November, 1987
TEBUTHIURON
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
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 aodel 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. 34014-18-1
Structural Formula : ^
0 XH
(CH,)aCHCH2vXSXxN-C-N
II
{J
N-t5-(1,1-Dimethyl ethyl)-1,3,4-thiadiazol-2-yl]-N,N«-dimethylurea
Synonyms
0 Combine; Herbic; Graslan; Perflan; Spike.
Uses
0 Herbicide for total vegetation woody plant control in noncropland
areas and for brush and weed control in rangeland (Meister, 1983).
Properties (Meister, 1983)
Chemical Formula CgH16ON4S
Molecular Height 228 (calculated)
Physical State (25°C) White crystalline, odorless powder;
colorless solid
Boiling Point
Melting Point 159 to 161°C
Density
Vapor Pressure (25°C) —
Specific Gravity
Water Solubility (25«C, pH 7) 2,500 mg/L
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
Occurrence /
• Tebuthiuron has been detected in groundwater in Texas over a 4 nonth
period at levies between 10 to 300 ppb (STORET, 1987).
Environmental Fate
0 Tebuthiuron is resistant to hydrolysis'." ^C-Tebuthiuron, at 10
and 100 ppm, did not degrade during 64 days of incubation in sterile
aqueous solutions at pH 3, 6 and 9 in the dark at 25°C (Hosier and
Saunders, 1976). ,
• After 23 days of irradiation with artificial light (20-W black light),
tebuthiuron accounted for 87 to 89% of the applied radioactivity in
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Tebuthiuron November, 1987
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deionized (pR 7.1) and natural (pH 8.1) water treated with thiadiazole
ring-labeled 14C-tebuthiuron at 25 ppm (Elanco Products Company, 1972;
Rainey and Magnussen, 1976b). After 15 days of irradiation with a
black light or a sunlamp, tebuthiuron accounted for approximately
82 and 53%, respectively, of the applied compound in natural Water
treated with 14C-tebuthiuron at 2.5 ppm.
0 Thiadiazole ring-labeled 14c-tebuthiuron in loam soil degraded from
8 ppm immediately post-treatment to 5.7 ppm at 273 days posttreatment
indicating a half-life greater than 273 days (Rainey and Magnussen,
1976a, 1978).
0 14c-Tebuthiuron, at 1.0 ppm, degraded with a half-life of greater
than 48 weeks in a loam soil maintained under anaerobic conditions in
the dark at 23°C (Berard, 1977). N-[5-(1,1-Dimethylethyl)-1,3,4-
thiadiazol-2-yl]-N-methylurea was the major degradate.
0 Ring-labeled 14C-tebuthiuron was very mobile (>94% of that applied
was found the leachate) in a 12-inch column of Lakeland fine sand
soil leached with 20 inches of water (Holzer et al., 1972). It was
mobile in columns of loamy sand (approximately 73% at 6 to 10 inches),
loam (approximately 84% at 1 to 8 inches) and muck (100% at 0 to 4
inches) soils leached with 4 to 8 inches of water.
0 Based on column leaching studies, tebuthiuron is mobile to very mobile
in loam, loamy sand, and Lakeland sand soils and has low mobility in
silty loam soil (Day, 1976a).
° 14c-Tebuthiuron residues aged 30 days were mobile in a column of
sandy loam soil; 39% of 14C-residues were found in the soil and 40%
of 14c-residues were in the leachate (Day, 1976b).
• 14c-Tebuthiuron degraded with half-lives of greater than 33 months
in field plots in California (loam soil), 12 to 15 months in Louisiana
(clay soil), and 12 to 15 months in Indiana (loam soil). The three
sites were treated with thiadiazole ring-labeled 14C-tebuthiuron at
8.96, 2.24 and 8.96 kg/ha, respectively (Rainey and Magnussen, 1976a,
1978). N-[5-(1f1-Dimethylethyl)-1,3,4-thiadiazol-2-yl]-N-methylurea
was the major degradate at all three sites. Radioactivity was detected
in the 15- to 30-cm depth of soil (10.2% of the applied compound at
18 months) at the California site, in the 30- to 45-cm depth of soil
(1.3% of the applied compound at 33 months) at the Louisiana site,
and in the 30- to 45-cm depth of soil (4.7% of the applied compound
at 15 months) at the Indiana site. 14c-Tebuthiuron residues did not
appear to accumulate in silt loam soil in Louisiana after three
applications of 14c-tebuthiuron (0.84 kg/ha at zero time; 1.4 kg/ha at
22 and 73 weeks). —
III. PHARMACOKINETICS
«««^^^»^^—"•^^•^"^^^^•^^ S
Absorption
• Morton and Hoffman (1976) reported that 94 to 96% of a single oral
dose of tebuthiuron (10 mgAg) w*s excreted in the urine of rats,
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Tebuthiuron November, 1987
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rabbits and dogs. In mice, 66% was excreted in the urine, and 3O% in
the feces. These data indicate that tebuthiuron was well absorbed
(about 70 to 96%) from the gastrointestinal tract.
