Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 1 of 24 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 MEMORANDUM Date: 26 July 2006 Subject: Bifenazate ( PC Code 000586). Application of Bifenazate to Tuberous and Corm Vegetables, Succulent Peas and Stone Fruit. HED Human Health Risk Assessment. DP Nos.: 323893 and 330737. Registration: 5E6992 and 400 503 Acramite 50 WS. Decision Nos.: 360901 and 362741. 40 CFR 180.572.

From: Thomas Bloem, Chemist Lisa Austin, Ph. D., Toxicologist Mark Dow, Ph. D., Biologist Registration Action Branch 1 ( RAB1) Health Effects Division ( HED) ( 7509P)

Through: Felicia Fort, Branch Chief PV Shah, Ph. D., Senior Toxicologist RAB1/ HED ( 7509P)

To: Daniel Rosenblatt/ Sidney Jackson; RM 05 Daniel Kenny/ Rita Kumar; RM 01 Registration Division ( RD) ( 7505P)

RD of the Office of Pesticide Programs ( OPP) requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from all registered and proposed uses of bifenazate. A summary of these findings is provided in this document. The risk assessment, residue chemistry review, and dietary exposure assessment were provided by Tom Bloem of RAB1; the hazard characterization was provided by Lisa Austin of RAB1; the occupational/ residential exposure and risk assessment was provided by Mark Dow of RAB1; and the drinking water assessment was provided by Thuy Nguyen, of the Environmental Fate and Effects Division ( EFED).

NOTE: In 2002, HED completed a Section 3 risk assessment for the application of bifenazate to fruiting vegetables, cucurbit vegetables, tree nuts pistachio, okra, and mint ( D286170, T. Bloem et al., 30 May 2003). The current document contains only those aspects of the risk assessment which are affected by the addition of the proposed bifenazate uses. OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 2 of 24 Table of Contents 1.0 EXECUTIVE SUMMARY......................................................................................................... 3 3.0 HAZARD CHARACTERIZATION............................................................................................ 8 3.1 Endocrine Disruption............................................................................................................. 9 3.2 Residues of Concern for Dietary Risk Assessment.................................................................. 9 4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION................................................... 10 4.1 Summary of Registered Uses ............................................................................................... 10 4.2 Summary of Proposed Uses ................................................................................................. 10 4.3 Dietary Exposure/ Risk Pathway........................................................................................... 11 4.5 Dietary Exposure Analysis ................................................................................................... 15 4.6 Residential Exposure and Risk Assessment .......................................................................... 16 4.7 Non occupational Off Target Exposure ............................................................................... 16 6.0 CUMULATIVE RISK .............................................................................................................. 18 7.0 OCCUPATIONAL EXPOSURE AND RISK ASSESSMENT .................................................. 18 7.1 Handler Exposure and Risk Assessment ............................................................................... 18 7.2 Post Application Exposure and Risk Assessment ................................................................. 21 7.3 REIs.................................................................................................................................... 23 8.0 DEFICIENCIES ....................................................................................................................... 23 8.1 Toxicology.......................................................................................................................... 23 8.2 Residue Chemistry............................................................................................................... 23 8.3 Occupational/ Residential...................................................................................................... 23 Attachment 1: chemical structures .................................................................................................... 24 Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 3 of 24 1.0 EXECUTIVE SUMMARY Bifenazate ( 1 methylethyl 2( 4 methoxy[ 1,1' biphenyl] 3 yl) hydrazinecarboxylate; see attachment 1 for structures) is a selective miticide which controls the motile stage of mites either by direct contact or through contact with foliar residues. The petitioner indicated that bifenazate blocks or closes the gamma aminobutyric acid ( GABA) activated chloride channels of susceptible pests resulting in over excitation of the peripheral nervous system. Bifenazate is currently registered for application to pome fruit, fruiting vegetable, cucurbit vegetable, tree nut, nectarine, peach, plum, grape, strawberry, cotton, hops, okra, peppermint, and spearmint and for with tolerances ranging from 0.1  35 ppm ( 40 CFR 180.572( a)( 1)). Section 18 registrations have also been established for application of bifenazate to cherry, tomato, soybean, potato, and timothy with tolerances ranging from 0.05 150 ppm ( 40 CFR 180.572( b)). Tolerances, as a result of secondary residues, are established in milk, ruminant meat, ruminant fat, and ruminant meat byproducts at 0.02 0.10 ppm ( 40 CFR 180.572( a)( 1) and ( a)( 2)). Bifenazate is also registered for application by homeowners to ornamentals.

The Interregional Research Project Number 4 ( IR 4) requested a Section 3 registration for the application of bifenazate to succulent pea and the tuberous and corm vegetables ( subgroup 1c). Crompton Corporation ( Bethany, CT) also requested a label ammendment for application of bifenqazate to stone fruit. The following tolerances for the combined residues of bifenazate and D3598 were proposed:

pea, garden....................................................................................................................... 0.2 ppm pea, edible podded............................................................................................................ 4.0 ppm vegetable, tuberous and corm, subgroup 1c .................................................................... 0.01 ppm fruit, stone, crop 12, except plum........................................................................................ 2 ppm Hazard Assessment: The acute toxicity data for bifenazate show that this chemical is not acutely toxic by the oral, inhalation, or dermal routes of exposure ( Toxicity Categories IV). It is minimally irritating to the eye ( Toxicity Category IV) and slightly irritating to the skin ( Toxicity Category IV). Bifenazate is a dermal sensitizer by the Magnusson/ Kligman method, but not the Buehler method.

Subchronic and chronic studies in rats and dogs indicate that the liver and hematopoietic system ( spleen and/ or bone marrow with associated hematological findings) are the primary target organs in these species, with additional toxicity in the kidney ( chronic dog) and adrenal gland ( male rats) also identified. Similarly, the hematopoietic system ( spleen) was the primary target organ in the repeatdose dermal toxicity study. Also associated with this toxicity in several studies were decreased body weight, body weight gain, and food consumption. No evidence of carcinogenicity was seen in the rat and mouse studies and the HED Hazard Identification Assessment Review Committee ( HIARC) classified bifenazate as " not likely" to be a human carcinogen by any relevant route of exposure. A full battery of mutagenicity studies were negative for mutagenic or clastogenic activity. The developmental studies in rats and rabbits did not demonstrate increased sensitivity of fetuses to bifenazate. Similarly, increased qualitative or quantitative susceptibility to offspring were not observed with bifenazate during pre or postnatal development in the reproduction study. There was no evidence of neurotoxicity ( clinical signs or neuropathology) in any of the toxicology studies conducted with bifenazate, although guideline acute and subchronic neurotoxicity studies were not conducted. A bifenazate developmental neurotoxicity study was not required by the HIARC. It should be noted that bifenazate contains hydrazine as part of its chemical structure. This side chain is structurally similar to unsymmetrical dimethyl hydrazine ( UDMH), a B2 animal carcinogen ( possible human carcinogen). Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 4 of 24 Carcinogenicity studies performed with bifenazate on rats and mice did not result in any carcinogenic effects at a maximum dose of 10 mg/ kg/ day and 35 mg/ kg/ day, respectively. The rat, livestock, and plant metabolism studies indicate that metabolism of bifenazate proceeds via oxidation of the hydrazine moiety of bifenazate to form D3598 ( diazene). D3598 is then metabolized to D1989 ( methoxy biphenyl) and to bound residues by reaction with natural products. The petitioner proposed that the degradation route for D3598 to D1989 involved the formation of N2 and CO2 and not biphenyl hydrazine. The HED Metabolism Assessment Review Committee ( MARC) reviewed the petitioner's proposed degradation route and agreed that formation of free biphenyl hydrazine or other hydrazines is unlikely due to oxidation of the parent to the conjugated diazene. The MARC did suggest that if a future metabolism study is submitted, the petitioner should monitor for biphenyl hydrazine. Subsequently, Crompton Corporation submitted a radish metabolism study which did not result in the identification of biphenyl hydrazine. Based on the radish metabolism study, the lack of carcinogenic effects in the bifenazate carcinogenic studies, and since biphenyl hydrazine was not identified in the excreta in the rat metabolism study, RAB1 concluded that issues concerning the formation of hydrazine( s) in plants and livestock have been addressed.

