820K88004
FLUOMETURON
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
August, 1987
DRAFT
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 -nodel is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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Fluometuron
Auqust, 1987
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II. GENERAL INFORMATION AND PROPERTIES
CAS No. 2164-17-2
Structural Formula
0
II
H-N-C-NCCH,),
N,N-DiTnethyl-N-(3-(trifluoromethyl)phenyl)-urea
Synonyms
0 C 2059; Cotoron; Cottonex; Lanex (Meister, 1983).
Uses
0 Herbicide (Windholz et al.f 1983).
Properties (Windholz et al., 1983; CHEMLAB, 1985; TDB, 1985)
C1oH11ON2F3
232.21
White crystals
163-164.5°C
5 x 10~7 rrtn Hg
80 mg/L
1.88 (calculated)
Chemical Formula
Molecular Weight
Physical State (25°C)
Boiling Point
Melting Point
Density
Vapor Pressure (20°C)
Specific Gravity
Water Solubility (25°C)
Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
Occurrence
° Fluometuron was not found in any of 31 ground water samples analyzed
from 29 locations (STORET, 1987). No surface water samples were
tested.
Environmental Fate
o 14c-Fluometuron (test substance not characterized) was intermediately
mobile (Rf = 0.50) in a silty clay loam soil (2.5% organic matter)
based on thin-layer chromatography (TLC) tests of soil (Helling, 1971;
Helling et al., 1971).
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0 14c-Fluometuron (test substance not characterized), at various concen-
trations, was very mobile in a Norge loam soil (1.7% organic matter)
with a Freundlich-K of 0.31 (Davidson and McDougal, 1973). Freundlich-K
values, determined in soil:water slurries (5-10 g/100 mL) treated with
14c-fluometuron (test substance not characterized) at 0.05 to 10.0 ppm,
were 0.37 for Uvrier sand (1% organic matter), 1.07 for Collombey sand
(2.2% organic matter), 1.66 for Les Evouettes loam (3.6% organic matter),
3.16 for Vetroz sandy clay loam (5.6% organic matter), and 1.36 for
Illarsatz high organic soil (22.9% organic matter) (Guth, 1972).
0 Fruendlich-K values were positively correlated with the organic matter
content of the soil. Fluometuron (test substance not characterized),
at 10 to 80 uM/kg, was adsorbed at 10 to 51% of the applied amount to a
loamy sand soil (1.15% organic matter) and 16 to 67% of the applied to a
sandy loam soil (1.9% organic matter) in water slurries during a test
period of 1 minute to 7 days, with adsorption increasing with time
(LaFleur, 1979). Approximately 22% of the applied fluometuron desorbed
in water from the loamy sand soil and 15% desorbed from the sandy loam
soil during a 7-day test period.
0 Fluometuron (50% wettable powder, WP) dissipated from the 0- to 5-cm
depth of a sandy clay loam soil (3.2% organic matter) in central
Europe with a half-life of less than 30 days (Guth et al., 1969).
Fluometuron residues (not characterized) dissipated with a half-life
of 30 to 90 days.
III. PHARMACOKINETICS
Absorption
0 Boyd and Foglemann (1967) reported that fluometuron is slowly absorbed
from the gastrointestinal (GI) tract of female CFE rats (200 to 250 g).
Based on the radioactivity recovered in the urine and feces of four
rats given 50 mg 14Olabeled f luometuron after a 2-week pretreatment
with 1,000 ppm unlabeled fluometuron [estimated as 100 mg/kg/day,
assuming 1 ppm equals 0.1 mg/kg/day in the young rat (Lehman, 1959)],
the test compound appears not to have been fully absorbed within 72
hours. Of an orally administered dose (50 mg/kg), up to 15% was
excreted in the urine and 49% in the feces.
Distribution
0 Boyd and Foglemann (1967) detected radioactivity in the liver, kidneys,
adrenals, pituitary, red blood cells, blood plasma and spleen 72 hours
after oral administration of 14C-labeled fluometuron at dose levels of
50 or 500 mg/kg in rats. The highest concentration was detected in
red blood cells.
Metabolism
0 Boyd and Foglemann (1967) concluded that, by thin-layer chromatographic
analysis, the urine of rats in their study contained m-trifluoromethyl-
aniline, desmethyl-fluometuron, demethylated fluometuron, hydroxylated
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Fluometuron August, 1987
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desmethyl-fluometuron, hydroxylated demethylated fluometuron, and
hydroxylated aniline.