Distribution „
0 No quantitative data were found in the available literature on the
tissue distribution of tebuthiuron in exposed animals.
0 Adams et al. (1982) administered tebuthiuron in the diet to 20
pregnant Wistar rats at levels of 100 or 200 ppm for 6 days prior
to delivery. Forty-eight hours after delivery, radiolabeled tebu-
thiuron was reintroduced into the diet at the same levels as before.
Radioactive label was detected in the milk at levels of 2.7 and
6.2 ppm for the 100- and 200-ppm groups, respectively.
Metabolism
0 Morton and Hoffman (1976) reported that tebuthiuron was metabolized
extensively by mice, rats, rabbits and dogs. Tebuthiuron was
administered by gavage to male and female ICR mice, Marian rats,
Dutch-Belted rabbits and beagle dogs at a dose of 10 mg/kg. Examin-
ation of urine extracts by thin-layer chromatography (TLC) showed the
presence of eight radioactively labeled metabolites in rat, rabbit
and dog urine and seven in mouse urine. Small amounts of unchanged
tebuthiuron also were detected in each case (except for the mouse).
The major metabolites were formed by N-demethylation of the substituted
urea side-chain in each species examined. Oxidation of the dimethylethyl
group also occurred in all species examined.
Excretion
Morton and Hoffman (1976) reported that tebuthiuron was excreted
rapidly in the urine of several species. Radiolabeled tebuthiuron
was administered to male and female ICR mice, BarIan rats, Dutch-
Belted rabbits and beagle dogs at a dose of 10 mg/kg by gavage.
Elimination of radioactivity was virtually complete within 72 hours
and recovery values at 96 hours were 96.3, 94.5, 94.3 and 95.7% in
the mouse, rat, rabbit and dog, respectively. In the rats, rabbits
and dogs, the radioactivity was excrfeted almost exclusively in the
urine. In the mice, 30% of the radioactivity was excreted in the
feces.
IV. HEALTH EFFECTS
Humans
No information on the health effects of tebuthiuron in humans was
found in the available'literature.
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Tebuthiuron November, 1987
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Animals • .
Short-tern Exposure
• Todd et al. (1974) reported the acute oral 1050 values of tebu,thiuron
in cats, mice and rabbits to be 644, 579 and 286 mg/kg, respectively.
In cats, oral doses of 200 mgAg were not lethal, while 500 mgAg
given orally was not lethal to dogs, quail, ducks or chickens*
0 Todd et al. (1972a) supplied Sprague-Dawley rats (age, sex and number
not specified) with food containing tebuthiuron (purity not stated)
at levels of 2,500 ppm for 15 days. Based on the dietary assumptions
of Lehman (1959), 1 ppm in the diet of a rat is equivalent to 0.05
mg/kg/day; therefore, this level corresponds to 125 mg/kg/day. The
animals were observed for an additional 15-day recovery period. All
the animals exhibited reduced body weight gain during the treatment
period. Light and electron microscopic evaluation revealed formation
of vacuoles containing electron-dense bodies and myeloid figures in
pancreatic acinar cells. This condition was rapidly reversed during
the recovery period.
Dermal/Ocular Effects
0 Todd et al. (1974) administered 200 mgAg tebuthiuron to the shaved,
abraded backs of male and female New Zealand White rabbits. During
the study, one rabbit died following development of diarrhea and
emaciation. All surviving rabbits gained weight over the 14-day
observation period and were without signs of dermal irritation.
0 Todd et al. (1974) tested tebuthiuron for sensitization in 2- to
3-month-old female albino guinea pigs. Each animal received topical
applications of 0.1 mL of an ethanolic solution containing 2% tebu-
thiuron to the region of the flank three times per week for 3 weeks.
