homy 1 toxldty 1n workers of a pesticide manufac-
turing plant. CUn. Toxlcol. 15(1): 13-21.
Nakamura, I., Y. Kudo, Y. Horle and N. N1sh1da. 1977. Changes 1n periph-
eral red blood cells of rabbits caused by pesticides. Proc. Ann. Meet. Jap.
Assoc. Ind. Health. 50: 254-255. (Jap.) (Taken from PESTAB 77:1731)
NAS (National Academy of Sciences). 1983. Drinking Water and Health. V.
Safe Drinking Water Committee. NAS, Washington, DC. p. 57-61, 99-117.
Nlshlda, N., Y. Kudo, I. Nakamura, N. Haruyama, T. Nambu and H. Kagaml.
1980. On the resistance of erythrocytes to osmotic pressure, examined on
Inhabitants In an agricultural region. Dal Ka1 Nippon Sangyo Elsel Sakkal
Koenshu. 53: 493-494. (Jap.) (Taken from PESTAB 80:2551)
N1sh1uch1, Y. and K. Yoshlda. 1972. Tox1cH1es of pesticides to some fresh
water snails. Noyaku Kensasho Hokoku. 12: 86-92.
0121d -71- . 07/14/88
-------
Njagl, G.D.E. and H.N.B. Gopalan. 1980. Hutagenldty testing of some
selected food preservatives, herbicides and Insecticides. 2. Ames test.
Bangladesh J. Bot. 9(2): 141-146.
NTIS (National Technical Information Service). 1988. Federal Research 1n
Progress. Online: Feb. 24, 1988.
Ouellette, R.P. and J.A. King. 1977. Chemical Meek Pesticides Register.
McGraw-Hill Book Co., New York. p. 224.
Quarles, J.M., M.W. Sega, C.K. Schenley and M. HJInsky. 1979. Transforma-
tion of hamster fetal cells by nltrosated pesticides 1n a transplacental
assay. Cancer Res. 39(11): 4525-4533.
Roberts, H.H., Jr., J.E.. Warlnner, C.F. Tsal, D. Wright and I.E. Cronln.
1982. Comparison of estuarlne species sensitivities to three toxicants.
Arch. Environ. Contain. Toxlcol. 11(6): 681-692.
Schneider, B.A. 1979. Toxicology Handbook Mammalian and Aquatic Data.
Book 1. Toxicology data. Office of Pesticide Programs, U.S. EPA, Wash-
ington, DC. EPA 540/9-79-003A. NTIS PB80-196876. p. 1-14.
Seller, J.P. 1977. NHrosatlon Vn vitro and jji vivo by sodium nitrite, and
mutagenldty of nitrogenous pesticides. Mutat. Res. 48: 225-236.
Selmed-Antal, M., M. Barta-Bedo, G. Constant1nov1ts, K. Nagy and J.
Szepvolgyl. 1980. Nutritional toxlcologlcal studies with Lannate: Inter-
actions with caffeine and ethanol. Arch. Toxlcol. Suppl. 4: 443-445.
0121d -72- 07/14/88
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Simmon,-V.-.F., O.C. Poole and G.W. Newell. 1976. In vitro mutagenlc studies
of twenty pesticides. Toxlcol. Appl. Pharmacol. 37(1): 109.
Simmon, V.F., A.D. Mitchell and T.A. Jorgenson. 1977. Evaluation of
selected pestlddss and chemical mutagens. ln_ vitro and In vivo studies.
NTIS PB268647. p. 4-5, 12-27, 100-101, 129, 143, 149, 161.
Slmonet, D.E., W.I. Knausenberger, L.H. Townsend, Jr. and E.G. Turner, Jr.
1978. A b1omon1tor1ng procedure utilizing negative phototaxls of first
Instar Aedes aeqyptl larvae. Arch. Environ. Contam. Toxlcol. 7(3): 339-347.
SRI (Stanford Research Institute). 1987. 1986 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park. p. 851.
StMckman, D. 1985. Aquatic bloassay of 11 pesticides using larvae of the
mosquito, Myeomyla smlthll (D1ptera:Cul1c1dae). Bull. Environ. Contam.
Toxlcol. 35: 133-142.
Ta'naka, I., H. Iglsu, J. Haratake, et al. 1987. Cumulative tox1c1ty
potential of methomyl aerosol by repeated Inhalation. Am. Ind. Hyg. Assoc.
J. 48(4): 330-334.
Thomas, R.G. 1982. Volatilization from water. In.: Handbook of Chemical
Property Estimation Methods, W.J. Lyman, W.F. Reehl and D.H. Rosenblatt, Ed.
McGraw-Hill Book Co. p. 15-1 to 15-34.
0121d -73- 07/14/88
-------
USDA (U.S. Department of Agriculture). 1983. Inputs Outlook and Situation.
Oct. 1983 IOS-2. U.S. Department of Agriculture, Washington, DC. p. 6,
9-11.
U.S. EPA. 1980.- • Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1981. Pesticide Registration Standard S-Methyl N-(Methyl-
carbamoyl) Oxy-Th1oacet1m1date (Methomyl). U.S. EPA, Washington, DC. NTIS
PB82-180738. p. 2-2, 6-1 to 6-3.
U.S. EPA. 1982. Tolerances and exemptions for tolerances for pesticide
chemicals 1n or on raw agricultural commodities. Methomyl. 40 CFR 180.253.
