FLUORIDE ACTION NETWORK PESTICIDE PROJECT
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Trifloxystrobin (Novartis). August 17, 1998. Pesticide Tolerance Petition for CGA-279202. Federal Register.
Note from EC:
CGA-279202 is Trifloxystrobin
http://www.epa.gov/fedrgstr/EPA-PEST/1998/August/Day-17/p22012.htm
[Federal Register: August 17, 1998 (Volume 63, Number 158)] [Notices] [Page 43937-43944] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr17au98-61] ----------------------------------------------------------------------- ENVIRONMENTAL PROTECTION AGENCY [PF-819 FRL-6018-2] Notice of Filing of Pesticide Petitions AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. ----------------------------------------------------------------------- SUMMARY: This notice announces the initial filing of pesticide petitions proposing the establishment of regulations for residues of certain pesticide chemicals in or on various food commodities. DATES: Comments, identified by the docket control number PF-819 must be received on or before September 16, 1998. ADDRESSES: By mail submit written comments to: Public Information and Records Integrity Branch, Information Resources and Services Division (7502C), Office of Pesticides Programs, Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. In person bring comments to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA. Comments and data may also be submitted electronically to: opp- docket@epamail.epa.gov. Follow the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential business information should be submitted through e-mail. Information submitted as a comment concerning this document may be claimed confidential by marking any part or all of that information as ``Confidential Business Information'' (CBI). CBI should not be submitted through e-mail. Information marked as CBI will not be disclosed except in accordance with procedures set forth in 40 CFR part 2. A copy of the comment that does not contain CBI must be submitted for inclusion in the public record. Information not marked confidential may be disclosed publicly by EPA without prior notice. All written comments will be available for public inspection in Rm. 1132 at the address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. FOR FURTHER INFORMATION CONTACT: The product manager listed in the table below: ------------------------------------------------------------------------ Office location/ Product Manager telephone number Address ------------------------------------------------------------------------ Joanne I. Miller.............. Rm. #227, CM #2, 703- 1921 Jefferson 305-6224, e- Davis Hwy, mail:miller.joanne@ep Arlington, VA amail.epa.gov. Cynthia Giles-Parker.......... Rm. #247, CM #2, 703- Do. 305-7740,e-mail:giles- parker.cynthia@epamai l.epa.gov. ------------------------------------------------------------------------ SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as follows proposing the establishment and/or amendment of regulations for residues of certain pesticide chemicals in or on various food commodities under section 408 of the Federal Food, Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions contain data or information regarding the elements set forth in section 408(d)(2); however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition. The official record for this notice of filing, as well as the public version, has been established for this notice of filing under docket control number [PF-819] (including comments and data submitted electronically as described below). A public version of this record, including printed, paper versions of electronic comments, which does not include any information claimed as CBI, is available for inspection from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The official record is located at the address in ``ADDRESSES'' at the beginning of this document. Electronic comments can be sent directly to EPA at: opp-docket@epamail.epa.gov Electronic comments must be submitted as an ASCII file avoiding the use of special characters and any form of encryption. Comments and data will also be accepted on disks in Wordperfect 5.1 file format or ASCII file format. All comments and data in electronic form must be identified by the docket number FRL-6018-2 and appropriate petition number. Electronic comments on notice may be filed online at many Federal Depository Libraries. List of Subjects Environmental protection, Agricultural commodities, Food additives, Feed additives, Pesticides and