Ten days after the last of the nine treatments, a challenge application
was made, followed by a second challenge 15 days after the first.
Tebuthiuron induced no dermal or systemic responses indicative of
contact sensitization.
0 Todd et al. (1974) instilled 0.1 mL (71 mg) of tebuthiuron into one
eye and conjunct!val sac of each of six New Zealand White rabbits (2-
to 3-Bonths old)* No irritation of ^he cornea or iris was observed,
but there was slight transient hyperemia of the conjunctiva.
All eyes were normal by the end of the 7-day test period.
Long-term Exposure
0 Todd et al. (1972b) administered tebuthiuron (purity not stated) in
the diet to groups of male and female BarIan rats (10/sex/group, 28-
to 35-days old, 74 to 156 g) at levels of 0, 40, 100 or 250 mgAg/day
for 3 months. Body weights and food consumption were measured weekly.
Blood obtained prior to" necropsy was evaluated for blood sugar, blood
urea nitrogen (BUN) and serum glutamic-pyruvic transaminase (SGPT).
Sections of organs and tissues were prepared for gross and microscopic
evaluation. There were no clinical signs of toxicity or mortality in
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Tebuthiuron November, 1987
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any of the groups. A moderate reduction in body weight gain and a
decrease in efficiency of food utilization in males and females in
the highest dose group (250 mgfkg/Aay) was evident from week 1 of the
study. Tebuthiuron had no clinically important effects on any of the
hematological or clinical chemistry parameters measured.: All-Tats
receiving 250 mg/kg/day tebuthiuron showed diffuse vacuolation of
the pancreatic acinar cells. The degree of this change ranged from
moderate to severe, but the effect was not associated with necrosis
or with the presence of an inflammatory response. One rat receiving
100 mg/kg/day tebuthiuron showed similar but very slight pancreatic
changes. Based on these results, a Mo-Observed-Adverse-Effect-Level
(NOAEL) of 40 mg/kg/day and a Lowest-Observed-Adverse-Effect-Level
(LOAEL) of 100 mgAg/day were identified.
0 Todd et al. (1972c) administered tebuthiuron (purity not stated) in
gelatin capsules to groups of four beagle dogs (two/sex/group, 13- to
23-months old, 7 to 23 kg) at dose levels of 0, 12.5, 25 or 50 mg/kg/day
for 3 months. The physical condition of the animals was assessed
daily, and body weights were recorded weekly. Gross and microscopic
histopathology examinations were performed. Anorexia was noted,
especially in the high-dose animals, leading to some weight loss.
There was no mortality. Behavior and appearance were unremarkable at
all test levels. Mo abnormalities were seen in the hematological or
urinalysis studies. Clinical chemistry findings indicated increased
BUN in the 50-mg/kg females. In addition, this group and the 50-mg/kg
males exhibited increasing levels of alkaline phosphatase, up to
four-fold over those of controls; however, these levels had returned to
normal at the terminal sampling. There were no urinary abnormalities.
The 25-mg/kg females and males demonstrated increased thyroid-to-body
weight ratios, and the 50-mg/kg females also showed increased spleen-
to-body weight ratios. Histopathological findings were unremarkable.
The LOAEL was identified as 12.5 mg/kg» based on increased thyroid-to-
body weight ratios, increased alkaline phosphatase values and increased
BUN levels in test animals.
0 Todd et al. (1976a) administered tebuthiuron (purity not stated)
in the diet to groups of Harlan rats (40/sex/dose) for 2 years at
dietary levels of 0, 400, 800 or 1,600 ppm. Based on the dietary
assumptions of Lehman (1959), 1 ppm in the diet of a rat is equivalent
to 0.05 mg/kg/day; therefore, these doses correspond to 20, 40 or
80 «gAg/day» Physical appearance, behavior, food intake, body
weight gain and mortality were recorded. Hematologic and blood
chemistry values were obtained throughout the study; urinalysis was
also performed. At necropsy, organ weights were determined and
organs and tissues were examined grossly and histologically. Mortality
in exposed animals was similar to, or less than, that observed in the
control group. Variations in hematology, blood chemistry and urinalysis
data from all groups were slight and unrelated to the test compound.
