820K88116 August, 1987
METOLACHLOR
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 51218-45-2
Structural Formula
2$
2-Chloro-N-(2-ethyl-6-methyiphenyl)-N-(2-methoxy-1-me thylethyl) acetamide
Synonyms
e o-Acetanilide; 2-chloro-6'-ethyl-N-(2-methoxy-1-methylphenyl);
Dual*; Bicep*; Metetilachlor; Pimagram; Primextra; CGA-24705.
Uses (Meister, 1986)
0 Selective herbicide for pre-emergence and preplant incorporated weed
control in corn, soybeans, peanuts, grain sorghum, pod crops, cotton,
safflower, woody ornamentals, sunflowers and flax.
Properties (Meister, 1986; Ciba-Geigy, 1977; Windholz et al., 1983; Worthing,
1983)
Chemical Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Density
Vapor Pressure (20°C)
Specific Gravity
Water Solubility (20°C)
Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
Occurrence
283.46
White to tan liquid
100°C (at 0.001 mm Hg)
1.3 x 10-5 mm Hg
530 mg/L
Metolachlor has been found in 1,644 of 1,997 surface water samples
analyzed and in 45 of 239 ground water samples (STORET, 1987).
Samples were collected at 312 surface water locations and 297 ground
water locations, and Metolachlor was found in 14 states. The 85th
percentile of all nonzero samples was 11.5 ug/I. in surface water and
0.25 ug/L in ground water sources. The maximum concentration found
was 138 ug/L in surface water and 0.25 ug/L in ground water.
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0 Metolachlor residues resulting from agricultural use have also been
detected in ground water in Iowa and Pennsylvania with concentrations
ranging from 0.1 to 0.4 ppb.
Environmental Fate
(Forthcoming from OPP)
III. PHARMACOKINETICS
Absorption
0 In studies conducted by Hambock (1974a,b), rats were administered a
single oral dose (28.6 or 52.4 mg/kg) of metolachlor (purity riot
specified, but 14C-labeled and unlabeled metolachlor were synthesized
for these experiments). The chemical was readily absorbed, since 70
to 90% of the metolachlor was excreted as metabolites within 48 hours.
Distribution
0 Data from rats given radioactive metolachlor (approximately 3.2 to
3.5 mg/kg) orally demonstrated that the chemical is rapidly metabolized.
Residues in meat tissues and blood were very low and only blood
contained residue levels in excess of 0.1 ppm (Hambock, 1974c).
Metabolism
0 Studies conducted to identify urinary and fecal metabolites in the
rat indicated that metolachlor is metabolized via dechlorination,
O-methylation, N-dealkylation and side-chain oxidation (Hambock, 1974
a,b). Urinary metabolites included 2-ethyl-6-methylhydroxyacetanilide
(MET-002) and N-(2-ethyl-6-methylphenyl)-N-(hydroxyacetyl)-DL-alanine)
(MET-004). Fecal metabolites included 2-chloro-N-(2-ethyl-6-methyl-
phenyl)-N-(2-hydroxy-1-methylethyl) (MET-003) and MET-004.
Excretion
When treated with 14C-metolachlor (approximately 31 mg/kg orally),
male rats excreted 21.5% and 51.4% of the administered dose in the
urine and feces, respectively, in 48 hours (Hambock, 1974a,b). The
excreta contained 1, 15 and 22% of the administered dose as MET-002,
MET-003 and MET-004, respectively. No unchanged chemical was isolated,
and no glucuronide or sulfate conjugates were identified.
IV. HEALTH EFFECTS
Humans
Signs of human intoxication from metolachlor and/or its formulations
(presumably following acute deliberate or accidental exposures)
include abdominal cramps, anemia, ataxia, dark urine, methemoglobinemia,
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cyanosis, hypothermia, collapse, convulsions, diarrhea, gastrointestinal
irritation, jaundice, weakness, nausea, shock, sweating, vomiting, CNS
depression, dizziness, dyspnea, liver damage, nephritis, cardiovascular
failure, skin irritation, dermatitis, sensitization dermatitis, eye
and mucous membrane irritation, corneal opacity and adverse reproductive
effects (HAZARDLINE, 1985).