pests, Reporting and recordkeeping requirements. Dated:August 4, 1998. Arnold E. Layne, Acting Director, Registration Division, Office of Pesticide Programs. Summaries of Petitions Petitioner summaries of the pesticide petitions are printed below as required by section 408(d)(3) of the FFDCA. The summaries of the petitions were prepared by the petitioners and represent the views of the petitioners. EPA is publishing the petition summaries verbatim without editing [[Page 43938]] them in any way. The petition summary announces the availability of a description of the analytical methods available to EPA for the detection and measurement of the pesticide chemical residues or an explanation of why no such method is needed. 2. Novartis Crop Protection, Inc. PP 8F4955 EPA has received a pesticide petition (PP 8F4955) from Novartis Crop Protection, Inc., PO Box 18300, Greensboro, NC 27419 proposing pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of CGA-279202 in or on the raw agricultural commodity on pome fruit at 0.4, cucurbit vegetables at 0.25, grapes at 1.5, peanuts at 0.02, peanut hay at 4.0, apple pomace at 1.5 and imported bananas at 0.1 ppm. EPA has determined that the petition contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The metabolism of CGA-279202 in plants (cucumbers, [[Page 43942]] apples, wheat and peanuts) is well understood. Identified metabolic pathways are substantially similar in plants and animals (goat, rat and hen). Novartis proposes CGA-279202, per se, as the residue of concern for tolerance setting purposes. 2. Analytical method. Novartis Crop Protection Inc. has submitted practical analytical methodology for detecting and measuring levels of CGA-279202 in or on raw agricultural commodities. The limit of detection (LOD) for each analyte of this method is 0.08 ng injected, and the limit of quantitation (LOQ) is 0.02 ppm. The method is based on crop specific cleanup procedures and determination by gas chromatography with nitrogen-phosphorus detection. 3 Magnitude of residues--Residue trials. CGA-279202 was applied to apples in 10 States and to pears in 4 States for a total of 19 field trials. Twelve field trials were conducted in the following 8 representative peanut-growing States: Alabama, Florida, Georgia, North Carolina, Oklahoma, South Carolina, Texas, and Virginia. Eighteen cucurbit field trials in 10 States were successfully harvested, including 8 cucumber, 5 cantaloupe, and 5 summer squash field trials. Twelve field trials in 5 States, accounting for 94% of the U.S. grape production, were conducted to generate residue data on grapes, raisins, and raw and pasteurized juice. Thirteen banana field trials were conducted in Costa Rica, Ecuador, Colombia, Guatemala, Mexico, Honduras, and Puerto Rico. B. Toxicological Profile 1. Acute toxicity. Studies conducted with the technical material of CGA-279202 include a rat acute oral toxicity study with a LD<INF>50</INF> >5,000 mg/kg; a mouse acute oral toxicity study with a LD<INF>50</INF> >5,000 mg/kg; a rabbit acute dermal toxicity study with a LD<INF>50</INF> >2,000 mg/kg; a rat acute dermal toxicity study with a LD<INF>50</INF> >2,000 mg/kg; a rat acute inhalation toxicity study with a LC<INF>50</INF> >4.65 mg/L; a rabbit eye irritation study showing slight irritation (Category III); a rabbit dermal irritation study showing slight irritation (Category IV); a Guinea pig dermal sensitization study with the Buehler's method showing negative findings; a Guinea pig dermal sensitization study with the maximization method showing some positive findings. 2. Genotoxicty. No genotoxic activity is expected of CGA-279202 under in-vivo or physiological conditions. The compound has been tested for its potential to induce gene mutation and chromosomal changes in 5 different test systems. The only positive finding was seen in the in vitro test system (Chinese hamster V79 cells) as a slight increase in mutant frequency at a very narrow range (250 - 278 <greek-m>g/ml) of cytotoxic and precipitating concentrations (compound solubility in water was reported to be 0.61 <greek-m>g/ml; precipitate was visually noted in culture medium at 150 <greek-m>g/ml). The chemical was found to be non-mutagenic in the in vivo system or all other in vitro systems. Consequently, the limited gene mutation activity in the V79 cell line is considered a nonspecific effect under non-physiological in vitro conditions and not indicative of a real mutagenic hazard. 