U.S. EPA 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlclty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response, Wash-
ington, DC.
U.S. EPA. 1985a. Methomyl; Renewal of Temporary Tolerances. Federal
Register. 50(176): 37052-37053.
U.S. EPA. 1985b. 40 CFR 117 and 302. Notification Requirements; Report-
able Quantity Adjustments; Final Rule and Proposed Rule. Federal Register.
50(65): 13475, 13491.
0121d -74- 07/14/88
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U.S. EPA. 1986a. Methodology for Evaluating Cardnogenldty In Support of
Reportable Quantity Adjustment Pursuant to CERCLA Section 102. Prepared by
the Office of Health and Environmental Assessment, Carcinogen Assessment
Group, Washington, DC for the Office of Solid and Emergency Response,
Washington, DC. ' •
U.S. EPA. 1986b. Health and Environmental Effects Profile for Methyl
Isocyanate. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Solid Waste and Emergency Response, Washington, DC. p. 2-3.
U.S., EPA. 1986c. Integrated Risk Information System (IRIS): Reference Dose
(RfD) for Oral Exposure for Methomyl. Online. (Verification date 04/22/86).
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH. p. 1-7.
U.S. EPA. 1986d. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986e. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1987a. Health Advisories for 50 Pesticides: Methomyl. Office of
Drinking Water, Washington, DC. NTIS PB86-118338. p. 1-19.
0121d -75- 07/14/88
-------
U.S. EPA. 1987b. Pesticide Tolerances for Methomyl. Federal Register.
51(184): 35730-35731.
U.S. EPA. 1987c. 21 CRF 193. Methomyl; Pesticide Tolerance. Federal
Register. 52(218):- 43324.
U.S. EPA. 1988. STORET Water Quality Data Base. Online: February, 1988.
Valencia, R. 1981. Mutagenesls Screening of Pesticides Using Drosophlla.
NTIS P881-160848. EPA 600/1-81-017. p. 1-15, 40.
Waters, M.D., V.F. Simmon, A.D. Mitchell, T.A. Jorgenson and R. Valencia.
1980. Overview of short-term tests for the mutagenlc and carcinogenic
potential of pesticides. J. Environ. Sd. Health Part B. 15: 867-906.
Waters, M.D., S.S. Sandhu, V.F. Simmon, et al. 1982. Study of pesticide
genotoxldty, Basic Life Sd. 21: 275-326.
WHO (World Health Organization). 1976a. Pesticide Residues In Food Report
of the 1975 Joint Meeting of the FAO Working Party of Experts on Pesticide
Residues and the WHO Expert Committee on Pesticide Residues. WHO, Tech.
Rep. Ser. No. 592. p. 1-45.
WHO (World Health Organization). 1976b. Evaluation of Some Pesticide
Residues 1n Food. WHO Pestle. Res. Ser. p. 289-312.
0121d -76- . 07/14/88
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WHO (World Health Organization) 1977. Pesticide Residues 1n Food. WHO
Tech. Rep. Ser. 612. p. -1-35.
Willis, G.H. and L.L. McDowell. 1987. Pesticide persistence on foliage.
Rev. Environ. Contam. Toxlcol. 100: 23-73.
Wojc1echowsk1, J.P. and P. Kaur. 1980. Cell-mediated mutagenesls of V79
cells with four carbamates. In VHro. 16: 235-236.
'Wojcleehowsk1, J.P., P. Kaur and P.S. Sabharwal. 1982. Induction of
ouabaln resistance In V-79 cells by four carbamate pesticides. Environ.
Res. 29(1): 48-53.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual, 7th ed.
The British Crop Protection Council, Croydon, England, p. 363.
Yeboah, P.O. and W.W. Kllgore. 1984. Analysis of airborne pesticides In a
commercial pesticide storage building. Bull. Environ. Contam. Toxlcol. 32:
629-634.
0121d -77- 07/14/88
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APPENDIX A
' LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted 1n February 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John WHey and
Sons, NY. p. 3817-5112.
0121d -78- . 06/08/88
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Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo.-
pedla of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the- Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). .1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call 1n
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
0121d -79- . 06/08/88
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In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
BatteHe's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
OlZld -80- . 06/08/88
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o
CO
00
00
APPENDIX B
Summary Table for Methomy1
0
rj
Species
Inhalation Exposure
Subchronlc ID
Chronic ID
Carclnogenlclty ID
Oral Exposure
( Subchronlc dog
CD
1
Chronic dog
Carclnogenlclty ID
REPORTABLE QUANTITIES
Exposure
ID
ID
ID
100 ppra In diet
for 24 months
(2.5 rog/kg/day)
100 ppro In diet
for 24 months
(2.5 mg/kg/day)
ID
Effect
ID
ID
ID
mild kidney lesions
In males at 400 ppra
mild kidney lesions
In males at 400 ppm
ID
RfD or qi*
ID
ID
ID
0.025 mg/kg/day
or 2 mg/day for
a 70 kg human
0.025 mg/kg/day
or 2 mg/day for
a 70 kg human
ID
Reference
1
ID
ID
ID
Kaplan and
Sherman. 1977
Kaplan and
Sherman, 1977
ID
Based on chronic toxlclty:
Based on Carclnogenlclty:
100
ID
Hazelton
Laboratories,
1981
ID
ID = Insufficient data
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