Notice of Filing of Pesticide Tolerance Petitions

EPA has received pesticide petitions as follows proposing the establishment of regulations for residues of certain pesticide chemicals in or on various raw 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 grantinig of the petition. Additional data may be needed before EPA rules on the petition. The official record for this notice, as well as the public version, has been established for this notice of filing under docket control number PF-825 (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''. 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. Comment and data will also be accepted on disks in Wordperfect 5.1/6.1 file format or ASCII file format. All comments and data in electronic form must be identified by the docket control number (PF-825) and appropriate petition number. Electronic comments on this notice may be filed online at many Federal Depository Libraries.

Authority: 21 U.S.C. 346a.

List of Subjects

Environmental protection, Agricultural commodities, Food additives, Feed additives, Pesticides and pests, Reporting and recordkeeping requirements.

Dated: August 10, 1998.

James Jones, Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

Below summaries of the pesticide petitions are printed. The summaries of the petitions were prepared by the petitioners. 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.

1. Novartis Crop Protection, Inc.

PP 7E4919 and 8F4978

EPA has received two pesticide petitions (7E4919 and 8F4978 from Novartis Crop Protection, Inc., 410 Swing Road, 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 tolerances for residues of fludioxonil (4-(2,2-difluoro- 1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile) in or on the raw agricultural commodities: grapes at 1.00 parts per million (ppm) (7E4919); canola, peanuts, sunflowers, leafy vegetables except brassica (Crop Group 4); brassica leafy vegetables (Crop Group 5); legume vegetables (Crop Group 6); foliage of legume vegetables (Crop Group 7); fruiting vegetables (Crop Group 8); cucurbit vegetables (Crop Group 9); forage, fodder, and straw of cereal grains (Crop Group 16); grass , forage, fodder, and hay (Crop Group 17); and non-grass animal feeds (Crop Group 18) at 0.01 ppm; root and tuber vegetables (Crop Group 1); leaves of root and tuber vegetables (Crop Group 2); bulb vegetables (Crop Group 3); cereal grains (Crop Group 15); and herbs and spices (Crop Group 19) at 0.02 ppm; and cotton at 0.05 ppm (8F4978). 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 fludioxonil is adequately understood for the purpose of the proposed tolerances. The residues of regulatory concern is the parent compound only. Metabolism in grapes involves oxidation of the pyrrole ring, primarily at the 2 and 5 positions. Subsequent opening of the oxidized pyrrole ring yields a metabolite with an amide plus a carboxylic acid group. This open-ring metabolite undergoes further oxidation at the bridgehead carbon followed by decarboxylation. 2. Analytical method. Novartis has developed and validated analytical methodology for enforcement purposes as part of the original corn, sorghum, and potato registrations. This method (Novartis Crop Protection Method AG-597B) has passed an Agency petition method validation (PMV) and is currently the enforcement method for potatoes. As part of this petition, Novartis has validated the method on the crops, fractions, and crop representatives of each crop grouping associated with this submittal. The method validation study (ABR-97060) contains recovery data on over eighty individual substrates. In most cases, a limit of quantitation of 0.01 ppm of fludioxonil was achieved. For several very difficult substrates, a limit of quantitation of 0.02 ppm and for cotton substrates a limit of 0.05 ppm were achieved.