Dose Response Assessment: The HIARC met on four occasions to examine the toxicology database for bifenazate and to determine the appropriate toxicological endpoints for dietary and occupational/ residential exposure assessment ( meeting dates  21 Aug 2001 ( TXR No. 0014658), 24 Apr 2001 ( TXR No. 0014576), 13 Apr 1999 ( TXR No. 0013335), and 4 Feb 1999 ( TXR No. 0013277)). The HIARC found the toxicological database to be complete with the exception of a 28 day inhalation study. The HED Food Quality Protection Act Safety Factor Committee ( FQPA SFC) met on 27 August 2001 to evaluate the bifenazate toxicological database in reference to the potential for enhanced sensitivity to infants and children and concluded that the FQPA SF may be reduced to 1x ( TXR No. 0014661); therefore, based on toxicological considerations, the complete residue chemistry and environmental fate databases, and the conservative assumptions used when generating the dietary and residential exposure estimates, HED concludes that the FQPA SF may be reduced to 1x.

Bifenazate has been classified as " not likely" to be a human carcinogen by any relevant route of exposure and an acute dietary endpoint was not identified for the general population including infants and children; therefore, acute dietary and cancer exposure assessments were not conducted. Since the HIARC did not assign any additional uncertainty factors to the endpoints selected for the various routes of exposure assessment and since the FQPA SF has been reduced to 1x, the total uncertainty factor for all exposure assessments is 100x ( 10x for interspecies extrapolation, and 10x for intraspecies variation). Oral studies were selected for all durations of inhalation exposure assessment and the HIARC determined that a 100% inhalation absorption factor is appropriate for route to route extrapolation. Since a dermal study was selected for all durations of dermal exposure assessment, a dermal absorption factor is not necessary. Oral, dermal, and inhalation exposures can be aggregated based on common endpoints ( changes in body weights and body weight gains, and hematological effects). Exposure assessments were conducted for the specific scenarios listed below.

Table 1. Summary of Toxicological Endpoints used in the Current Risk Assessment1 chronic dietary NOAEL = 1.0 mg/ kg/ day chronic RfD and cPAD = 0.01 mg/ kg/ day short term oral NOAEL = 10 mg/ kg/ day LOC for MOEs   100 short term dermal dermal NOAEL = 6.3 mg/ kg/ day LOC for MOEs   100 ( occupational/ residential) 1 short term inhalation oral NOAEL = 10 mg/ kg/ day2 LOC for MOEs   100 ( occupational/ residential) 1 1 NOAEL = no observable adverse effect level; RfD = reference dose = NOAEL ÷ 100; PAD = population adjusted dose = RfD ÷ FQPA SF; LOC = level of concern; MOE = margins of exposure = NOAEL ÷ exposure 2 100% inhalation absorption factor Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 5 of 24 Exposure Assessment Residential Exposure: HED reviewed and approved homeowner application of FloramiteTM SC ( EPA Reg. No. 400 508) to ornamentals and non bearing fruit trees. Based on the proposed use patterns, only short term dermal and short term inhalation exposure are expected for homeowner applicators ( exposures calculated using the 18 Dec 1999 HED Draft Residential Standard Operational Procedures ( SOPs)). The individual and aggregate MOEs did not exceed HED's level of concern ( aggregate MOE = 4200). Post application exposure is anticipated to be negligible and was not assessed.

Dietary Food Exposure: Chronic dietary risk assessments were conducted using the Dietary Exposure Evaluation Model  Food Consumption Intake Database ( DEEM FCID   , ver. 2.03). DEEM FCID   incorporates the food consumption data from the USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII; 1994 1996 and 1998). The chronic analyses incorporated tolerance level residues for all commodities excluding squash, peach, tomato, and soybean ( average field trial residues were assumed) and milk ( anticipated residue was assumed). The chronic analyses incorporated average percent crop treated information provided by the Biological Economic Analysis Division ( BEAD; J. Carter, 13 Jul 2006). DEEM   ( ver. 7.81) default processing factors were assumed for all commodities excluding apple juice, grape juice, wine/ sherry, tomato paste, and tomato puree. The processing factors for these commodities were reduced to 0.23, 0.17, 0.17, 5.0, and 5.0, respectively, based on data from processing studies. The analyses also included the chronic surface water point estimate generated using the Tier 1 model FIRST and the strawberry application scenario ( 2 x 0.50 lb ai/ acre; 21 day retreatment interval ( RTI); highest registered/ proposed rate). The chronic exposure estimates are   94% cPAD and are, therefore, less than HED's level of concern ( children 1 2 years old were the most highly exposed population).

Occupational Exposure Estimates: Based on the proposed use patterns, commercial handlers and grower/ applicators are anticipated to have only short term dermal and short term inhalation exposures ( intermediate and long term exposures are not anticipated). Workers entering fields following applications are anticipated to have only short term dermal exposures. Chemical specific data were not available to assess pesticide handler exposure. Therefore, surrogate data from studies in the August 1998 Pesticide Handler Exposure Database ( PHED; Ver. 1.1) Surrogate Exposure Guide were used to estimate mixer/ loader and applicator exposure. The mixer loader and applicator exposure estimates were generated assuming baseline work clothing ( long sleeved shirt, long pants, shoes plus socks) and baseline plus gloves. Standard HED methodology was used to provide an estimate of postapplication exposure. Transfer coefficients were from an interim transfer coefficient policy developed by HED's Exposure Science Advisory Council ( ExpoSAC; Policy No. 3.1; Revised 7 Aug 2000; amended by ExpoSAC meeting notes 13 Aug 2001). Provided the handlers applicators wear gloves, the resulting individual and aggregate short term MOEs did not exceed HED's level of concern ( calculated MOEs   170).

Aggregate Exposure Assessment: In general, aggregate exposures are calculated by summing dietary ( food and water) and residential exposures ( residential or other non occupational exposures). Based on the anticipated residential exposure scenarios and since acute and cancer risk assessments are not required, only short term ( residential, food, and water) and chronic ( food and water) aggregate exposure assessments were conducted. Aggregate short term ( food, water, and residential) exposures resulted in MOEs   1600 and aggregate chronic ( food and water) exposures were   94% the cPAD; therefore, aggregate exposure to bifenazate as a result of all registered/ proposed uses, is less than HED's level of concern. Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 6 of 24 Recommendation for Tolerances and Registration: Separate recommendations are written for the tuberous and corm vegetable and succulent pea petition and the stone fruit label amendment.