Lin et al. (1976) reported that after incubation of 14CF3-labeled
fluometuron with cultured human embryonic lung cells for up to 72
hours, 95% of the compound remained unchanged. Human embryonic lung
cell homogenate metabolized small amounts of fluometuron through
oxidative pathways to N-(3-trifluoromethylphenyl)-N-formyl-N-methylurea,
N-(3-trifluoromethylphenyl)-N-methylurea, and N-(3-trifluoromethylphenyl)
urea.
Excretion
Boyd and Foglemann (1967) reported that urinary excretion of radio-
active label peaked at 24 hours after administration of 14c-fluometuron
(50 mg/kg) and decreased during the remaining 48 hours. Seventy-two
hours after oral administration of the radioactive label, up to 15%
of the administered dose was eliminated in the urine.
In the study by Boyd and Foglemann (1967), fecal excretion of fluometuron
peaked by 48 hours postdosing and decreased over the remaining 24 hours.
Forty-nine percent of the administered dose (50 mg/kg) was eliminated
in the feces.
IV. HEALTH EFFECTS
Humans
No information was found in the available literature on the health
effects of fluometuron in humans.
Animals
Short-term Exposure
0 NIOSH (1985) reported the acute oral LD5Q values of fluometuron as
6,416, 2,500, 900 and 810 mg/kg in the rat, rabbit, mouse and guinea
pig, respectively.
0 Sachsse and Bathe (1975) reported an acute oral LD^Q value of
4,636 mg/kg for both male and female Tif RA1 rats.
0 Foglemann (1964a) reported the acute oral LD50 values for CFW albino
mice as 2,300 mg/kg in females and 900 mg/kg in males.
Dermal/Ocular Exposure
0 Siglin et al. (1981) conducted a primary dermal irritation study in
which undiluted fluometuron powder (80%) was applied to intact and
abraded skin of six young adult New Zealand White rabbits for 24
hours. The test substance was severely irritating, with eschar
formation observed at 24 and 72 hours.
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0 Foglemann (1964b) exposed the skin of eight albino rabbits (four/sex)
to a 10% aqueous suspension of fluometuron (applied under rubber
dental damming) for 6 hours/day for 10 days. No contact sensitization
developed during the exposure period. Weight depression at day 130
was evident in the treated group.
0 Galloway (1984) reported no sensitizing reactions in Hartley albino
guinea pigs exposed to undiluted fluometuron on alternate days for
22 days and on day 36.
0 Technical fluometuron was not found to be an eye irritant in rabbits
(Foglemann, 1964c).
Long-term Exposure
0 Foglemann (1965a) conducted a 90-day feeding study in which CFE rats
(15/sex/dose) were administered technical fluometuron (purity not
specified) in the diet at dose levels of 100, 1,000 or 10,000 ppm
(reported as 7.5, 75 or 750 mg/kg/day). Following exposure, various
parameters including hematology, clinical chemistry and histopathology
were evaluated. Enlarged, darkened spleens were observed grossly in
male rats given 75 mg/kg/day. At the highest dose level, a depression
in body weight and congestion in the parenchyma of the spleen, adrenals,
liver and kidneys were evident. A mild deposition of hemosiderin in
the spleen was also evident. Spleens were large and dark; livers
were brownish and muddy colored; and kidneys were small with discolored
pelvises in high-dose males. Histopathological findings were confined
to mild congestion in various organs and mild hemosiderin deposits
in the spleens of high-dose rats. No effects were evident in rats
given the 7.5 mg/kg/day dose level for any parameter measured. This
dose level was identified as the No-Observed-Adverse-Effect-Level
(NOAEL) for this study.
0 Foglemann (1965b) administered technical fluometuron (purity not
stated) in feed to three groups of beagle pups (three/sex/dose) at
dose levels of 40, 400 or 4,000 ppm (reported as 1.5, IS or 150
mg/kg/day) for 90 days. At 150 mg/kg/day, mild inflammatory-type
reactions and congestion in the liver and kidneys and mild congestion
and hemosiderin deposits in the spleen were observed. Also at this
high dose, the spleen to body weight ratio was slightly increased.
No adverse systemic effects were observed in dogs administered 1.5 or
15 mg/kg/day (NOAEL).
