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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   .Tebuthiuron                                                November, 1987

                                        -2-


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

                                          -3-


             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

                                         -4-
            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
                                     -5-
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

                                     -6-
        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

                                     -7-
     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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   Tebuthiuron                                                November,  1937

                                        -9-


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

                                     -10-


               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

                                     -11-
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

                                         -12-


         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

                                           -13-


 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

                                         -14-


IX. REFERENCES

    Adams,  E., J.  Magnussen,  J.  Emmerson  et al.*  1982.   Radiocarbon levels  in the
         milk of lactating rats  given  14C-tebuthiuron (compound 75503) in the diet.
         Eli Lilly and Company,  Greenfield,  IN.   Unpublished study.  ;MRID-00106081.

    Berard, D.F.*   1977.   14C-Tebuthiuron degradation study in anaerobic soil.
         Prepared  and submitted  by Eli  Lilly and Co., Greenfield,  IN.
         MRID 00900098.

    Cline,  J.C., G.Z. Thompson and R.I. McMahon.*  1978.   The effect of Lilly Com-
         pound 75503 (tebuthiuron) upon bacterial systems known to detect mutagenic
         events.  Eli Lilly and  Company,  Greenfield,  IN.   Unpublished study.
         MRID 000416090.

    Day,  G.W.*  1976a. Laboratory soil leaching studies  with tebuthiuron.  Unpublished
         study received Feb.  18,  1977  under 1471-109; submitted by Blanco Products
         Co., Div. of Eli  Lilly  and Co.,  Indianapolis, IN.  CDL:095854-1.
         MRID 00020782.

    Day,  G.W.*  1976b. Aged  soil leaching study with herbicide tebuthiuron.  Unpub-
         lished study received Feb. 18, 1977 under 1471-109; submitted by Blanco
         Products  Co., Div. of Eli Lilly  and Co., Indianapolis, IN.   CDL:095854-J.
         MRID 00020783.

    Elanco  Products Company.* 1972.   Environmental safety studies with EL-103.
         Unpublished study received Mar.  13, 1973 under 1471-97; prepared in
         cooperation with  United States Testing  Co.,  Inc.  CDL:120339-1.
         MRID 00020730.

    Hill, L.*  1984.  The  effect of tebuthiuron  (Lilly Compound 75503) on the
         induction of DNA  repair synthesis in primary cultures of adult rat
         hepatocytes.  Eli Lilly and Company., Greenfield, IN.  Unpublished study.
         MRID 00141692.

    Holzer, F.J.,  R.F. Siek,  R.L. Large et al.*   1972.  EL-103:  Leaching study.
         Unpublished study received Mar.  13, 1973 under 1471-97 and prepared in
         cooperation with  Purdue Univ., Agronomy Dept., and United States Testing
         Co., Inc., and submitted by Elanco Products Co., Division of Eli Lilly
         and Co.,  Indianapolis,  IN.  CDL: 120339-K.  MRID 00020732.
                                                /
    Hoyt, J.A., E.R. Adams and N.V. Owens.*  1981.  A two-generation reproductive
         study with tebuthiuron  in the Wistar rat.  Eli Lilly and Company, Green-
         field, IN.  Unpublished study.  MRID 00090108.

    Lehman, A.J.  1959. Appraisal of  the safety of chemicals in foods, drugs, and
         cosmetics,  Assoc. Food Drug  Off. U.S., Q.^ Bull.

    Meister, R., ed.  1983.  Farm chemicals handbook.  Willoughby, OH:  Meister
         Publishing Company.

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                                     -15-
Morton, D.M., and D.G. Hoffman.  1976.  Metabolism of a new herbicide, tebu-
     thioron (1-(5-(1,1-dimethylethyl)-1,3,5-thiadiazol-2-yl)-1,3-dimethylurea),
     in mouse, rat, rabbit, dog, duck and fish.  J. Toxicol. Environ. Health.
     1i757-768.
                                                                ' - •'•  •»•
Hosier, J.W., and D.G. Saunders.*  1976.  A hydrolysis study on the herbicide
     tebuthiuron.  Includes undated method.  Unpublished study received
     Feb. 18, 1977 under 1471-109; submitted by Elanco Products Co., Div. of
     Eli Lilly and Co., Indianapolis, IN.  CDL:09S854-F.  MRID 00020779.