Animals
Short-term Exposure
• The acute oral LD5Q of technical metolachlor [>90% active ingredient
(a.i.)] in the rat was reported to be 2,780 mg/kg (95% confidence
range of 2,180 to 3,545 mg/kg; Bathe, 1973).
* Technical metolachlor in corn oil (>90% a.i.) was shown to be emetic
in beagle dogs, precluding the establishment of an LDjg (AMR, Inc.,
1974a). However, an "emetic dose" of 19 ^ 9.7 mg/kg was established.
0 Beagle dogs were fed technical metolachlor in the diet for 7 days in
a range-finding study (Goldenthal et al., 1979). Each test group
consisted of one male and one female. Doses were 1,000, 3,000 or
5,000 ppm with the controls receiving a basic diet plus the test
material solvent (ethanol). The mean doses were 0, 13.7, 22.7 or
40.2 mg/kg. Decreased food consumption and body weight indicated
that the two higher doses were unpalatable. No changes were observed
at the lowest dose, although the animals exhibited soft stools and/or
diarrhea over the study period. No other signs of overt toxicity,
morbidity or mortality were observed in any animal. Accordingly, the
lowest dose (13.7 mg/kg) is the NOAEL in this study.
Dermal/Ocular Effects
0 The LD50 of technical metolachlor (> 90% a.i.) in the rabbit when
tested by the unabraded dermal route is greater than 10,000 mg/kg
(AMR, Inc., 1974b).
0 Sachsse (1973b) evaluated the dermal irritation potential of technical
metolachlor (>90% a.i.) on the New Zealand rabbits. The chemical was
applied to abraded and unabraded skin for observation periods up to
72 hours. The results demonstrated that technical metolachlor is
non-irritating to rabbit skin.
0 Sachsse (1977) studied skin sensitization in the guinea pig by the
intradermal-injection method. Technical metolachlor (>90% a.i.)
dissolved in the vehicle (propylene glycol) and the vehicle alone
were intradermally injected into the skin of two groups of Pilbright
guinea pigs. A positive reaction was observed in the animals injected
with metolachlor in vehicle, but not in animals treated with the
vehicle alone. It was concluded that technical metolachlor is a skin
sensitizer.
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0 A study of eye irritation by technical metolachlor (>90% a.i.) in the
New Zealand White rabbit was conducted by Sachsse (1973a). The
chemical was applied at a dose level of 0.1 mL/eye. Evaluation of
both washed and unwashed eyes 24 hours and 7 days later revealed no
evidence of irritation.
Long-term Exposure
0 Beagle dogs (four/sex/dose) were administered technical metolachlor
(>90% a.i.) in their feed for up to 15 weeks (Coquet et al., 1974).
Initial doses were 0, 50, 150 or 500 ppm (equivalent to 0, 4 to 5,
or 14 to 19 mg/kg/day). However, after 8 weeks, the group receiving
50 ppm was switched to a diet that delivered 1,000 ppm (27 to
36 mg/kg/day) for the remaining 6 weeks. The dose was increased
because no signs of toxicity were observed in the 500-ppm group after
8 weeks. No animals died during the study and no significant changes
were observed in gross or histological pathology, blood or urine
analyses. Except for a decrease in food consumption and associated
slight weight loss at the 1,000-ppm dose, no compound-related effects
were observed. The NOAEL for this study is 500 ppm (14 to 19 mg/kg/day).
0 A 6-month feeding study in dogs was conducted at levels of 0, 100,
300 or 1,000 ppm (Jessup et al., 1979). The average compound consump-
x tion was 0, 2.9, 9.7 or 29.6 mg/kg/day for the males and 0, 3, 8.8 or
29.4 mg/kg/day for the females, as determined by the investigators.