For the analysis of grapes, grape juice, and wine the analytical Method AG-579B14 is proposed as the regulatory enforcement method. It has been validated by the Agency as an enforcement method for fludioxonil as AG-57912. In Method AG-579B14, whole fruit or wine samples are extracted with acetonitrile/water (90/10). Red and white grapes, as well as red and white wine samples were analyzed by this method. Recoveries (from 0.02 ppm to 1.0 ppm) ranged from 73% to 114% with a mean of 92% (n=15). 3. Magnitude of residues. Residue trials were conducted on cotton, wheat, radishes, lettuce, cucumbers and peas in the major crop growing areas of the U.S. in addition to residue trials previously on corn, sorghum, potatoes and grapes. Several trials were conducted on each crop. Rates were 0.5 x , 1.0 x , 2.5 x and 5.0 x of the proposed use rate on all crops except cotton where 1.0 x and 3.0 x were used. From 6 cotton trials, field trash, gin trash, un-delinted seed and cottonseed fractions (hulls, meal, refined oil) were analyzed for fludioxonil at a method limit of determination of 0.05 ppm. At this level, no quantifiable residues of fludioxonil were found in any RAC or fraction at the proposed or the exaggerated (3 x ) rate. Seven trials were completed on wheat. At a method limit of quantification of 0.02 ppm, no quantifiable residues of fludioxonil were observed in any RAC at the proposed treatment rate or at rates up to 5 x the proposed treatment rate. Five trials were completed on radishes which represents the absolute worst case for potential uptake of residues because of its very rapid growth and short growing season (27-55 days in these studies). Both root and top samples from all rates in all 5 trials were analyzed at a method limit of determination of 0.01 ppm. No fludioxonil residue (50 = 50-200 mg/kg), and after a 4-hr inhalation exposure (LC50 value of > 0.47 mg/L); and was minimally to slightly toxic to rats following a single dermal dose (LD50 >5,000 mg/kg). In a guideline acute neurotoxicity study with triazamate in the rat, the NOEL for clinical signs was 5 mg/kg based on the observation of cholinergic signs in 1 of 10 male rats at 25 mg/kg. Triazamate was practically non-irritating to the skin, moderately irritating to eyes in rabbits and did not produce delayed contact hypersensitivity in the guinea pig. 2. Genotoxicty. Triazamate is not mutagenic or genotoxic. Triazamate Technical was negative (non-mutagenic) in an Ames assay with and without hepatic enzyme activation. Triazamate Technical was negative in a hypoxanthine guanine phophoribosyl transferase (HGPRT) gene mutation assay using Chinese hamster ovary (CHO) cells in culture when tested with and without hepatic enzyme activation. In isolated rat hepatocytes, triazamate did not induce unscheduled DNA synthesis (UDS) or repair when tested up to the maximum soluble concentration in culture medium. Triazamate did not produce chromosome aberrations in an in vitro assay using Chinese hamster ovary cells (CHO) or an in vivo mouse micronucleus assay. 3. Reproductive and developmental toxicity. In a developmental toxicity study in rats with Triazamate Technical, the no-observed- effect-level (NOEL) for developmental toxicity was 64 mg/kg (highest dose tested) (HDT). The NOEL for maternal toxicity was 16 mg/kg based on clinical signs of cholinergic toxicity at 64 mg/kg. In a developmental toxicity study in rabbits with Triazamate Technical, the NOEL for developmental toxicity was 10 mg/kg (HDT). The NOEL for maternal toxicity was 0.5 mg/kg based on clinical signs and decreased body weight at 10 mg/kg. In a two-generation reproduction study in rats with Triazamate Technical, the NOEL for reproductive effects was 1,500 ppm (101 and 132 milligrams/kilograms/day (mg/kg/day) for males and females, respectively; HDT). The NOEL for parental toxicity was 10 ppm (0.7 and 0.9 mg/kg/day for males and females, respectively) based on decreased plasma and RBC cholinesterase activities at 250 ppm (17 and 21 mg/kg/ day for males and females, respectively). The acceptable developmental studies (prenatal developmental toxicity studies in rats and rabbits and two-generation reproduction study in rats) provided no indication of increased sensitivity of rats or rabbits to in utero and or post-natal exposure to triazamate. Triazamate Technical is not a developmental or reproductive toxicant. 4. Subchronic toxicity. In subacute and subchronic dietary toxicity studies, Triazamate Technical produced no evidence of adverse effects other than those associated with cholinesterase inhibition: i. In a 90-day dietary toxicity study with Triazamate Technical in the rat, the NOEL for blood cholinesterase inhibition was 50 ppm (3.2 and 3.9 mg/kg/day for males and females, respectively), based on decreases in plasma and RBC cholinesterase activities at 500 ppm (32 and 39 mg/kg/day for males and females, respectively). The NOEL for brain cholinesterase inhibition and/or clinical signs was 500 ppm (32 and 39 mg/kg/day for males and females respectively) based on decreased brain cholinesterase activity and decreased body weight gain and feed consumption at 1,500 ppm (93 and 117 mg/kg/day for males and females, respectively). ii. In a guideline subchronic neurotoxicity study (90-day dietary feeding) with Triazamate Technical in the rat, the NOEL for blood cholinesterase inhibition was 10 ppm (0.6 and 0.7 mg/kg/day for males and females, respectively), based on reductions in plasma and RBC cholinesterase activities at 250 ppm (14.3 and 17.1 mg/kg/day for males and females, respectively). The NOEL for brain cholinesterase inhibition and/or clinical signs was 250 ppm (14.3 and 17.1 mg/kg/day for males and females respectively) based on decreases in brain cholinesterase activity and cholinergic signs at 1,500 ppm (87 and 104 mg/kg/day for males and females, respectively). iii. In a 90-day dietary toxicity study with Triazamate Technical in the mouse, the NOEL for blood cholinesterase inhibition was 2 ppm (0.4 and 0.5 mg/kg/day for males and females, respectively) based on decreases in plasma cholinesterase activity at 25 ppm (4 and 6 mg/kg/ day for males and females, respectively). The NOEL for brain cholinesterase and/or clinical signs was 250 ppm (46 and 67 mg/kg/day for males and females, respectively) based on decreases in brain cholinesterase and decreases in body weight and feed consumption at 1,000 ppm (164 and 222 mg/kg/day for males and females, respectively). iv. In a 90-day dietary toxicity study with Triazamate Technical in the dog, the NOEL for blood cholinesterase inhibition was 1 ppm for males only (0.03 mg/kg/day) based on decreases in plasma cholinesterase at 10 ppm (0.3 mg/kg/day). The dose of 1 ppm was a lowest-observed- effect level (LOEL) for females based on the presence of decreased plasma cholinesterase activity (24%). The NOEL for clinical signs was 10 ppm (0.3 mg/kg/day for males and females) based on a few clinical signs at 100 ppm (3.1 mg/kg/day for males and females). v. In a 21-day dermal toxicity study with Triazamate Technical, the NOEL blood and brain cholinesterase inhibition was 10 mg/kg based on decreases in plasma, RBC and brain cholinesterase activities at 100 mg/ kg.