Tuberous and Corm Vegetable ( subgroup 1c) and Succulent Pea ( 5E6992): Provided the petitioner submits revised Sections B and F, HED concludes that the toxicology, residue chemistry, and occupational/ residential databases are sufficient for a conditional registration and establishment of the following permanent tolerances for the combined residues of bifenazate and D3598 ( expressed as bifenazate):

pea, garden, succulent ......................................................................................................... 0.20 ppm pea, edible podded, succulent ................................................................................................ 4.0 ppm vegetable, tuberous and corm, subgroup 1c ......................................................................... 0.02 ppm An unconditional registration may be established upon submission of data addressing the following deficiency.

  succulent shelled pea ( Regions 1 or 2 ( n= 1), 5 ( n= 3), 11( n= 1), and 12 ( n= 1)) and edible podded pea ( n= 3; Regions at the discretion of the petitioner) field trial data ( storage stability data validating the relevant intervals should also be submitted)

Stone Fruit label Amendment ( 400 503 Acramite 50 WS): The initial petition requested registration for application of bifenazate to cotton, grape, hop, pome fruit, strawberry, and stone fruit; since the petitioner did not submit cherry or apricot residue data, HED concluded that a tolerance in/ on stone fruit was not appropriate ( D277089, T. Bloem, 16 Aug 2001; D288660, T. Bloem, 20 Mar 2003). The petitioner has subsequently submitted these data. Provided a Section F is submitted specifying the tolerance listed below, HED concludes the toxicology, residue chemistry, and occupational/ residential databases are sufficient for a conditional registration and establishment of the permanent tolerances listed below for the combined residues of bifenazate and D3598 ( the current plum tolerance may be replaced in favor of that recommended here; currently established fat tolerance is 0.1 ppm).

fruit, stone, group 12 ( except plum) ...................................................................................... 2.5 ppm plum.................................................................................................................................... 0.20 ppm cattle, fat ............................................................................................................................. 0.10 ppm goat, fat .............................................................................................................................. 0.10 ppm hog, fat ............................................................................................................................... 0.10 ppm horse, fat ............................................................................................................................. 0.10 ppm sheep, fat............................................................................................................................. 0.10 ppm An unconditional registration may be established upon submission of data addressing the following deficiencies.

  storage stability data for hops ( 175 days; 7 day interval from homogenization to analysis should also be validated)

  grape field trial data ( Region 1 ( n= 1))

  confirmation concerning the identification of D9569 as the major residue in milk ( see page 13); conclusions concerning the need for a new ruminant feeding study will be made upon submission of data confirming the identity of the major residue in milk Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 7 of 24 2.0 PHYSICAL/ CHEMICAL PROPERTIES Bifenazate is a selective miticide which controls the motile stage of mites either by direct contact or through contact with foliar residues. The petitioner indicated that bifenazate blocks or closes the GABA activated chloride channels of susceptible pests resulting in over excitation of the peripheral nervous system.

Table 2. Test Compound Nomenclature.

Compound O NH N H O CH 3 O CH 3 CH 3 Common name Bifenazate Company experimental name D2341 IUPAC name isopropyl 2( 4 methoxy 1,1' biphenyl 2 yl) hydrazinecarboxylate CAS name hydrazine carboxylic acid, 2( 4 methoxy[ 1,1' biphenyl] 3 yl), 1 methylethyl ester CAS registry number 149877 41 8 End use products ( EPs) AcramiteTM 50WS ( 50% WP; EPA Reg. No. 400 503)

Table 3. Physicochemical Properties of the Technical Grade of Bifenazate.

Melting range 124 125 º C pH 6.78 Density 1.19 g/ cm3 Water solubility 2.1 mg/ L ( 20 ° C)

Solvent solubility 102 mg/ mL ethyl acetate ( 20 ° C)

Vapor pressure < 1 x 10 8 atm M3/ mole ( 25 ° C)

Dissociation constant, pKa 12.94 at 23 ° C Octanol/ water partition coefficient, Log( KOW) 3.4 UV/ visible absorption spectrum Max 264 nm in water MRID 46064101 Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 8 of 24 3.0 HAZARD CHARACTERIZATION A detailed hazard characterization for bifenazate is presented in a previous HED risk assessment ( D286170, T. Bloem et al., 30 May 2003) and a summary of the bifenazate toxicological profile is provided in the executive summary. The HIARC met on four occasions to examine the toxicology database for bifenazate and to determine the appropriate toxicological endpoints for dietary and occupational/ residential exposure assessment ( meeting dates  21 Aug 2001 ( TXR No. 0014658), 24 Apr 2001 ( TXR No. 0014576), 13 Apr 1999 ( TXR No. 0013335), and 4 Feb 1999 ( TXR No. 0013277)). The HIARC found the toxicological database to be complete with the exception of a 28 day inhalation study. The FQPA SFC met on 27 August 2001 to evaluate the bifenazate toxicological database in reference to the potential for enhanced sensitivity to infants and children and concluded that the FQPA SF may be reduced to 1x ( TXR No. 0014661); therefore, based on toxicological considerations and the residue assumptions used in the dietary ( D330587, T. Bloem, 19 July 2006) and residential ( D284802, M. Dow and D. Vogel, 15 Aug 2002) exposure analyses, HED concluded that the FQPA SF may be reduced to 1x. Table 4 is a summary of the endpoints used in the current assessment.

Table 4. Summary of Toxicological Dose and Endpoints for Bifenazate1 Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and LOC for Risk Assessment Study and Toxicological Effects Acute Dietary; all populations An acute dietary endpoint was not selected based on the absence of an appropriate endpoint attributed to a single dose.

Chronic Dietary; all populations NOAEL= 1.0 mg/ kg/ day UF = 100 cRfD = 0.01 mg/ kg/ day FQPA SF = 1x cPAD = 0.01 mg/ kg/ day LOAEL = 8.9/ 10.4 mg/ kg/ day [ M/ F] based on changes in hematological and clinical chemistry parameters, and histopathology in bone marrow, liver, and kidney in the One Year Dog Feeding Study Incidental Oral, Short Term ( 1  30 days) oral NOAEL = 10 mg/ kg/ day LOC for MOE   100 ( residential and occupational) maternal LOAEL = 100 mg/ kg/ day based on clinical signs, decreased body weight and food consumption during the dosing period in the Rat Developmental Study Incidental Oral, Intermediate Term ( 30 days  six months) oral NOAEL = 0.9 mg/ kg/ day LOC for MOE   100 ( residential and occupational) LOAEL = 10.4/ 10.7 mg/ kg/ day [ M/ F] based on changes in hematologic parameters in the 90 Day Subchronic Dog Study Short, Intermediate and Long Term Dermal ( 1 30 days, 30 days  six months, and six months to lifetime) dermal NOAEL = 80 mg/ kg/ day LOC for MOE   100 ( residential and occupational) LOAEL = 400 mg/ kg/ day based on decreased body weight and food consumption, hematologic effects, increased spleen weight and extramedullary hemapoiesis in the spleen in the 21 Day Dermal Toxicity Study in Rats Short Term Inhalation ( 1 30 days) oral NOAEL= 10 mg/ kg/ day inhalation absorption rate = 100% LOC for MOE   100 ( residential and occupational) maternal LOAEL = 100 mg/ kg/ day based on clinical signs, decreased body weight and food consumption during the dosing period in the Rat Developmental Study Intermediate Term Inhalation ( 30 days six months) oral NOAEL= 0.9 mg/ kg/ day inhalation absorption rate = 100% LOC for MOE   100 ( residential and occupational) LOAEL = 10.4/ 10.7 mg/ kg/ day based on changes in hematologic parameters in the 90 Day Dog Feeding Study Long Term Inhalation ( six months lifetime) Oral study NOAEL= 1.0 mg/ kg/ day ( inhalation absorption rate = 100%) LOC for MOE   100 ( residential and occupational) LOAEL = 8.9/ 10.4 mg/ kg/ day [ M/ F] based on changes in hematological and clinical chemistry parameters, and histopathology in bone marrow, liver, and kidney in the One Year Dog Feeding Study Cancer ( oral, dermal, inhal.) bifenazate is classified as " not likely" to be a human carcinogen 1 UF = uncertainty factor; NOAEL = no observed adverse effect level; LOAEL = lowest observed adverse effect level; RfD = reference dose ( NOAEL ÷ 100); PAD = population adjusted dose ( NOAEL ÷ FQPA SF); LOC = level of concern; MOE = margin of exposure Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 9 of 24 3.1 Endocrine Disruption EPA is required under the Federal Food Drug and Cosmetic Act ( FFDCA), as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there was scientific bases for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA has authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

In a 90 day oral toxicity study ( MRID 44464941), bifenazate caused vacuolation of the zona fasicula in the adrenal cortex of male rats. When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, bifenazate may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption.