Reduced body weight gain (10% or greater) was observed in the highest
dose group animals. There was also a slight increase in the kidney
weights of the high-dose males. Microscopic examination revealed a
low incidence of slight vacuolation of the pancreatic acinar cells in
animals in the highest dose group. The NOAEL for this study, based
on acinar vacuolation, was 40 mg/kg.
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Tebuthiuron November, 1987
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0 Todd et al. (1976b) administered tebuthiuron (purity hot stated) in
the diet for 2 years to groups of Harlan ICR mice (40/sex/dose) at
levels of 0, 400, 800 or 1,600 ppm. Based on the dietary assumptions
of Lehman (1959), 1 ppm in the diet of a mouse is equivalent to 0.150
mqAg/day; therefore, these dietary levels correspond to approximately
60, 120 or 240 mgAg/day. Physical appearance, behavior, appetite,
body weight gain and mortality were recorded. Hematologic, blood
chemistry and organ weight values were obtained for animals surviving
the test period. Gross and microscopic evaluations were conducted on
organs and tissues obtained at necropsy. No important differences
were observed between treated and control groups for ai/ o«: i:'^
parameters evaluated. The vacuolation of pancreatic acinar cells
noted in the Todd (1976a) rat studies was not evident in this study
in mice. Based on this, the NOAEL for this study was identified as
240 mgAg/day.
Reproductive Effects
0 Hoyt et al. (1981) studied the effects of tebuthiuron (98% active
ingredient) in a two-generation reproduction study in rats. Weanling
Wistar rats (25/sex/dose, FQ generation) were maintained on diets
containing tebuthiuron at 0, 100, 200, and 400 ppm based on the
active ingredient (0, 5, 10 or 20 mgAg/day, based on Lehman, 1959)
for a period of 101 days preceding two breeding trials. First gene-
ration (FI) offspring were maintained on the same diets for a period
of 124 days preceding two breeding trials. Spermatcgenesis and sperm
morphology were examined in 10 ?Q "rates per treatment group. In
addition, representative Fja and F2a weanlings and FI adults were
necropsied and given histopathologic examinations after live-phase
observations were completed. No changes in the efficiency of food
utilization (EFU) were noted during the FQ growth period, but during
the FI growth period, a statistically significant (p Ł0.05) depression
in cumulative (124 days) EFU values occurred in both male and female
rats receiving 20 mgAg/day. EFU was not affected at the other dose
levels. A dose-related depression in mean body weight occurred among
female rats of the Fj generation receiving 10 or 20 mgAg/day; mean
body weight was depressed significantly (p <0.05) only in the high-
dose females. In the 5 mgAg/day group, body weights of either s<«
were not affected. The reproductive capacity of the animals was not
affected at any level; no dose-related conditions or lesions were
found in any offspring. In adult males from the FQ generation, no
dose-related histologic lesions were found, and sperm morphology and
spermatogenesis were normal. A LOAEL of 10 mgAg/day was determined
for a lower rate of body weight gain during the 101-day pre-mating
period in FI females, and a NQAEL of 5 ragAg/day, the lowest dose
tested, was identified.
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Tebuthiuron November, 1987
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Developnental Effects
0 Todd et al. (1972d) administered tebuthiuron (purity not stated) in
the diet to groups of 25 adult Wistar-derived female rats (245 to
454 g) at levels of 0, 600, 1,200 or 1,800 ppm based on the aptive
ingredient (0, 30, 60 or 90 mgAg/day, based on Lehman, 1959) on days
6 to 15 of gestation* Fetal and uterine parameters were normal and
the fetal defects that occurred were not attributed to the test
compound. The NOAEL for developmental effects was greater than
1,800 ppm, the highest dose tested.
0 Todd et al. (1975) administered tebuthiuron (purity not stated) by
gavage to groups of 15 adult female Dutch-Belted rabbits at levels of
10 or 25 mgAg/day on days 6 to 18 of gestation. No developmental or
toxic effects were observed.
Mutagenicity
0 Hill (1984) reported that primary cultures of adult rat hepatocytes
incubated with concentrations of tebuthiuron ranging from 0.5 to
1,000 ug/mL did not induce unscheduled DNA synthesis.
0 Rexroat (1984) reported that tebuthiuron did not induce Salmonella
revertants (strains TA1535, 1537, 1538, 98 and 100) when tested at
concentrations ranging between 100 and 5,000 ug/plate, with or without
metabolic activation. It was concluded that tebuthiuron was not
mutagenic in the Ames Salmonella/mammalian microsome test for bacterial
mutation.
