 muscle and bone. The metabolic pathway is essentially an oxidative pathway. Vulnerable sites of the molecule are the thiazoline ring, the isobutyric side chain and the pyridine rings. Thiazopyr appears to be rapidly and extensively eliminated with low amounts of residues remaining in the tissues and carcasses. The percentage of radiolabel remaining in the carcasses following feeding thiazoline-labeled thiazopyr was between 6.9 and 10.8%. 16. Special mechanistic studies for mode of toxic action on thyroid function. The results of three studies on the effects of thiazopyr on thyroid function and mechanisms involved in the disposition of T4 in rats were reviewed. These studies are described below: a. Thiazopyr was administered through the diet, in rats, at 0 and 150 mg/kg/day to determine the subchronic effect on hormone level and other biochemical endpoints. Animals were [[Page 9976]] assayed at 7, 14, 28, 56 or 90 days. Significant decreases in body weight gain were observed at 90 days. Early in the study the treated rats showed increases in TSH (ranging from 133 to 200% of controls) and decreases in T4 (ranging from 43% to 76% of controls). In addition there were increases in liver and thyroid weights and increases in thyroid follicular cell hypertrophy/hyperplasia. Reverse T3 was increased at 28 days, and T3 was either not affected or increased. There were indications of increases in hepatic UDPGT activity and significant increases in T4 UDPGT activity. Hepatic 5'-monodeiodinase activity was either not affected or decreased. The effects observed in this study were supportive of the theory that thiazopyr may induce thyroid tumors through a disruption in the thyroid-pituitary hormonal feedback mechanisms. b. A second study on the effects of thiazopyr on the biochemical mechanisms of thyroid toxicity in rats at doses of 0, 0.5, 1.5, 5, 15, 50 or 150 mg/kg/day was conducted. Dose response effects on various biochemical parameters were observed. Two groups of the rats in the study were observed for reversibility of effects observed up to 56 and 112 days. Doses at 15, 50 and 150 mg/kg/day significantly increased the liver weights. Thyroid weights were increased at doses of 50 and 150 mg/kg/day. There was no significant effect on body weight or body weight gains during the study. The T4 UDPGT levels were increased by 117 and 376% above controls at the 50 and 150 mg/kg/day dosages, respectively. Effects of 150 mg/kg/day were increases in T3, TSH and rT3 serum concentrations, and increased incidence of follicular cell hypertrophy/hyperplasia at the 150 mg/kg/day dose. A NOEL of 1.5 mg/kg/ day was determined based on liver weight increases. Thyroid weight was the only parameter that did not return to those similar to the controls. At the 56 and 112 day recovery periods the thyroid weights were 120 and 123% of control values, respectively. c. A third thyroid function study on the biochemical mechanisms involved with disposition of T4 in rats fed dosages of 0 and 150 mg/kg/ day for 56 days was conducted. Rats feed thiazopyr had increase T4 UDPGT activity and total deiodinase activity in their livers. There was also a two-fold increase in mixed function oxidase enzyme activity. Results of the three studies suggest that increased glucuronidation, deiodination of T4 and T3, and increased rate of clearance of T4 from the blood and excretion of the hormone and its metabolites in the bile could significantly reduce the level of circulating T4 in the male rat. Results of these studies support the hypothesis that thiazopyr may induce thyroid tumors through a disruption of the thyroid-pituitary hormonal feedback mechanism circulating T4 in the male rat. II. Aggregate Exposures 1. Food and feed uses. The primary source for human exposure to thiazopyr will be from ingestion of both raw and processed agricultural commodities as proposed in the November 22, 1996 notice of filing cited above. Based on tolerances of 0.05 ppm in or on orange and grapefruit, the Theoretical Maximum Residue Contributions (TMRC) for the U.S. adult population and for U.S. children (1 to 6 years of age) were determined. In deriving the dietary exposure to thiazopyr and its metabolites, EPA assumed that 100% of the orange and grapefruit crops were cultured with the aid of this herbicide. A chronic exposure was used to estimate the TMRC. The TMRC for the U.S. population was estimated to be 0.000118 mg/ kg/day. The TMRC for children, 1 to 6 years of age was 0.000324 mg/kg/ day. The TMRC for children, 7 to 12 years of age was 0.000173 mg/kg/day. 2. Potable water. There is presently no EPA