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Chlorfenapyr (American Cyanamid). March 27, 1998. Pesticide Tolerance Petition. Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/1998/March/Day-27/p8065.htm
[Federal Register: March 27, 1998 (Volume 63, Number 59)] [Notices] [Page 14926-14936] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr27mr98-78] ----------------------------------------------------------------------- ENVIRONMENTAL PROTECTION AGENCY [PF-799; FRL-5579-6] 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-799, must be received on or before April 27, 1998. ADDRESSES: By mail submit written comments to: Public Information and Records Integrity Branch, Information Resources and Services Division (7506C), 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 by following 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 reviewer listed in the table below: ------------------------------------------------------------------------ Office location/ Product Manager telephone number Address ------------------------------------------------------------------------ Ann Sibold.................... Rm. 212, CM #2, 703- 1921 Jefferson 305-6502, e- Davis Hwy, mail:sibold.ann@epama Arlington, VA il.epa.gov. Joseph M. Tavano.............. Rm. 214, CM #2, 703- Do. 305-6411, e-mail: tavano.joseph@epamail .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-799] (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. Comment and data will also be accepted on disks in [[Page 14927]] Wordperfect 5.1 file format or ASCII file format. All comments and data in electronic form must be identified by the docket number (insert docket number) 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: March 19, 1998 Peter Caulkins, 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 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. 1. American Cyanamid Company PP 6F4623 EPA has received a pesticide petition (PP 6F4623) from American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400, 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 of 0.5 ppm for residues of 4-bromo-2-(4-chlorophenyl)-1-(ethoxymethyl)- 5-(trifluoromethyl)-1-pyrrole-3-carbonitrile, (chlorfenapyr) in or on the raw agricultural commodity citrus. As citrus processed commodities fed to food animals may be transferred to milk and edible tissues, tolerances are also proposed for the following ruminant food items: milk at 0.01 parts per million (ppm); milk fat at 0.15 ppm; meat at 0.01 ppm; and meat by-products (including fat) at 0.10 ppm. The proposed analytical method is capillary gas chromatography using an electron capture detector. 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 nature of the residues of chlorfenapyr in plants is adequately understood and the residue of concern in citrus consists of the parent molecule. Expressed on a whole basis, the parent compound accounted for 56-75% of the total radioactive residue (TRR), 98% of which was associated with the external rinse and peel. 2. Analytical method. The GC analytical method, M2284, which is proposed as the enforcement method for the residues of chlorfenapyr in citrus, has a limit of detection (LOD) of 0.01 ppm (0.025 ppm for juice) and a limit of quantitation (LOQ) of 0.05 ppm. 3. Magnitude of residues. Extensive citrus field trials have been conducted over multiple growing seasons in all major citrus growing regions of the US. The results of these studies indicate that at the highest proposed use rate of 1.05 lbs ai/A, the maximum expected chlorfenapyr residues are 0.4 ppm in oranges, 0.38 ppm in lemons and 0.27 ppm in grapefruit in/on citrus samples harvested 7 days following the last application. These field trial data are adequate to support the proposed tolerance of 0.5 ppm in/on citrus harvested 7-days following the last application. The results of processing studies indicate that chlorfenapyr residues do not concentrate in molasses and juice. The actual concentration factors in dried pulp (2.4x) and citrus oil (70x) are well below the maximum theoretical concentration factors for these commodities. Although citrus oil is not considered to be a ready-to-eat item and is not expected to contribute to the dietary exposure, a tolerance at 35 ppm (0.5 ppm x 70) is proposed for enforcement purposes. B. Toxicological Profile 1. Acute toxicity. Based on the EPA's toxicity category criteria, the acute toxicity category for chlorfenapyr technical is Category II or moderately toxic (signal word WARNING) and the acute toxicity category for the 2SC formulation is Category III or slightly toxic (signal word CAUTION). Males appear to be more sensitive to the effects of chlorfenapyr than females. The acute toxicity profile indicates that absorption by the oral route appears to be greater than by the dermal route. The following are the results from the acute toxicity tests conducted on the technical material: i. Rat Oral LD<INF>50</INF>: 441/1152 milligram/kilograms (mg/kg) bwt.