0 In the NCI (1980) study, B6C3F.] mice and F344 rats (10 of each sex)
were given fluometuron (>99% pure) in the diet for 90 days to estimate
1,000, 2,000, 4,000, 8,000, and 16,000 ppm. Decreased body weight gain
(>10%) was apparent with doses above 2,000 ppm. Treatment-related
splenomegaly was found in rats with doses above 1,000 ppm. Microscopic
examination was done on spleens only from rats given more than 2,000
ppm, and this assessment indicated dose-related changes including
hyperemia of red pulp with atrophy of Malpighian corpuscles and
depletion of lymphocytic elements. Body weight gain was reduced
(>10%) in male and female mice given more than 2,000 ppm. Assuming
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that 1 ppm in the diet equals 0.10 mg/kg/day in the young rat and
0.15 mg/kg/day in the mouse (Lehman, 1959), 1,000 ppm (NOAEL)
corresponds to 100 mg/kg/day in rats and 2,000 ppm (NOAEL) corresponds
to 300 mg/kg/day in mice.
0 Hofmann (1966) administered 0, 3, 10, 30 or 100 mg/kg technical
fluometuron (Cotoron = C-2059, purity not specified) as a suspension
in 1% Mulgafarin six times per week for 1 year by pharnyx probe to
four groups of Wistar rats (25/sex/dose) . Following treatment,
general behavior, mortality, growth, food consumption, clinical
chemistry, blood, urine, and histopathology were evaluated. Males
dosed with 30 or 100 mg/kg/day and females dosed with 100 mg/kg/day
showed significant (p <0.05) reductions in body weight at the end of
the study compared to controls. No toxicological effects were observed
in rats administered 3 or 1 0 mg/kg/day (NOAEL).
0 In the NCI (1980) study, F344 rats (10 of each sex) were given
fluometuron (>99% pure) at dietary levels of 250, 500, 1,000, 2,000
and 4,000 ppm in a repeat of the 90-day study to examine splenic
effects more closely. Splenomegaly in all treated groups was noted.
A dose-related increase in spleen weights and a dose-related decrease
in circulating red blood cells was observed in females fed 250 ppm
and higher. Increased spleen weights were evident in males given
doses above 500 ppm. However, statistical analysis of the data was
not done. Stated in the report without presentation of data is the
observation of a dose-related increase in red blood cells with
polychromasia and anisocytosis in male and female rats and congestion
of red pulp with corresponding decrease of white pulp in spleen.
Assuming that 1 ppm equals 0.10 mg/kg/day in the young rat (Lehman,
1959), a Lowest-Observed-Adverse-Effect-Level (LOAEL) of 250 ppm (25
) is suggested in this study.
0 No noncarcinogenic effects (survival, body weight and pathological
changes) in B6C3Fi mice and F344 rats were found in the NCI (1980)
bioassay discussed under Carcinogenicity.
Reproductive Effects
0 No information was found in the available literature on the effects
of fluometuron on reproduction.
0 A reproduction study with technical fluometuron in rats is in progress
to satisfy U.S. EPA Office of Pesticide Programs (OPP) data requirements.
Developmental Effects
0 Fritz (1971) reported a teratology study in rats in which dams were
given C-2059 suspension in carboxymethylcellulose during days 6
through 15 of gestation. Offspring were removed on day 20 of ges-
tation for examination. The NOAEL was indicated as 100 mg/kg/day,
and higher doses reduced fetal body weight. However, this study was
invalidated by the U.S. EPA OPP because of inadequate reporting.
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8 A teratology study in which pregnant Spf New Zealand rabbits were
given technical fluometuron (purity not specified) by gavage at dose
levels of 50, 500, and 1,000 mg/kg/day during gestation days 6 through
19 was reported by Arhur and Triana (1984). Does were examined for
body weight, food consumption and pathological and developmental
effects, and laparohysterectomy was done on gestation day 29 for
pathological evaluation of fetuses. Increased liver weights and
increased mean number of resorptions were found with all doses
(p <0.05 at the low and mid doses; insufficient number of fetuses for
statistical analysis at the high dose). A LOAEL of 50 mg/kg/day was
identified. Reductions in body weights and food consumption occurred
in does given 500 and 1,000 mg/kg/day. Deaths, abortions and perforated
stomachs were observed in does given 1,000 mg/kg/day.
Mutagenicity
0 In bacterial assays (Dunkel and Simmon, 1980), fluometuron (6.6 mg/plate)
was not mutagenic in Salmonella strains TA 1535, TA 1537, TA 1538,
TA 98 and TA 100, either with or without metabolic activation.