The control and high-dose groups consisted of eight animals/sex; the
low- and mid-dose groups consisted of six animals/sex. The extra
control and high-dose animals were used in a recovery period study
following sacrifice of the remaining animals at 6 months. The following
significant changes were observed at the end of the study. Mean body
weight gain was reduced in animals of both sexes fed 1,000 ppm; in
addition,•food consumption was reduced in the females at this level.
Male dogs at the 300- and 1,000-ppm levels had significantly reduced
activated partial thromboplastin time (APTT) after 5 and 6 months of
observation. In females, significant changes in this parameter were
observed for dogs at month 4 fed 100 ppm, at month 6 at the 300 ppm
level, and at months 5 and 6 in the 1,000 ppm group. Additional
studies demonstrated that the changes were not attributable to the
pesticide. There were sporadic, but not treatment-related, changes
in platelet and red blood cell counts and hemoglobin over the course
of the study. Serum alkaline phosphate (SAP) levels decreased more
slowly in the test groups than in the controls. These changes were
significant in the groups fed 300 and 1,000 ppm. Therefore, the
NOAEL in this study was 100 ppm (3 mg/kg/day).
0 Tisdel et al. (1980) presented the results of a study in which
metolachlor (95% a.i.) was administered to Charles River CD-1 mice
(68/sex/dose) for 2 years at dietary concentrations of 0, 300, 1,000
or 3,000 ppm. Time-Weighted Average (TWA) concentrations, based upon
diet analyses, were equal to 0, 287, 981 and 3,087 ppm. The dietary
doses, from reported food intake and body weight data, were calculated
to be equal to 0, 50, 170 or 526 mg/kg/day for the males and 0, 64,
224 or 704 mg/kg/day for the females. No treatment-related effects
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Metolachlor August, 1987
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were observed in terms of physical appearance, food consumption,
hematology, serum chemistry, urinalysis or gross or histopathology.
However, mortality was increased significantly in females fed
3,000 ppm (704 mg/kg/day). Statistically significant reductions in
body weight gain were observed in both sexes at the highest dose.
Also, statistically significant changes in absolute and organ-to-body
weight ratios were noted occasionally (e.g. kidney- and liver-body
weight ratios and decreased seminal vesicle to body weight ratio in
high dose males). Based on this information, a NOAEL of 1,000 ppm
(170 mg/kg/day for males and 224 mg/kg/day for females) is identified.
0 Tisdel et al. (1983) presented the results of a study in which
metolachlor (purity not specified) was administered to CD-Crl:CD
(SD) BR rats for 2 years at dietary concentrations of 0, 30, 300
or 3,000 ppm. Assuming that 1 ppm in the diet of rats is equal to
0.05 mg/kg/day (Lehman, 1959), these dietary concentrations would be
equal to 0, 1.5, 15 or 150 mg/kg/day. The control and 3,000-ppm
groups consisted of 70 rats/sex. The 30- and 300-ppm groups consisted
of 60 rats/sex. No treatment-related effects were noted in terms of
mortality, organ weight and organ-to-body weight ratios. A variety
of differences in clinical pathology measurements was found between
control and treatment groups at various time intervals, but no
consistent dose-related effects were apparent with the exception of
a decrease in glutamic-oxaloacetic transaminase activity in high dose
males at 12 months. Mean body weights of high-dose females were
consistently less than controls from week 2 until termination of the
study. This difference was statistically significant (p <0.01) for
26 of the 59 intervals at which such measurements were made. Food
consumption in high-dose females also was generally less than controls.
Gross pathology findings were described by the investigators as being
unremarkable. Microscopically, atrophy of the testes with degenera-
tion of the tubular epithelium was noted to a greater extent in the
300- and 3,000-ppm groups than in the controls. Additionally, an
increased incidence of eosinophilic foci was observed in the livers
of both sexes exposed at 3,000 ppm. Based on this data, a NOAEL of
30 ppm (1.5 mg/kg/day) is identified.
Reproductive Effects
0 A three-generation rat reproduction study was reported by Smith and
Adler (1978). Targeted dietary exposures were 0, 30, 300 or 1,000
ppm. Tne actual exposures were analyzed to be 0, 30, 250 or 850 ppm.