3.2 Residues of Concern for Dietary Risk Assessment Table 5 is a summary of the MARC decisions concerning the residues of concern in plants, livestock, rotational crops, and drinking water ( D276801, T. Bloem, 16 Aug 2001; D290053, T. Bloem, 29 May 2003). Subsequent to these decisions, the petitioner submitted radiovalidation data for the livestock enforcement method ( 46691301. der. wpd; D313261, T. Bloem, 19 July 2006). These data indicated that, contrary to what was presented in the ruminant metabolism study, the major residue in milk is D9569 not A1530 sulfate. HED requested that the petitioner submit data confirming the identity of the major residues in milk. Based on structure activity relationships and/ or the identification of the residues of concern in the rat metabolism study, HED concludes that the metabolites/ degradates are not likely to be more toxic than parent and that use of bifenazate toxicological endpoints for risk assessment is acceptable.

Table 5. Residues for Tolerance Expression and Risk Assessment Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants bifenazate, D3598 ( expressed as parent) bifenazate, D3598 ( expressed as parent)

Livestock ( excluding fat) 1 bifenazate, D3598 ( expressed as parent), A1530, A1530 sulfate ( expressed as A1530) bifenazate, D3598 ( expressed as parent), A1530, A1530 sulfate ( expressed as A1530)

Livestock  fat bifenazate, D3598 ( expressed as parent) bifenazate, D3598 ( expressed as parent)

Rotational Crops could not be determined2 could not be determined2 Drinking Water D1989 D1989 1 HED has requested additional information concerning the residues of concern in milk ( 46691301. der. wpd; D313261, T. Bloem, 19 July 2006) 2 based on the results of the confined rotational crop study conducted 0.5 lb ai/ acre and the application rate for the registered crops which are likely to be rotated, HED concluded that residues in rotated crops were unlikely and that tolerances were unnecessary Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 10 of 24 4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION D324430, T. Bloem, 19 July 2006 ( residue chemistry  tuberous and corm vegetables and succulent pea) D277089, T. Bloem, 16 Aug 2001; D288660, T. Bloem, 20 Mar 2003; D313261, T. Bloem, 19 July, 2006 ( residue chemistry summary  stone fruit) D330587, T. Bloem, 19 July 2006 ( dietary exposure) D286171, T. Nguyen, 9 Oct 2003 ( drinking water). D285897, M. Dow, 13 March 2003 ( residential exposure assessment)

4.1 Summary of Registered Uses Bifenazate is currently registered for application to nectarine, peach, plum, grape, strawberry, cotton, hops, peppermint, spearmint, tree nuts, pome fruit, fruiting vegetables, and cucurbit vegetables ( 0.25 0.75 lb ai/ acre; 0 60 day preharvest interval ( PHI)) with tolerances for the combined residues of bifenazate and D3598 ranging from 0.20  35 ppm ( 40 CFR 180.572). Section 18 registrations have also been established for application of bifenazate to cherry, potato, soybean, and timothy with tolerances for the combined residues of bifenazate and D3598 of 0.05 150 ppm. Milk, fat ( cattle, goat, hog, horse, and sheep), meat ( cattle, goat, hog, horse, and sheep), and meat byproduct cattle, goat, hog, horse, and sheep) tolerances are also established as a result of secondary residues ( 0.02 0.10 ppm).

4.2 Summary of Proposed Uses The proposed Acramite ®  50WS ( 50% wettable powder ( WP) in water soluble bags, EPA Reg. No.  400 503) and Acramite ®  4SC ( 4 lb ai/ gal soluble concentrate; EPA Reg. No.  400 514) labels include a restricted entry interval ( REI) of 12 hours Stone Fruit: The 50% WP bifenazate formulation ( WP in water soluble bags) is currently registered for application to nectarine, peach, and plum ( 1 x 0.375 0.500 lb ai/ acre; PHI = 3 days). The petitioner proposed expanding this use to cover all stone fruits ( proposed application scenario is identical to that registered for nectarine, peach, and plum). The proposed label indicates that application through irrigation equipment is prohibited. The submitted label adequately describes the proposed application scenario. Table 6 is a summary of the proposed application scenario.

Tuberous and Corm Vegetables and Succulent Pea: The petitioner proposed single foliar applications of Acramite ®  4SC ( 4 lb ai/ gal; EPA Reg. No.  400 514) to succulent pea and tuberous and corm vegetables ( crop subgroup 1c). The proposed label indicates that application through irrigation equipment is prohibited and does not include rotational crop restrictions. Based on the current rotational crop data, HED concludes that a 30 day rotational crop restriction is appropriate for all nonlabeled crops ( labeled crops may be planted at anytime; see section OPPTS 860.1850). A revised Section B is requested. Table 6 is a summary of the proposed application scenario. Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 11 of 24 Table 6: Proposed Application Scenarios Formulation Crop App. Rate ( lb ai/ acre) PHI1 ( days) Comments tuberous and corm veg. ( crop subgroup 1c) 2 1x 0.50 0.75 14  apply with ground ( min 20 gallons per acre ( GPA)) or aerial ( min 5 GPA) equipment  do not apply more than one application per year  12 hour restricted entry interval 4 lb ai/ gal SC succulent pea 1x 0.38 0.50 14  apply with ground ( min 20 GPA) or aerial ( min 5 GPA) equipment  do not apply more than one application per year  12 hour restricted entry interval 50% WS ( in water soluble bags) stone fruit3 1 x 0.375 0.500 3  apply in a minimum of 50 GPA  do not apply more than one application per season  12 hour restricted entry interval 1 PHI = preharvest interval 2 arracacha, arrowroot, Chinese artichoke, Jerusalem artichoke, edible canna, cassava, bitter and sweet chayote ( root), chufa, dasheen ( taro), ginger, leren, potato, sweet potato, tanier, yam bean, true yam 3 apricot, cherry ( sweet and tart), nectarines, peach, plum/ prune, chickasaw plum, damson plum, Japanese plum, and plumcot 4.3 Dietary Exposure/ Risk Pathway Nature of the Residue  Plants: Based on apple, orange, and cotton metabolism studies, the MARC determined that for tolerance expression and risk assessment purposes, the residues of concern in these crops are bifenazate and D3598 ( D276801, T. Bloem, 16 Aug 2001). The metabolic route in apple, orange, and cotton were similar and proceeded via oxidation of the hydrazine moiety of bifenazate to form D3598 which is further degraded to D1989, D9963, D4642, and/ or A1530 and to bound residues by reaction with natural products.

Subsequent to this decision, the petitioner submitted a radish metabolism study. The metabolic route in radish was similar to that of apple, orange, and cotton with the major identified residues being bifenazate and D3598. HED concludes that the nature of the residue in plants is adequately understood and the residues of concern for tolerance expression and risk assessment purposes are bifenazate and D3598.

Nature of the Residue  Livestock: The MARC reviewed goat and hen metabolism studies and determined that for tolerance expression and risk assessment purposes, the residues of concern in livestock tissue ( excluding fat), eggs, and milk are bifenazate, D3598 ( expressed as bifenazate), A1530, and A1530 sulfate ( expressed as A1530). The residues of concern for tolerance expression and risk assessment purposes in fat are bifenazate and D3598 ( expressed as bifenazate). The metabolic route in goats and hens were similar and proceeded via oxidation of the hydrazine moiety of bifenazate to form D3598 which is further degraded to D1989, D9569, A1530, and/ or A1530  sulfate and to bound residues by reaction with natural products ( D276801, T. Bloem, 16 Aug 2001).