0 Seiler (1978) reported that fluometuron (2,000 mg/kg bw) given as a
single oral dose of an aqueous suspension by gavage resulted in a
strong inhibition of mouse testicular DNA synthesis in mice killed
3.5 hours after treatment. Results were inconclusive in a subsequent
micronucleus test.
0 In yeast assays (Seibert and Lemperle, 1974), a commercial formulation
of fluometuron was ineffective in inducing mitotic gene conversion
in Saccharomyces cerevisiae strain D4 without exogenous metabolic
activation.
Carcinogenicity
0 In a long-term bioassay (NCI, 1980), fluometuron was administered in
feed to F344 rats and B6C3Fi mice. Groups of rats (50/sex/dose) were
fed diets containing 125 or 250 ppm fluometuron for 103 weeks. Mice
(50/sex/dose) were fed 500 or 1,000 ppm for an equivalent period
of time. Assuming that 1 ppm equals 0.05 mg/kg/day in the older rat
and 0.15 mg/kg/day in the'mouse (Lehman, 1959), 125 and 250 ppm
equaled 6.25 and 12.5 mg/kg/day in rats and 500 and 1,000 ppm equaled
75 and 150 mg/kg/day in mice. Results based on survival, body weights,
and nonneoplastic pathology (including spleen) were negative in rats.
Following treatment, there were no significant increases in tumor
incidences in male or female F344 rats or in female B6C3Fi mice com-
pared to controls. In male B6C3F-) mice, an increased incidence
of hepatocellular carcinomas and adenomas was noted. The incidences
were dose-related and were marginally higher than those in the corre-
sponding matched controls or pooled controls from concurrent studies
[matched control, 4/21 or 19%; low dose, 13/47 or 28%; high dose,
21/49 or 43% (p = 0.049); pooled controls, 44/167 or 26%]. NCI (1980)
concluded that additional testing was needed because of equivocal
findings for male mice and because both rats and mice may have been
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able to tolerate higher doses. The NOAELs identified for rats and
mice are 12.5 and 75 mg/kg/day, respectively.
0 Chronic feeding studies with technical fluometuron in rats and mice
are ongoing to satisfy OPP data requirements.
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) = /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/OEW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
No information was found in the available literature that was suitable
for determination of the One-day HA value for fluometuron. The teratology
study by Arhur and Triana (1984) was not selected because a NOAEL was not
identified. It is therefore recommended that the Longer-term HA value for a
10-kg child (1.5 mg/L, calculated below) be used at this time as a conservative
estimate of the One-day HA value.
Ten-day Health Advisory
No information was found in the available literature that was suitable
for determination of the Ten-day HA value for fluometuron. The teratology
study by Arhur and Triana (1984) was not selected because a NOAEL was not
identified. It is therefore recommended that the Longer-term HA value for a
10-kg child (1.5 mg/L, calculated below) be used at this time as a conservative
estimate of the Ten-day HA value.
Longer-term Health Advisory
The 90-day feeding study in dogs by Foglemann (1965b) has been selected
to serve as the basis for the Longer-term HA value for fluometuron. In this
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study, dogs given technical fluometuron at dose levels of 0, 1.5, 15 or 150
ing/kg/day in the diet for 90 days showed pathological effects in spleen,
liver and kidney at the highest dose and no observable effects at the lower
doses. The 90-day feeding studies with rats by Foglemann (1965a) and NCI
(1980) were not selected because the 15 mg/kg/day NOAEL in the Foglemann
(1965b) study was below the lowest doses of 75 mg/kg/day in the Foglemann
(1965a) and 25 mg/kg/day (estimated) in the NCI (1980) repeat 90-day study
where effects were noted. Additionally, pathological changes in spleen found
with the lowest dose (250 ppm) in the repeat NCI (1980) study in rats were
not found with this dose in the initial 90-day study and in the 2-year bioassay
in rats by the NCI (1980). Because 7.5 mg/kg/day in the Foglemann (1965a)
study and 12.5 mg/kg/day (estimated) in the NCI (1980) carcinogenicity bioassay
were NOAELs, it is concluded that 15 mg/kg/day would be consistent with a
NOAEL in these 90-day studies in rats. The study by Hofmann (1966) in which
rats were given technical fluometuron as a suspension by gavage at dose
levels of 0, 3, 10, 30 and 100 mg/kg, six times per week for 1 year, was not
selected because feeding the substance in the diet is preferred over giving
it as a suspension by gavage for estimating exposure from drinking water,
although the 10 mg/kg NOAEL in this study approximates the 15 mg/kg/day NOAEL
in the Foglemann (1965b) study. The 90-day feeding study in mice by NCI
(1980) was not selected because the NOAEL of 300 mg/kg/day (estimated) is
above the effect levels in the other studies considered. The 15 mg/kg/day
dose level in dogs was, therefore, identified as the NOAEL.