Neal, S.B.*  1984.  The effect of tebuthiuron (Lilly Compound 75503) on the
     ill vivo induction of sister chromatid exchange in bone marrow of Chinese
     hamsters.  Eli Lilly and Company, Greenfield, IN.  Unpublished study.
     MRID 00141693.

Rainey, D.P., and J.D. Magnussen.*  1976a.  Behavior of 14C-tebuthiuron in
     soil.  Unpublished study received Feb. 18, 1977 under 1471-109; prepared
     in cooperation with A & L Agricultural Laboratories and United States
     Testing Co., Inc., and submitted by Elanco Products Co., Div. of Eli
     Lilly and Co., Indianapolis, IN.  CDL:095854-C.  MRID 00020777.

Rainey, D.P., and J.D. Magnussen.*  1976b.  Photochemical degradation studies
     with 14c-tebuthiuron.  Unpublished study received Feb. 18, 1977 under
     ..1471-109; submitted by Elanco Products Co., Div. of Eli Lilly and Co.,
     Indianapolis, IN.  CDL:095854-D.  MRID 00020778.

Rainey, D.P., and J.D. Magnussen.*  1978.  Behavior of 14C-tebuthiuron in
     soil: Addendum report.  Unpublished study received June 1, 1978 under
     1471-109; submitted by Elanco Products Co., Div. of Eli Lilly and Co.,
     Indianapolis, IN.  CDL:097100-C.  MRID 00020693.

Rexroat, M.*  1984.  The effect of tebuthiuron (Lilly Compound 75503) on the
     induction of reverse mutations in Salmonella typhimurium using the Ames
     test.  Eli Lilly and Company, Greenfield, IN.  Unpublished study.
     MRID 00140691.

STORET.  1987.

Todd, G.E., W.J. Griffing, W.R. Gibson et al.*  1972a.  Special subacute rat
     toxicity study.  Eli Lilly and Company,  Greenfield, IN.  Unpublished study.
     MRID 00020798.                         !

Todd, G.C., W.R. Gibson and G.F. Kiplinger.*  1972b.  The toxicological
     evaluation of EL-103 in rats for 3 months.  Unpublished study.
     MRID 00020662.

Todd, G.C., W.R. Gibson and G.F. Kiplinger.*  JL972c.  The toxicological
     evaluation of EL-103 in dogs for 3 months.  Unpublished study.
     MRID 00020663.

Todd, G.C., J.K. Markham, E.R. Adams et al.*  1972d.  Rat teratology study
     with EL-103.  Unpublished study.  MRID 00020803.

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Tebuthiuron                                                 November, 1987

                                     -16-
Todd, G.C., W.R. Gibson and C.C. Kehr.  1974.  Oral toxicity of tebuthiuron
     (1-(5-t«rt-butyl-1,3,4-thiadiazol-2-yl)-1,3-dimethylurea) in experimental
     aninals.  Pood Cosmet. Toxicol.  12:461-470.

Todd, G.C., J.K. Markham, E.R. Adams, M.V. Owens, P.O. Gossett and D.M,. Morton.*
     1975.  A teratology study with EL-103 in the rabbit.  Eli Lilly and
     Company, Greenfield, IN.  Unpublished study.  MRID 00020644.

Todd, G.C., W.R. Gibson, D.G. Hoffman, S.S. Young and D.M. Morton.*  1976a.
     The toxicological evaluation of tebuthiuron (EL-103) in rats for two
     years.  Eli Lilly and Company, Greenfield, IN.  Unpublished study.
     MRID 00020714.

Todd, G.C., W.R. Gibson, D.G. Hoffman, S.S. Young and D.M. Morton.*  1976b.
     The toxicological evaluation of tebuthiuron (EL-103) in mice for two
     years.  Eli Lilly and Company, Greenfield, IN.  Unpublished study.
     MRID 00020717.

U.S. EPA.  1986a.  U.S. Environmental Protection Agency.  Guidelines for
     carcinogenic risk assessment.  Fed. Reg.  51(185):33992-34003.  September 24.

U.S. EPA.  1986b.  U.S. Environmental Protection Agency.  U.S. EPA Method II
     - Determination of nitrogen and phosphorus containing pesticides in
     ground water by GC/NPD, January 1986 draft.  Available from U.S. EPA's
     Environmental Monitoring and Support Laboratory, Cincinnati, OH.
•Confidential Business Information submitted to  the Office  of  Pesticide
 Programs

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