Subsequent to this decision, the petitioner submitted a radiovalidation study which, for purposes of sample generation, dosed goats with 14C bifenazate uniformly labeled in the o methyl phenyl ring for four consecutive days ( 20 ppm daily dietary burden; 46691301. der. wpd). Milk, liver, and fat samples were collected, extracted with a variety of solvents, and analyzed using the same methods employed in the goat metabolism study ( lactating goat; 10 ppm dietary burden; D277089, T. Bloem, 16 Aug 2001). Residue identification was performed via retention time comparison with a mixed standard containing bifenazate, D3598, A1530, A1530 sulfate, D9569, D9472, and D1989. For liver and fat, Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 12 of 24 these analyses yielded some difference from those attained in the original goat metabolism study but none of which are of concern to HED. For milk, the major identified residue in the goat metabolism study was A1530 sulfate ( 41% total radioactive residue ( TRR)) while in the radiovalidation study the major identified residue was D9569 ( 24% TRR; A1530 sulfate was included as a reference standard but was not identified). HED notes that the mixed reference standard resulted in D9569 and A1530 sulfate eluting very close to one another. HED requested that the petitioner submit data confirming the identification of D9569 in milk ( D313261, T. Bloem, 19 Jul 2006).

Magnitude of the Residue  Plants: The following are summaries of the stone fruit, potato tuber, and succulent shelled/ podded pea magnitude of the residue studies.

Tuberous and Corm Vegetables ( crop subgroup 1c)  Combined residues of bifenazate/ D3598 were < 0.01 0.015 ppm in/ on potato tuber samples harvested 13 15 days following two broadcast spray applications at 0.75 lb ai/ acre ( 2x; RTI = 13 14 days; n= 28) and were < 0.01 ppm in/ on potato tuber samples harvested 14 days following two broadcast spray applications at 3.73 lb ai/ acre ( 10x; RTI = 13 days; n= 2).

Based on Tables 3 and 5 of OPPTS 860.1500, an additional potato field trial in Region 11 is needed to fulfill the requested geographical distribution to support a crop subgroup 1c registration. In addition, the potato storage stability data indicate that residues may have declined 83 89% during the interval from harvest to analysis. However, HED concludes the currently available data indicate that a 0.10 ppm tolerance, for the combined residues of bifenazate and D3598 in/ on tuberous and corm vegetables crop subgroup 1c, is acceptable for the following reasons ( a revised Section F is requested; no additional field trial data are required): ( 1) all of the field trials were conducted at 2x the proposed seasonal rate and resulted in residues   0.015 ppm; ( 2) the exaggerated rate field trial ( 10x the proposed seasonal rate) resulted in residues < LOQ; and ( 3) the radish metabolism study result in TRRs in the root of   0.0043 ppm ( 1 x 0.75 lb ai/ acre; 7 day PHI).

Succulent Shelled/ Podded Pea  Combined residues of bifenazate/ D3598 were 0.028 0.173 ppm in/ on succulent shelled pea ( n= 12) and were 0.91 3.74 ppm in/ on edible podded pea samples ( n= 10) harvested 2 4 days following two broadcast spray applications at 0.75 lb ai/ acre ( 3x; RTI = 12 14 days; n= 28).

The succulent shelled pea and edible podded pea residue data were conducted with application rates 1.5x the single application rate and 3.0x the seasonal application rate. As a result, these data are not indicative of the magnitude of the residue following application at the proposed rate. Therefore, HED requests that the petitioner submit succulent shelled pea ( Regions 1 or 2 ( n= 1), 5 ( n= 3), 11( n= 1), and 12 ( n= 1)) and edible podded pea ( n= 3; Regions at the discretion of the petitioner) field trial data conducted at the proposed rate ( storage stability data supporting the relevant storage intervals should also be submitted). Provided the petitioner agrees to submit these data, HED concludes that the available data support a tolerance for the combined residues of bifenazate and D3598 in/ on succulent garden pea and edible podded pea of 0.20 ppm and 4.0 ppm, respectively. A revised Section F is requested. Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 13 of 24 Stone Fruit  Following a single application at 0.50 lb ai/ acre ( 1x; PHI = 3 days), combined residues of bifenazate/ D3598 were as follows: cherry  0.107 1.670 ppm; peach  0.100 1.450 ppm; apricot  0.219 0.899 ppm; and plum  0.010  0.150 ppm.

Based on Tables 2 and 5 of OPPTS 860.1500, the submitted field trial data fulfill the requested geographical distribution to support a stone fruit crop group registration. Using the tolerance spreadsheet, cherry, peach, apricot, and plum tolerances for the combined residues of bifenazate and D3598 of 2.5 ppm, 1.5 ppm, 1.1 ppm, and 0.20 ppm, respectively, were recommended. Based on these data, HED concludes that the following tolerances for the combined residues of bifenazate and D3598 are appropriate: fruit, stone, group 12 ( except plum)  2.5 ppm; plum  0.20 ppm. A revised Section F is requested.

Magnitude of the Residue  Livestock: Cattle, goat, hog, horse, and sheep meat ( 0.02 ppm), meat byproduct ( 0.02 ppm), and fat ( 0.1 ppm) tolerances are currently established; a milk ( 0.01 ppm) tolerance is also currently established. Poultry tolerances are not currently established. These ruminant tolerances are derived from secondary residues resulting from the wet apple pomace ( 1.2 ppm) and cotton gin byproduct ( 20 ppm) tolerances.

The only feed items associated with the current petition are potato culls and processed potato waste ( ruminant feed commodities; no poultry feed commodities). Based on the wet apple pomace and cotton gin byproduct tolerances and the recommended tuberous and corm vegetable tolerance of 0.02 ppm, HED concludes that the contribution to the dietary burden from the currently requested crops is minimal and adjustment in the livestock tolerances are unnecessary. However, HED notes that the current fat tolerance is 0.1 ppm. The risk assessment associated with the establishment of the fat tolerance recommended for a 0.10 ppm fat tolerance ( D264893, W. Dykstra et. al., 27 Sep 2001). Therefore, HED requests a section F which indicates a cattle, goat, hog, horse, and sheep fat tolerance of for the combined residues of bifenazate, D3598, A1530, and A1530 sulfate of 0.10 ppm.

As indicated in the nature of the residue in livestock section, the petitioner submitted data which indicates that the major residue in milk is D9569 and not A1530 sulfate as previously indicated. HED requested that the petitioner submit data confirming the identity of the major residues in milk ( D313261, T. Bloem, 19 July 2006). The ruminant metabolism study indicated that major residue in milk, originally identified as A1530 sulfate but now thought to be D9569, occupied 41% of the TRR and combined residues of bifenazate and D3598 occupied 9% of the TRR. Therefore, the ratio of the major residue in milk to combined residues of bifenazate/ D3598 is 4.6. The ruminant feeding study resulted in combined residues of bifenazate/ D3598 in/ on milk of < 0.01 ppm (< LOQ) at a 10 ppm dietary burden. Based on the current maximum theoretical dietary burden of 6.99 ppm and 4.6 ratio from the ruminant metabolism study and assuming a combined bifenazate/ D3598 residue of 0.01 ppm ( A1530 was included as a residue of concern only because the method did not distinguish between A1530 sulfate and A1530), a milk residue of 0.0391 ppm is calculated (( 0.01 + ( 0.01 x 4.6)) x ( 6.99 ÷ 10) = 0.0391). Therefore, for purposes of risk assessment, HED will assume a residue of 0.0391 in milk and will assume the maximum theoretical concentration factor for milk fat of 25x. Conclusions concerning the need for a new ruminant feeding study will be made upon submission of data confirming the identity of the major residue in milk. Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 14 of 24 Residues in Rotational Crops: A confined rotational crop study has been previously submitted and reviewed ( D277089, T. Bloem, 16 Aug 2001; field rotational crop study has not been submitted). The MARC concluded that residues of concern in/ on rotational crops could not be determined from the available data ( D276801, T. Bloem, 16 Aug 2001). On the basis of the confined rotational crop study and the proposed maximum seasonal application rates, HED concludes that a 30 day plantback interval ( PBI) for the currently requested crops is appropriate.