(M/F) -- Tox. Category II ii. Rabbit Dermal LD<INF>50</INF>: >2,000 mg/kg bwt.(M/F) -- Tox. Category III iii. Acute Inhal. LC<INF>50</INF>: 0.83/>2.7 mg/L (M/F) -- Tox. Category III iv. Eye Irritation: Moderately Irritating -- Tox. Category III v. Dermal Irritation: Non-Irritating -- Tox. Category IV vi. Dermal Sensitization: Non-Sensitizer -- Non Sensitizer vii. Acute Neurotoxicity: NOEL 45 mg/kg bwt. -- Not An Acute Neurotoxicant 2. Genotoxicty. Chlorfenapyr technical (94.5% a.i.) was examined in a battery ofin vitro and in vivo tests to assess its genotoxicity and its potential for carcinogenicity. These tests are summarized below. Microbial/Microsome Mutagenicity Assay: Non-mutagenic Mammalian Cell CHO/HGPRT Mutagenicity Assay: Non-mutagenic In Vivo Micronucleus Assay: Non-genotoxic In Vitro--Chromosome Aberration Assay in CHO: Non-clastogenic In Vitro--Chromosome Aberration Assay in CHLC: Non-clastogenic Unscheduled DNA Synthesis (UDS) Assay: Non-genotoxic. 3. Reproductive and developmental toxicity. Chlorfenapyr is neither a reproductive or developmental toxicant and is not a teratogenic agent in the Sprague-Dawley rat or the New Zealand white rabbit. This is demonstrated by the results of the following studies: Rat Oral Teratology -- No-Observed-Effect-Level (NOEL) for maternal toxicity 25 mg/kg bwt./day and NOEL for fetal/develop. toxicity 225 milligram/kilograms body weight/day (mg/kg bwt./day) Rabbit Oral Teratology -- NOEL for maternal toxicity 5 mg/kg bwt./ day and NOEL for fetal/develop. toxicity 30 mg/kg bwt./day Rat 2-Generation Reproduction -- NOEL for parental toxicity /growth and offspring development 60 ppm (5 mg/kg bwt./day) NOEL for reproductive performance 600 ppm (44 mg/kg bwt./day). 4. Subchronic toxicity. The following are the results of the subchronic toxicity tests that have been conducted with chlorfenapyr: 28-Day Rabbit Dermal -- NOEL 100 mg/kg bwt./day 28-Day Rat Feeding -- NOEL >600 ppm (< 71.6 mg/kg bwt./day) 28-Day Mouse Feeding -- NOEL >160 ppm (<32 mg/kg bwt./day) 13-Week Rat Dietary -- NOAEL 150 ppm (11.7 mg/kg bwt./day) [[Page 14928]] 13-Week Mouse Dietary -- NOEL 40 ppm (8.2 mg/kg bwt./day) 13-Week Dog Dietary -- NOAEL 120 ppm (4.2 mg/kg bwt./day) 5. Chronic toxicity. Chlorfenapyr is not oncogenic in either Sprague Dawley rats or CD-1 mice and is not likely to be carcinogenic in humans. The following are the results of the chronic toxicity tests that have been conducted with chlorfenapyr: 1-Year Neurotoxicity in Rats -- NOEL 60 ppm (2.6/3.4 mg/kg bwt./day M/F) 1-Year Dog Dietary -- NOEL 120 ppm (4.0/4.5 mg/kg bwt./day M/F) 24-Month Rat Dietary -- NOEL for Chronic Effects 60 ppm (2.9/3.6 mg/kg bwt./day M/F) and NOEL for Oncogenic Effects 600 ppm (31/37 mg/kg bwt./day M/F) 18-Month Mouse Dietary -- NOEL for Chronic Effects 20 ppm (2.8/3.7 mg/kg bwt./day M/F) and NOEL for Oncogenic Effects 240 ppm (34.5/44.5 mg/kg bwt./day M/F) 6. Animal metabolism. A metabolism study was conducted in Sprague Dawley rats at approximately 20 and 200 mg/kg bwt. using radiolabeled chlorfenapyr. Approximately 65% of the administered dose was eliminated during the first 24 hours (62% in feces and 3% in urine) and by 48 hours following dosing, approximately 85% of the dose had been excreted (80% in feces and 5% in urine). The absorbed chlorfenapyr-related residues were distributed throughout the body and detected in tissues and organs of all treatment groups. The principal route of elimination was via feces, mainly as unchanged parent plus minor N-dealkylated, debrominated and hydroxylated oxidation products. The metabolic pathway of chlorfenapyr in the laying hen and the lactating goat was also similar to that in laboratory rats. 7. Metabolite toxicology. The parent molecule is the only moiety of toxicological significance which needs regulation in plant and animal commodities. 