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January 1992
FINAL
DRINKING WATER CRITERIA DOCUMENT
FOR
OXAMYL (VYDATE)
Health and Ecological Criteria Division
Office of Science and Technology
Office of Water
U.S. Environmental Protection Agency
Washington, DC 20460
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TABLE UF CONTENTS
Page
LiST OF FIGURES vii
LIST OF TABLES vii-
FOREWORD viii
AUTHUHS, CONTRIBUTORS, AND REVIEWERS . . . ix
I. SUMMARY .« 1-1
II. PHYSICAL A.NO CHEMICAL PROPERTIES II-l
A. General Properties . . II-l
B. Product ion ana Use II-l
C. Environmental Fate and Effects II-3
1. Stability-.in Water II-3;.
2. Mooility in Soil II-4V
3. Decomposition in Soil 11-6,
4. Metabolic Faie in Plants II-9
5. Environmental Toxicity 11-10
III. TOX1CUKIHETICS HI-1
A. Absorption III-l
B. Dist-ioution III-l
C. MstaDOlism III-2
U. Elimination III-o
E. Bioaccumulation and Retention III-7
F. Summary 111-7
IV. HUMAN EXPOSURE IV-1
V. HEALTH EFFECTS IN ANIMALS • V-l
A, Sno-u-term Exposure ._ V-l
1. Lethality '. . . V-l
2. Otner Effects .' . V-3
B. Long-term Exposure V-4
1. SuDChronic Toxicity , V-4
2. Cnronic Toxicity V-5
C. Teratogenic/Reproauctive Effects V-9
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TABLE OF.CONTENTS (continuea)
Page
V. HEALTH EFFECTS IN ANIMALS (continued)
D. Mutayenicity t V_15
1. Gane Mutation Assays (Category 1) V-16
2. Chromosome Aberration Assays (Category 2) V-18
3. Other Mutagenic Mechanisms (Category 3) V-lb
E.- Carcinogenicity V-19
F. Summary „...*..... V-21
VI. HEALTH EFFECTS IN HUMANS ". ." ..'... VI-1
VII. MECHANISMS UF TOXICITY .''.. . . VII-1
VIII. QUANTIFICATION UF TUXICOLQGICAL EFFECTS VIII-1
*
"A. Procedures for Quantification of Toxicological Effects .... VIII-1'
t"
1. Noncarcinogenic Effects VIII-1
2. Carcinogenic Effects ; . . . . VIII-4 11
r
B. Quantification of Noncarcinogenic Effects for Uxamyl VHI-6
;i
1. One-day Health Advisory . . . . . VIII-6 ;
2. Ten-day Healtn Advisory -.;..-...... .VIII-6 •;
3. Longer-term Healtn Advisory VIII-6 ,'.
4. Reference Dose and Drinking Water Equivalent Level .... VIII-9 ''
C. Quantification of Carcinogenic Effects for Oxamyl VIII-12 i'
0. Summary ." VI11-13 !
IX. KEFERENCES
IX-1
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LIST OF FIGURES
Figure No. . - • ° . .
» * *
III-l In Vitro Metabolism of Uxamyl fay Kat Liver Microsomes . . III-3
LIST OF TABLES
Table No.
II-2
li-l
V-l
v-z .
' V-3.
V-4
V-is
y-e
V-7
V-8
V-9
VIII-1
VIII-2
VIII-3
Summary of Acute Toxi city Values in Laboratory Animals
Mean Maternal Body Weights of Rats Fed Oxamyl During
The Effects of Dietary Administration of Uxamyl on
Mean Maternal Soay Weight Gains in Rai>bi4s~£;ve.n -Ora-l
Summary of Viscaral and Skeletal Findings in Fetuses
Effects of Uxamyl Ingestion on Litter Size and Body
Weignts of Weanlinys in Three Generations of Rats ....
Summary of Histopatnologi cal Findings in Rats Fed
Summary of Tumor Data From Mice Fed Oxamyl for 2 Years . .
Summary of Subcnronic Feeding Stuaies Considered in
the Development of the Longer-term Healtn Aavisory for
Summary of Chronic Feeding Studies Considered in the
Development of the Reference Dose and Drinking Water
Summary of Quantification of Toxicological Effects for
V-2
' V-7
V-10:
*.
V-12*
V-13
V-L5
V-17
V-20
V-22
VIII-7
VIII-10
VIII-14
V11
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FOREWORD
Section 1412 (b)(3)(A) of the Safe Drinking Water Act, as amended in 1986,
requires the Administrator of the Environmental Protection Agency to publish
Maximum Contaminant Level Goals (MCLGs) and promulgate National Primary Drinking
Water Regulations, for each contaminant, which,-in the judgment of the Administra-
tor, may have an adverse effect on public health and which is known or
anticipated to occur in public water systems. The MCLG is nonenforceable and is
set at a level at which no known or anticipated adverse health effects in humans
occur and which allows for an adequate margin of safety. Factors considered in
setting the MCLG include health effects data and sources of exposure other than
drinking water.
This- document provides the health effects basis to be considered in
establishing the MCLG. To achieve this objective, data on pharmacokinetics,
human exposure, acute and chronic toxicity to animals and humans, epidemiology,
and mechanisms of toxicity were evaluated. Specific emphasis is placed on
literature data providing dose-response information. Thus, while the literature
search and evaluation performed in support of this document was comprehensive,
only the reports considered most pertinent in the derivation of the MCLG are
cited in the document. The comprehensive literature data base in support of this
document includes information published up to April 1987; however, more recent^
data have been added during the review process and in response to public
comments. • '
When adequate health effects data exist, Health Advisory values for less-
than-lifetime exposures (One-day, Ten-day, and Longer-term, approximately 10% of
an individual's lifetime) are included in this document. These values are not
used in setting the MCLG, but serve as informal guidance to municipalities and
other organizations when emergency spills or contamination situations occur.
James R. Elder
Director
Office of Ground Water and Drinking Water
. . Tudor T. Davies
Director
Office of Science of Technology
viii
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I. SUMMARY •
•Jxamyl, S-rcetnyl N' ,N' -dimethyl -N-(methyl caraamcyl oxy)-1-thiooxami -
miaate, is the active ingredient found in the insecticide/nematicide Vydate
L*, wnicn contains 2*- oxamyl in methanol. Vycate* is widely used for control
of insects, mites, ana nematodes on field crops, fruits, and ornamentals.
Uxamyl is stable in the solid form and relatively stable in aqueous solu-
tions at acidic pH. At alkaline pH, however, oxamyl is rapidly hydrolyzed
to an oximino compound. Exposure to liyht, particularly at low concentra-
tions, results in rapid and -extensive'decomposition of oxamyl. Decomposition
in soils under both aerobic and anaerobic conditions is also rapid and extensive.
to f .
Fielc studies indicate tnat the mobility of oxamyl in soil is limited. *
i
Uxamyl is rapidly aosorbea, metabolized, and eliminated by rodents. Rats
eliminated greater than aQ* of an oral dose of oxamyl in the urine within
3 days of administration. Mice yiven an intraparitoneal (1p) injection of .-
oxamyl excrsted more than 87» of the dose in the urine witnin 3 days. Relatively
small percentages of each dose were found in the feces of rats or mice within
72 nours postadministration. There was little accumulation of oxamyl in the
tissues, altnouyh appreciable amounts (7 to 12.5-) were found in tne skin and
nair of two rats witnin 3 days of dosiny. Oxamyl appears to be extensively
metaoolizac after oral or ip administration. The primary metabolites recovered
in urine of both rats and mice were methyl N-nydroxy-N1 ,N'-dimetny1-.l-thiooxa-
minndate (i»Tu)', N,N-dimethyloxamic acid (DMOA), N-methyloxamic acid (MOA), and
metnyl N-nydroxyN'-methyl-l-thiooxamimidate (MTO). In addition, oxamyl and
fo,N-dimethyl-lcyanoformamide (DMCF) were also found in tne urine of mice.
Oxamyl has been shown to be metabolized by hepatic microsomes via two major
pathways. Une pathway involves hydrolysis to DMTO, and the second involves
1-1
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enzymat-ic conversion via UMCF to DMOA. A third, minor enzymatic process results
in partial cemetnylation of oxamyl and its metabolites.
Tne major mechanism of toxicity of oxamyl appears-to be cholinesterase
inhibition. Acute oral, intraperitoneal., or inhalation exposure to lethal
aoses of oxamyl resulted in typical clinical siyns of cholinesterase inhioition
prior to aeath in rats, mice, racbits, guinea pigs, and doys. Oxamyl is
extremely toxic via oral, inirapejM toneal, and inhalation routes of administra-
t
tion; oral LD^y values were Z.b to '3.U mg/kg in rats, 2.3 to 3-.3 mg/kg in mice,
A
and 7 mg/ky in yuinea pigs. Tne.insecticide (in solution) has only limited
aDsorption through the skin as evidenced by dermal LD^ values of 7bO and >1,2UO
mg/ky in raooits and rats, respectively. ' ' ^
f
Treatment witn atropine after aaministrati on of lethal doses of oxamyl is.
antiaotal in rats due to its competitive binding of acetylcholine receptor sites
on pcstsynaptic memoranes.
Oxamyl is also toxic following long-term oral exposure. Although clinical
siuns of cnolinesterase innioition were not observed, statistically significant
decreases in body weiynt were noted in male and female rats fed 100 ppm in the
diet .(b.U my/kg/day) for 90 aays or 2 years. Serum cnolinesterase activity was
siynificantly decreased in females fed 150 ppm (7.^ mg/kg/day) after 4 days and
in males fed IbU ppm (7.3 mg/icy/day) after b days of exposure to oxamyl. No
specific target organs were identified. Histopathologic examination revealed
no increased inciaences of tumors after inyestion of up to 150 ppm (7.5 mg/kg/day)
for 2 years in rats.
Similar results were obtained in a 2-year study in mice fed oxamyl in the
diet at levels up to 75 ppm (11.25 mg/kg/day). Significant decreases in body
1-2
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wei^nts were noted in males and females fed 50 ppm (7,3 mg/kg/'day). NO increases
in inciaence or type of neoplastic or nonneoplastic lesions were observed in
mice fea up to 7b ppm wnen compared to -controls. From the results of the
feeciny studies, oxamyl was not carcinogenic in rats fed up to .150 ppm or mice
fed up to 7b ppm for 2 years. This is supported by negati-ve results of several
i_n vitro vjenetic toxicity assays.
In yo-say ana 2-year feeding studies in beagles, dietary levels of oxamyl
»
up to IbO ppm (3.a my/ky/day) did not elicit any changes in body weight, food
consumption, clinical signs, hematologic and urinary parameters,.or histopath-
oloyy wnen compared to controls. • Statistically significant increases in se-rum
V
alkaline phospnatase activity .and cholesterol levels were, observed in groups *
fea IsU ppm after 2 years of exposure, suggesting some effect on the liver.
This was not supported oy histopstnologic findings, however,
Altnouyn maternal toxicity {significantly decreased body weight) was
marked at 1QU ppm (5.0 mg/kg/day), oxamyl fed to pregnant rats at levels up to
3uu ppm (ib mcj/ky/day) was not teratogenic. Oral doses of up to 4 mg/ky/cay
aaministerea to pregnant rabbits were not teratogenic, although significantly
6
decreased maternal body weiynts were observed at 2 mg/kg/day.
Developmental toxicity, as evidenced by .decreases in the litter size of
.. **"*.? '' ' ••""
cams fed cxamyl at 10U ppm (b.O my/kg/cay) was demonstrated in both one- and
tnree-generation reproduction studies in rats. Decreased growth (significantly
decreased oody weiynt) of weanlinys from the yroups fed 10U ppm was also
noted. Similarly, parental toxicity in the form of significantly decreased
Dody weiynts was observed in both males and females fed 100 ppm. In this
study, oxamyl did not affect fertility or elicit increases in the incidences of
1-3
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variations or malformations of tne offspring of dams fed up to ISO ppm (7.5
mg/kg/aay).