Using a NOAEL of 15 mg/kg/day, the Longer-term HA for a 10-kg child is
calculated as follows:
Longer-term HA = (15 mg/kg/day) (10 kg) = 1>5 mg/L (1,500 ug/L)
(100) (1 L/day)
where:
15 mg/kg/day = NOAEL, based on absence of pathological changes in the
spleen, liver and kidneys of dogs exposed to the test
substance in the diet for 90 days.
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 = (15 mg/kg/day) (70 kg) = 5>3 mg/L (5/30o ug/L)
(100) (2 L/day)
where:
15 mg/kg/day = NOAEL, based on absence of pathological changes in the
spleen, liver and kidneys of dogs exposed to the test
substance in the diet for 90 days.
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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). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight 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, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The NCI (1980) carcinogenicity bioassay in F344 rats has been selected
to serve as the basis for determination of the Lifetime HA value for fluo-
meturon. Rats were exposed to dose levels of 0, 125 and 250 ppm fluometuron
in the diet (estimated as 6.25 and 12.5 mg/kg/day) for 103 weeks. No observable
effects were evident in this study. Although pathological changes in spleens
of rats given 250 ppm fluometuron in the diet (estimated as 25 mg/kg/day)
were noted in the repeat 90-day study in rats by NCI (1980), it appears that
splenic lesions were either not evident or were able to reverse in the rats
given the 250-ppm dietary level for 2 years (only one rat died by 1 year into
the bioassay). Furthermore, pathological changes in the spleen were not
evident with doses below 2,000 ppm in the initial 90-day study in F344 rats
by NCI (1980). The 90-day and 1-year studies discussed under Longer-term
Health Advisory have not been selected for calculation of a Lifetime HA
because of their short duration compared to the 103-week NCI (1980) bioassay
and because, although not as many end points were assessed in the NCI (1980)
bioassay compared to these studies, major effects observed in these studies
(pathology, body weight) were evaluated in the NCI (1980) bioassay. The NCI
(1980) bioassay in B6C3Fi mice was not considered because higher dose levels
(500 and 1,000 ppm, estimated as 75 and 150 mg/kg/day) were used.
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Using the NCI (1980) bioassay in rats with a NOAEL of 12.5 mg/kg/day,
the Lifetime HA is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (12'5 nig/kg/day) = 0.0125 mg/kg/day
(100X10)
where:
12.5 mg/kg/day = NOAEL, based on absence of observable effects in rats
exposed to fluometuron in the diet for 103 weeks.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
10 = additional uncertainty factor used by U.S. EPA OPP
to account for data gaps (chronic feeding studies in
rats and dogs, reproduction study in rats, teratology
studies in rats and rabbits).
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.0125 mg/kg/day) (70 kg) , 0.438 /L (438 /L)
(2 L/day)
where:
0.0125 mg/kg/day = RfD.
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 = (0.438 mg/L) (20%) = 0.09 mg/L (90 ug/L)
where:
4.38 mg/L = DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
NCI (1980) determined that fluometuron was not carcinogenic in male
and female F344 rats and female mice (B6C3F-|). The marginal increase
in the incidence of hepatocellular carcinomas and adenomas in male
B6C3F-| mice was concluded to be equivocal evidence in the NCI (1980)
report on its bioassay.
0 IARC (1983) has classified fluometuron in Group 3: This chemical
cannot be classified as to its carcinogenicity for humans.
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0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), fluometuron may be classified in
Group D: not classified. This category is used for substances with
inadequate animal evidence of carcinogenicity.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 The U.S. EPA/OPP previously calculated an ADI of 0.008 mg/kg/day
based on a NOAEL of 7.5 mg/kg/day in a 90-day feeding study in rats
(Foglemann, 1965a) and an uncertainty factor of 1,000 (used because
of data gaps). This has been updated to 0.013 mg/kg/day, based on a
2-year feeding study in rats using a NQAEL of 12.5 mg/kg/day and an
uncertainty factor of 1,000.