5. Chronic toxicity -- i. Rat, mouse and dog studies. In chronic dietary toxicity studies, Triazamate Technical produced no evidence of adverse effects other than those associated with cholinesterase inhibition and was not oncogenic in the rat and mouse. In a combined chronic dietary toxicity/oncogenicity study (24 months) in rats with Triazamate Technical, no evidence of oncogenicity was observed at doses up to 1,250 ppm (62.5 mg/kg/day for males and females; HDT). The NOEL for blood cholinesterase inhibition was 10 ppm (0.5 and 0.6 mg/kg/day for males and females respectively) based on decreases in plasma and RBC cholinesterase activity at 250 ppm (11.5 and 14.5 mg/kg/day in males and females, respectively). The NOEL for brain cholinesterase inhibition and/or clinical signs was 250 ppm (11.5 and 14.5 mg/kg/day in males and females, respectively) based on clinical signs and decreases in brain cholinesterase inhibition at 1,250 ppm (62.5 mg/kg/day for males and females). In a combined chronic dietary toxicity study (18 months) in mice with Triazamate Technical, no evidence of oncogenicity was observed at doses up to 1,000-1,500 ppm (130-195 mg/kg/day for males and females; HDT). The NOEL for blood cholinesterase inhibition was 1 ppm (0.1 and 0.2 mg/kg/day for males and females, respectively) based on decreased plasma cholinesterase activity at 50 ppm (6.7 and 8.4 mg/kg/day for males and females, respectively). The NOEL for brain cholinesterase inhibition and/or clinical signs was 50 ppm (6.7 and 8.4 mg/kg/day for males and females, respectively) based on decreased brain cholinesterase activity and other evidence of systemic toxicity at 1,000-1,500 ppm (130-195 mg/kg/day for males and females). In a chronic dietary toxicity study (12 months) in dogs with Triazamate Technical, the NOEL for blood cholinesterase inhibition was 0.9 ppm (0.023 and 0.025 mg/kg/day for males and females, respectively) based on decreased plasma cholinesterase activity at 15.0 ppm (0.42 mg/ kg/day for both males and females). The NOEL for brain cholinesterase inhibition was 15.0 ppm (0.42 mg/kg/day for both males and females) based on decreased brain cholinesterase activity at 150 ppm (4.4 and 4.7 mg/kg/day for males and females, respectively). ii. Human Studies. A randomized double-blind, ascending dose study was conducted in human male volunteers to determine the safety and tolerability of Triazamate Technical and to establish a NOEL for adverse clinical toxicity. Single doses of Triazamate Technical, when administered orally by capsule to healthy male subjects, were tolerated up to and including a dose of 1.0 mg/kg. The 3.0 mg/kg dose of triazamate was not clinically tolerated well. Clinically, the NOEL was 0.3 mg/kg of triazamate based on minimal clinical signs at 1.0 mg/kg that were considered possibly related to treatment. Transient decreases in plasma and RBC cholinesterase occurred at doses lower than the dose that elicited adverse clinical signs. Using its Guidelines for Carcinogen Risk Assessment published September 24, 1986 (51 FR 33992), Rohm and Haas Company considers triazamate to be classified as a Group ``E,'' not a likely human carcinogen. A Reference dose (RfD) of 0.01 mg/kg/day is proposed for humans, based on the clinical NOEL in the human study (0.3 mg/kg) and applying an Uncertainty Factor (UF) of 30. The dose of 0.3 mg/kg was the highest dose in humans that did not produce toxicologically significant adverse effects (i.e., signs of cholinergic toxicity) and is 10 times lower than a dose that produced unequivocal signs of cholinergic toxicity in man. In addition, the clinical NOEL in humans is comparable to the no- observable-adverse-effect level (NOAEL) of 0.42 mg/kg/day following chronic dosing in the dog, the most sensitive laboratory animal species. An Uncertainty Factor of 10 is applied to the clinical NOEL in humans to account for potential variability within humans with respect to sensitivity towards triazamate. An additional Uncertainty Factor of 3 is included, since at 0.03 mg/kg (i.e., 1/10th the dose that was a clinical NOEL) there was a transient but measurable depression in plasma cholinesterase in humans. Although a change in the plasma pseudo-cholinesterase (i.e., butyl-cholinesterase) is not toxicologically significant since this enzyme is not molecularly similar to acetyl-cholinesterase, the additional uncertainty factor of 3 establishes a reference dose at a level where a measurable response of any kind, irrespective of the toxicological significance of the finding, will not plausibly occur. 6. Animal metabolism. The absorption, distribution, excretion and metabolism of triazamate in rats, dogs and goats was investigated. Triazamate is rapidly absorbed when given orally (capsule or gavage) but slower following dietary intake. Peak blood levels following dietary administration were 10-fold lower than after gavage administration of an equivalent mg/kg/dose. Elimination is predominately by urinary excretion and triazamate does not accumulate in tissues. The metabolism of triazamate proceeds via ester hydrolysis and then a rapid stepwise cleavage of the carbamoyl group. The free acid, (RH-0422) is the only toxicologically significant metabolite, given that it contains the carbamoyl group. Other metabolites of triazamate, which are seen in other animal and plant metabolism studies, do not contain the carbamoyl group and do not produce cholinesterase inhibition. 7. Metabolite toxicology. Common metabolic pathways for triazamate have been identified in both plants (apple, potato, sugar beet) and animals (rat, goat, hen). The metabolic pathway common to both plants and animals involves oxidative demethylation of the carbamoyl group. Extensive degradation and elimination of polar metabolites occurs in animals such that residues are unlikely to accumulate in humans or animals exposed to these residues through the diet. 8. Endocrine disruption. The toxicology profile of triazamate shows no evidence of physiological effects characteristic of the disruption of mammalian hormones. In developmental and reproductive studies there was no evidence of developmental or reproductive toxicity. In addition, the molecular structure of triazamate does not suggest that this compound would disrupt the mammalian hormone system. Overall, the weight of evidence provides no indication that triazamate has endocrine activity in vertebrates.