No suitable data. were found in the literature for derivation of the One-
and Ten-day Health Advisories (HAs) for oxamyl . A Longer-term HA of 200 ug/L
for a 10-ky child was calculated, based on a No-Observed-Adverse-Effect Level
(HOAEL) of 2.5 mg/kg/day identified in a 90-day feeding study with rats. This
was substituted as a cpnservative estimate of both the One- and Ten-day HA
values. A Drinking Water Equivalent Level (UWEL) -of yuu uy/L for a 70-kg
adult was .developed, based on a NUAEL of '2.5 mg/kg/day identified in a 2-year
feeafng study with rats. Oxamyl is classified in Group E: Evidence of Non-
carcinog'enici-ty for 'Humans, based on the results 'of a 2-year feeding study'
with rats and a 2-year feeding study with mice.
ugh no information on tne exposure to or toxicity of oxamyl in humans
was found in tne literature, the results of animal toxicity studies indicate
tnat acute oral, i ntraperi toneal , or inhalation exposure to lethal doses-of.-
oxamyl at 2.3 to 7 mg/ky can cause rapid death in laboratory animals. However,
because of tne "reversiole" nature of oxamyl toxicity owing to its mode of
action and tne rapid .metaoolism and elimination of oxamyl and its metabolites,
tnis insecticide appears to have a wide margin of safety.
1-4
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II. PHYSICAL AND CHEMICAL PROPERTIES
A. GENERAL PROPERTIES
Oxamyl, S-nnetnyl N' ,N'-aimethyl-N-{methylcarbamoy-loxy}-l-thiooxamimidate
(CAS No. 23135-22-0), In its pure state, forms colorless crystals with a slight
sulfurlike odor and is considered extremely toxic. The compound was introduced
oy E.I. duPont de Neumours and Company, Inc., as the main active ingredient in
the pesticide Vydate*. As a solid, it is stable. In aqueous solutions, it
decomposes slowly. This process is accelerated by aeration, sunlight, alkali,
or elevated temperatures. A summary of the physical and chemical properties is
listed in Table -II-l (Gosselin, 1981; duPont, 1986; U.S. EPA, 1986; Worthing
ana Walker, 1963; Kennedy, 1986a). . .l
f
B. PRODUCTION AND USE
E.I. auPont de Nemours and Company, Inc., is the sole producer of oxamyl.
Oxamyl is tne active ingredient in the insecticide/nematicide-Vydate L*. In
1982, production of oxamyl was reported to be 0.4 million pounds/year (0.3
million pounas/year for use as the insecticide and 0.1 million pounds/year for
use as tne nematicide) (SRI, 1985). Vydate* consists of 24% oxamyl in methanol.
In tnis form, it is classified as a poison B, which is defined as: "a less
aanue-ous poison: substance, liquid, or solid, other than Class A or irritating
material, wnich is Known to be so toxic to man as to afford a hazard to health
during transportation or whicn, in the absence of adequate data on Human toxicity,
is presumed to be toxic to man." It is used to control insects, mites, and/or
nematodes on many field crops, fruits, and ornamentals (O'Bannon and Selhime,
1980; French, 1982; Timmer and French, 1979). Application may be by broadcast or
band to soils, as a transplant water treatment, or a foliar spray (duPont, 1986;
II-l
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Table II-l. Physical and'Chemical Properties of Oxamy]
Parameters
Value
CAS number
23135-22-0
Synonyms
Color/form
Molecular weignt
Melting point
Vapor pressure at 25°C
Specific gravity at 2iJ0C
Svaoility
Structure
Thioxamyl; diovamyl; duPont 1410;
DP* 1410; .Vydate*
Clear crystalline solid
219-.3'
108-11U°C
2.3 x 10-4 mmHg
0.98 -
Staole in solid form, and in liquid form
at acidic pH
0
0
II
(CH3}2-N-C-C=N-0-C-N-CH3
SCH3
Soluoility at 25°C
water
Acetone
Etnanol
Toluene
280 g/L
670 g/L
330 g/L
1U g/L
SOURCE: Adapted from Worthing and Walker (1983); Kennedy (1986a);
U.S. EPA (1986); duPont (1986); Gosselin (1981).
II-2
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19S6; 'Kennedy, 19B6a). It is registered for use on a variety of vegetation for
preplant, at planting, or postplant featments (Agriculture Research Service,
1986). Some or all applications may oe classified by tne U.S. EPA as Restricted
Use Pesticides (HUP).
C. ENVIRONMENTAL FATE AND EFFECTS
Because oxamyl is applied to a wide variety of crops at different stages
of cultivation, the compound inevitaoly comes into contact with soil and water.
Thus, its fate in these media is important.
1. Stability in Water . . _ •
« i
'Harvey and Han (157ba) reported that in water, oxamyl {1.2UU pom) was
<3 •
staale for "at least 11 days at pH 5 or lower; but was hydrolyzed rapidly to the
c
oxirnino compound at pH 9. Peeples (1977) calculated a half-life of approxi-
mately 3 days for a 1,200-ppm aqueous solution of oxamyl at pH 9.1 and a naif-
life of 14 aays for tne same concentration of oxamyl in an aqueous solution
witn a pri of b.9.
The effect of liyht on tne hydrolysis of oxamyl was also examined. Harvey
ana Han (1973a) prepared 1 and 1,000 pom [l*C]oxamyl solutions using either
—\
distilled or river water. A set of samples was exposed to ultraviolet lignt
continuously for 7 days, while control samples were stored in the dark for 10
days. Aliquots of ultraviolet-exposed samples were analyzed for total radio-
activity and composition at U, 3, and 19 hours, and at 2, 4, and 7 days.
Controls were examined only at the end of the 10-day holding period. In all
lignt-exposed samples, decomposition of oxamyl was extensive and rapid. The
most dramatic effects were seen in the 1-ppm sample from river water, in which
99% of tne raciolaoeled oxamyl was nydrolyzed within 48 hours of the initiation
II-3
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-------
of exposure. At the end of "l'week, 22 to 61% of the parent compound persisted
In the other ultraviolet-exposed water samples. The pesticide was converted
primarily to the ox:ml no derivative (18 to 51% of the total radioactivity
recovered) and Its :somer'-(3% In. l.-ppm sample In distilled water; 24 to 36% In
all otners). A polar fraction N,N-dimetnyl (oxamic acid) was present In high
concentrations (18 and 23%) In the samples containing 1 ppm only. The level of
oxamyl In tnree of the control samples remained essentially unchanged; however,
'In river water samples containing 1,OOU ppm, 16% of the parent compound was
converted to the oxlmlno form after 1U days. Recovery of at least 98% of. tne
original radioactivity was reported for all samples.
In a similar study, 6 gallons of river water spiked with 1 ppm [-4C]- -i
oxamyl were left .outdoors and exposed to direct sunlight for 6 weeks (Harvey. '
and Han, 19?8a). No oxamyl remained at tne end of the study. The radiocarbon
was present primarily as the oximino derivative (46% of total radioactivity
recovered) and its isorner (34%). Polar compounds, .including N,N-dimethyloxamic
acid and two unknown compounds, comprised the remaining 20% of the carbon
label. Tne autnors reported that oxamyl was hydrolyzed completely to the
oximino compound oy the end of the second day of the study. This compound was
gradually converted to its syn-anti-isomer until an apparent equilibrium state
was reacned. Following this, additional degradation products were formed.
Approximately 17% of the total radioactivity was not accounted for during the
6-week experiment. This was presumably lost as
2. Mobility in Soil
Conflicting data exist concerning the mobility of oxamyl in the soil.
Harvey and Han (1978a) reported that, under laboratory conditions, oxamyl
(levels not specified) was fairly mobile in four soils (muck, loamy sand,'and
II-4
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two types .of silt-loam). Thin-layer chromatograpnic (TLC) analysis gave
reference (Rf) values ,.(0.53 to l.OU) reflective of a moderately to nighly
moDile compound (Harvey and Han, 1978a). The moDility of oxamyl Increased as
-------
^s of a 2-year field study conducted by Mclntosh et al. (1984)
that oxamyl probably does not accumulate in liynt-textured soils that
y irrigated. In tnis experiment, oxamyl was applied at an approximate
.U pound ai/acre/montn to sandy desert soils in a southern California
ve. ' Ten pounds/acre were applied during the first year of the study,
ids/acre were added to tne soil in tne second year. Five -eplications
-e lots were used. Kater-only areas served as controls. Samples we-e
• depths of U to 4, 4 to b, and 8 to 12 incnes, and at each foot between 1
•et below the surface of tne soil. Analysis of samples obtained between
•days posttreatment showed that, under the conditions outlined, oxamyl • .
* * " • *
ienetrate tne soil to depths greater tnan 5 feet. Uxamyl w'as rapidly
•to its oximino metabolite in these samples. Levels of both compounds
by 21 days postapplication. Similar results regarding
n and degradation were obtained when a single 10-pound (ai)/
stment (lUx the normal use rate) of Vydate® was applied to a previously
a site. " ' •
field study data described above disagree with laboratory data indicating
myl is moaerately to nignly mobile in soil. Harvey and Han (1978a)
d that, under practical conditions, rapid degradation of oxamyl precludes
?ment in sell despite heavy rainfall.
:omposition in Sol 1
gradation and metabolism of oxamyl were examined in three moist soils:
andy loam, and silt loam (Ou and Rao,.1986). Approximately SOU ug
Dxamyl were added to 1UO g dry soil to give a final pesticide concen-
. About 59 to 84% of the original carbon label appeared
2 by day 63 postapplication. At this time, most of the remaining
II-6
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radiolaoel was nonextractable (i .e.,° bound). The exception was the silt •
loam with a high so-il-water tension (33 kPa); in this soil, 24.5% of the
•origi-nal 14c dose appeared as oxamyl, small amounts of N,N-dimethyl-2-(methyl-
tnio)acetamide oxime, and polar metabolite.- As the soil-water tension increased,
degradation of oxamyl decreased. Unchanged parent compound accounted for 28 to
47% and 53 to 7y% of the recovered radioactivity at the lowest (10 kPa) and
highest {1.5 x 103) tension levels, respectively. Half-lives (tjy2) for ex"
tractable 14C disappearance ranged from 8 to 5U days; tjy2 values'for oxamyl
disappearance were estimated to be shorter.
Extensive field studies on the decomposition of Vydate® in soil were
'conducted by Harvey and Han (1978a), In one investigation, three types of soil :
* ' £
(silt loam, loamy-sand, and fine sand) were treated with [14c]oxamyl at a rate ,
equivalent to 6 pounds ai/acre. All sites'were exposed to normal weather conci-
tions and similar amounts of rainfall. Samples were analyzed at 1 week, 1
month, and 3 or 5 months posttreatment. In all three soils, oxamyl was rapidly
decomposed; less than 5% of tne parent compound remained at the 1-month collec-
tion time. After 1 month, volatility losses (presumably as 1*C02) comprised
65.b to 73.0% of the original 14C application. The oximino derivative of
Vydate® and a polar fraction appeared early in the study (at 1 week) and in
consideraole amounts. However, only trace levels of these radioactive compo-
nents we-e detected at the end of tne study. Unextracted residue contained 6.3
to 27.0% of the original radioactivity; these levels varied greatly w-ith regard
to time ana soil type. Five months after sprayiny, approximately 9% of the
original laoel was extracted from the loamy sand residue and was distributed :n
the soil as follows: alphahumus, 32%; soluble numin, 18%; fulvic acid, 13%;
beta-humus and insoluole humus, 6% each; hymatomelanic acid, 4%; and a volatile
compound lost during analysis, 21%. Detailed analysis of the other soils was
II-7
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not reported, leacnate water Detained from loamy sand and'"fine sand, contained
no raaioacti vity at 1 week and 1 month and only trace amounts ("less than 6% of
tne original carbon laDel) at the last sampling time.
Aerated silt loam was treated with [14c]oxamyl (0.98 uCi) at a rate
equivalent to 4 pounds/acre (Harvey and Han, iy78a). The experiment was repeated
under anaerooic conditions at a level of 6 ppm [l^CJoxamy'l (7.12 uCi). Both
soils were placed in metabolic chambers for 42 days. In the presence of air,
51% of the labeled chemical was converted to 14CU2, 11* appeared as a polar
fraction, .and 4% remained unchanged.. Only a trace amount of the parent com-
pound was present as the oximino form. Approximately 26% of the original
radioactivity was incorporated into normal soil organic material. Nearly
i.
two-tnirds of tnis'residual radioactivity was divided among several soil frac- ,
tions: fulvic acid, 62%; alpha-humus, 25%; hymatomelanic acid, 6%; and beta-
nuraus, 6*. Aoout 7% of the original radioactivity in tne aerocic soil samples
was not accounted for. . ..-•-..-
Under anaerooic conditions, decomposition of [l^Cjoxamyl was almost as
rapid and extensive as in the aerobic system in that only 8% of the parent com-
pound remained after 42 days (Harvey and Han, 1978a). However, only 3% of the
0,-iyinal racioactivity was converted to ^COg, and more than 80% appeared as the
oximino compound and the polar fraction. Residual levels of radioactivity were
low (5%) at tne 42-day-..mark, indicating a delay in botn" the oxidation of oxamyl
to COj and tne incorporation of the pesticide into organic matter.