Assuming that 1 ppm equals 0.05 mg/kg/day (Lehman, 1959), the doses
were calculated to be 0, 1.5, 22.5 or 42.5 mg/kg bw/day. No adverse
effects were noted at any dose. A minimal NOAEL of 42.5 mg/kg is
identified for reproductive effects.
8 Smith et al. (1981) conducted a two-generation reproduction study
in which Charles River CD rats (15 males and 30 females/dose) were
administered technical-grade metolachlor (purity not specified) at
dietary doses of 0, 30, 300 or 3,000 ppm. The TWA concentrations of
metolachlor, based upon dietary analysis, were 0, 32, 294 or 959 ppm.
Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day
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(Lehman, 1959), these dietary concentrations are approximately equal
to 0, 1.6, 14.7 or 48 mg/kg/day. Mating, gestation, lactation, and
female and male fertility indices were not affected in either generation.
Additionally, pup survival was not affected. However, pup weights in
the 959-ppm dose group, but not the 32- and 294-ppm dose groups, were
significantly reduced in the F-|a and F2a litters. Food consumption was
reduced significantly for F-| females receiving 32 ppm (1.6 mg/kg/day)
and greater at various study intervals. Other effects that appeared
to be treatment-related included increased liver-to-body weight ratios
for both F-| parental males and females at 1,000 ppm and increased
thyroid-to-body weight and thyroid-to-brain weight in F-j males at
1,000 ppm. Based on reduced pup weights, a reproductive NOAEL of
294 ppm (14.7 mg/kg/day) is identified.
0 Tisdel et al. (1980) gave metolachlor (95% a.i.) to CD-1 mice
(68/sex/dose) in the food for 2 years at concentrations of 0, 300,
1,000 or 3,000 ppm (the TWAs based on diet analyses were 0, 287, 981
or 3,087 ppm and corresponded to 0, 50, 170 or 520 mg/kg/day in males
and to 0, 64, 224 or 704 mg/kg/day in the females). At the high dose,
males were found to have a reduced seminal vesical-to-body weight
ratio.
0 Tisdel et al. (1983) exposed CD-Crl:CD (SD) BR rats (70/sex/dose) to
metolachlor (purity not specified) in the diet for 2 years at 0, 30,
300 or 3,000 ppm (the doses correspond to 0, 1.5, 15 or 150 mg/kg/day).
They observed greater testicular atrophy and degeneration of the
tubular epithelium in the 300- and 3,000-ppm groups than in the
control group.
Developmental Effects
0 Fritz (1976) conducted a rat teratology study in which pregnant
females (25/dose level) were administered doses of technical metola-
chlor (purity not specified) orally at 0, 60, 180 or 360 mg/kg/day
during days 6 to 15 of gestation. No fetotoxic or developmental
effects were noted.
0 Lightkep et al. (1980) evaluated the teratogenic potential of metola-
chlor in New Zealand White rabbits (16/dose). The compound was
administered as a suspension in aqueous 0.75% hydroxymethylcellulose
at levels of 0, 36, 120 or 360 mg/kg/day. Single oral dcses were
given on days 6 to 18 of gestation. Abortions occurred in two rabbits:
one in the 120-mg/kg/day group on day 25 (one early resorption) and
one in the 360-mg/kg/day group on day 17 (one fetus) and day 20 (eight
additional implantations). They did not consider these abortions to
be treatment-related. Maternal toxicity (decreased food consumption
and pupillary constriction) was observed in animals receiving the two
highest doses. The highest dose group also exhibited blood in the
cage pan and body weight loss over the treatment period. No signifi-
cant .developmental or fetotoxic effects were observed in the 319
fetuses, pups or late resorptions evaluated from all dose groups.
Thus, a minimal NOAEL of 360 mg/kg/day for fetotoxicity and a NOAEL
of 36 mg/kg/day for maternal toxicity were identified.