C. Aggregate Exposure

1. Dietary exposure. A RfD of 0.01 mg/kg/day is proposed for humans, based on the clinical NOEL in the human study (0.3 mg/kg) and applying an Uncertainty Factor of 30. 2. Food -- i. Acute risk. An acute dietary risk assessment (Dietary Exposure Evaluation Model , Novigen Sciences Inc., 1997) was conducted for triazamate using a Tier 3 Monte Carlo simulations approach using the distribution of residues for apples, pears, head and leaf lettuce, spinach, celery, broccoli, cabbage and mustard greens, the entire distribution of daily food consumption data for pome fruit and leafy and cole crop vegetables and adjustments for percent crop treated. The Margins of Exposure (MOEs) for the 95th percentile exposures were 270 for the U.S. population and 388 for the most sensitive sub-population, Children 1-6 years old. This indicates that acute dietary risk is acceptable because the MOE is greater than 30, and 30 is the appropriate Uncertainty Factor when

the assessment is based on a human clinical study. ii. Chronic risk. Chronic dietary risk assessments (Dietary Exposure Evaluation Model , Novigen Sciences Inc., 1997) were conducted for triazamate using two approaches: (1) using a tolerance levels and assuming 100% of crop is treated, and (2) using anticipated residue concentration levels adjusted for projected market share or percentage of crop treated. The Theoretical Maximum Residue Contribution (TMRC) and Anticipated Residue Contribution (ARC) from these two scenarios represents 35.0% and 3.6%, respectively, of the RfD for the U.S. populution as a whole. The subgroup with the greatest chronic exposure is Children 1-6 years old for which the TMRC and ARC estimates represents 59.4% and 7.0%, respectively, of the RfD. The chronic dietary risks from these uses do not exceed EPA's level of concern. 3. Drinking water. Both triazamate and its cholinesterase- inhibiting metabolite RH-0422 are degraded rapidly in soil This rapid degradation has been observed in both laboratory and field studies and makes it highly unlikely that measurable residues of either compound would be found in ground or surface water when triazamate is applied according to the proposed label use directions. 4. Non-dietary exposure. Triazamate is not registered for either indoor or outdoor residential uses. Non-occupational exposure to the general population is therefore not expected and not considered in aggregate exposure estimates.