Analytical Enforcement Method  Plants: A method is available for enforcement of the currentlyestablished plant tolerances ( D281973, T. Bloem, 29 Aug 2002; D281979, T. Bloem, 29 Aug 2002). The methods used in the field trial and processing studies were similar to the current enforcement method ( D281973, T. Bloem, 29 Aug 2002; D281979, T. Bloem, 29 Aug 2002). Since the procedures are similar and adequate method validation and concurrent recoveries were attained in the field trial and processing studies, HED concludes that the current enforcement method is appropriate for enforcement of the tolerances associated with this petition.

Multiresidue Methods: HED reviewed the petitioner submitted Food and Drug Administration ( FDA) Multiresidue Method studies for bifenazate, D3598, A1530, and A1530 sulfate. These data indicate that bifenazate, D3598, A1530, and A1530 sulfate are not quantitatively recovered through the FDA Multiresidue Methods.

International Harmonization of Tolerances: Canada, Codex, and Mexico do not have maximum residue limits ( MRLs) for residues of bifenazate in/ on tuberous and corm vegetables or succulent pea; therefore, harmonization is not an issue for these crops. However, Codex MRLs are established in/ on peach, nectarines, plum, and prunes ( no Canadian or Mexican stone fruit MRLs) Since the Codex MRL residue definition is for bifenazate per se, harmonization is not possible.

Tolerance Summary: Based on the proposed application rates and the magnitude of the residue, processing, and feeding studies, HED concludes that the tolerances listed in Table 7 for the combined residues of bifenazate and D3598 are appropriate.

Table 7. HED Recommended Tolerances Commodity Definition Tolerance ( ppm)

pea, garden, succulent 0.20 pea, edible podded, succulent 1.0 vegetable, tuberous and corm, subgroup 1C 0.10 fruit, stone, group 12 ( except plum) 2.5 plum 0.30 Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 15 of 24 4.4 Water Exposure/ Risk Pathway Environmental Fate Assessment: Parent bifenazate degrades rapidly in aerobic soil conditions with a half life of approximately 30 minutes. The first degradate formed ( D3598; half life of 7 hours) was reported in a concentration of 95% of the applied radioactivity. D3598 degrades to D1989 ( reported at a maximum of 26% of the applied radioactivity), which is moderately persistent with an EFEDcalculated half life of approximately 96 days. Photodegradation and other routes of dissipation of parent bifenazate do not appear to be significant.

Ground and Surface Water EECs: The MARC concluded that the residue of concern in drinking water is D1989 ( D276801, T. Bloem, 16 Aug 2001). Parent and D3598 were not included as a residue of concern in drinking water due to the short half lives of these compounds and the lack of an acute dietary endpoint ( toxicity of D3598 is assumed to be equivalent to bifenazate). Since ground or surface water monitoring data are not available, EFED provided Tier I ground ( SCI GROW) and surface water ( FIRST) EECs for D1989. Both models were conducted using the strawberry application scenario ( 2 x 0.50 lbs ai/ acre; 21 day RTI; highest registered/ proposed application rate). The resulting ground and chronic surface water EECs are < 0.001 ppb and 6.38 ppb, respectively.

4.5 Dietary Exposure Analysis Chronic dietary risk assessments were conducted using DEEM FCID   ( ver. 2.03). DEEM FCID   incorporates the food consumption data from the USDA's CSFII ( 1994 1996 and 1998). The chronic analyses incorporated tolerance level residues for all commodities excluding squash, peach, tomato, and soybean ( average field trial residues were assumed) and milk ( anticipated residue was assumed). The chronic analyses incorporated average percent crop treated information provided by the BEAD ( J. Carter, 13 Jul 2006). DEEM   ( ver. 7.81) default processing factors were assumed for all commodities excluding apple juice, grape juice, wine/ sherry, tomato paste, and tomato puree. The processing factors for these commodities were reduced to 0.23, 0.17, 0.17, 5.0, and 5.0, respectively, based on data from processing studies. The analyses also included the chronic surface water point estimate generated using the Tier 1 model FIRST and the strawberry application scenario ( 2 x 0.50 lb ai/ acre; 21 day RTI; highest registered/ proposed rate). The chronic exposure estimates are   94% cPAD and are, therefore, less than HED's level of concern ( children 1 2 years old were the most highly exposed population). Based on a critical commodity analysis conducted in DEEM FCID   , the major contributor to the risk was soybean oil ( 16 55% of the cPAD). Table 8 is a summary of the chronic dietary exposure estimates.

Table 8. Summary of Chronic Dietary Exposure and Risk ( drinking water included)

Population cPAD ( mg/ kg/ day) Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.003835 38 All Infants (< 1 year old) 0.007938 79 Children 1 2 years old 0.009386 94 Children 3 5 years old 0.008595 86 Children 6 12 years old 0.005942 59 Youth 13 19 years old 0.003712 37 Adults 20 49 years old 0.003084 31 Adults 50+ years old 0.002554 26 Females 13 49 years old 0.01 0.002864 29 Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 16 of 24 4.6 Residential Exposure and Risk Assessment HED previously reviewed a petition for homeowner application of bifenazate to " all ornamental plants, including bedding plants, flowering plants, foliage plants, bulb crops, perennials, trees, and shrubs." In conjunction with this petition, labeling for FloramiteTM SC ( 2lb ai/ gal) was submitted and the assessment was conducted using the instructions on this label. HED noted that the petition indicated that Florimite, Floramite LS, Floramite GN, and Floramite SC/ LS may also be applied to ornamentals. Copies of those product labels were not forwarded for review; therefore, HED is not aware of any differences in labels that might exist.

HED anticipated only short term dermal and inhalation exposure for residential handlers. The proposed formulation was appropriate for application via pump up sprayers, garden hose end sprayers, or similar " homeowner" pesticide devices. HED policy indicates a larger area per day may be treated with a hose end sprayer than with a " pump up" compressed air sprayer, which in turn results in possibly greater contact with the active ingredient per day. Therefore, exposure from a hose end sprayer was assessed rather than that of a compressed air sprayer. The resulting dermal and inhalation MOEs were 4200 and 430000, respectively, and yielded a combined MOE of 4200; therefore, residential exposure to bifenazate is less than HED's level of concern. With respect to post application residential exposures, current HED policy ( see minutes to ExpoSAC meeting, 26 Jul 2001) specifies that no significant post application exposure is anticipated from landscape ornamentals, either by residents or professional applicators; therefore, no residential post application assessment was conducted.