•Tne rate of aerooic and anaerobic decomposition of 6 ppm [l^Cjoxamyl in
«
loamy sand, fine sand, and silt loam was investigated by Harvey ana Han (1978a).
Soil samples were analyzed for radioactivity and composition at 0, 7, 14, and
28 days after treatment. Uxamyl concentrations declined steadily in both
II-8
-------
aercoic.and anaerobic samples; after 23 days, approximately 28% of the parent
compound remained in aerated sands, and only 2% persisted in the silt loam
deprived of oxygen, unaer aerooic conditions, tne half-life of oxamyl was 15
days for the fine sandy soil and 11 days for the loamy sand samples. In the
aos'ence of oxygen, tne naif-life of oxamyl was approximately 6 days. Un the
basis of results from a 2-year field study, Mclntosh et al. (1984) reported a
half-life of 1 to 4 days for oxamyl when the compound was applied at a -ate of
1 pound ai/acre/month to1 irrigated, sandy desert soils. In a field study conducted
oy Harvey and Han {1978a), e-1,200 ft2 area of silt loam was treated with 5.65
9 • ' '
pourias a:/acre.'' Soi-1 samples reaching'depths of 3U inches were analyzed on U,
•a
.2, o, 9, lt», 23, 30, and 6U days after oxamyl. application. The half-life of
a
Vydate* unaer the conditions of this study was 8 days. ,
t
4. Metabolic Fate in Plants
Tne metaoolic patnway of L-*C]oxamyl was studied in peanut and tobacco
seedlings treated with 2 and 6 pounds ai/acre, respectively (Harvey, 1973). In-
extracts of young peanuts, peanut hay and seedlings, and mature tobacco, the
majority of -aaioactivity (73 to 1UO%) was detected in a "polar fraction." At
'i to 6 weeks postspraying, this polar fraction consisted primarily of a gluco-
siae conjugate of a hyarolyzed oximino compound. Demethylation gradually
occurred, producing a monomethyl oximino glucoside witnin 1 to 2 months and
an IS-aeme.nylated oximino glucosiae several months after exposure to the nemati-
cide. Smell amounts of oxamyl and its oximino derivative were found-in the
plant extracts at various stages of harvesting. N,N-dimethyloxamic acid was
also aetectea in tobacco raised in growth chambers. Below are the chemical
structures for tnese compounds. The author.sugyested that the presence of this
compound may represent a minor or alternate metabolic pathway for oxamyl.
II-9
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COMPC'JND . ' " ' NAME
OXAUYL UFTHY1. N1, N1—OIMETKY1—N1 [METHYLCAfl.
BAMOYU) OXYJ—I-THIOOXAMIUICATE
0
,f NOCNMCK,
QXIUINOUETABOUTE CMv
USTHYl N—HYDRO*—N'. N'—DIMETHYL—1—
TKOCXAMIMIOATt „„ /
, II /
N-0-«C
NOH
CtV
N. N—OIUETHMOXAUlC ACID
N-C— "COOH
CM,
In anotner study, a 1% solution (w/v) of [l^Cloxamyl in U.2% aqueous Tween
2u was spotted on the surface of green tomatoes (Cv. Bonny Best) being grown in
a greenhouse (Harvey, 1976). 'A total of 0.37 mg oxamyl was applied to each
tomato. Fruit was allowed to' ripen and'was harvested.in pairs at 7, 11, 14,
• '
(13%) and its glucose conjugate (5%). Approximately 4% of the radioactivity
was associated witn N,N-aimethyl-l-cyanot'ormamiae (UHCr). The remainder of
the radiocarbon (19%) was present as a mixture of -polar or natural products.
Comparable levels of oxamyl and its metabolites were found at 21 days, altnough
a steady decline in oxamyl and an increase in the oximino compound were observed
during the 3-week harvesting time.
5. £nvi"onmenta1 Toxicity
<3
4
Technical grade (93.5% pure) or 1% granule oxamyl was dissolved in water
at concentrations of 13.5, 18, 24, 32, 42, or 56 ppm (Watanabe, 1975). A
75-ppm solution of tne granular formulation was also included in the study.
Tne solutions were t-ansferred to 50-L tanks, and 10 carp (approximately 6.1 cm
long and weigning bt> y) were placed in each tank for 48 hours for the purpose of
evaluating tne acute toxicity of Vydate®. No fish survived the highest concen-
tration level of either type of oxamyl. All animals survived exposure to the
11-10
-------
13. b- and 13-ppm solutions, and 1U to 9U% of the carp-. were still alive after
swimming In waters containing Intermediate concentrations of oxsmyl . "Op to 50%
of the flsn were found turning slaeways while In -the treated water; the bodies
of many flsn were bent In a U-snape following exposure to the' chemical . Fish
that died during tne study, had enlarged gall ol adders, 'hematocel la, and anemia
In tne gills. Bent bodies did not return to normal after carp were placed back
Into fresn water. Forty-eight hour median tolerance limit (Tl_m) values we~e '
29 ppm'Ui) and 3b ppm (ai) for carp exposed to 1% granule and technical grade
oxamyl, respectively, indicating that granule Vydate® is slightly more- toxic to
ca~p tnan is the technical grade. The authors concluded that, at the
o " "
concentrations investigated, botn forms of oxamyl could do consideraole harm
to fish.
i
Tadpoles (kana temporaria) exposed to oxamyl exhibited slowed growth,
delayed development, and physical deformities. In this field study (Cooke,
, eignt cayes of 4U tadpoles each .vere maintained for 6U to 8U days
<3
adjacent to sugar oeet, barley, and potato fields that had been sprayed .with
the pesticiae (exposure levels not noted). No other chemicals were used during
tne experiment. In cages kept Detwesn fields of barley and potatoes, mortality
was nigh, development and growth were slow, deformities particularly vertical
curvature and tail tip,, were also found. However, cages kept between barley and
sugaroeet, survival was good, development was rapid, and growth was satisfactory.
Deformities occurred late in the study showing lateral kinks. Cages kept between
sugaroeet and potatos showed high mortality during the first month but leveled
for tne rest of the study. Lateral curves and tail tip deformities were also
observed. A cage kept in a nature reserve pond served as a control; all
parameters measured were normal, except for a few lateral kinks. In a parallel
laboratory study, approximately 9U% of tadpoles exposed to 1UU ppm oxamyl for
11-11
-------
1 hour, developed vertical curvature deformities similar to those seen in the
field (Cooke, 1981). No tail tip defects developed in the 100-ppm oxamyl-treated
tadpoles. Tne deformities observed under laboratory conditions appeared to be
related to abnormal posturing, unlike those found in the field wnich appear to
be of muscular origin. Experimental evidence therefore did not prove conclusively
that oxamyl caused tne harmful effects observed in field tadpoles. It did indicate
however, that oxamyl warrants further consideration.
A significant increase in the mortality rate for bees was observed after
oxamyl was sprayed over alfalfa fields (Atkins et al ., 1974). Early morning-^
fol'iar applications of Vydate® (U.S'and 1.0'pound/acre) suppressed bee foraging
for at least 4 days. More than 9b% of the bees exposed directly to either
i
concentration of the pesticide dieo within 24 hours; of tne bees placed in the ^
I
field 1 nour after spraying either u.b or l.U pound/acre, only 29 and 12% died
during the next 24 nours, respectively. Approximately 3% of control bees ciie^
under similar exposure conditions and times. The overall hazard of Vydate® \
to Dees was moderately nigh at tne 1.0-pound/acre level and moderate for the
U.i-pouna/acre concentration.
Under laboratory conditions, oxamyl was toxic to one type of earthworm,
the night crawler (Lumbricus terrestris) (Ruppel and Laugnlin, 1977). In this
study, Vyaate* was mixed with ary potting soil at rates equivalent to 0, 2, 4,
8, 16, and 32 pounas ai/acre. Ten active niynt crawlers were added to eacn test
soil. A -eiatively nigh level of tne pesticide, 13.U6 pounds ai/acre, was
required to cause death in bu% of the niynt crawler population. According to
the autnors, tnese data support evidence of high night crawler mortality rates
ooserved in fields sprayed with oxamyl.
11-12
-------
Tne effect of ID ppm oxamyl on bacterial growth was studied in three types
of soil: fine sand, silt loam, and sandy loam (Peeples, 1977). Dilution plate
counts were used to determine soil microbial populations at 1, 2, 4, and 8
weeks after treatment. CC>2 evolution was used to measure microbial activity.
Oxamyl had no adverse effects on either fungal or bacterial population or on
microoial respiration in any of the soil types.
11-13
-------
III. TUXICOKINETICS - *
A. ABSORPTION
Seventy-two Hours after two male Charles River-CU rats were given a
single oral dose of 1.0 mg (3:74 or 5.6 uCi) [l-Hc]oxamyl, about 55% of the
original radioactivity was recovered in the urine (Harvey and Han, 1978&).
About 19% of the radiocaroon was found in the hide (skin and nair), the carcass,
and various tissues (including plasma, but excluding the gastrointestinal tract}
at t-ie time, of sacrifice (72 hours postdosing). Plasma-levels of radioactivity
accounted-for only 1.55 and 2.13% of the original 1*C dose at 72 hours. These
data suyyest'that at least 74% of-the dose is absorbed from the gastrointestinal
c *
tract following oral administration.' *
r
Chang and Knowles (1979) gave 2U male Swiss-Webster mice a single intra-
yeritones! (ip) dose of 1.16 my/kg (0.13 uCi) [l-14c]oxamyl. Within 96 hours
9
after oeing injected with the pesticide, mice excreted 88.7 and 7.7% of the
radioactive label in the urine and feces, respectively. More than 75% of the
original radioactive dose was eliminated during the first 6 hours of the
study, with the majority (72.7%) appearing in the urine. At 96 hours after
injection, tne 14c concentration in the plasma was only 30.5 ppb; plasma
• • • f
radioactivity levels were not measured at any other time.
B. DISTRIBUTION
Tissue levels of radioactivity were generally low following administration
of radiolaoeled oxamyl. About 22% of a single oral dose of 1.0 mg [l-14c]oxamyl
(3.74 or 5.6 uCi) retained by two male Charles River-CD rats was distributed
among 13 body fractions 3 days after administration (Harvey and Han, 1978b).
Approximately 6.98 and 12.55% of the original radiocarbon were recovered in the
III-l
-------
rVide (skin and hair), 6.34 and 4.18% were retained in the carcass, 4-.76 and
1.32% were found in the gastrointestinal tract, and 1.5b and 2.13% were present
in tne olood. The.liver of one animal contained 1.^8% of the original radio-
activity, wnile tne hepatic 1*C level in the second rat was only 0.2U%. Other
tissues contained no more than U.36% of tne original 14c label (Harvey and Han,
1978D).
In the study conducted by Chang and Knowles (iy7y), radiocarbon residues
in tissues of 2U Swiss-Webster male mice given single intraperitoneal injections
of 1.16 mg/kg (U.13 ud) [1-14C] oxamyl were very low. Residue levels ranged
from 11.U ppb in tne testes to 37.U ppb in the liver 96 hours after dosing.
C. METABOLISM . k
Uxamyl is metabolized extensively in rats and mice. Urine and feces
collected from two male Charles River-CD rats given a single oral dose of
l.U my [l-14c]oxamyl were analyzed 72 hours9after dosing; more than 70% of the
recovered radioactivity appeared as conjugates of the oximino-metabolite of
oxamyl (metnyl N-hydroxy-N'a,N'-dimethyl-l-thiooxamimidate, OMTO; Fig. III-l-I) •
and N,N-dimethyloxamic acid (DM(JA; Fig. IiI-1-III), and as the monomethyl
o
derivatives metnyl N-hydroxy-N'.-methyl-l-thiooxamimidate (MTO; Fig. III-l-II)
and N-metnyloxamic acid (MUA). The percent distribution of these four metabolii
was "ougnly equivalent in both urine and feces, although the urine contained
approximately bb% of the original radioactivity and feces contained about 15%.
No oxamyl or other organosoluble metabolites, including N,N-dimethyl-l-cyano-
formamiae (UMCF), were found in urine, feces, or tissues. Approximately 43 and
61% of tne radioactivity recovered, respectively, In the plasma and hide of
rats was incorporated into various ami no acids (Harvey and Han, 1978b). In the
tes :»
II1-2
-------
-COOK
Figure III-l. In vitro metabolism of oxamyl by rat liver microsomes.