3. Reproductive and developmental toxicity. FFDCA section 408 provides that EPA may apply an additional safety factor for infants and children in the case of threshold effects to account for pre- and post- natal toxicity and the completeness of the database. Based on the current toxicological data requirements, the database on CGA-279202 relative to pre- and post-natal effects for children is complete. In assessing the potential for additional sensitivity of infants and children to residues of CGA-279202, Novartis considered data from teratogenicity studies in the rat and the rabbit and a 2-generation reproduction studies in the rat. The teratogenicity studies are designed to evaluate adverse effects on the developing embryo as a result of chemical exposure during the period of organogenesis. Reproduction studies provide information on effects from chemical exposure on the reproductive capability of mating animals and systemic and developmental toxicity from in-utero exposure. In the rat teratology study, reductions in body weight gain (bwtg) and food consumption were observed in the dam at 100 mg/kg. No teratogenic effects or any other effects were seen on pregnancy or fetal parameters except for the increased incidence of enlarged thymus, which is a type of variation, at 1,000 mg/kg. The developmental NOEL was 100 mg/kg. In the rabbit teratology study, body weight loss and dramatically reduced food consumption were observed in the dam at <gr-thn-eq>250 mg/ kg. No teratogenic effects or any other effects were seen on pregnancy or fetal parameters except for the increase in skeletal anomaly of fused sternebrae-3 and -4 at the top dose level of 500 mg/kg. This finding is regarded as a marginal effect on skeletal development that could have resulted from the 40-65% lower food intake during treatment at this dose level. The developmental NOEL was 250 mg/kg. In the 2-generation rat reproduction study, bwtg and food consumption were decreased at <gr-thn-eq>750 ppm, especially in females during lactation. Consequently, the reduced pup weight gain during lactation (<gr-thn-eq>750 ppm) and the slight delay in eye opening (1,500 ppm) are judged to be a secondary effect of maternal toxicity. No other fetal effects or any reproductive changes were noted. The low developmental NOEL, 50 ppm (5 mg/kg), seen in this study was probably due to the lack of intermediate dose levels between 50 and 750 ppm. Based on an evaluation of the dose-response relationship for pup weight at 750 ppm and 1,500 ppm, the NOEL should have been nearly ten-fold higher if such a dose was available. Based on all these teratology and reproduction studies, the lowest NOEL for developmental toxicity is 5 mg/kg while the lowest NOEL in the subchronic and chronic studies is 2.5 mg/kg/day (from the rat chronic study). Therefore, no additional sensitivity for infants and children to CGA-279202 is suggested by the data base. 4. Subchronic toxicity. In subchronic studies, several mortality related changes were reported for the top dose in dogs (500 mg/kg) and rats (800 mg/kg). At these dose levels, excessive toxicity has resulted in body weight loss and mortality with the associated and nonspecific changes in several organs (such as atrophy in the thymus, pancreas, bone marrow, lymph node, and spleen) which are not considered specific target organs for the test compound. In the dog, specific effects were limited to hepatocellular hypertrophy at <gr-thn-eq>150 mg/kg and hyperplasia of the epithelium of the gall bladder at 500 mg/kg. Target organ effects in the rat were noted as hepatocellular hypertrophy (<gr-thn-eq>200 mg/kg) and the related liver weight increase (<gr-thn-eq>50 mg/kg). In the mouse, target organ effects included single cell necrosis (<gr-thn-eq>300 mg/kg) and hypertrophy (1,050 mg/ kg) in the liver and extramedullary hematopoiesis (<gr-thn-eq>300 mg/ kg) and hemosiderosis in the spleen (1,050 mg/kg). In general, definitive target organ toxicity, mostly in the liver, was seen at high feeding levels of over 100 mg/kg for an extended treatment period. At LOEL, no serious toxicity was observed other than mostly non-specific effects including a reduction in body weight and food consumption or liver hypertrophy. 