4.7 Non occupational Off Target Exposure Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from ground application. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, State Lead Agencies for pesticide regulation, and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift with specific products with significant risks associated with drift. Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 17 of 24 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION In general, HED conducts aggregate risk assessments by summing dietary ( food and water) and residential exposures ( residential or other non occupational exposures). Based on the registered/ proposed agricultural and residential uses and since a common toxicological endpoint has been identified for assessment of oral, dermal, and inhalation exposures ( all durations; changes in body weights and body weight gains, and hematological effects), HED conducted short term ( food, water, residential dermal, and residential inhalation) and chronic ( food and water) aggregate risk assessments. The HIARC did not select an acute dietary endpoint for the general US population, infants, children, and females 13 50 years old and bifenazate has been classifieds as " not likely" to be a human carcinogen according to EPA Proposed Guidelines for Carcinogen Risk Assessment ( 10 Apr 1996). Therefore, acute and cancer aggregate exposure analyses were not conducted.

Short Term Aggregate Risk Assessment: Since a common endpoint has been identified for assessment of short term oral, dermal, and inhalation exposures ( changes in body weights and bodyweight gains, and hematological effects) the short term aggregate risk assessment considered exposure from food, water, and residential sources. Since the doses corresponding to the identified oral, dermal, and inhalation endpoints were different but the level of concern for all three routes of exposure are identical, the short term aggregate exposures were calculated using the 1 ÷ MOE approach. HED combines chronic dietary ( food and water) exposure estimates with residential exposure estimates when conducting short term aggregate risk assessments. Short term exposure has been defined as from 1 30 days and HED has concluded that chronic dietary exposure estimates will more accurately reflect actual dietary exposure over these time periods than will highend acute dietary exposures. The proposed residential scenarios result in exposure to only adults. Therefore, short term aggregate assessments were not conducted for infants and children. Table 9 is a summary of the short term aggregate exposures and risk estimates. Since the aggregate MOEs are   1600, short term aggregate exposure to bifenazate is less than HED's level of concern.

Table 9. Short Term Aggregate Exposure Population Target Aggregate MOE1 dietary MOE2 dermal MOE3 inhalation MOE4 agg. MOE ( dietary and residential) 5 General U. S. pop. 2600 4200 430000 1600 Youth 13 19 years old 2700 4200 430000 1600 Adults 20 49 years old 3200 4200 430000 1800 Adults 50+ years old 3900 4200 430000 2000 Females 13 49 years old 100 3500 4200 430000 1900 1 total uncertainty factor for all routes of exposure is 100x; therefore, the target MOE is 100 2 dietary MOE = short term incidental oral NOAEL ÷ chronic dietary exposure 3 dermal MOE = short term dermal NOAEL ÷ dermal residential exposure ( see Section 4.5) 4 inhalation MOE = short term inhalation NOAEL ÷ inhalation residential exposure ( see Section 4.5) 5 aggregate MOE ( dietary and residential) = 1 ÷ ( ( 1 ÷ MOEdietary)+ ( 1 ÷ MOEdermal) + ( 1 ÷ MOEinhalation))

Chronic Aggregate Risk Assessment: Since there are no registered/ proposed uses which result in chronic residential exposures, the chronic aggregate exposure assessment is concerned only with exposure from food and water. Since the dietary exposure analysis included drinking water, the discussion and exposure estimates presented in Section 4.5 represent aggregate chronic exposure. Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 18 of 24 6.0 CUMULATIVE RISK Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for bifenazate and any other substances, and bifenazate does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA assumed that bifenazate does not have a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

7.0 OCCUPATIONAL EXPOSURE AND RISK ASSESSMENT D324431, M. Dow, 7 Feb 2006 ( tuberous and corm vegetables) D277204, J. Swackhammer, 21 Aug 2001 ( stone fruit)

HED previously conducted occupational exposure assessment for application of bifenazate to apricot, nectarine, peach, plum, and prune orchards as well as apples, cotton, grape, hops, pears, and strawberries. The assessment was not conducted for all stone fruit. HED concludes that the previous assessment is adequate for all stone fruits for the following reasons: ( 1) application methods and post application activities for all stone fruit are similar and ( 2) the proposed stone fruit application scenario is the same as that previously evaluated.

7.1 Handler Exposure and Risk Assessment HED notes that the Acramite ®  4SC ( 4 lb ai/ gal; EPA Reg. No.  400 514) and Acramite ®  50WS ( 50% ai; EPA Reg. No.  400 503) labels indicate that applicators and other handlers should wear a long sleeved shirt, long pants, shoes, and socks. The Acramite ®  4SC label also indicates that when not using a closed system, an apron and chemical resistant gloves should be worn for mixing loading activities ( this statement is not included on the Acramite ®  50WS label). HED notes that the Acramite ®  50WS is a wettable powder in water soluble bags and is therefore considered a closed system by HED.

No chemical specific data were available with which to assess potential exposure to pesticide handlers. The estimates of exposure to pesticide handlers are based upon surrogate study data available in the PHED. For pesticide handlers, it is HED standard practice to present estimates of dermal exposure for " baseline," that is, for workers wearing a single layer of work clothing consisting of a long sleeved shirt, long pants, shoes plus socks and no protective gloves as well as for " baseline" and the use of protective gloves or other personal protective equipment ( PPE) as might be necessary. The proposed product label involved in this assessment directs applicators and other handlers to wear long sleeved shirt, long pants, shoes plus socks. When not using a closed system, handlers must wear an apron and chemical resistant gloves made of any waterproof material for mixing/ loading activities. HED notes that, for stone fruit, the formulation is packed in water soluble bags and that this is considered a closed loading system. Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 19 of 24 It is expected that some private ( i. e., grower) applicators may perform all tasks, that is mix, load and apply the material. However, ExpoSAC draft SOP ( 29 March 2000) directs that although the same individual may perform all tasks, in some cases they shall be assessed separately. The available exposure data for combined mixer/ loader/ applicator scenarios are limited in comparison to the data available for monitoring of these two activities separately. These exposure scenarios are outlined in the PHED Surrogate Exposure Guide ( August 1998). HED has adopted a methodology to present the exposure and risk estimates separately for the job functions in some scenarios and to present them as combined in other cases. Most exposure scenarios for hand held equipment ( such as hand wands, backpack sprayers, and push type granular spreaders) are assessed as a combined job function. With these types of hand held operations, all handling activities are assumed to be conducted by the same individual. The available monitoring data support this and HED presents them in this way. Conversely, for equipment types such as fixedwing aircraft, groundboom tractors, or air blast sprayers, the applicator exposures are assessed and presented separately from those of the mixers and loaders. By separating the two job functions, HED determines the most appropriate levels of PPE for each aspect of the job without requiring an applicator to wear unnecessary PPE that might be required for a mixer/ loader ( e. g., chemicalresistant gloves may only be necessary during the pouring of a liquid formulation).

Stone Fruit: As stated above, the stone fruit occupational exposure assessment evaluated occupational exposure to stone fruit as well as apples, cotton, grape, hops, pears, and strawberries. To evaluate occupation handler exposure to these crops, the assessment picked the application scenario which was likely to result in the highest exposure. Therefore, the specific assessment evaluated may not have been for stone fruit but it can be stated that the calculated occupational exposures will be equal to or greater than that expected for stone fruit. The following is a summary of the previous occupational assessment for stone fruit, apples, cotton, grape, hops, pears, and strawberries ( D277204, J. Swackhammer, 21 Aug 2001):

Based on the proposed use patterns of bifenazate, commercial applicators and grower/ applicators are anticipated to have short term exposures ( 1 30 days).... dermal and inhalation exposure assessments for the following scenarios are presented based on the rationale discussed below:

( 1) commercial mixer/ loaders supporting aerial applications ( cotton); rationale: cotton crops are considered to be higher acreage crops as compared to the other crops in the proposed use, and aerial application methods can treat more acres per day than ground based applications.

( 2) commercial applicators for groundboom applications, open cab ( cotton); rationale: groundboom applicators are anticipated to have a higher exposure potential as compared to aerial applicators.