• I: DMTO
II: Metnyl N-hydroxy-N'-methyl-1-thiooxamimidate (MTO)
III: DMOA
V: DMCF
VI: Metnyl N'-methyl-N-[(methylcarbamoyl)oxy]-l-thio-
oxaraimidate (DM0).
SOURCE: Adapted from Harvey and Han (1978b).
III-3
-------
-------
skin and hair, 14C was associated primarily with glycine, trypt-ophan, leucine,
phenylalanine, and aspartic acid; leucine, glutamic acid, lysine, arginine, and
tryptopnan contained the greatest proportions' of radiocarbon recovered in the
blood.
The metabolic profile of urine collected from 2U male Swis»s-Weoster mice
yiven single ip injections of 1.16 my/kg [l-l^Joxamyl was similar to that in
rats (Chang and Knowles, 1979). The major urinary metabolite was DMTO, which
accounted for an average, of 43.5% of the radioactivity excreted by the animals'
during tne 96-hour postdose collection period. Urinary DMOA ranged from 8.9
6
to 27.2% of the recovered radioactivity, with the highest concentrations appearing
early in the study. MOA levels increased steadily from 2.3 to 9.9% during the
i * °
••
96 hours after dosing, and MTU levels, which peaked at 15% after 2 days, dropped
(
to 6.9% during the last interval of the study (72 to 96 hours after dosing).
In contrast to rats, mice excreted both unchaged oxamyl.and OMCF, wnich comprised
up to 18.3.and 3,U% of the total radioactivity recovered in the urine, respectively.
Six unknown compounds we.^e also excreted by mice. Results from this study
indicate tnat demetnylation of oxamyl and its metabolites occurs with time.
The data also suggest that, altnough tne metabolism of oxamyl varies sligntly
oetween rats and mice, oxamyl degradation in these two species is generally
similar to that in plants and in tne environment (see Chapter II, Pnysical and
Chemical P-operties).
In anotner experiment by Harvey and Han (iy78b), one rat dosed with 1.1 mg
(1U.7 uCi) [l-14c]DMCF (rather than oxamyl) excreted conjugates of DMOA and MOA
(lb and 7%, respectively,-of the total radioactivity) in the urine over a
72-hour period after dosing. An additional 27% of the radiocarbon recovered in
the urine was associated with amino acids. The authors postulated that the
III-4
-------
remaining'l^C-was prooably Incorporated Into other natural constituents.
Tissues, carcass, and blood from the [l-14C]DMCF-treated rat contained very low
levels of radioactivity; 23 to B9% of the 1*C residues from these fractions
appeared as amlno acids. 7-3 absence of DMCF In rat urine and the similarities
In metabolites from oxamyl- and DMCF-treated rats suggests that DMCF Is only an
Intermediate In the metabolism of oxamyl In the rat.
In vj_tr_o oat a support In vl^vo metabolism studies In rats and mice. In a
stady conducted by Harvey and Han (1973b), three levels of [l-l*C]oxaniyl (0.3,
1.0, and 2.U 119) were Incubated for 2 hours with mlcrosomalt and/or soluble
(cytosollc) fractions obtained from the livers of Charles River-CD rats:' A
control system containing 1.0 mg of [l"4C]oxamyl 'but no hepatic mlcrosomal
fraction accompanied each test system. In addition to oxamyl, DMTO, DMCF, and ,
DMOA were present In substantial amounts at the end of the 2-hour reaction
period. Tnese four compounds comprised 93.b to 96.8% of the total radioactivity.
Small amounts of the monomethyl derivatives of oxamyl and Its oxlmlno compound..
(DMTO) were also present In the Incubation medium. The control medium contained
only DMTO In approximately tne same concentration as In the test samples,
suggesting tnat hydrolysis of-oxamyl Is Independent of the liver microsomal
fraction.
B
After a 2-hour In vitro Incubation period with [l-l^joxamyl (200,000 dpm)
and mouse liver suocellular fractions, the primary metabolite formed was DMTO
;iZ.5 to 24.u% of the total recovered radiocarbon) {Chang and Knowles, 1979).
Oxamyl as parent compound represented approximately 70 to 8U% of the total
radioactivity. DMCF, DMOA, MOA, methyl N1-methyl-M-[(methylcarbomoyl)oxy]-l-
tniooxamimlaate (DM0), and several unknown compounds were also present, but in
very low concentrations.
III-5
-------
Un tne oasis' of In vivo and supporting in vitro data, Harvey and Han
(1978b) postulated that oxamyl metabolism occurs by two major pathways: by
hydrolysis .to DMTO ana by enzymatic conversion via DMCF to DMOA. 'Superimposed
on tnese two pathways is another slower enzymatic process that results in
partial demethylation of the dimethyl carbamoyl group. The proposed vn vitro
metasolism of oxamyl by rat liver microsome (Harvey and Han, 1978b) appears in
Figure III-l. Tne authors did not comment on the metabolic'incorporation of
14C into tne various amino acids, nor did they report the position(s) of the
carbon label associated with radiolabeled amino acids.
*• *
Oxamyl metabolism in vitro and in vivo is very similar. The two path-
e>
ways share tnree major products: DMTO, DMOA, and MTU. Rats and. mice also •
excrete MOA following either oral or ip dosing. Demethylation has been
demonstrated in Doth in vivo and in vitro studies. Differences in oxamyl
metabolism oecome evident when comparing species. DMCF is considered a
metabolic intermediate only in rats, but the compound is actually excreted in
the urine of mice. Unchanged oxamyl is completely metabolized by orally dosed
*ats and by microsomes isolated from rat hepatocytes, wnereas the urine of
ip-aosed mice contained up to 18.3% of the unchanged parent compound (Harvey
and Han, IS/BD}.
D. ELIMINATION
Oxamyl is rapidly eliminated following ingestion in rats and ip dosing in
mice. In ooth species, elimination occurs primarily via the urine. -Two Charles
River-CD rats treated with a single oral dose (1.0 mg) of [l-14C]oxamyl excreted
an average of 55 and 15% of the original radiocarbon in the urine and feces,
repectively, duriny the 72-hour period that followed dosing (Harvey and Han,
198D). Little radioactivity (less than 0.3%) appeared in expired air of dosed
111-6
-------
F. SUMMARY
Oxamyl is rapidly aosorbed, metabolized, and eliminated. In orally treated
-3-5, mo.-e tnan half (54.3%) of an oxamyl dose was eliminated in the urine and
about 15% in the faces within 3 days after ingestipn. Mice excreted approxi-
mately 87% of an ip dose of oxamyl in the urine and 7.2% in the feces Dy 4 days
postaaministration.
Due to -apid elimination of a large proportion of administered
aoses, individual tissue levels of radioactivity remain low in ip-dosed mice.
Oxamyl, or its metabolites, did not accumulate to any appreciable amount in any
rats. In- a study witn 20 male Swiss-Webster mice, 88 and 7% of a 1.16-my/k-g
ip-aose of [^Cjoxamyl appeared in the urine and feces, respectively, by 72 hours; ij
more than 75% of the dose was eliminated in the urine (72.7%) and feces (3.U%)
during the initial 6 hours after administration (Chang'Snd Knowles, 1979).
E. 3IUACCUMULATION AND RETENTION
No information on tne bioaccumulation or retention of oxamyl following
repeated dosing was found in the 'available literature. Due to the rapid excre-
tion and metabolism'of the compound, and low ttssue levels in 20 ip-dosed mice,
significant accumulation and retention of the pesticide are not expected. How-
eve.-, tne presence (at 72 hours postadministrati on) of approximately 19% of an
oral aose of 1.0 mg [l—4c]oxamyl in each of the bodies of two rats given the
f
cnemical suyyests tnat oxamyl or its metabolites may accumulate in or be retained
oy various body fractions, such as the skin, hair, carcass, liver, and Dlood.
Incorporation of i*C from the tagged parent compound into natural constituents
^e.g., amino acics) also points to retention of oxamyl by the body.
III-7
-------
tissue in mat'species, although in two orally dosed rats, 7 to 12.B* of the
original 1*C was recovered in the hide (skin and hair) 3 days after dosing, and
a total of 19% was retained by the whole body.
Uxamyl was extensively metabolized following oral administration to rats
and ip administration to mice. The primary urinary metabolites excreted by
both species were DMTO, OMOA, MOA, and MTO. Unlike rats, mice excreted the
unchanged parent compound as well as DMCF. In vitro studies demonstrate that
3
oxamyl is metabolized by hepatic microsomes via two major pathways; the first
involves hydrolysis to UMTU, and the seco'nd involves enzymatic conversion via
• * . a
DMCF to DMUA. A minor enzymatic process,'which results in partial demethylation.
of oxamyl and its metabolites, was also noted. . ' -f
*' 4
Based on the" above findings, accumulation and retention of oxamyl in the
body is not expected, altnough radiolabfil from the oxamyl moiety [14C] has been
found in amino acids.
III-8
-------
IV. HUMAN EXPOSURE
To be provided by Science and Technology Branch, Office of Drinking
Water.
IV-1
-------
V. HEALTH EFFECTS IN ANIMALS
A. SHORT-TERM EXPOSURE
1. Lethality
... ' t
Uxamyl has been snown to be extremely toxic when administered orally to
laboratory animals. Kennedy (1986a) reported acute oral LD5Q values of 2.5. to
3.1 mg/kg for fasted rats, 2.3 to 3.3 trig/kg for mice, and 7.0 mg/kg for guinea
pigs. Typical signs of cholinesterase inhibition such as tremors, salivation,
B
and lacrimati.on were noted 'immediately after dosing {Kennedy, 1986a).
»
, Qxamyl is also extremely toxic after intraperitoneal injection. An LD5Q i
o
,...i.n .-rats of 4.U mg/kg w,as reported by Kennedy (1986a). Single intraperitoneal •
i
injections of oxamyl in saline resulted in mortality within '2 hours in mice
yiven doses of 2.3 m^/ky or greater and in guinea pigs given doses of 5.1
mg/kg or greater (Kennedy, 1986a). Oxamyl is less toxic via -the: dermal route;
LDjj values of 750 and >1,200 mg/kg were reported in rabbits and rats, respec-
tively. From these results,- oxamyl appears to be only partially absorbed
througn tne SKin. However, clinical signs of cholinesterase inhibition were
noted in animals given dermal doses -of oxamyl (Kennedy, 1986a).
Tne 1-hour LC^Q for rats exposed to oxamyl via inhalation (head-only
exposure) were 0.17 mg/L for males and 0.12 mg/L for females. The 4-hour LCgQ
was U.U54 mg/L for male rats. Clinical signs noted during exposure included
exopnthalmos, salivation, lacrimation, and gasping (Kennedy, 1986a).
A summary of the
and
values of oxamyl is presented in Table V-l
V-l
-------
Taole V-l. Summary of Acute Toxicity Values in Laboratory Animals
After Exposure to Oxamyl
Species (Sex)
Rat (M)
Rat (F)
Rat (M)
Rat (F)
Mouse (M)
Mouse (F)
Guinea yiy (M)
Rat
Rat .