D. Cumulative Effects

The potential for cumulative effects of triazamate with other substances that have a common mechanism of toxicity was considered. It is recognized the triazamate, although structurally a pseudo-carbamate, exhibits toxicity similar to the carbamate class of insecticides, and that these compounds produce a reversible inhibition of the enzyme cholinesterase. However, Rohm and Haas Company concludes that consideration of a common mechanism of toxicity is not appropriate at this time since EPA does not have the methodology to resolve this complex scientific issue concerning common mechanisms of toxicity. Based on these points, Rohm and Haas Company has considered only the potential risks of triazamate and RH-0422 in its cumulative exposure assessment.

E. Safety Determination

1. U.S. population. The acute and chronic dietary exposures to triazamate and its metabolite from the proposed use on leafy and cole crop vegetables were evaluated. Exposure to triazamate and its toxicologically significant metabolite in or on pome fruit or leafy and cole crop vegetables does not pose an unreasonable health risk to consumers including the sensitive subgroup non-nursing infants. In Tier 3 acute analyses for the 95th percentile exposures, MOEs were 270 for the general U.S. population. Using the TMRC and assuming 100% of crop treated, the most conservative chronic approach, chronic dietary exposures represents 35.0% of the RfD for the U.S. population. 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. Using the two conservative exposure assessments described above and taking into account the completeness and reliability of the toxicity data, Rohm and Haas Company concludes that there is a reasonable certainty that no harm will result from aggregate exposure to residues of triazamate and its toxicologically significant metabolite to the U.S. population. 2. Infants and children. In assessing the potential for additional sensitivity of infants and children to residues of triazamate, data from developmental toxicity studies in the rat and rabbit and two two- generation reproduction studies in the rat are considered. The developmental toxicity studies are designed to evaluate adverse effects on the developing organism resulting from pesticide exposure during prenatal development to one or both parents. Reproduction studies provide information relating to effects from exposure to the pesticide on the reproductive capability of mating animals and data on systemic toxicity. FFDCA section 408 provides that EPA may apply an additional Uncertainty Factor for infants and children in the case of threshold effects to account for pre-and post- natal effects and the completeness of the toxicity database. Based on current toxicological data requirements, the toxicology database for triazamate relative to pre- and post- natal effects is complete. For triazamate, developmental toxicity was not observed in developmental studies using rats and rabbits. The NOEL for developmental effects in rats was 64 mg/kg/day and rabbits was 10 mg/kg/day. In the two-generation reproductive toxicity study in the rat, the reproductive/developmental toxicity NOEL was 101-132 mg/kg/day. These NOELs are 10-fold or higher than those observed for systemic toxicity, i.e., cholinesterase inhibition. In Tier 3 acute dietary analyses for the 95th percentile exposures, MOEs were 388 for Children 1-6 years old. Using the TMRC and assuming 100% of crop treated, the most conservative chronic approach, chronic dietary exposures represents 59.4% of the RfD for Children 1-6 years old. Using the ARC and adjusted for an anticipated market share or percentage of crop treated, the chronic dietary exposure to this subgroup represents 7.0% of the RfD. Therefore Rohm and Haas Company concludes that there is a reasonable certainty that no harm will result from aggregate exposure to residues of triazamate and its toxicologically significant metabolite to infants and children.

F. International Tolerances

There are no approved CODEX maximum residue levels (MRLs) established for residues of triazamate. MRLs have been established for vegetables at 0.05 ppm in Italy, for sugar beets at 0.05 ppm in the Czech Republic and 0.15 ppm in the U.K., for potatoes at 0.02 ppm in France, for cabbage at 0.1 ppm in Hungary, and for peas at 0.05 ppm in the Czech Republic and 0.02 ppm in Hungary and for green peas at 0.05 ppm in Hungary. (Mark Dow)

[FR Doc. 98-22428 Filed 8-25-98; 8:45 am] BILLING CODE 6560-50-F