0 Tolerances have been established for negligible residues of fluometuron
in or on cottonseed and sugar cane at 0.1 ppm (U.S. EPA, 1985a). A
tolerance is a derived value based on residue levels, toxicity data,
food consumption levels, hazard evaluation and scientific judgment,
and it is the legal maximum concentration of a pesticide in or on a
raw agricultural commodity or other human or animal food (Paynter
et al., undated).
VII. ANALYTICAL METHODS
0 Analysis of fluometuron is by a high-performance liquid chromatographic
(HPLC) method applicable to the determination of certain carbamate
and urea pesticides in water samples (U.S. EPA, 1985b). This method
requires a solvent extraction of approximately 1 liter of sample with
methylene chloride using a separatory funnel. The methylene chloride
extract is dried and concentrated to a volume of 10 mL or less. HPLC
is used to permit the separation of compounds, and measurement is
conducted with a UV detector. The method detection limit for
fluometuron is 11.1 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Available data indicate that granular activated carbon (GAC) adsorption
will remove fluometuron from water.
0 Whittaker (1980) experimentally determined adsorption isotherms for
fluometuron on GAC.
0 Whittaker (1980) reported the results of GAC columns operating under
bench-scale conditions. At a flow rate of 0.8 gpm/sq ft and an empty
bed contact time of 6 minutes, fluometuron breakthrough (when effluent
concentration equals 10% of influent concentration) occurred after
1,640 bed volumes (BV). When a bi-solute solution of fluometuron
diphenamide was passed over the same column, fluometuron breakthrough
occurred after 320 BV.
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GAC adsorption appears to be the most promising treatment technique
for the removal of fluometuron from contaminated water. However,
selection of individual or combinations of technologies to attempt
fluometuron removal from water must be based on a case-by-case
technical evaluation, and an assessment of the economics involved.
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Fluometuron August, 1987
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IX. REFERENCES
Arhur, A., and V. Triana.* 1984. Teratology study (with fluometuron) in
rabbits. Ciba-Geigy Corporation. Report No. 217-84. Unpublished
study. MRID 842096.
Boyd, V.F., and R.W. Foglemann.* 1967. Metabolism of fluometuron (1,1-dimethyl-
3-(alpha, alpha, alpha-trifluoro-m-tolyl) urea) in the rat. Ciba
Agrochemical Company. Research Report CF-1575. Unpublished study.
MRID 00022938.
CHEMLAB. 1985. The chemical information system. CIS, Inc., Bethesda, MD.
Davidson, J., and J. McDougal. 1973. Experimental and predicted movement
of three herbicides in a water-saturated soil. J. Environ. Qual.
2(4):428-433.
Dunkel, V.C., and V.F. Simmon. 1980. Mutagenic activity of chemicals
previously tested for carcinogenicity in the National Cancer Institute
bioassay. PROGRAM. IARC. Sci. Publ. 27:283-302.
Foglemann, R.W.* 1964a. Compound C-2059 technical — acute oral toxicity —
male and female mice. AME Associates for CIBA Corporation. Project No.
20-042. Research Report CF-735. Unpublished study. MRID 00019032.
Foglemann, R.W.* 1964b. Compound C-2059 80 WP-repeated rabbit dermal toxicity.
AME Associates for CIBA Corporation. Project No. 20-0242. Research
Project CF-740. Unpublished study. MRID 00018593.
Foglemann, R.W.* 1964c. Compound C-2059 Technical — Acute eye irritation —
Rabbits. AME Associates for CIBA Corporation. Project No. 20-042.
Unpublished study. MRID 0019032. MRID 00018593.
Foglemann, R.W.* 1965a. Cotoran — 90-day feeding rats. AME Associates for
CIBA Corporation. Project No. 20-042. Unpublished study. MRID 00019034,
Foglemann, R.W.* 1965b. Subacute toxicity — 90 day administration -- dogs.
AME Associates for CIBA Corporation. Project No. 20-042. Unpublished
study. MRID 00019035.
Fritz, H.* 1971. Reproduction study: Segment II. Preparation C-2059:
Experiment No. 22710100. CIBA-GEIGY, Ltd. Unpublished study. MRID
000019211.
Galloway, D. * 1984. Guinea pig skin sensitization. Project No. 3397-84.
Unpublished study. Stillmeadow, Inc. for CIBA-GEIGY Corporation. MRID
00143601.