8. Endocrine effects. Collective organ weights and histopathological findings from the 2-generation rat reproduction study, as well as from the subchronic and chronic toxicity studies in two or more animal species, demonstrate no apparent estrogenic effects or effects on the endocrine system. There is no information available which suggests that chlorfenapyr would be associated with endocrine effects. C. Aggregate Exposure 1. Dietary exposure-- i. Food. For purposes of assessing the potential dietary exposure, a Theoretical Maximum Residue Contribution (TMRC) has been calculated from the tolerance of chlorfenapyr in/on citrus at 0.5 ppm. This exposure assessment is based on very conservative assumptions, namely 100% of all citrus is treated with chlorfenapyr and that the residues of chlorfenapyr in citrus are at the tolerance level. Although there are no other established US permanent tolerances for chlorfenapyr, a petition for a permanent tolerance at 0.5 ppm in cottonseed is pending at the Agency. Therefore, the dietary exposures to residues of chlorfenapyr in or on food will be limited to residues in cottonseed, citrus and food and feed items derived from them. As dried citrus pulp is a dairy and beef cattle feed item, a cold feeding study with dairy cattle was conducted. Since this study demonstrated that measurable residues of chlorfenapyr may occur in milk, meat and meat by products, appropriate residue tolerances for these items are proposed. The contribution of the citrus tolerances alone to the daily consumption uses only 0.23% of the reference dose (RfD) for the overall US population. The combined contributions of the citrus and the pending cottonseed tolerances to the daily consumption uses less than 1% (actual 0.85%) of the reference dose for the overall US population and less than 3% (actual 2.23%) and less than 1% (actual 0.89%) of the reference doses for children aged 1-6 and for non-nursing infants, respectively. ii. Drinking water. There is no available information about chlorfenapyr exposures via levels in drinking water. There is no concern for exposure to residues of chlorfenapyr in drinking water because of its extremely low water solubility (120 ppb at 25 deg.). Chlorfenapyr is also immobile in soil and does not leach because it is strongly adsorbed to all common soil types. In addition, the label explicitly prohibits applications near aquatic areas There is a reasonable certainty that no harm will result from dietary exposure to chlorfenapyr, because dietary exposure to residues on food will use only a small fraction of the (RfD) (including exposure of sensitive subpopulations), and exposure through drinking water is expected to be insignificant. 2. Non-dietary exposure. There is no available information quantifying non-dietary exposure to chlorfenapyr. However, based on the physico-chemical characteristics of the compound, the proposed use pattern and available information concerning its environmental fate, non-dietary exposure is expected to be negligible. The vapor pressure of chlorfenapyr is less than 1 x 10<SUP>-7</SUP> mm of Hg; therefore, the potential for non-occupational exposure by inhalation is insignificant. Moreover, the current proposed registration is for outdoor, terrestrial uses which severely limit the potential for non- occupational exposure. D. Cumulative Effects The pyrrole insecticides represent a new class of chemistry with a unique mechanism of action. The parent molecule, AC 303,630 is a pro- insecticide which is converted to the active form, CL 303,268, via rapid metabolism by mixed function oxidases (MFOs). The active form uncouples oxidative phosphorylation in the insect mitochondria by disrupting the proton gradient across the mitochondrial membrane. The production of ATP is inhibited resulting in the cessation of all cellular functions. Because of this unique mechanism of action, it is highly unlikely that toxic effects produced by chlorfenapyr would be cumulative with those of any other pesticide chemical. In mammals, there is a lower titer of MFOs, and chlorfenapyr is metabolized by different pathways (including dehalogenation, oxidation and ring hydroxylation) to other polar metabolites without any significant accumulation of the potent uncoupler, CL--303,268. In the rat, approximately 85 % of the administered dose is excreted in the feces within 48-hours, thereby reducing the levels of AC 303,630 and CL 303,268 that are capable of reaching the mitochondria. This differential