Raooit
Rat (M)
Rat (F)
Exposure
route
oral
oral
oral
oral
oral
oral
oral
*P
aermal . . -
dermal
inhalation
inhalation
Acute
LU50:
LL)5U:
LU50:
LDsJi
LD50:
'LD5U:
LD5U:
LD50:
LCsS:
toxicity value
3.1 mg/kg
2.5 mg/kg
4.0 my/kg
2.8 mg/kg
3.3 mg/kg
2.3 mg/kg
7.0 mg/kg
4.0 mg/kg
>1200 mg/kg
740 mg/kg
0.17 mg/L (1-hr)
U.12 my/L {1-hr}
Reference
Kennedy (l'yb6a)
Reinhart (iy?l)
Kennedy (1986a)
Kennedy (1986a)
Kennedy (1986a)
Kennedy (1986a)
Kennedy (1986a)
Kennedy (iy86a)
Rat (M)
innalation
U.064 mg/L (4-nr) Kennedy (1986a)
V-2
-------
2. Uther Effects • . • -
Tne ability of oxamyl to innioit serum cholinesterase activity was studied •
in 10 rats given a single oral dose of 4.86 my/kg oxamyl approximately 90% of
LDjg. Tnis dose resulted in an approximately 40% decrease in serum choli nesterase
activity (decreased from a mean pretreatment value of 4.3 to a posttreatment
value of 2.b umol substrate hyarolyzed/ml/5 min) 5 minutes after exposure and a
6U% decrease (1.8 _+ 0.7 um substrate hyarolyzed/mL/5 min) 4 hours after
administration. Activity returned to normal level of 5.7 24 hours after
aaministrati on (Kennedy, 1986a). Little or no cholinesterase innibition was
observed whfen atropine sulfate (bO mg/kg) was admini'stered by ip injection
*3 ' "
immediate-ly after oxa'myl administration. No mortality occurred when atropine
was injected after a dose of pxamyl tna't normally would kill 50% of tne rats; • ' • • -.
t
however, fasciculations were noted in rats'receiving the oxamyl/atropine
«
comoination (Kennedy, 1986a).
p
Rats (six males) given repeated oral doses of 2.4 mg/kg of oxamyl 5 days/
week for 2 weeks exhioited mild fasciculations that lasted 2 to 4 hours during
tne first wee* ana 1 to 2 hours during tne second week. Slight decreases in
oody weignt were noted. The author stated that rats exhibited salivation and
sliynt pai lor after the first two doses, but no clinical signs were noted tnereafter
(Kennedy, 1986a). Hence, it appears that the rats developed a slight tolerance
to oxamyl after 1 week of oral dosing.
uxamyl appears to be less toxic to aogs after oral administration. Male
oeagles were given single oral doses of 5, 10, 15, or 3U mg/kg and observed for
21 days. All the oxamyl-treated dogs exhibited clinical signs of cholinesterase
inhibition, and one dog given 3U mg/kg died (Kennedy 19b6a).
V-3
-------
Repeated application of 50 or lUO my/kg of oxamyl in a dimethylformamiae
(DMF) vehicle to the abraded or intact skin of groups of five male and five female!
rabbits, 6 nours/day for 15 days, resulted in fasciculations, irregular breathing,!
reduced coordination, and salivation after each dose. These effects lasted •
approximately 4 nours (Kennedy, 19b6a). No effects were reportedly noted in
controls-exposed to DMF only. In a similar study, minimal effects were noted ;|
in groups of six male rabbits after application of 50 or 100 mg/kg oxamyl in an
aqueous methanol vehi-cle to intact or abraded skin.' Apparently, tne dimethyl-
•formamiae vehicle increased the absorption of oxamyl through the skin, resulting
in greater toxicity.
Minimal effects were noted after instillation of oxamyl (10 mg) into the "
- ' . ' i
eyes of rabbits. Slight constriction of the pupils, minimal congestion of the -
iris, and mild reaness and swelling of tne conjunctiva were reported (Kennedy
lyBoa). Eyes were essentially normal oy 24 hours postadministrati on. Kennedy
(1936a) reported that one of four rabbits exhibited reduced muscular co-
ordination in the hind limbs 20 minutes postdose; therefore, it appears that
some absorption of oxamyl occurred after ocular exposure.
B. LONG-TERM EXPOSURE
1. SUPi chronic Toxicity .
Haskell Laboratory conducted a study in wnich groups of 1U weanling
C.-1:CD rats of each sex were fed diets containing 0, 50, 100, or 150 ppm
of oxamyl (>9b% purity) for 90 days. These were comparable to dose levels of
app-oximately U, 2.5, b.O, and 7.5 mg/kg/day. Initially, for the first 4 days
of feeding, the high-dose group actually received 500 ppm of oxamyl in the
V-4
-------
diet. Thi-s aose caused Immediate, excessive weight loss, as well as fascicuia-
tlon, ruffled fur, and mild diarrhea In male rats. The males- and females fed
. the nigh dosaye were then placed on control diets for 3 days. From day 8 to
termination of tne study, the nigh-dose group received IBU'ppm In the diet.
fne only obvious.sign of toxlclty que to oxamyl administration was In body
weignt. Body weights were significantly lower (p y5* purity} in tne diet
(equivalent to dose levels of approximately U, 1.2, 2.b, and 3.8 myAg/aay,
respectively). No compound-related changes in body weight gain, food consump-
.
tion, clinical siyns, nematology, clinical chemistry, or pathologic findings •
were noted in ooth the control and compound-treated dogs. Only one control
male aoy lost 1.1 kg weignt; the rest maintained or gained weight. -Ine
autivfrr reuo-teo i-nfrequent, sporadic incidences of bloody mucoid diarrnea, eye
"c. *
discharge, inflammation, aenydration, thinning nair on cnest, and cysts in aogs
receiving oxamyl, but these were not considered to be related to oxamyl adminis-
tration (Kennedy, 19afab).
V-b
-------
2. Chronic Toxicity
Tnree long-term feeding studies with oxamyl nave been reported (Kennedy,
1986b). In trie first-study conducted^ at Haskell Laboratory, groups of 35
weanling CM:CD rats of each sex were yiven 0, 50, 1UO, or 150 ppm of oxamyl
(95% purity) in the aiet for 2 years, corresponding to doses of approximately
Q, 2.3, 5.0, and 7.5 my/kg/day. An additional control group of 36 male and 36
female rats was-fed a diet containing 0 ppm oxamyl. A-three-generation repro-
duction study was conducted simultaneously using 16 male-and 16 female rats
'from'each test group and one control group. "Animals were mated after 12 weeks
of exposure to test diets. Further details on the reproduction study' will be
*
given in tne following section. Cholinesterase activity in the whole blood .
• *.
(umol acetyltniocholine hydrolyzed in 5 min/mL blood) from control animals, and,
animals fed 1UU or 150 ppm was measured periodically during the study. Signif-
icant decreases (p £0.05) in cholinesterase activity were noted in females
receiving .tne hign dose (approximately 20% inhibition) after 4 cays and in males
receiving tne nigh oose (approximately 33% inhibition) after 8 days on study.
However, after 1 month, cnolinesterase activity retur-ed to normal and remained
within normal range tnroughout the remaining 2 years of exposure to 150 ppm of
oxamyl. Body weights were decreased in a dose-related manner with significant
reductions (p £U.05) noted in tne groups fed 100 and 150 ppm (males and females)
compared to controls throughout the study (Taole V-2). Females fed 50 ppm
oxamyl snowed no change in body weight tnroughout the study except at. 24 months
when mean oody weignt was significantly reduced (P <0.05). Slignt decreases in
food consumption of tne group fed IbO ppm compared to the control group were
reported. No clinical signs of toxicity attributable to oxamyl administration
were noted, and mortality rates were comparable between control and test groups.
Slight decreases in absolute organ weights (liver, spleen, kidneys) were noted
V-6
-------
" ' »
Table V-2. Mean Body Weights of Rats Fed Uxarny] for 2 Years
Months
on study
0
1 •
3
6
12
18
24 .
0
140
343
.'.so?
614
744
762
"799
Dietary
0
Males', (weight
142
• • 341
507 •
•601
738
778
806
Females (weight
0
1 . • •
3
6
12
18
24
118
208'
'287
343
- 446
569
640
119
211)
293
348
469
562
63b
level
50
In gr
142
326
492
584
725
782
744
(pom)
100
ams)
140
304*
474*
565
697*
754
750
150
139
282*
442*
511*
626*
768*
675*
in grams)
121
206
254
338
440
555
588*
119
186*
252*
290*
345*
.432*
460*
119 i
183* • •
248*
282*
328*
389*
415*
-- - , ,
'Significantly different from control value (p _
-------
in males and females fed 1UU or 1SU ppm of oxamyl, but tnese changes were not-
statistical ly significant. Organ-to-body weight ratios were comparable between
controls and. test.groups. Therefore, tne organ weight changes we~e attributed
* ^ 4
to decreased body weight. Histopatnologic examination revealed no_compound-
related abnormalities. Tumor incidences were comparable between controls and
test groups. The NOAEL for this study was identified as 5U ppm (2.5 -^/kg/day)
of oxamyl.
0
A second chronic study was conducted at WIL Research Laboratory (1981).
Groups of 80 .male and 80 female CD-I mice were fed 0, 25, 50, or 75 ppm of
Q
oxamyl (y?.l% purity) in the aiet for 2 years. These dietary levels'were
equivalent to mean doses of U, 3.75, 7.5, and 11.25 mg/kg/day. Initially, *
tne nigh-dosage group received 1UO ppm of oxamyl. However, excessive mortality'
occurred at this dietary level (10 males and 8 females in the first montn on
study); therefore, the high dosage was reduced to 75 ppm at week 6. The only
-clinical signs attributable to oxamyl administration were noted in animals . .
dying prior to terminal sacrifice. These included emaciation, lethargy, and
moriDundity. Slight, sporadically significant decreases (p £0.05) in body
weights were noted in animals from the groups fed 50 or 75 ppm, particularly
in the first 6 months of tne study. Several hematoloyic parameters (hemo-
glooin, hematocrit, and red cell count) were significantly reduced (p <0.01)
in tne males fed the nigh dose compared with controls at week 4. These para-
meters were within normal ranges from week 13 to study terminat-ion. Histo-
patnological examination revealed no lesions attributable to oxamyl administra-
tion. Chronic nephritis was noted in a number of animals at terminal sacrifice.
However, increased incidences were noted in control animals compared to other
groups; control males had an incidence of 52% compared with 23, 20, and 13% for
the males fed oxamyl at 25, 5U, and 75 ppm, respectively. The incidence of
V-8
-------
chronic nephritis in control fema.les was 15% compared wltn 6, 10, and 3% for
females fed oxamyl at 25, 50, and 75 ppm, respectively.' Tumor incidences were
similar for control and test groups (WIL, 1981; Kennedy, 1986b). The NOAEL for
tnis study was 25 ppm (3.75 my/kg/day).
Kennedy (1986b) aVso reported the results of a 2-year feeding study in
beadle dogs conducted at Haskell Laboratory. Groups of four dogs of each sex
were fed diets containing U, 50, 100, or 150 ppm of oxamyl for 2 years. These
dietary levels were equivalent to approximately 0, 1.3, 2.5, and 3.8 mg/kg/day,
respectively. No mortalities occurred during the study. Body'weights, food
consumption, clinical observations, and hematological and urinalysis parameters
*
•were comparable between control's and test groups. Serum alkaline phospha£ase \
' *
activity and cholesterol levels were increased (2 standard deviations above
pretest values for all groups) in animals fed 150 ppm compared to all other
aose groups including controls (significance was not reported). Histopatnologic
findings were observed with equal frequency in all groups including controls.
Tnere were no increases in incidences of lesions that could be attributed to
the inyestion of oxamyl.
C. TEKATUGENIC/REPROUUCTIVE EFFECTS
Kenneay (1986o) reported the results of a teratogenicity study in rats
conducted oy Haskall Laboratory (1971). rive groups of at least 22 timed-
pregnant Crl:CD rats were fed diets containing 0, 50, 1UO, 150, or 300 ppm of
oxamyl on days 6 to 15 of gestation, corresponding to doses of 0, 2.5, 5.0,
7.5, and ib mg/kg/day, respectively. Although not significantly different,
body weights of dams fed oxamyl were decreased in a dose-related manner. An
approximately 42% decrease in body weight gain was observed during the study
in dams fed 3UU ppm of oxamyl compared to controls (Taole V-3). A corresponding
V-9
-------
Table V-3. Mean Maternal Body Weights of Rats Fed
Oxamyl During Gestation
Mean body weights (g) during
Dietary
level
(ppm)
0
50
10U
150
3UU
gestatl
6
a
218
221
218
214 .
216
on days:
16
295
289
264
25U
'228
20
362
358
334 •
—324'
3UO
Standard deviations were not reported.
SOURCE': Adapted from Haskell Laboratory (1971).
V-1U
-------
dose-related decrease In food consumption was observed In dams fed oxamyl. 'No
significant differences were noted-In number of Implantation sites, live fetuses,
or resorptions between test groups and controls (Table V-4). Fetal growth, as
measured by Dody weight and crown-to-rump length, was comparable between control
and test groups. The Incidences and types of soft tissue and.skeletal abnor-
malities were similar in fetuses from dams fed either control or test diets.
In tnis study, oxamyl was not teratogenic in rats.
In.a teratogenicity study with raboits conducted at Hazleton Laboratories
(Snyaer, iy»U; Kennedy, iyb6o), groups of 17 artificially inseminated New
o »
Zealand White rabbits were given oral doses of 0, 1, 2, or 4 mg/kg/day of
oxamyl (97.1% purity) on days 6 to 19 of gestation. Two rabbits died during ?
