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. ------- .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 ------- 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, ------- 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. ------- 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 ------- 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. ------- 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. ------- Tebuthiuron November, 1987 -8- 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. ------- 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. ------- 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) ------- 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. ------- 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. ------- 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. ------- 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. ------- Tebuthiuron November, 1987 -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. ------- 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 ------- |