metabolism of AC 303,630 to CL 303,268 in insects versus to other polar metabolites in mammals is responsible for the selective insect toxicity of the pyrroles. E. Safety Determination 1. U.S. population. The RfD of 0.03 mg/kg bwt./day for the residues of chlorfenapyr in citrus is calculated by applying a 100-fold safety factor to the overall NOEL of 3 mg/kg bwt./day. This NOEL is of based on the results of the chronic feeding studies in the rat and mouse and the 2-generation reproduction study in the rat (see Item 2). The TMRC for the proposed tolerances in citrus alone, (0.0000692 mg/kg bwt./ day), will utilize only 0.23% of the RfD for the general U.S. population and the combined TMRC for the proposed chlorfenapyr tolerances in cottonseed, citrus, milk and meat (0.0002558 mg/kg bwt./ day) will utilize approximately 0.85% of the RfD for the general U.S. population. 2. Infants and children. The TMRC in milk consumed by a non-nursing infant [[Page 14929]] (>1-year of age) is 0.0002435 mg/kg bwt./day. The combined tolerances will use less than 1% (actual 0.89%) of the RfD for non-nursing infants. The TMRC in milk consumed by a child (1-6 years of age) is 0.0003886 mg/kg bwt./day. The combined TMRC for the proposed chlorfenapyr tolerances in cottonseed, citrus meat and milk consumed by a child 1-6 years of age is 0.0006708 mg/kg bwt./day, which is less than 3% (actual 2.23%) of the RfD. Therefore, the results of the toxicology and metabolism studies support both the safety of chlorfenapyr to humans based on the intended use as an insecticide- miticide on citrus and cottonseed and the granting of the requested tolerances in cottonseed, citrus, milk, milk fat solids, meat and meat by-products. Based on the conservative assumptions used in proposing the above tolerances and the absence of other non-dietary routes of exposure to chlorfenapyr, and since the calculated exposures are well below 100% of the reference dose, there is a reasonable certainty that no harm will result from aggregate exposure to residues of chlorfenapyr, including all anticipated dietary exposure and all other non-occupational exposures. The use of a 100-fold safety factor ensures an acceptable margin of safety for both the overall U. S. population as well as infants and children. As the toxicology database (reproduction/ developmental and teratology studies) is complete, valid and reliable, no additional safety factor is needed. The 100-fold margin of safety is adequate to assure a reasonable certainty of no harm to infants and children from the proposed use. As stated earlier, the NOEL is based on the effects observed in the rat and mouse chronic oncogenicity studies, (reduced body weight gains, increased globulin and cholesterol values and increased liver weights in the rat and reduced body weight gains and vacuolation of white matter of the mouse brain), the one-year neurotoxicity study in the rat, (reduced body weight gains and vacuolar myelinopathy of the brain and spinal cord that is completely reversible following termination of treatment and is not associated with any damage to neuronal cell bodies or axons; vacuolation of the white matter is a consequence of edema (water) formation between the myelin layers which result from the unrestricted movement of ions across the cell membranes) and the 2- generation rat reproduction study, (reduced body weight gains for parental animals and reduced pup body weights for the F1 and F2 litters; however no behavioral changes were observed in either F1 or F2 offsprings in the 2-generation reproduction study). Moreover, as the NOELs for fetal/developmental toxicity are significantly higher than those for maternal toxicity, the results indicate that chlorfenapyr is neither a developmental toxicant nor a teratogenic agent in either the Sprague-Dawley rat or New Zealand White rabbit. Thus, there is no reliable information to indicate that there would be a variability in the sensitivities of infants and children and adults to the effects of exposure to chlorfenapyr. F. International Tolerances Section 408 (b)(4) of the amended FFDCA requires EPA to determine whether a maximum residue level has been established for the pesticide chemical by the Codex Alimentarius Commission. There is neither a Codex proposal, nor Canadian or Mexican tolerances/limits for residues of chlorfenapyr in/on citrus. Therefore, a compatibility issue is not relevant to the proposed tolerance.