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Mutagenicity
0 Technical metolachlor (purity not specified) was tested in the Ames
Salmonella test system, using ^. typhimurium strains TA1535, TA1537,
TA98 and TA100 (Arni and Muller, 1976). No increase in mutagenic
response was observed, with or without microsomal activation, at
concentrations of 10, 100, 1,000 or 10,000 ug/plate. Toxicity was
observed at 1,000 and 10,000 ug/plate without activation and at
10,000 ug/plate with activation.
0 Ciba-Geigy (1976) reported the results of a dominant lethal study in
the mouse using technical metolachlor (purity not specified). The
compound was administered orally in single doses of 0, 100 or 300 mg/kg
to males that then were mated to untreated females over a period of
6 weeks. No evidence of adverse effects were observed, as expressed
by increased implantation loss or resorptions.
Carcinogenicity
0 Marias et al. (1977) presented the results of a study in which
technical-grade metolachlor (purity not specified) was administered
to Charles River CD-1 mice (50/sex/dose) at dietary concentrations of
0, 30, 300 or 3,000 ppm. Assuming that 1 ppm in the diet of the mouse
is equal to 0.15 mg/kg/day (Lehman, 1959), these dietary levels are
approximately 0, 4.5, 150 or 450 mg/kg/day. Males received £he test
material for 18 months; females received the test material for 20
months. Results of this study indicated no evidence of oncogenicity
in either sex.
0 Tisdel et al. (1980) presented the results of a study in which
metolachlor (95% a.i.) was administered to Charles River CD-1 mice
(68/sex/dose) for 2 years at dietary concentrations of 0, 300, 1,000
or 3,000 ppm. From food intake and body weight data, the doses were
calculated to be equal to 0, 50, 170 or 526 mg/kg/day for the males
and 0, 64, 224 or 704 mg/kg/day for the females. A statistically
significant increase in the incidence of alveolar tumors in high-dose
males was noted at the 18-month sacrifice; however, this effect was
not confirmed by the final sacrifice at 24 months or by total tumor
incidences for all animals.
0 In 1979, Ciba-Geigy reported the results of a study in which technical
metolachlor was administered to Charles River albino rats in their
diet for 2 years at doses equivalent to 0, 1.5, 15 or 50 mg/kg/day.
A statistically significant increase in the incidence of primary
liver tumors was observed in the high-dose females (15/60 compared
with 5/60 at mid doses and 3/60 at the low dose and control). These
tumors included hypertrophic-hyperplastic nodules, angiosarcoma,
cystic cholangioma and hepatocellular carcinoma. The variety of
tumor expression forms suggests that a variety of cell types and
locations may be affected in the liver.
0 Tisdel et al. (1983) presented the results of a study in which
metolachlor (purity not specified) was administered to CD-Crl:CD
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(SD) BR rats for 2 years at dietary concentrations of 0, 30, 300 or
3,000 ppm. These doses were assumed to be equal to 0, 1.5, 15 or
150 mg/kg/day. An increased incidence of proliferative hepatic
lesions (combined neoplastic nodules/carcinomas) was found in the
high-dose females at terminal sacrifice (p <0.018 by the Fisher exact
test). Six of the 60 had neoplastic nodules (p <0.05) and 7 of the
60 had liver tumors (one additional tumor was diagnosed as a carcinoma;
p <0.01).
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (approximately 7 years) and lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula;
HA = (NOAEL or LOAEL) x (BW) . mg/L ( /L)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/OCW guidelines.
_^_^ L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
No suitable information was found in the available literature for
determination of a One-day HA for metolachlor. Accordingly, it is recommended
that the Ten-day HA value for the '10 kg child (1.4 mg/L, calculated below) be
used at this time as a conservative estimate of the One-day HA value.
Ten-day Health Advisory
The 7-day dietary study in dogs by Goldenthal et al. (1979) has been
selected to serve as the basis for the Ten-day HA. Doses were 1,000, 3,000
or 5,000 ppm with the controls receiving a basic diet plus the solvent (ethanol)
(one/sex/group). Actual mean doses were 0, 13.7, 22.7 or 40.2 mg/kg. The
results indicated that the two higher doses were unpalatable, resulting in
decreased 'food consumption and body weight. No changes were observed at the
lowest dose, although the animals exhibited soft stools and/or diarrhea over
the study period. No other signs of overt toxicity, morbidity or mortality
were observed in any animal. The lowest dose, 13.7 mg/kg/day, is identified
as the NOAEL.