*
tne study (one each from tne control and 30U-ppm groups), but these deaths were
probaoly due to technical errors in dosing. Significant decreases (p <0.05) in
body weight gain were noted in dams administered 2 and 4 mg/kg/day during the
treatment period (days 6 to 19 of gestation) compared to controls. (Table Vr5),-
Th=~e was a corresponding decrease in food consumption in the rabbits adminis-
tered 2 and 4 mg/ky/day during the treatment period. After tne dosing reyimen
enaea, nowever, the rabbits appeared to recover: body weight gains of dams
aaministereo 2 and 4 mg/kg/day exceeded those of controls during days 19
to 29 of gestation, and body weight gains for the entire study were comparable
between controls and all test groups. Mean numoer of implantations and live
fetuses, and sex ratios were comparable between controls and all test groups.
Boih Snyaer and Kennedy reported a slight increase (not significant) in the
incidence of resorptions in the yroup administered 4 mg/kg/day (mean incidence
of resorptions was 10.4 and 24.8 for control and high-dose groups, respectively),
indicating a slignt embryotoxic effect. Fetal oody weights and crown-to-rump
measurements were similar in control and test groups. Slight increases (not
V-ll
-------
TaDle V-4. Effects of Dietary Administrat-ipn of Oxamyl on Pregnant
Rats and Their Offspring .' : • • ,,
. • . • • • •• .11
Dietary level (ppm) •
Parameter
Femal
femal
es preynant/
e on study
0
22/26
50
26/27 .
No. of implantations/
litter
Live
Litre
fetuses/1
rs with
•> ft of
. UUw^
resorptions (%)
Total numoer of
res or
Fetal
ptions (»
body wei
)
ynt (g)
10.6
10.0
9
13
3.8
i 1.8
± 2-2
(41)
(6)
jf 0.4
10.8
10.2
11
'. 17
4.0
i 2.2
±2.1
(42)
(6)
^ 0.3
100
150
•
: 25/28., ' 26/28
•^
11.3^1.9 10.3
10.8 i 2.0 9.8
9 (36) 9
12 (4) 14
3.9 jf 0.3 4.0
± 2-5
i 2.5
(35)
(5)
•*• 0.4
•.!
i!
300 i
i
1 *
23/28
*
' 10.8 i!
10. ri *_
f
«••**'
2.c
10 (ji£^
P
16 (ci)
3.8 ^||0.4
!l
SOURCE: Adapted from Kennedy (1986b).
V-12
-------
Table V-5. Mean Maternal Body Weight Gains in Rabbrts Given
Oral Doses of Qxamyl During Gestation
Dose level
(my/ kg/day)
0
1
2
4
Body
0-6
58. U
66.0
59.7
113.1
weight gain'
6-19
169.5
154.4
65.2*
55.6*
(g) on oestation
19-29'
138.4
' 144.1
0
157.1
218.6 '.
day:
.0-29
36b.9
368.7
282.0
387.3
6 . «
*Significant1y different from controls at p
-------
significant) were observed in the number of visceral and skeletal abnormalities
•(variants and anomalies) in. litters from dams administered 1 mg/kg/day'compared
to otner groups including controls (Table V-6). These increased incidences did
*
not occur in a dose-related manner and were not statistically significant.
Therefore, they were considered to be incidental occurrences. The author
concluded tnat oxamyl was not teratogenic in rabbits under the conditions of
.•*•-' . ' *
tnis" study. . - . " '
A one-yeneration reproduction study-was conducted by Haskell Laboratory
(Kennedy, 1986b). Groups of six Crl:CD rats of each sex were fed diets con-
taining oxamyl at levels of U, 5U, 1UU, or 150 ppm (equivalent to doses of 0,
2.5, o.O, and 7.5 my/kg/day) continuously for -31 to 95 days and mated to produce
j£
two litters (Fia-and FID). This study was run concur-ently with a 90-day feeding
study (see Section V.B.I.). Body weights were significantly decreased (p £0.05)
in parental males fed 100 or 150 ppm starting 28 days after initiation of
tne study. Decreases were also ooserved in parental females from, the groups
fed 100 and 150 ppm, but significant changes were sporadic. Fertility did not
appear to oe affected by ingestion of oxamyl. The number of Fia pups delivered
to flams from the 1UO- and 150-ppm groups, and the number of F^J PUPS delivered
to clams fed IbO ppm of oxamyl, were slightly decreased compared to controls.
Survival of pups was not affected during lactation. Significant decreases
(p £U,Ob) were observed in the body weights of weanlings from both F}a and F^b
litters in the groups fed 50, 100, and 150 ppm compared to controls..
A suosequent tnree-generation reproduction study in rats was conducted con-
currently with a 2-year feeding study (Section V.3.2.). After approximately
12 weeks of ingestation of oxamyl at dietary levels of 0, 50, 100, or 150 ppm,
16 male and 16 female Crl:CD rats from each group were paired (Fg parental
V-14
-------
Table V-6. Summary of Visceral and Skeletal Findings in Fetuses
of Rabbits Given Oxamyl During Gestationa
Dosage levels (mg/kg/day)
Observation
No. examined
Variants: -. '
Intermediate lobe of lung
absent
Very small stomach
Slightly dilated renal pelves
Anomalities,;
Hydrocephaly
Cleft palate
Ectopic kidney
Variants:
Angulated hyoid wing
Fused sternebrae
Fused rios
0 1
113 90
Visceral
0 3
U 2bc
1 2
.
0 2bc
0 1C
0 • 1
Skeletal
3 3
0 2
0 2 .
, 2
89
Examination
1 .
U
1
0
0
. o
Examination
1
1
1
4
75
,
0
0
0
0
0
U
0
0
0
aNumoers represent the number of pups arfected in
bcihe same superscripts indicate tne same pup.
SUURCE: Adapted from Synder (1980).
V-15
-------
" generatio'n^ to produce two litters"(Fla and Flb generations). The"Flb and F2b
generations we.-e mated at approximately 111) days of age to produce F2 and f^
generations (two litters each), respectively. Reproductive indices such
as fertility index, gestation length, pup viability, and lactation index were
comparaole between control and test groups for all generations. .Litter size
and mean body weights of weanlings from 'dams ingesting the 1UO- or 15U-ppm
-levels of oxamyl were significantly decreased (p <0.05) in the majority of
generations compared to controls (TaDle V-7). Histopathological'examination of
animals from each generation (parents and offspring) revealed no abnormalities
attributable to oxamyl ingestion (Kennedy, 1986b).
e
D. MUTAuENICITY • ;
j
Limited information was available in the literature on the mutagenicity of
oxamyl. '
1. Gene Mutation Assays (Category 1) ......
a. Gene mutation in prokaryotej
Moriya et al. (1983) reported the evaluation of oxamyl in the mammalian/
microsome "everse mutation assay (Ames test). Sa1 mone 11 a typhrimyriurn,
strains 7A100..TA98, TA1535, .TA1537, and TA1538, and Escnerichia coli, strain
WP2 ncr, were exposed to concentrations of up to 5.UOO ug/plate of oxamyl with
or without activation (rat liver S9 mix). Results were negative, indicating
that oxamyl is not mutagenic to _S. typnimurium or IE. coli. Negative results
were also reported oy Shirasu et al. (1976) following a reverse mutation assay
conducted in S_. typnimurium strains TA1535, TA1537, TA1538, TA98, and TA100,
and £. coli strain WP2 her. Concentrations of 10 to 1,000 ug/plate of oxamyl
V-16
-------
Table V-7. Effects of Uxamyl Ingestion on Litter Size and Body Weights
. of Weanlings In Three Generations of Rats
Dietary
level
(ppm) Gene.-ation
0 Fla
50
100
150
0 Flb
50
100
150
0 F2a
50.
100
150
0 F2b
bO
100
150
y p^
50
100
IDO
U F3b
50
100
150
Mean
litter size3
12.3
10.9
10.2*
10.4
13.6
12.3
11.3*
11.1*
11.9 .
12.3
10.6
10.4*
12.9
12.5
11.0*
11.0*
12.4
12.2.
10.2*
9.9*
12.6
13.1
12.2
10.3*
Mean weanli ng
body weight
(g.)
53
52
44*
39*
57
55
47*
• 42*
53
49
41*
36* . '
57
52
42*
37*
52
48
43*
37*
52
50
39*
37*
er of pups per litter.
*Significantly different from control value (p £0.05).
SOURCE: Adapted from Kennedy (1986b).
V-17
-------
in the absence or presence -of an activation system (rat liver S9 mix) were not
mutagenic.
' *- ' *. ' "
D. In vi t ro gene mutati ons " - .
No mutagenic response was obtained in a host-mediated assay-with S_.
typnimurium, strain G 46 hys, after oral administration of oxamyl at total
doses of 2 or 4 my/kg to male ICR mice (two equal doses were administered over
a 24-hour period) (Snirasu et al., 1976).
The mutagenic potential of oxamyl was tested in Chinese hamster V79 target
cells with fcr without activation (irradiated Syrian hamster fetal cells).
«• . a
Treatment with oxamyl (concentrations not specified) for 72 hours, with or
without activation,_ hacLno..significant effect on mutagenic frequency (Wojciechowski
and Kaur, 1980).
2. Chromosome Aberration Assays (Category 2) -.
!i
NO chromosome aberration studies with oxamyl were found in the available
literature. • /> o
3. (finer Mutaoenic Mechanisms (Category 3)
V
The evaluation of tne'effect"of oxamyl (94% purity) on DNA-damage/repair
a
capaoility was evaluated using Bacillus subtil is strains H-17 Rec+ and M-45
Rec-. Concenta.tions of 2U to 2,UUO ug/disk did not preferentially inhibit the
repair-deficient strain (M-45 Rec-) compared to the repair-competent strain
(H-17 Rec^} (Shirasu et al., 1976).
V-18
-------
E.. CARCINOGEN 1CITY . '
Two chronic feeding studies In rodents have been conducted and were
described earlier (see Section V.B.2.) In the feedlny study conducted with
rats at Haskell Laboratory (Sherman et al., 1972), groups of 36 male and 36
female Crl:CU rats were fed oxamyl at 0, bO, 100, or 150 ppm for 2 years (equi-
valent to mean doses of U, 2.5, b'.U, and 7.b mg/kg/day, respectively. Significant
decreases In body weight were observed In both males and females fed 100 or 15U
ppm compared to controls. A summary of the histopathological findinys Is
presented In Taole V-8. The Incidence of mammary tumors was 67% In control
females ana 33% In females fed IbO ppm; no mammary tumors occurred In males.
Pituitary tumors occurred In incidences of 23 (one of the control groups) to
. 9
33% in males- fed Ibtl. ppm and b7 (one of the control groups) to 37% in treated ?
female's." After reanaljcsis of the statistics, there appeared to be a significant
: . - o . . . . » p
increase (p <0.u5) in the incidence of liver microgranulomas in both males and
' ' a *
females fed 15U°ppm compared to controls. This lesion is characterized by a
»... •
granular cnanae in tne liver and considered nohneoplastic. Tumor Jjictqences
„
were comparaole between the control group and the hign-dose group. In this
study, oxaffiyl aid not induce a carcinogenic response in rats (Kennedy, 1986b).
It should De noted, however, that several deficiencies existed in this study.
Adequate numoers of animals were not tested or examined histopathologically
(36/sex/group). Possible target organs such as the liver or reproductive
organs were apparently not histologically examined in all dose groups. In
addition, tumors observed, i.e., tnose found in mammary and pituitary tissue,
were not aaequately descrioed in the report.
In tne second feeding study, groups of 8U CD-I mice of each sex were fed
diets containing oxamyl at U, 25, 5U, or 7b ppm for 2 years, corresponding to
mean dosayes of U, 3.7b, 7.5, and 11.25 my/kg/day. Decreases in body weight
V-19
-------
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V-20
-------
(sporadically significant) in the 5U- and 75-ppm groups were noted (see Section
V.B.2.) Histopathological examination revealed no significant increases in
tumor incidence in. test groups compared to controls. A summary of the tumor
data is presented in Table V-9. Tumors observed were those commonly found in
aging animals and were not considered to be attributable to oxamyl administration.
The incidences of hepatomas were 11 and 25% for control males and males fed
150 ppm, respectively, for mice surviving to terminal sacrifice; no hepatomas
were observed in females. Lung adenomas occurred at incidences of 22 and 23%
for control males and males fed 150 ppm, respectively, and 0 and 3% in control
and high-dose females, respectively, for mice surviving to termination of the
study. There were no significant increases in tumor.incidence in test groups .
V
compared to controls. Oxamyl was not carcinogenic in mice under tne conditions
of tnis study.