5. Chronic toxicity. The liver appears to be the major primary target organ based on the chronic studies conducted in mice, rats, and dogs. It was identified as a target organ in both the mouse and [[Page 43943]] the dog studies with CGA-279202. However, no liver effect was seen in the chronic rat study which produced the lowest NOEL of 2.5 mg/kg based on reduced bwtg and food consumption seen at higher dose levels (HDL). The compound did not cause any treatment-related increase in general tumor incidence, any elevated incidence of rare tumors, or shortened time to the development of palpable or rapidly lethal tumors in the 18- month mouse and the 24-month rat studies. Dosages in both studies were sufficient for identifying a cancer risk. In the absence of carcinogenicity, Novartis believes that a Reference Dose (RfD) rapproach is appropriate for quantitation of human risks. 6. Animal metabolism. CGA-279202 is moderately absorbed from the gastrointestinal tract of rats and is rapidly distributed. Subsequent to a single oral dose, the half life of elimination is about 2-days and excretion is primarily via bile. CGA-279202 is extensively metabolized by the rat into about 35 metabolites, but the primary actions are on the methyl ester (hydrolysis into an acid), the methoxyimino group (O- demethylation), and the methyl side chain (oxidation to a primary alcohol). Metabolism is dose dependent as it was almost complete at low doses but only about 60% complete at high doses. In the goat, elimination of orally administered CGA-279202 is primarily via the feces. The major residues were the parent compound and the acid metabolite (CGA-321113) plus its conjugates. In the hen, CGA-279202 is found as the major compound in tissues and in the excreta, but hydroxylation of the trifluormethyl-phenyl moiety and other transformations, including methyl ester hydrolysis and demethylation of the methoxyimino group, are also seen. In conclusion, the major pathways of metabolism in the rat, goat, and hen are the same. 7. Metabolite toxicology. Metabolism of CGA-279202 has been well characterized in plants, soil, and animals. In plants and soil, photolytically induced isomerization results in a few minor metabolites not seen in the rat; however, most of the applied materials remained as parent compound as shown in the apple and cucumber studies. All quantitatively major plant and/or soil metabolites were also seen in the rat. The toxicity of the major acid metabolite, CGA-321113 (formed by hydrolysis of the methyl ester), has been evaluated in cultured rat hepatocytes and found to be 20-times less cytotoxic than the parent compound. Additional toxicity studies were conducted for several minor metabolites seen uniquely in plants and/or soil. The studies indicate that these metabolites, including CGA-357261, CGA-373466, and NOA- 414412, are not mutagenic to bacteria and are of low acute toxicity (LD<INF>50</INF> >2,000 mg/kg). In conclusion, the metabolism and toxicity profiles support the use of an analytical enforcement method that accounts for parent CGA-279202. 8. Endocrine disruption. CGA-279202 does not belong to a class of chemicals known for having adverse effects on the endocrine system. Developmental toxicity studies in rats and rabbits and reproduction study in rats gave no indication that CGA-279202 might have any effects on endocrine function related to development and reproduction. The subchronic and chronic studies also showed no evidence of a long-term effect related to the endocrine system. C. Aggregate Exposure 1. Dietary exposure. For the purposes of assessing the potential dietary exposure under the proposed tolerances for the residue of CGA- 279202 and its metabolites, Novartis has estimated aggregate exposure based upon the Theoretical Maximum Residue Concentration (TMRC). The values range from 0.0031 ppm in milk to 1.5 ppm in grapes and include tolerances for various crops; pome fruit - 0.4 ppm for the raw agricultural commodities (RAC); cucurbits - 0.25 ppm for the RAC; grapes - 1.5 ppm for the RAC; peanuts - 0.02 ppm for the RAC; banana - 0.1 ppm for the RAC. The TMRC is a ``worst case'' estimate of dietary exposure since it assumes 100% of all crops for which tolerances are established are treated and that pesticide residues are at the tolerance levels, resulting in an overestimate of human exposure. 