Lifetime Health Advisory level for thiazopyr and its degradates as drinking water contaminates. Thiazopyr has not been found in ground water. A monoacid degradate was found in wells at concentrations of up to 7.6 parts per billion (ppb). The wells were being monitored as part of a prospective ground water study in the state of Florida. Using a standard potable water ingestion of 2 liters per day by adults and 1 liter per day by children, the exposure from potable water to adults was determined to be 0.000217 mg/kg/day. Exposure to children was determined to be 0.00076 mg/kg/day. 3. Non-dietary uses. There are no non-dietary uses registered under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), as amended..'' While the Agency has some information in its files that may turn out to be helpful in eventually determining whether a pesticide shares a common mechanism of toxicity with any other substances, EPA does not at this time have the capability to resolve the scientific issues concerning common mechanism of toxicity in a meaningful way. EPA is commencing a pilot process to study this issue further through the examination of particular classes of pesticides. The Agency hopes that the results of this pilot process will enable the Agency to apply common mechanism issues to its pesticide risk assessments. At present, however, the Agency does not know how to apply the information in its files concerning common mechanism issues to risk assessments, and therefore believes that in most cases there is no ``available information'' concerning common mechanism that can be scientifically applied to tolerance decisions. Where it is clear that a particular pesticide may share a significant common mechanism with other chemicals, or where it is clear that a pesticide does not share a common mechanism with other chemicals, a tolerance decision may be affected by common mechanism issues. The Agency expects that most tolerance decisions will fall into the area in between, where EPA can not reasonably determine whether a pesticide does or does not share a common mechanism of toxicity with other chemicals (and, if so, how that common mechanism should be factored into a risk assessment). In such circumstances, the Agency will reach a tolerance decision based on the best, currently available and usable information, without regard to common mechanism issues. However, the Agency will also revisit such decisions when the Agency learns how to apply common mechanism information to pesticide risk assessments. In the case of thiazopyr, EPA has determined that it does not now thiazopyr, if reexamination is appropriate, after the Agency has determined how to apply common mechanism issues to its pesticide risk assessments. III. Determination of Safety for U.S. Population and Non-nursing Infants 1. The U.S. population. Based on a NOEL of 0.8000 milligrams per kilogram of body weight per day (mg/kg bwt/day) from a 2-year dog feeding study that showed a liver effect of hepatocellular hypertrophy and hyperplasia, and using a safety or uncertainty factor of 100 to [[Page 9977]] account for the interspecies extrapolation and intraspecies variability, the Agency has determined a Reference Dose (RfD) of 0.008 mg/kg bwt/day for this assessment of risk. Based on the available toxicity data and the available exposure data identified above, the proposed tolerances will utilize 1.5% of the RfD for the U.S. population. Including an estimated exposure of 7.6 ppb in potable water, the dietary exposure for the U.S. adult population, assuming the ingestion of 2 liters of water per day, increases to 0.000335 mg/kg/day and utilizes 4.6% of the RfD. 2. Non-nursing infants. Using the RfD of 0.008 mg/kg/bwt/day as described above and the TMRC of 0.000251 mg/kg/day determined of non- nursing infants, the proposed tolerances utilize 13.97% (3.1% dietary and 10.87% potable water) of the RfD. 3. Nonfood uses. There are no nonfood uses of thiazopyr registered under FIFRA, as amended. IV. Determination of Safety for Infants and Children Risk to infants and children was determined by use of two developmental toxicity studies. One study in rats had a NOEL for developmental toxicity of 100 mg/kg/day, based on an increase in the incidence of unossified sternebrae and 7th cervical rib variations. The maternal NOEL was also 100 mg/kg/day based on toxic effects of increased liver weights, salivation, decreased body weight gains and food consumption. Fetal toxicity was only observed at maternally toxic doses. No malformations were observed at any dose. A second study in rabbits had a maternal NOEL of