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chlorfenapyr Tolerance Petition Filing 1/97

>ENVIRONMENTAL PROTECTION AGENCY
>[PF-697; FRL-5584-4]


>American Cyanamid Company; Pesticide Tolerance Petition Filing 

>AGENCY: Environmental Protection Agency (EPA). 

>ACTION: Notice of filing.

>----------------------------------------------------------------------- 

>SUMMARY: This notice announces the filing of a pesticide petition proposing regulations establishing tolerances for residues of 4-bromo- 2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-1-pyrrole-3- carbonitrile, (chlorfenapyr) in or on cottonseed. This notice includes a summary of the petition that was prepared by the petitioner, American Cyanamid Company.

>DATES: Comments, identified by the docket control number [PF-697], must be received on or before March 7, 1997.

>ADDRESSES: By mail, submit written comments to: Public Response and Program Resources Branch, Field Operations Division (7506C), Office of Pesticide Programs, Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. In person, bring comments to: Crystal Mall #2, Room 1132, 1921 Jefferson Davis Highway, Arlington, VA. 
>Comments and data may also be submitted electronically by sending electronic mail (e-mail) to: opp-docket@epamail.epa.gov or by submitting disks. Electronic comments must be submitted either in ASCII format (avoiding the use of special characters and any form of encryption) or in WordPerfect in 5.1 file format. All comments and data in electronic form must be identified by the docket control number [PF- 697]. Electronic comments on this notice may be filed online at many Federal Depository Libraries. The official record for this notice, as well as the public version described above, will be kept in paper form. Accordingly, EPA will transfer all comments received electronically into printed, paper form as they are received and will place the paper copies in the official record, which will also include all comments submitted directly in writing.
>Information submitted as comments concerning this notice may be claimed confidential by marking any part or all of that information as ``Confidential Business Information'' (CBI). The 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 Room 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: Dennis Edwards (PM 19), Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. Office location, telephone number, and e-mail address: Crystal Mall #2, Room 207, 1921 Jefferson Davis Highway, Arlington, VA, 703-305-6386, 

>[[Page 5400]]

>e-mail: edwards.dennis@epamail.epa.gov. 

>SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition from American Cyanamid Company. The petition proposes, pursuant to section 408 of the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C. 346a, to amend 40 CFR part 180 to establish tolerances for the insecticide, 4-bromo-2-(4-chlorophenyl)-1(ethoxymethyl)-5-(trifluoromethyl)-1- pyrrole-3-carbonitrile, (chlorfenapyr), in or on the raw agricultural commodity cottonseed.
>The proposed analytical method is capillary gas chromatography using an electron capture detector.
>As required by section 408(d) of the FFDCA, as recently amended by the Food Quality Protection Act (FQPA) Pub. L. 104-170, American Cyanamid Company included in the petition a summary of the petition and authorization for the summary to be published in the Federal Register in a notice of receipt of the petition. The summary represents the views of American Cyanamid; EPA is in the process of evaluating the petition. As required by section 408(d)(3) of the FFDCA, EPA is including the summary as a part of this notice of filing. EPA may have made minor edits to the summary for the purpose of clarity. 

>I. Petition Summary

>The American Cyanamid Company has petitioned EPA, under pesticide petition number PP-5F4456, for a permanent tolerance of 0.5 parts per million (ppm) for the residues of chlorfenapyr in or on cottonseed. As cottonseed 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: 0.01 ppm
>Milk fat: 0.15 ppm
>Meat: 0.01 ppm
>Meat by-products (including fat): 0.10 ppm Section 408(b)(2)(A) of the amended FFDCA allows EPA to establish a tolerance if it determines that the tolerance is ``safe, '' i.e., ``there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposure, and all other exposures for which there is reliable information.''
>All of the studies required for the proposed use pattern have been completed according to EPA requirements. American Cyanamid believes that the available information indicates there is a reasonable certainty that no harm will result from various types of exposure. 
>The following is a summary of the information on chlorfenapyr submitted to the EPA which supports the establishment, under section 408(b)(2)(D) of the amended FFDCA, of the proposed tolerances in or on cottonseed and in food items derived from ruminants exposed to processed cottonseed commodities.