F. SUMMARY
Uxamyl has been shown to be extremely toxic to laboratory animals following
acute oral, intraperitoneal, or inhalation exposure. Acute 1$$$ values in rats
ranged from 2.5 mg/kg for oral ingestion to 4.0 mg/kg after ip injection.
Mortality occurred immediately after dosing, and signs of cholinesterase inhioi-
tion such as salivation, fasciculation, and tremors were observed prior to
death. No delayed deaths occurred. Cholinesterase innibition appears to be
the major mechanism of toxicity following oxamyl administration. Administration
of atropine after treatment with lethal doses of oxamyl prevented mortality and
cholinesterase inhibition in rats. Dermal absorption of oxamyl (in solution)
appears to be limited. The acute dermal LDso for rabbits was 740 mg/kg. Clinical
signs of cholinesterase inhibition were observed prior to death, and mortalities
V-21
-------
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V-22
-------
usually occurred witnin 4.5 hours postadministration. Histopatholoy-ical examina-
tion of tissues did not reveal any abnormalities after acute exposure.
Oxamyl is also hiyhly toxic to rats and mice following lony-term oral
exposu-e. Kats fsa 1UU ppm (6.U to 7.0 mg/kg/aay) for 91) days exnioited
significant decreases in Dody weight gains compared to controls. Decreases in
Dody weiynt occurred in 28 days for male rats inyesting oxamy'l at 1UO or
IbU ppm {t>.U and 7.6 my/ky/day). In this study, clinical signs of crriinesterase
innibition and severe weiynt loss were observed in rats fed 500 ppm for 2 days.
No target organs were ioentified. Histopathological examination of tissues did •
not reveal any abnormalities attributable to oxamyl ingestion.
Similarly, decreases in body weight yain were observed in rats fed 1UO or
i
IbU pum (b.U and 7.6 my/kg/day) of oxamyl for 2 years. Rats inyesting 150 ppm'
t
aid not exnibit overt clinical signs of cnolinesterase inhibition. However,
cnolinesterase activity in blood was lower in females after 4 days and in males
after 8 days of exposure to oxamyl at 151) ppm. The type, onset, and distribution
of neoplastic and nonneoplastic lesions were unaffected &y inyestion of .oxamyl.
Tumor incidences and types were comparable between controls and mice fed 150 ppm.
Mice fed oxamyl at 5U ppm (B.7 to 10.8 my/kg/day) for 2 years exhibited
o
decreases in ooay weight yain, particularly in the first 6 months of study.
In tnis stuay, excessive mortality and aecreases in body weight were observed
in mice fed 1QU ppm du-ing the first month of study. 'This necessitated reduction
of tne luu-ppm dietary level to 7sj ppm. Histopathological findings-were com-
paraole between control and test groups. There were no compound-related
increases in incidence or type of neoplastic or nonneoplastic lesions.
Uogs fed diets containing up to 16'0 ppm of oxamyl for 90 days did not
exnioit any signs of toxicity compared to control animals. Uogs fed 150 ppm of
V.-23
-------
oxamyl .for 2 years- exhibited increases in serum alkaline phosphatase activity
and cholesterol levels, suggesting some effect on the l:ver; however, histo-
patnoloyical examination of the liver and otner tissues did not reveal any
aDno~malities. No differences in body weights, food consumption, clinical
siyns, or hematological parameters were observed in doys investing up to 15U
ppm of oxamyl.
Ingestion of up to 15p ppm of oxamyl for 2 years did not affect the
longevity of rats, mice,.or doys. Oxamyl was not considered to be carcinogenic
in rats or mice following cnronic exposure to 15U -or 7b ppm of oxamyl, respec-
tively, in the diet. This is supported by the negative results of several j_n_
(
vitro mutayenicity assays.
Tne teratogeniciry and reproductive toxicity of oxamyl were studied in
rats and raboits. A teratogenicity study in rats revealed that, although
ma~ernal toxicity eviaenced by decreased body weight gain was observed in
pregnant rats.fed oxamyl at 1UU ppm (8.2 mg/kg/day), -no increase in fetal
variations or malformations were noted in oxamyl-treated groups fed up to 3UU
ppm (2U.b mg/kg/day) compared to controls. Similarly, in pregnant rabbits
given oral doses of oxamyl at 2 my/kg/cay, decreases in maternal body weight
gain were noted during the treatment period (day 6-15 .of gestation). No
compound-related effects on tne fetuses were noted. Tnerefore, oxamyl is. not
consiaered to be teratogenic in rats or raooits.
Developmental toxicity of oxamyl was demonstrated in both one- and tnree-
generation reproduction studies in rats by decreases in the litter size of
dams fed oxamyl at 1UU ppm (6.2 to 7 mg/kg/day). In addition, reductions were
observed in tne body weignts of weanlings from dams fed 1UO ppm of oxamyl.
V-24
-------
Parental • toxicity was apparent at luu ppm, as evidenced by decreases in body ..
weight gain of both males'and females. Oxamyl-did not affect fertility of rats
fed up to 15U ppm (9.3'to lu.l mg/kg/day}, and no increases in incidences of
variations or malformation i-n pups from the 15U-ppm group were observed.
V-2b
-------
-------
VI. HEALTH EFFECTS IN HUMANS
No studies *ere found in the available literature on the effects of
oxamyl exposure in humans.
VI-1
-------
i
VII. MECHANISMS UF TQXICITY
* "
Specific., studies on the mode of .action of oxamyl were not found in tne
availaole literature. However, the results of tne acute animal toxicity
studies (ci-ted in.Chapter V) indicate .that the primary mechanism of .toxicity
of oxamyl, as is the case witn otner caroamate insecticides, is cholinesterase
innio.ition. Tnis is evidenced oy the typical clinical signs of cholinesterase
inhioition sucn as salivation, lacrimation, tremors, and fasciculations.
Carbamate insecticides appear to interfere witn the cholinesterase trans-
mission of nerve impulses across nerve synapses (Kuhr and Dorough, 1976).
Specifically, caroamates enter the synapse, reacting with or inhibiting acetyl-
cnolinesterase (ACnE), thus preventing the cleavage of tne normal suostrate, i
acetylcndline. There is an accumulation of acetylene line in the nerve «
synapse causing continued depolarization of tne postsynaptic membrane, wnich .
results in eventual failure of the peripheral nerve or effector tissue due ^o
prolonyed stimulation. Since peripheral cholinesterase synapses control vital -- ||
functions sucn as heartbeat and respiration, acute' exposure to lethal concen- ,.«-.-.[••.
trations of oxamyl causes rapid mortality in animals. i
il
The following equations illustrate the reaction of an N-metnylcarbamate il
insecticide with ACh£. Tnis is also the mechanism for aimethyl carbamate and \
-oryanopnospnorus insecticides (Kuhr and Dorougn, 1976). [!
Steo 1:
U U
<
HAChS + XUCNHCH^ > HAChE XUCNHCH3
Steo 2:
U 0
ii ii
H > HOX •»•
VII -1
-------
Steo 3:
H.,0 + ACnECNHCH^ ---- > HACnt +
Tne enzyme couples with tne insect-ici'de to form an intartneaiate complex
(Step i)., wnich can dissociate or decompose into a staole carsamylated enzyme
r»
(Step 2) plus a leaving yroup (the parent pnenol , naphthal. or oxime). The
caroarnylated enzyme then nydrolyzes to generate free enzyme and methyl carbamic
acid (Step 3). Tnus, the reaction _aes not result in destruction of ACnE.
However, hydrolysis of tne insecticide molecule occurs. Normally (without tne
presence of the insecticide), AChE cleaves acetylcnoline according to tne
aoove reaction, very rapidly. In the presence of tne insecticide (ouriny
«,
poisoniny), nowever, there is competition between tne insecticide and
t
acetylcholine for an active site on tne enzyme. Studies on the kinetics of
eitner reaction have snown that caroamates in yeneral have yreater affini-y for
» *
AChE tnan acatylcholine (O'Brien et al., 1966; Reiner and Aldridge, 1967).
unce attachment occurs, tne insecticide "ties up" .or inni^ts the- enzym§"t, s-ince
.''..«.. •
tne reactions in Steps 2 and 3 are much' slower for the enzyme-insecticide
complex tn&n for tne acetylcnoline-enzyme complex. The half-life for
aecarDamylction is approximately 30 to 40 minutes (Reiner and Aldridge, 1967).
VII-2
-------
VIII.. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
The quantifier-:"on of -toxicoloyical effects of a chemical consists of an
assessment of noncarcinogenic and carcinogenic effects. Chemicals that do not
produce carcinogenic effects are,believed to have a threshold dose below wnich
no adverse, noncarcinogenic health effects occur, whereas carcinogens are
assumed to act without a threshold.
A. PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS
1. Noncaj'ci nogeni c Effects
In the quantification of noncarcinogenic effects, a Reference Dose (RfD),
i
formerly called the Acceptaole Daily Intake (ADI), is calculated. .The. RfD is '
f
an estimate of a daily exposure of the human population that is likely to be
without appreciable risk of deleterious health effects, even if exposure occurs
over a lifetime. The RfD is derived from a No-Observed-Adverse-Effect Level
(NOAEL), or Lowest-Observed-Adverse-Effect Level (LOAEL), identified from a
suocnronic or chronic study, and divided by an uncertainty factor (UF). The
RfD "s calculated as follows:
RfD = (NOAEL or LOAEL 1
Uncertainty factor
= mg/kg bw/day
Selection of the uncertainty factor to be employed in the calculation of
the RfD is based on professional judgment while considering the enti're data
base of toxicological effects for the chemical. To ensure that uncertainty
factors are selected and applied in a consistent manner, the Office of Dr-'nking
Water (ODW) employs a modification to the guidelines proposed oy the National
Academy of Sciences (NAS, 1977, 198U) as follows:
VIII-l
-------
o An uncertainty factor of 10 is generally uSed when-good chronic or
subchronic human exposure data identifying a NOA&L are' available and
are supported by good chronic or subchronic toxicity data in other
spec'es.
o An uncertainty factor of 100 is generally used when good chronic
toxicity data identifying"a .NOAEL are available for one or more animal
•5
species (and human data are not available), or when good chronic or
-------
DWEL =
_ Rr'D x (body weight in _
Drink:ng water volume In L/oey
mg/L ( ug/L)
Body weight = assumed to be 70 kg for an adult.
Drinking water volume - assumed to be 2 I per day for an adult.
In addit'on to the RfD and the DWEL, Health Advisories (HAs) for exposures
of shorter duration {One-day, Ten-day, and Longer-term HAs) are determined.
The HA values are used as informal guidance to municipalities and other organi-
zations when emergency spills or contamination situations occur. The HAs are
calculated using a similar equation to the RfD and DWZL; however, tne NOAELs
*.
or LOAELs are identified from acute or subcnronic studies. The HAs are derived
as follows:
HA - (NQAEL or LQAEL) x (bw) =
• ( L/aayJ. x .( "
mg/L ( ug/L)
Using the above equation, the following drinking water HAs are developed
for noncarcinogenic effects:
1. One-day HA for a 10-kg child ingesting 1 L water per day.
2. Ten-day HA for a 10-kg child ingesting 1 L water per day.
3. Longer-term HA for a 10-kg child ingesting 1 L water per day.
4. Longer-term HA for a 70-kg adult ingesting 2 L water per day..
The One-day HA calculated for a 10-kg child assumes a single acute expo-
sure to the cnemical and Is generally derived from a study of less than 7 days'
duration. The Ten-day HA assumes a limited exposure period of 1 to 2 weeks and
is generally derived from a study of less than 30 days' duration. A Longer-
term HA ^s derived for both a 10-kg child and a 70-kg adult and assumes an
VIII-3
-------
exposure period of approximately 7 years (or 10% of an individual's lifetime).
9
A Longer-term HA is generally der'ved from ;a _st'Jdy of subchrcmic duration
• (exposure for 10% of an animal's lifetime).
2. Carcinogen*c Effect!
The EPA categorizes the carcinogenic potential of a chemical, based on
the overall weight of-evidence, according to the following scheme:
o Group A: Known Human Carcinogen. Sufficient evidence exists from
epidemiology studies to support a causal association between
exposure to the chemical and human cancer.
o Group B: Probable'Human Carcinogen. Sufficient evidence of care:no- '
, t
genicity in animals with limited (Group Bl) or inadequate
(Group 32) evidence 'n humans. -
o Group C: Possible Human Carcinogen. Limited evidence'of.carcinogeni-
city in animals in the absence of human data.
o Group D: Not Classified as to Human Carcinogenicity. Inadequate human
and animal evidence of carcinogenicity or for whicn no data
are available.
o Group •: Evidence of Noncarcinogenicity for Humans. No evidence of
carcinogenicity in at least two adequate animal tests in
different species or in both adequate epidemi ologic and
animal studies.