0 Neal (1984) reported that tebuthiuron did not induce sister chromatid
exchange _in vivo in bone marrow cells of Chinese hamsters administered
oral doses of 200, 300, 400 or 5OO mg/kg tebuthiuron.
0 Cline et al. (1978) reported that histadine auxotrophs of Salmonella
typhimurium (strains G46, TA1535, 100, 1537, 1538, 98, C3076 and
D3052) and tryptophan auxotrophs of Escherichia coli were not
reverted to the prototype by tebuthiuron at levels of 0.1 to 1,000
ug/mL, with or without metabolic activation.
Carcinogenicity
/
• Todd et al. (1976a) administered tebuthiuron (purity not stated) in
the diet to groups of Harlan rats (40/sex/dose) at levels of 0, 400, 800
or 1,600 ppm based on the active ingredient (0, 20, 40 or 80 mgAg/day,
based on Lehman, 1959) for 2 years. The authors reported no influence
of the test compound on the incidence of neoplasms at any dose level.
0 Todd et al. (1976b) administered tebuthluron in the diet to groups
of Harlan ICR nice (40/sex/dose) at levels of 0, 400, 800 or 1,600
ppm (0, 60, 120 or 240 mgAg/day, based on Lehman, 1959) for 2 years.
The authors reported no. statistical evidence of increased incidence
of tumors at any dose level.
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V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (H'V.) ara generally determined for one-day, ten-day,
longer-terra (approximately 7 years) and lifetime exposures if adeguate data
are available that identify a sensitive noncarcinojs iio eid point of toxicity.
The HAs for .noncarcinogenic toxicants are derived using the following formula:
HA = (NOftEL or LOAEL) x (BW) = ^A, (_
(tJF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mgAg bw/day.
BW = assumed body weight of a child (10 kg) or
•in adult (70 kq).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
No information was found in the available literature that was suitable
for the determination of the One-day HA value for tebuthiuron. It is therefore
r*o wTunI»>1 that the Ten-day value for a 10-kg child, 2.5 mg/L (2,500 ug/L,
calculated below), be used at this time as a conservative estimate of the
One-flay HA \/alue.
Ten-day Health Advisory
The study by Todd et al. (1975) has been selected to serve as the basis
for the Ten-day HA value for tebuthiuron because the NOAEL in the Dutch-Belted
rabbit was the lowest end point observed in a short-term developmental study.
This study identified a NOAEL of 25 mgAq/day (the highest dose tested) based
on an absence of maternal toxicity. In another developmental study in rats
by Todd et al. (1972d), a NOAEL of 90 mgAg/day (the highest dose tested) was
recorded. Since it is unknown vihether the rabbit or the rat is more sensitive,
the lower NOAEL was conservatively chosen in deriving the 10-day HA.
Using a NOAEL of 25 mgAg/day, the Ten-day HA for a 10-kg child is
calculated as follows:
Ten-day HA = (25 mgAg/day) (10 kg)-= 2.5 rogA (2,500 ug/L)
(100) (1 L/day)
where:
25 mgAg/day = NOAEL, based on the absence of maternal toxicity in
Dutch-Belted rabbits exposed to tebuthiuron by diet.
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Tebuthiuron November, 1987
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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.
Longer-term Health Advisories
The subchronic (90-day) feeding study in beagle dogs reported by Todd
et al. (1972c) has been selected to serve as the basis for the Longer-term HA
values for tebuthiuron. The study identified a dose response relationship
and a LOAEL for female dogs administered tebuthiuron in gelatin capsules at
dose levels of 0, 12.5, 25 or 50 mgAg/day for 3 months. There was an increased
BUN in the 50-mg/kg females and a four-fold increase in alkaline phosphatase.
The males also had a four-fold increase in alkaline phosphatase. Both the
males and females demonstrated increased thyroid-to-body weight ratios. Based
on these results, the LOAEL was .12.5 mgAg/day, the lowest dose tested. The
two-generation reproduction study by Hoyt et al. (1981) was not selected,
even though an apparent LOAEL of 10 mgAg/day was identified. This LOAEL was
based on a slight decrease in weight gain in exposed females, along with a
decrease in EFU values. This value was rejected because it is not clear that
the effects are biologically significant, and because no effects on weight
gain or EFU were seen at comparable dose levels in subchronic feeding studies
in rats and dogs (Todd et al., 1972b,c) or in chronic studies in rats and
mice (Todd et al., 1976a,b).