>A. Residue Chemistry

>1. Plant metabolism. American Cyanamid believes that the nature of the residues of chlorfenapyr in plants is adequately understood and that the residue of concern in cotton consists of the parent molecule. Expressed on a whole seed basis, the parent compound accounted for 59- 68% of the total radioactive residue (TRR). 
>2. Analytical method. Section 408(b)(3) of the amended FFDCA requires EPA to determine that there is a practical method for detecting and measuring levels of the pesticide chemical residue in or on food and that the tolerance be set at a level at or above the limit of detection of the designated method. The gas chromatographic (GC) analytical method, M2216.01, which is proposed as the enforcement method for the residues of chlorfenapyr in cottonseed, has been validated at the EPA laboratories in Beltsville, MD and has a limit of detection (LOD) of 0.05 ppm and a limit of quantitation (LOQ) of 0.5 ppm.
>3. Magnitude of residue. Extensive cotton field trials were conducted over multiple growing seasons in all major cotton growing regions of the U.S. Residues of chlorfenapyr were <ls-thn-eq>0.32 ppm and <ls-thn-eq>0.31 ppm in/on cottonseed samples harvested 21 and 28 days, respectively following the last of 5 foliar broadcast applications for a total of approximately 2x the proposed current maximum seasonal application rate of 1.05 lbs active ingredient/acre/ season (ai/acre/season). These field trial data are adequate to support the proposed tolerance of 0.5 ppm in/on cottonseed harvested 21 days following the last application. Processing studies have also demonstrated that there is no concentration of chlorfenapyr residues apparent in crude or refined oils or in the meal and hull and no tolerances are needed for these commodities. 

>B. Toxicological Profile

>American Cyanamid has conducted a full battery of acute and chronic toxicology studies to characterize any potential toxic effects of chlorfenapyr. The data base is complete, valid, and reliable and all meet EPA requirements. The following are important conclusions from these studies:
>1. Acute toxicity. Based on the EPA's toxicity category criteria, the acute toxicity category for chlorfenapyr technical and the 3SC formulation 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: 





>Rat oral LD<INF>50................... 441/1152 milligram/ Tox. Category II 
>kilogram of body
>weight (mg/kg
>b.w.)(M/F).
>Rabbit dermal LD<INF>50.............. >2000 mg/kg b.w.(M/ Tox. Category III 
>F).
>Acute inhaltion LC<INF>50............ 0.83/>2.7 mg/L (M/ Tox. Category III 
>F).
>Eye irritation.................. Moderately	Tox. Category III
>irritating.
>Dermal irritation............... Non-irritating.... Tox. Category IV Dermal sensitization............ Non-sensitizer.... Non-sensitizer Acute neurotoxicity............. NOEL 45 mg/kg b.w. Not an acute 
>neurotoxicant


>2. Genotoxicity. Chlorfenapyr technical (94.5% active ingredient (ai)) was examined in a battery of in vitro and in vivo tests to assess its genotoxicity and its potential for carcinogenicity. 

>[[Page 5401]]

>These tests are summarized below:





>Microbial/Microsome Mutagenicity Assay.... Non-mutagenic Mammalian Cell CHO/HGPRT Mutagenicity	Non-mutagenic
>Assay.
>In Vivo Micronucleus Assay................ Non-genotoxic In Vitro Chromosome Aberration Assay in	Non-clastogenic
>CHO.
>In Vitro Chromosome Aberration Assay in	Non-clastogenic
>CHLC.
>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.................. NOEL for maternal toxicity 25 mg/ 
>kg b.w./day
>NOEL for fetal/developmental
>toxicity 225 mg/kgb.w./day

>Rabbit oral teratology............... NOEL for maternal toxicity 5 mg/ 
>kg b.w./day
>NOEL for fetal/developmental
>toxicity 30 mg/kg b.w./day
>Rat two-generation reproduction...... NOEL for parental toxicity/growth 
>and offspring development 60 ppm
>(5mg/kg b.w./day)
>NOEL for reproductive performance
>600 ppm (44 mg/kg b.w./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 b.w./day 28-Day rat feeding................... NOEL <600 ppm (<71.6 mg/kg b.w./ 
>day)
>28-Day mouse feeding................. NOEL <160 ppm (<32 mg/kg b.w./ 
>day)
>13-Week rat dietary.................. No observed adverse effects level 
>(NOAEL) 150 ppm (11.7 mg/kg b.w./
>day)
>13-Week mouse dietary................ NOEL 40 ppm (8.2 mg/kg b.w./day) 13-Week dog dietary.................. NOAEL 120 ppm (4.2 mg/kg b.w./ 
>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 b.w./ 
>day M/F)

>1-Year dog dietary................... NOEL 120 ppm (4.0/4.5 mg/kg b.w./ 
>day M/F)

>24-Month rat dietary................. NOEL for chronic effects 60 ppm 
>(2.9/3.6 mg/kg b.w./day M/F)
>NOEL for oncogenic effects 600
>ppm (31/37 mg/kg b.w./day M/F)

>18-Month mouse dietary............... NOEL for chronic effects 20 ppm 
>(2.8/3.7 mg/kg b.w./day M/F)
>NOEL for oncogenic effects 240
>ppm (34.5/44.5 mg/kg b.w./day M/
>F)


>6. Endocrine effects. Collective organ weights and histopathological findings from the two-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.
>7. Animal metabolism. A metabolism study was conducted in Sprague- Dawley rats at approximately 20 and 200 mg/kg b.w. 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. 
>8. Metabolite toxicology. The parent molecule is the only moiety of toxicological significance which needs

>[[Page 5402]]

>regulation in plant and animal commodities. 