2. Food--i. Chronic. The RfD of 0.025 mg/ kg/day is derived from the 24-month rat NOEL of 2.5 mg/kg/day. Even under worst-case assumptions, dietary exposure analysis for CGA-279202 in the most exposed population (non-nursing infants <1-year old) shows the percent RfD utilization to be only 18.9%. Although tolerances in meat and milk are not required for these uses, anticipated residues in meat and milk were also included in this exposure analysis. For average U.S. populations (48 States), dietary exposure for CGA-279202 shows a minimal utilization of 3.4% of the RfD. ii. Acute. For CGA-279202, the appropriate NOEL for acute exposure is 2,000 mg/kg/day from the acute oral neurotoxicity study in rats. Acute dietary exposure analysis predicted the general population will be exposed to less than 0.0045 mg/kg/day of CGA-279202, which corresponds to a MOE of 44,237 at the 99.9 percentile. Children 1-6 years constitute the sub-population with the highest predicted exposure. Predicted acute exposure for this subgroup is less than 0.026 mg/kg/day, corresponding to a MOE of at least 7,797 for 99.9% of the individuals. 3. Drinking water. The potential for exposure to CGA-279202 through drinking water (surface or ground water) is low; this is due to the strong binding affinity of CGA-279202 to soil and to its low use rates (0.04-0.125 lb ai/acre/application). The highest average (56-days) surface water concentration due to runoff predicted by the GENEEC model is 0.06 ppb, resulting from application on turf. Assuming a daily water consumption rate of 2 L/day for an adult (70 kg), this would lead to an adult intake of 0.0000017 mg/kgrm: /diskb/cgi-bin-tmp/TMPBaaaambqa: No such file or directory /day which is only 0.007% of the chronic reference dose of 0.025 mg/kg/day. Assuming a three-fold increase in water consumption per unit body weight for children, the potential exposure increases only to 0.02% of RfD for this population subgroup. Estimated concentrations for treating other crops or for ground water are even lower and do not indicate any cause for concern. 4. Non-dietary exposure. Non-dietary exposure to CGA-279202 is considered negligible as the chemical is intended primarily for commercial and agricultural use. Exposure due to professional use on turf is considered negligible. For workers handling this chemical, acceptable margins of exposure (in the range of thousands) have been obtained for both acute and chronic scenarios. D. Cumulative Effects Consideration of a common mechanism of toxicity is not appropriate at this time since there is no information to indicate that toxic effects produced by CGA-279202 would be cumulative with those of any other types of chemicals. Furthermore, the oximinoacetate is a new type of fungicide and no compound in this general chemical class currently has a significant market share. Consequently, Novartis is considering only the potential exposure to CGA-279202 in its aggregate risk assessment. E. Safety Determination 1. U.S. population. Using the conservative exposure assumptions described above and based on the completeness and reliability of the toxicity data base for CGA-279202, [[Page 43944]] Novartis has calculated aggregate exposure levels for this chemical. The calculation shows that only 3.4% of the RfD will be utilized for the U.S. population based on chronic toxicity endpoints. EPA generally has no concern for exposures below 100% of the RfD because the RfD represents the level at or below which daily aggregate dietary exposure over a lifetime will not pose appreciable risks to human health. Novartis concludes that there is a reasonable certainty that no harm will result from aggregate exposure to CGA-279202 residue. 2. Infants and children. Developmental toxicity, manifested as reduced weaning pup weight, enlarged thymus, or fused sternabrae, was observed in the teratology study and 2-generation rat reproduction studies at maternally toxic doses. All of these findings are judged to be non-specific, secondary effects of maternal toxicity. The lowest NOEL for developmental toxicity was established in the rat reproduction study at 5 mg/kg, a level that is likely to be an overly low estimate (as a result of dose gap) but is still higher than the chronic NOEL of 2.5 mg/kg on which the RfD is based. Using the same conservative exposure assumptions as employed for the determination in the general population, Novartis has calculated that the percent of the RfD that will be utilized by aggregate exposure to residues of CGA-279202 is only 19% for non-nursing infants less than 1-year old (the most impacted sub-population). Therefore, based on the completeness and reliability of the toxicity data base and the conservative exposure assessment, Novartis concludes that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to CGA-279202 residues. F. International Tolerances No Codex MRLs have been established for residues of CGA-279202. (Janet Whitehurst). [FR Doc. 98-22012 Filed 8-14-98; 8:45 am] BILLING CODE 6560-50-F