Further, for the chemical metolachlor, the NOEL of 9.7 mg/kg/day from the metolachlor chronic dog study, which was used to calculate the RfD (discussed above), is already lower than the developmental NOEL's of 360 mg/kg/day from the metolachlor developmental toxicity studies in rats and rabbits.
7. Metabolite toxicology. The metabolism of S-metolachlor has been well characterized in standard FIFRA metabolism studies. S-metolachlor does not readily undergo dealkylation to form an aniline or quinone imine as has been reported for other members of the chloroacetanilide class of chemicals. Therefore, it is not appropriate to include S-metolachlor with the group of chloroacetanilides that readily undergo dealkylation, producing a common toxic metabolite (quinone imine). New toxicology data submitted by Syngenta demonstrate that the S-metolachlor metabolites ethane sulfonic acid (CGA 354743) and oxanilic acid (CGA 51202) are not absorbed by mammalian systems and / or have a significantly lower level of mammalian toxicity when compared to parent.
In fact, based on experience with metolachlor,[[Page 10614]]it is believed that metolachlor will be infrequently found in groundwater (less than 5% of the samples analyzed), and when found, it will be in the low ppb range.
Based on the available studies used by EPA to assess environmental exposure, Novartis anticipates that exposure to residues of metolachlor in drinking water will not exceed 20% of the RfD (0.02 mg/kg/day), a value upon which the Health Advisory Level of 70 parts per billion (ppb) for metolachlor is based.
1. Plant metabolism. [The qualitative nature of S-metolachlor residues in plants is adequately understood based upon available EPA approved corn, potato, and soybean metabolism studies. The metabolism of S-metolachlor involves conjugation with glutathione, breakage of this bond to form the mercaptan, conjugation of the mercaptan with glucuronic acid, hydrolysis of the methyl ether, and conjugation of the resultant alcohol with a neutral sugar. EPA has determined that residues of concern in plants include parent and metabolites, determined as the derivatives CGA-37913 and CGA-49751.
The developmental effect observed in the metolachlor rat study is believed to be a secondary effect resulting from maternal stress (lacrimation, salivation, decreased body weight gain and food consumption and death) observed at the limit dose of 1,000 mg/kg/day.
6. Animal metabolism. In animals, S-metolachlor is extensively absorbed, rapidly metabolized and almost totally eliminated in the excreta of rats, goats, and poultry. Metabolism in animals proceeds through common Phase 1 intermediates and glutathione conjugation.
Developmental toxicity (reduced mean fetal body weight, reduced number of implantations/dam with resulting decreased litter size, and a slight increase in resorptions/dam with a resulting increase in post-implantation loss) were observed in studies on metolachlor in rats and rabbits.
8. Endocrine disruption. S-Metolachlor does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system. There is no evidence that S-metolachlor has any effect on endocrine function in developmental or reproduction studies. Furthermore, histological investigation of endocrine organs in the chronic dog, rat and mouse studies did not indicate that the endocrine system is targeted by S-metolachlor, even at maximally tolerated doses administered for a lifetime. There is no evidence that S-metolachlor bioaccumulates in the environment.
5. Chronic toxicity. A combined chronic toxicity/carcinogenic study in the rat satisfies the requirements for both the chronic toxicity and carcinogenicity studies. No significant chronic toxicity was found in either rats or dogs. In the rat, a decrease in body weight was observed at the highest dose tested. In the chronic dog study that supports S-metolachlor, the only adverse effect was decreased body weight gain in females at 33 mg/kg/day; the NOAEL was 10 mg/kg/day.
4. Subchronic toxicity. In a 90-day dietary study in rats with S-metolachlor, no effects were observed in male or females at 208 and 236 mg/kg/day, respectively. In another 90-day dietary study in rats, decreased body weight, reduced food consumption and food efficiency in both sexes and increased kidney weight in males at 150 mg/kg/day; the NOAEL was 15 mg/kg/day. A 90-day dog study with S-metolachlor in dogs has been accepted by EPA; no effects were observed in males and females at 62 mg/kg/day and 74 mg/kg/day, respectively, the highest doses tested.
In the metolachlor reproduction study, the lack of severity of the pup effects observed (decreased body weight) at the systemic lowest-observed-effect level (LOEL) (equivalent to 75.8 to 85.7 mg/kg/day) and the fact that the effects were observed at a dose that is nearly 10 times greater than the NOEL in the chronic dog study (9.7 mg/kg/day) suggest there is no additional sensitivity for infants and children.
In assessing the potential for additional sensitivity of infants and children to residues of metolachlor, data from developmental toxicity studies in the rat and rabbit and a 2-generation reproduction study in the rat have been considered.