>C. Aggregate Exposure

>1. Dietary exposure--i. Food. The potential dietary exposure has been calculated from the tolerance of chlorfenapyr in/on cottonseed at 0.5 ppm. This exposure assessment is based on very conservative assumptions, namely 100% of all cotton is treated with chlorfenapyr and that the residues of chlorfenapyr in cottonseed are at the tolerance level. As there are no other established U.S. permanent tolerances for chlorfenapyr, the only dietary exposure to residues of chlorfenapyr in or on food will be limited to residues in cottonseed meal and food and feed items derived from cottonseed. As cottonseed meal 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 all these tolerances to the daily consumption uses less than 1% (actual 0.62%) of the reference dose (RfD) for the overall U.S. population and less than 2% (actual 1.8%) and less than 1% (actual 0.81%) of the RfDs 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 parts per billion (ppb) at 25 deg. C). Chlorfenapyr is also immobile in soil and does not leach because it is strongly absorbed in all common soil types. In addition, the label explicitly prohibits applications near aquatic areas. American Cyanamid believes that 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>-7millimeters (mm) of mercury (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, AC303,630 is a pro- insecticide which is converted to the active form, CL303,268, 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 adenosine triphosphate (ATP) is inhibited resulting in the cessation of all cellular functions. Because of this unique mechanism of action, American Cyanamid believes that 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, CL303,268. In the rat, approximately 85% of the administered dose is excreted in the feces within 48 hours, thereby reducing the levels of AC303,630 and CL303,268 that are capable of reaching the mitochondria. This differential metabolism of AC303,630 to CL303,268 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 b.w./day for the residues of chlorfenapyr in cotton is calculated by applying a 100-fold safety factor to the overall no observed effect level (NOEL) of 3 mg/kg b.w./day. This NOEL is based on the results of the chronic feeding studies in the rat and mouse and the two-generation reproduction study in the rat (see Unit I.E.2. of this document). Therefore, the combined exposure for the proposed chlorfenapyr tolerances in cottonseed, milk, and meat (0.0001866 mg/kg b.w./day) will utilize approximately 0.62% of the RfD for the general U.S. population. 
>2. Infants and children. The theoretical maximum residue contribution (TMRC) in milk consumed by a non-nursing infant (<1 year of age) is 0.0002435 mg/kg b.w./day. This will use less than 1% (actual 0.81%) 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 b.w./day. The combined TMRC for the proposed chlorfenapyr tolerances in meat and milk consumed by a child 1-6 years of age is 0.0005415 mg/kg b.w./day, which is less than 2% (actual 1.8%) of the RfD. Therefore, American Cyanamid believes that 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 cotton and the granting of the requested tolerances in cottonseed, 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 RfD, American Cyanamid believes that 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. American Cyanamid believes that 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. American Cyanamid concludes that the toxicology data base (reproduction/developmental and teratology studies) is complete, valid, and reliable, and therefore 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 1-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 two- generation rat reproduction study, (reduced body weight gains for parental animals and reduced pup body weights for the F<INF>1 and F<INF>2 litters; however no

>[[Page 5403]]

>behavioral changes were observed in either F<INF>1 or F<INF>2 offsprings in the two-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.
>Therefore, a chronic dietary exposure analysis for the residues of chlorfenapyr in cotton, meat, and milk, using the ``worst case'' proposed tolerance-level residues, demonstrates that these levels are well below the RfD of 0.03 mg/kg b.w./day and thus the proposed use of chlorfenapyr is toxicologically supported. 

>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 cottonseed. Therefore, a compatibility issue is not relevant to the proposed tolerance.

>II. Public Record

>EPA invites interested persons to submit comments on this notice of filing. Comments must bear a notification indicating the docket control number [PF-697]. All written comments filed in response to this petition will be available, in the Public Response and Program Resources Branch, at the address given above from 8:30 a.m. to 4 p.m., Monday through Friday, except legal holidays. 
>A record has been established for this notice under docket control numbers [PF-697] (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 public record is located in Room 1132 of the Public Response and Program Resources Branch, Field Operations Division (7506C), Office of Pesticide Programs, Environmental Protection Agency, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA. 
>Electronic comments can be sent directly to EPA at: opp-docket@epamail.epa.gov

>Electronic comments must be submitted as ASCII file avoiding the use of special characters and any form of encryption. The official record for this notice, as well as the public version, as described above will be kept in paper form. Accordingly, EPA will transfer all comments received electronically into printed, paper form as they are received and will place the paper copies in the official record which will also include all comments submitted directly in writing. 
>The official record is the paper record maintained at the address in ``ADDRESSES'' at the beginning of this notice. 

>List of Subjects

>Environmental protection, Agricultural commodities, Pesticides and pests, Reporting and recordkeeping.

>Dated: January 24, 1997.

>Stephen L. Johnson,
>Director, Registration Division, Office of Pesticide Programs. 

>[FR Doc. 97-2466 Filed 2-4-97; 8:45 am] BILLING CODE 6560-50-F