Using a LOAEL of 12.5 mgAg/day, the Longer-term HA for a 10-kg child is
calculated as follows:
Longer-term HA - (12.5 mgAg/day) (10 kg) . 0.125 mg/L (125 ug/L)
(1,000) (1 L/day)
where:
12.5 mgAg/day « LOAEL, based on a four-fold increase in alkaline
phosphatase levels, increased BUN levels and increased
thyroid-to-body weight ratios in dogs exposed to
tebuthiuron in the diet for 3 months.
10 kg - assumed body weight/of a child.
1,000 » uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
1 L/day - assumed daily water consumption of a child.
The Longer-term HA for the 70-kg adult is-calculated as follows:
Longer-term HA - (12.5 mg/kg/day) (70 kg) . 0.438 mg/L (438 ug/L)
(1,000) (2 L/day)
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Tebuthiuron November, 1987
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where:
12*5 mgA9/day - LOAEL, based on a four-fold increase in alkaline
phosphatase levels, increased BUN levels and increased
thyroid-to-body weight ratios in dogs exposed to
tebuthiuron in the diet for 3 months.
70 kg - assumed body weight of an adult.
1,000 « uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL 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, 1986a), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The two-generation reproduction study in rats (Hoyt et al., 1981) has been
selected to serve as the basis for the Lifetime HA value for tebuthiuron. In
this study, four groups of Wistar rats (25/sex) were fed tebuthiuron at 0, 5,
10 or 20 Bg/kg/day in the diet for 101 days (Fg rats) or 121 days (FI rats)
and then for a further period sufficient to mate, deliver and rear two
successive litters of young to 21 days of age (i.e., the test diet was fed
throughout mating, gestation and lactation). The Fja rats were parents of
the F2 offspring. No adverse effects were reported in this study except for
a lower rate of body weight gain during the premating period in FI females at
dietary levels of 10 and 20 mg/kg« The NOAEL was identified as 5 mg/kg/day.
The chronic study by Todd et al. (1976b) in mice was not selected because the
weight loss and vacuolation of pancreatic acinar cells noted in rats was not
observed in mice even at dose levels as high as 160 mg/kg/day, indicating
that the mouse is less sensitive than the rat.
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Tebuthiuron November, 1987
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Using the NOAEL of 5 mgAg/day, the Lifetime HA is calculated as follows:
Step Is Determination of the Reference Dose (RfD)
RfD - (5 mg/kg/day) » 0.05 mgAg/day
(100)
where:
5 mgAg/day - NOAEL, based on effects on the rate of weight gain in
rats exposed to tebuthiuron in the diet for 101 days.
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 = (0.05 mgAg/day) (70 kg) a 1>75 /L
(2 L/day)
where:
0.05 mgAg/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 « (1'75 m9/L) (20%) - 0.35 mg/L (350 ug/L)
where:
1.75 mg/L - DWEL.
20% • assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
* The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of tebuthiuron.
• Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986a), tebuthiuron may be classified
in Group D: not classifiable as to human carcinogenicity. This
category is for substances with inadequate human and animal evidence
of carcinogenicity. --
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 No other criteria, guidance or standards were found in the available
literature.
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Tebuthiuron November, 1987
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VII. ANALYTICAL METHODS
0 Analysis of tebuthiuron is by a gas chromatographic (GC) method
applicable to the determination of certain nitrogen-phosphorus-
containing pesticides in water samples (U.S. EPA, 1986b). 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 deter-
mined for tebuthiuron 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
0 No information on treatment technologies capable of effectively
removing tebuthiuron from contaminated water was found in the available
literature.
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Tebuthiuron November, 1987
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IX. REFERENCES
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milk of lactating rats given 14C-tebuthiuron (compound 75503) in the diet.
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Berard, D.F.* 1977. 14C-Tebuthiuron degradation study in anaerobic soil.
Prepared and submitted by Eli Lilly and Co., Greenfield, IN.
MRID 00900098.
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/
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' - •'• •»•
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Todd, G.C., W.R. Gibson and C.C. Kehr. 1974. Oral toxicity of tebuthiuron
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•Confidential Business Information submitted to the Office of Pesticide
Programs
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