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The Ten-day HA for a 10-kg child is calculated as follows:
Ten-day HA = (13.7 mg/kg/day) (10 kg) = 1>4 mg/L (1 400 ug/L)
(100) (1 L/day)
where:
13.7 mg/kg/day = NOAEL, based on absence of decreased food consumption
and body weight loss.
1 0 kg = assumed body weight of a child,,
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
Longer-term Health Advisory
The study by Jessup et al. (1979) has been selected to serve as the
basis for the Longer-term HA. A 6-month feeding study in dogs was conducted
at average compound consumption levels of 0, 2.9, 9.7 and 29.6 mg/kg/day
(males) and 0, 3.0, 8.8 and 29.4 mg/kg/day (females). Significant changes
observed at the end of the study included reduced mean body weight gain in
animals of both sexes fed 1,000 ppm and reduced food consumption in the
females at this level. Serum alkaline phosphate levels decreased more slowly
in the test groups than in the controls. These changes were statistically
significant in the groups fed 300 and 1,000 ppm. Therefore, the NOAEL in
this study is identified as 100 ppm (3 mg/kg/day).
The Longer-term HA for a 10-kg child is calculated as follows:
Longer-term HA = (3 ngAg/day) (10 kg) = Q>3 /L (300 /L)
(100) (1 L/day)
where:
3 mg/kg/day = NOAEL.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
The Longer-term HA for a 70-kg adult is calculated as follows:
Longer-term HA = (3 mg/kg/day) (70 kg) = K05 mq/L (, 050 ug/L)
(100) (2 L/day)
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where:
3 mg/kg/day = NOAEL.
70 kg » assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
2 L/day = assumed daily water consumption of an adult.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). Prom the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The study by Tisdel et al. (1983) has been selected to serve as the
basis for the Lifetime HA. In this study, rats were given dietary doses of
metolachlor equivalent to 0, 1.5,'15 or 150 mg/kg/day. No treatment-related
effects were noted in terms of mortality, organ weight and organ-to-body
weight ratios. The investigators noted a statistically significant decrease
in glutamic-oxaloacetic transaminase activity in high-dose males at 12 months.
Mean body weights of high-dose females were consistently less than controls
from week 2 until termination of the study. This difference was significant
(p <0.01) for 26 of the 59 intervals at which such measurements were made.
Food consumption in high-dose females also was generally less than controls.
Gross pathology findings were described as unremarkable. Microscopically,
testicular atrophy with degeneration of the tubular epithelium was observed
to a greater extent in the 300- and 3,000-ppm groups than in controls.
Additionally, an increased incidence of eosinophilic foci was observed in the
livers of both sexes exposed at 3,000 ppm. Based on the data presented,
a NOAEL of 30 ppm (1.5 mg/kg/day) was identified.
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The Lifetime HA is calculated as follows:
Step 1: Determination of the Reference Dose (RfD):
RfD = 1*5 mg/kg/day = 0.015 mg/kg/day
100
where:
1.5 mg/kg/day » NOAEL, based upon the absence of systemic effects in
rats exposed to metolachlor in the diet for two years>
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.015 mq/kg/day)(70 kg) „ 0<525 /L (525 /L)
(2 L/day)
where:
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (0*525 mg/L) (20%) _ 0>01 mg//L (10 ug/L)
(10)
where:
0.525 mg/L = DWEL.
20% = assumed relative source contribution from water.
10 » additional uncertainty factor per ODW policy to account
for possible carcinogenicity.