Guth, J.A. 1972. Adsorption and elution behavior of plant protective agents
in soils. A translation of: Adsorptions- und einwasch ver halten von
pflanzenschutzmitteln in boeden. Schriftenreihe des vereins fuer wasser,
boeden, and lufthygiene, Berlin-Dahlem (37):143-154.
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rl
Fluometuron August, 1987
-15-
Guth, J. A., H. Geissbuehler and L. Ebner. 1969. Dissipation of urea
herbicides in soil. Meded. Rijksfac. Landbouwwet. XXXIV(3):1027-1037.
Helling, C.S. 1971. Pesticide mobility in soils: II. Applications of soil
thin-layer chromatography. Soil Sci. Soc. Am. Proc. 35:737-738.
Helling, C.S., D.D. Kaufman and C.T. Dieter. 1971. Algae bioassay detection
of pesticides mobility in soils. Weed Sci. 19(6):685-690.
Hofmann, A.* 1966. Examinations on rats of the chronic toxicity of preparation
Bo-27 690 (Cotoran = C-2059). Hofmann-Battelle-Geneva. (Translation;
Unpublished study). MRID 00019088.
IARC. 1983. International Agency for Research on Cancer. Vol. 30. _ IARC
monographs on the evaluation of carcinogenic risk of chemicals to man.
Lyon: IARC.
LaFleur, K. 1979. Sorption of pesticides by model soils and agronomic
soils: Rates and equilibria. Soil Sci. 127(2):94-101.
Lehman, A.J. 1959. Appraisal of the safety of chemicals in foods, drugs,
and cosmetics. Association of Food and Drug Officials of the
United States.
Lin, T.H., R.E. Menzer and H.H. North. 1976. Metabolism in human embryonic
lung cell cultures of three phenylurea herbicides; chlorotoluron,
fluometuron and metobromuron. J. Agric. Food Chem. 24:759-763.
Meister, R., ed. 1983. Farm chemicals handbook. Willoughby, OH: Meister
Publishing Co.
NCI. 1980. National Cancer Institute. Bioassay of fluometuron for possible
carcinogenicity. NCI-CG-TR-195. Bethesda, MD.
NIOSH. 1985. National Institute for Occupational Safety and Health. Registry
of Toxic Effects of Chemical Substances. National Library of Medicine
Online File.
Paynter, O.E., J.G. Cummings and M.H. Rogoff. Undated. United States
Pesticide Tolerance System. U.S. EPA Office of Pesticide Programs.
Washington, DC. Unpublished draft report.
Sachsse, K., and R. Bathe.* 1975. Acute oral LD5Q of technical fluometuron
(C-2059) in the rat. Project No. Siss. 4574. Unpublished study. MRID
00019213.
Seiler, J.P. 1978. Herbicidal phenylalkylurea as possible mutagens. I.
Mutagenicity tests with some urea herbicides. Mutat. Res. 58:353-359.
Siebert, D., and E. Lemperle. 1974. Genetic effects of herbicides: Induction
of mitotic gene conversion in Saccharomyces cerevisiae. Mutat. Res.
22:111-120.
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Fluometuron August, 1987
-16-
Siglin, J.C., P.J. Becci and R.A. Parent.* 1981. Primary skin irritation in
rabbits (EPA - FIFRA): FDRL: Study No. 6817A. Food and Drug Research
Laboratories for Ciba-Geigy. Unpublished study. MRID 00068040.
STORET. 1987.
TDB. 1985. Toxicology Data Bank. Medlars II. National Library of Medicine's
National Interactive Retrieval Service.
U.S. EPA. 1985a. U.S. Environmental Protection Agency. Code of Federal
Regulations. 40 CFR 180.229. July 1, p. 293.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. U.S. EPA Method 632
- Carbamate and urea pesticides, Fed. Reg. 50:40701. October 4.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Fed. Reg. 51(185):33992-34003. September 24.
Whittaker, K.F. 1980. Adsorption of selected pesticides by activated carbon
using isotherm and continuous flow column systems. Ph.D. Thesis, Purdue
University.
Windholz, M., S. Budavari, R.F. Blumetti and E.S. Otterbein, eds. 1983.
The Merck Index -- an encyclopedia of chemicals and drugs, 10th ed.
Rahway, NJ: Merck and Company, Inc.
Confidential Business Information submitted to the Office of Pesticide
Programs.
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