If toxicological evidence leads to the classification of the contaminant
as a known, probanle, or possible human carcinogen, mathematical models are
VIII-4
-------
used to calculate the estimate of excess cancer risk 'associated with the.inges-
tion of the-contaminant in drinking water. The data used in-these estimates
usually come from lifetime exposure studies in animals. To predict the risk
for humans from anima-l data, animal doses must be converted to equivalent human
doses, This conversion includes correction'for noncontinuous exposure, less-
than-lifetime studies, and for differences in size. The factor that compen-
sates for the size difference is the cube root of the ratio of the animal and
human body weights. It is assumed that the average adult human body weight is
70 kg and that the average water consumption of an adult human is 2 liters of
water per day.
For contaminants with a carcinogenic potential, chemical levels are cor- :
related with a carcinogenic risk estimate by employing a cancer potency (unit ,
risk) value together with the assumption for lifetime exposure via ingestion of
water. The cancer unit risk is usually derived from a linearized multistage
model with a 95% upper confidence limit providing a. low-dose estimate; that is,
the true risk to humans, while not identifiable, is not likely to exceed the
upper rmit estimate and, in fact, may be lower. Excess cancer risk estimates
may also be calculated using other models such as the one-hit, Wei bull, logit,
and probit. There is- little basis in the current understanding of the biolog"!-
cal mechanisms involved in cancer to suggest that any one of these models is
able to predict risk more accurately than any others. Secause each model is
based on differing assumptions, the estimates that are derived for each model
can differ by several orders of magnitude.
The scientific data base used to calculate and support the setting of
cancer risk rate levels has an inherent uncertainty due to the systematic and
random errors in scientific measurement. In most cases, only studies using
VIII-5
-------
laDoratory animals nave been performed. Thus, there is uncertainty when tne
0
data are extrapolated to humans. When developing cancer risk rate levels,
several otner areas of uncertainty exist, such as the incomplete knowledge
concerning the healtn effects of contaminants in'drinking water; the impact of
tne laboratory animal's age, sex, and species; the nature of the target organ
system(s) examined; and the actual rate of exposure of the internal targets in
laboratory animals or humans. Dose-response data usually are available only
for high levels of exposure, not for the lower levels of exposure closer to
where a standard may be set. When there is exposure to more than one contami-
nant, additional uncertainty results from a lack of information about possible
synergistic or antagonistic effects.
«,
8. QUANTIFICATION OF NONCARC INOGEN 1C EFFECTS FOR OXAMYL • ...
1. One-clay Health Advisory
No suitaole data were found in tne literature for calculation of-the One-
aay HA for oxarnyl. Therefore, a conservative estimate of the-One-day HA of 200
uy/L, tne Lonyer-term HA for a 10-kg child, was substituted as the One-day HA.
2. Ten-cay Health Advisory
.No cata found in tne literature were appropriate for calculation of tne
Ten-uay HA. Therefore, the Longer-term HA for a 10-kg child of 20U ug/L can be
substituted as a conservative estimate of tne Ten-day HA.
3. Longer-term Health Advisory
Two subchronic feeding studies were considered for derivation of the Longer-
term HA (Taole VIII-1). In a 90-aay feeding study conducted by Haskell Laboratory
(Kennedy, 1986b; Sherman et al., 1972) in which Crl:CD rats were fed diets
' . • • VIII-6
-------
Table VIII-1. Summary of Subchronic-feeding Studies Considered in the
Development of the Longer-term'Health Advisory for Oxamyl
'
Reference
Kennedy (1986b)a
Kennedy (1986b)
Species
(sex)
Rat
(M/F)
Dog
(M/F)
Duration Dose
Route (days) (ppm)
dietary 90 50
1UO
150
dietary 90 50
100
150
Effects
NUAEL
Decreased body
weight
Decreased body
weight
NOAEL
^Previously reported by Sherman et al. (1972). .
VIII-7
-------
containing U, oi), 1UO, or 150 ppm of oxamyl at equivalent doses of 'approximately
2.5, 3.0, ana 7.b mg/kg/day (U.S. EPA, 1987), the NUAEl was bO ppm (approximately
2.5 mg/ky/cay),'oased on decreases In body weight of males and females 'fed 100
or 15U ppm of oxamyl. In the second 9U-day feeding study conducted at Hazleton
Laooratorles (Kennedy, 19865), oeagles were fed diets containing U, 50, 100, or
15U ppm (approximately equivalent to doses of 1.3, 2.b, or 3.8 mg/kg/day).
The NQAEL for tnls study was identified as 3.8 mg/kg/day, tne nighest dose
tested, based on lack of cnange in any parameter measured including body weight,
food consumption, hematology, clinical cnemistry, or histopathological examination.
The yo-day feeding study in rats was selected for calculation of the Longer-
term HA because it was of appropriate duration, dose levels appeared to be
adequately cnosen, and the study was adequately conducted.
i
The Longer-term HA for a lU-kg child is calculated as follows:
(2.b nu/kg/oay) (10 ky) = u.2b my/L (rounded to. 20U ug/L)
U L/aay) (I'M) • "'' " ": " "\
wnere:
2.3 my/kg/day = NUAEL, oased on the absence of decreases in booy weight
of rats.
lu ky = assumed body weignt of a child,
1 L/day = assumed daily water consumption of a child.
10U * uncertainty factor, chosen in accordance with NAS/
ODW guidelines for use with a NOAEL from an animal
study.
Tne Longer-term HA for a 70-kg adult is calculated as follows:
(2.S mg/ky/day) (70 kg) = 0.87b mg/L (rounded to 900 ug/L)
(2 L/day) (1UO)
VIII-8
-------
wnere:
-2.3 mg/ky/aay = NOAEL, based on tne absence of decreases In body weight
of rats.
7u ky ~ assumed &.ocy weiyht of an aault.
2 L/oay * assumed daily water consumption of an adult.
10U = uncertainty factor, cnosen in accordance with NAS/
OUW guidelines for use with a NQAEL from an animal
study.
4. Reference Dose and Drinking Hater Equivalent Level
Tnree-cnronic feeding studies were considered for derivation of the
Reference Dose (Rfu") ana Drinking Water Equivalent Level (DWEL) {Taole VIII-2).
In a study conducted by Haskell Laooratory (Kennedy, 19866; Sherman et al., 19/2),
Crl:CU rais were fed diets containing 0, 50, 100, or 150 ppm of oxamyl for 2
years. Tnese levels were approximately equal to doses of 0, 2.5, 5.0, and 7.5
my/kij/aay (U.S. tPA, lya7). Significant decreases (p _
-------
Table VIII-2. Summary of Chronic Feeding Studies Considered in the
Development of the Reference Dose and Drinking Water
Equivalent Level for Oxamyl
Reference
Kennedy (lybbo)a
Kennedy (19b6o)
Kennedy (19B5o)
Species Duration Dose
(sex) Route (years) (ppm)
Rat ' dietary 'i 5U '
(M/F)
1UO
150
Mouse dietary 2 25
(M/F)
bU
75
• Dog • dietary 2 bO
(M/F)
100
150
Effects
NQAEL
Decreases in
body weight
Decreases in
body weight
NOAEL
Decreases in
body weight
Decreases in
body weignt,
decreases .in
. hematological
parameters
NOAEL
Decreases in
serum alkaline
phosphatase
activity and
cholesterol
levels
apreviously reported oy Sherman et al. (1972).
VIII-10
-------
phosphatase activity and cholesterol levels were increased in dogs at the
150-ppm dose level compared to controls. The NOAEL for this study was 100 ppm'
.'(2.5 rng/kg/day) (Kennedy, 1986b).
CD-I mice were fed diets' containing 0, 2b, 50, or 75 ppm (equivalent to
doses of 0, 3.5, and 11.2b mg/kg/day, respectively). Significant decreases-.
(p £O.U6) in the body weights of animals fed 50 or 75 ppm of oxamyl were spor-
adically noted only in the first 6 months of exposure, after which body weights
of mice in the 50- and 75-ppm groups were comparable to controls. Hemoglobin,
hematocrit levels, and red blood call counts were signficantly decreased
(p <0.01) compared to controls after 4 weeks of exposure. However, these
values were within normal range for the remainder of the study. The NOAEL for i
tnis study was 25-ppm (3.5 mg/kg/day).
The rat feediny study conducted at Haskell Laboratory was selected for
calculation of the RfD and DWEL because Jt was a comprehensive, adequately.run
study of appropriate duration. In addition, tne NOAEL for this study (2.5 mg/
kg/day) was supported by NOAEL values of 2.5 and 3.5 mg/kg/day identified in
the cnronic dog and mouse studies, respectively.
The DWEL for a 70-kg adult is calculated as follows:
Step 1: Determination of the RfD
RfD = (2-5 mg/kg/day) = u>025 mg/kg/day (25 ug/kg/day)
where:
2.5 my/kg/day
100
NOAEL, based on absence of changes in body weight
in rats.
uncertainty factor, chosen in accordance with NAS/OOW
guidelines for use with a NOAEL from an animal study.
VIII-11
-------
Step 2: Determination of the DUEL
DWEL = (0.025 my/kq/day) (7U kg) = 0.875 mg/L (900 ug/L)
-
where:
0.025 my/kg/day = HfD.
70 kg = assumed body weight of an adult.
2 I/day = assumed daily water consumption of an adult.
C. QUANTIFICATION OF CARCINOGENIC EFFECTS FOR OXAMYL
Two studies were considered for derivation of carcinogenic risk estimates
for oxamyl. In a 2-year feeding study in which Crl:CD rats were fed oxamyl at
.levels of 0, 60, 100, or IbO ppm (equivalent to daily doses of 0, 2.5, 5.0, and
7.5 my/kg/day) systemic toxicity in the form of reduced body weights was noted
in males and females fed 100 or 150 ppm of oxamyl. Histopathologic evaluation
of tissues from control and high-dose animals revealed no increases in incidence
of neoplastic or nonneoplastic lesions attributable to oxamyl ingestion (see
Section V.E. and Table V-8) (Kennedy, 1986b; Sherman et al., 1972). A few
deficiencies were noted in this study. Numbers of animals tested and examined
histoloyically (36/sex/dose) were not adequate according to current standards.
In addition, possible target organs such as the liver and reproductive organs
were apparently not examined histologically in all groups.
Similar results were obtained in a 2-year feeding study in CD-I mice fed
0, 25, 50, or 75 ppm of oxamyl (equivalent to daily doses of 0, 3.5, 7.5, and
11.25 mg/kg/day, respectively). Decreases in body weight were noted in males
and females fed 50 or 75 ppm of oxamyl, particularly in the first 6 months of
study. As in the rat study, ingestion of up to 75 ppm (11.25 mg/kg/day) of
VIII-12
-------
-------
oxamyl did not result in increased incidences in type or frequency of tumors in
mice {see Section V.E. and Taole V-9) (Kennedy, 1986b; Snyder, 198U}.
The available aata suggest that orally ingested oxamyl is not carcinogenic
to laboratory animals. Therefore, no calculation of excess cancer risk was
performed.
D. SUMMARY
Taole VIII-3 summarizes the HA and-DUEL values for oxamyl.
Oxamyl may be classified in Group E: Evidence of Noncarcinogenicity for
Humans, based on the results of at least two adequate animal tests ui different"
ts
species in which no evidence of carcinogen!city was obtained (U.S. EPA, 1987).
VIII-13
-------
Table VIII-3. Summary of quantificat:on of Toxicoloyical Effects for Oxamyl
Value
Drinkingwater concentration
(uy/L)
Keference
One-day HA for lU-kg child
Ten-day HA for lU-kg cnild
Longer-term HA for lu-Kg child
Lonyer-tertn HA for 70-kg adult
UWEL (1UUS from drinking
water)
Excess cancer risk (lu~6)
a
a
9UU
900
' 9UU
Kennedy (1986D)
Kennedy (1S86D)
Kennedy (19B6o)
3Thsse numbers were based on the Longer-term HA because of lack of appropriate ,
daia for derivation of the One- and Ten-day HAS,
The Longer-term HA value is recommenced as a conservative estimate of "he
Une-aay and Ten-day HA values.
VIII-14
-------
IX. REFERENCES
Agricultural Research Service. 1986. Guidelines for the Control of Plant
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