Evaluation of Carcinogenic Potential
0 Four studies evaluating the carcinogenic potential of metolachlor
have been identified. In two of these studies (Marias et al., 1977,
and Tisdel et al., 1980), no evidence of carcinogenicity in mice was
observed. The other studies, both conducted using rats, showed an
increased tumor incidence related to treatment. Ciba-Geigy (1979)
reported a statistically significant increase in primary liver tumors
in female Charles River rats exposed to 150 mg/kg/day in the diet
for 2 years. Tisdel et al. (1983) also reported a statistically
significant increase in the incidence of proliferative hepatic lesions
(neoplastic nodules and carcinomas) in female rats at the same
dietary dose over the same time period. Additionally, there was a
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nonstatistically significant increase in the frequency of adenocarcinoma
of the nasal turbinates and fibrosarcoma of the nasal tissue in the
high-dose males (150 mg/kg/day).
The International Agency for Research on Cancer has not evaluated the
carcinogenicity of metolachlor.
Applying the criteria described in EPA's guidelines for the assessment
of carcinogenic risk (U.S. EPA, 1986a), metolachlor is classified in
Group C: possible human carcinogen. This category is for substances
with limited evidence of carcinogenicity in animals and absence of
human data.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 EPA/OPP has identified an ADI for metolachlor of 0.015 mg/kg/day based
on the NOAEL of 30 ppm (1.5 mg/kg/day) from the chronic rat feeding
study (Tisdel et al., 1983) and an uncertainty factor of 100 (U.S. EPA,
1986b). Using this ADI and an assumed body weight of 60 kg, the maximum
permissible intake has been calculated to be 0.9 mg/day. The total
maximum residue concentration is 0.07209 mg/day or about 8% of the ADI.
0 Residue tolerances ranging from 0.02 to 30 ppm have been established
for a variety of agricultural products (CFR, 1985).
VII. ANALYTICAL METHODS
0 Analysis of metolachlor is by a gas chromatographic (GC) method appli-
cable to the determination of certain nitrogen-phosphorus containing
pesticides in water samples (U.S. EPA, 1986c). In this method,
approximately 1 liter of sample is extracted with methylene chloride.
The extract is concentrated and the compounds are separated using
capillary column GC. Measurement is made using a nitrogen phosphorus
detector. The method detection limit has not been determined for
metolachlor but it is estimated that the detection limits for analytes
included in this method are in the range of 0.1 to 2 ug/L.
VIII. TREATMENT TECHNOLOGIES
Whittaker (1980) experimentally determined adsorption isotherms for
metolachlor on granular-activated carbon (GAC) Nuchar WV-G. Nuchar
WV-G, reportedly, exhibited the following adsorption capacities at
20°C: 0.173, 0.148 and 0.105 mg metolachlor/mg carbon at concentra-
tions of 79.84 mg/L, 10 mg/L and 1.74 mg/L, respectively.
0 Holiday and Hardin (1981) reported the results of GAC treatment of
wastewater contaminated with pesticides including metolachlor. The
column, 3.5 ft in diameter, was packed with 10 ft of granular acti-
vated carbon, or 3,150 Ib carbon/column. The column was operated at
1.04 gpm/ft2 hydraulic load and 72 minutes contact time. Under these
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Metolachlor August, 1987
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conditions, 99.5% of the metolachlor was removed from wastewater at
an initial average concentration of 16.4 mg/L.
GAC adsorption appears to be the most promising treatment technique
for the removal of metolachlor from water. However, more actual data
are required to determine the effectiveness of GAC in removing
metolachlor from contaminated drinking water supplies.
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Metolachlor
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August, 1987
IX. REFERENCES
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AMR, Inc.* 1974b. Affiliated Medical Research, Inc. Acute dermal LD50 of
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NC. MRID 16631.
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Metolachlor August, 1987
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Hambock, H.* 1974a. Project 7/74: Metabolism of CGA 24705 in the rat.
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Metolachlor
August, 1987
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Sachsse, K.* 1977. Skin sensitizing (contact allergenic) effects in guinea
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- Determination of nitrogen and phosphorus containing pesticides in
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Worthing, C.R., ed. 1983. The Pesticide Manual: A World Compendium, 7th ed.
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•Confidential Business Information submitted to the Office of Pesticide
Programs.
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