( 3) commercial airblast applicator, open cab ( hops); rationale: airblast application methods have a relatively high exposure potential as compared to groundboom applications, and the proposed maximum application rate to hops is higher than for tree fruit crops.

Provided handlers wear a single layer of work clothing, the estimated MOEs were   270 and therefore do not exceed HED's level of concern. Table 10 is a summary of the occupational exposures. Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 20 of 24 Tuberous and Corm Vegetables and Succulent Pea: Based upon the proposed use pattern, HED believes the most highly exposed occupational pesticide handlers are likely to be mixer/ loaders using open pour of liquids and applicators using open cab groundboom sprayers or aircraft. HED expects most exposures will be short term duration ( 1  30 days). Typical field size is expected to be small as compared to traditional field crops such as corn, cotton, soybeans or wheat. Most ground applications are likely to be made by the grower. There is only one application per acre per year. Therefore there may be several short term duration exposures but it is not likely that any particular applicator would be exposed from 1  6 months ( intermediate term duration exposure) applying bifenazate to succulent peas or tuberous/ corm vegetables. Provided handlers wear protective gloves in addition to a single layer of work clothing, the estimated MOEs were   660 and therefore do not exceed HED's level of concern ( label indicates when not using a closed system gloves should be worn for mixing loading activities). Table 10 is a summary of the occupational exposures.

Table 10. Pesticide Handlers Worker Exposure Estimates to Bifenazate.

Unit Exposure1 ( mg ai/ lb handled) App. Rate ( lb ai/ acre) Units Treated2 ( acres/ day) Avg. Daily Dose3 ( mg ai/ kg/ day) NOAEL ( mg ai/ kg/ day) MOE Combined MOE Tuberous and Corm Vegetable ( subgroup 1c) and Succulent Pea Mixer/ Loader  Liquid Open Pour  Supporting Aerial Operations Dermal SLNG 2.9 HC SLWG 0.023 HC Inhal 0.0012 LC 0.75 350 Dermal NG 10.87 WG 0.086 Inhal 0.0045 Derm  80 Inhal  10 Derm NG 7 WG 930 Inhal 2,200 NG 7 WG 660 Applicator  Open Cab Groundboom Dermal SLNG 0.014 HC SLWG 0.014 MC Inhal 0.00074 LC 0.75 350 Dermal NG 0.053 WG 0.053 Inhal 0.0028 Derm  80 Inhal  10 Derm NG 1,500 WG 1,500 Inhal 3,600 NG 1,100 WG 1,100 Applicator  Aerial Fixed Wing Dermal SLNG 0.0050 MC Inhal 0.000068 MC 0.75 350 Dermal NG 0.019 Inhal 0.00026 Derm  80 Inhal  10 Derm NG 4,211 Inhal 38,462 NG 3,800 Stone Fruit4 Mixer/ Loader  WP in Water Soluble Bags  Supporting Aerial Applications Dermal SLNG 0.021 LC SLWG 0.0098 LC Inhal 0.00024 LC 0.75 1200 Dermal NG 0.27 WG 0.126 Inhal 0.0031 Derm  80 Inhal  10 Derm NG 300 WG 630 Inhal 3,200 NG 270 WG 530 Applicator  Open Cab Groundboom Dermal SLNG 0.014 HC SLNG 0.014 HC Inhal 0.00074 LC 0.75 200 Dermal NG 0.030 WG 0.030 Inhal 0.0016 Derm  80 Inhal  10 Derm NG 2,700 WG 2,700 Inhal 6,300 NG 1,800 WG 1,800 Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 21 of 24 Table 10. Pesticide Handlers Worker Exposure Estimates to Bifenazate.

Unit Exposure1 ( mg ai/ lb handled) App. Rate ( lb ai/ acre) Units Treated2 ( acres/ day) Avg. Daily Dose3 ( mg ai/ kg/ day) NOAEL ( mg ai/ kg/ day) MOE Combined MOE Applicator  Open Cab Airblast Dermal SLNG 0.36 HC SLWG 0.24 HC Inhal 0.0045 HC 0.75 40 Dermal NG 0.154 WG 0.103 Inhal 0.0019 Derm  80 Inhal  10 Derm NG 520 WG 780 Inhal 4,400 NG 470 WG 680 1 taken from the PHED Surrogate Exposure Guide ( ver. 1.1; August 1998); SLNG = single layer of work clothing ( long sleeved shirt, long pants, shoes; socks] and no gloves. SLWG = single layer work clothing with gloves; HC = high confidence data; LC = lowconfidence data 2 Acres Treated are derived from ExpoSAC SOP. No. 9.1( rev. 25 Sep 01) 3 Average Daily Dose ( ADD) = Unit Exposure x Application Rate x Units Treated ÷ 70 kg. 4 The stone fruit occupational exposure assessment evaluated occupational exposure to stone fruit as well as apples, cotton, grape, hops, pears, and strawberries. To evaluate occupation handler exposure to these crops, the assessment picked the application scenario which was likely to result in the highest exposure. Therefore, the specific assessment evaluated may not have been for stone fruit but it can be stated that the calculated MOE will be equal to or greater than that expected for stone fruit.

7.2 Post Application Exposure and Risk Assessment It is possible for agricultural workers to have post application exposure to pesticide residues during the course of typical agricultural activities. HED in conjunction with the Agricultural Reentry Task Force ( ARTF) has identified a number of post application agricultural activities that may occur and which may result in post application exposures to pesticide residues. HED has also identified Transfer Coefficients ( TC) ( cm ² / hr) relative to the various activities which express the amount of foliar contact over time, during each of the activities identified. The transfer coefficients used in this assessment are from an interim transfer coefficient SOP developed by HED's ExpoSAC using proprietary data from the ARTF database ( SOP # 3.1). It is the intention of HED's ExpoSAC that this SOP will be periodically updated to incorporate additional information about agricultural practices in crops and new data on transfer coefficients. Much of this information will originate from exposure studies currently being conducted by the ARTF, from further analysis of studies already submitted to the Agency, and from studies in the published scientific literature.

Stone Fruit: As stated above, the stone fruit occupational exposure assessment evaluated occupational exposure to stone fruit as well as apples, cotton, grape, hops, pears, and strawberries. To evaluate occupational handler exposure to these crops, the assessment picked the application scenario which was likely to result in the highest exposure. Therefore, the specific assessment evaluated may not have been for stone fruit but it can be stated that the calculated occupational exposures will be equal to or greater than that expected for stone fruit. The following is a summary of the previous occupational assessment for stone fruit, apples, cotton, grape, hops, pears, and strawberries ( D277204, J. Swackhammer, 21 Aug 2001; D264893. W. Dykstra et al., 27 Sep 2001):

From the USDA Crop Profiles and ExpoSAC Policy No. 3.1 for these tree crops, typical cultural activities range from scouting, irrigation, pruning, weeding, thinning ( chemical and hand), and harvesting, mostly by hand. Of these activities, thinning and hand harvesting are considered to have Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 22 of 24 the highest exposure potential due to high foliar contact. The corresponding transfer coefficient ( TC) for both activities is 3,000 cm2/ hr for hand harvesting ( ExpoSAC Policy No. 3, revised policy on apple thinning ( see ExpoSAC minutes, 13 Sep 2001), MRID 424281 01). For apples specifically, chemical thinners can be used during bloom or immediately following petal fall. Hand thinning is often used to " clean up" the tree after chemical thinning ( Dr. Curt R. Rom, Professor of Horticulture, University of Arkansas, Gerber Newsletter, Spring 2001). Also, hand thinning the fruit about six to eight weeks after bloom is a very common practice ( USDA). Fruit thinning serves to ensure the highest fruit quality by spacing the fruit on the limb, reducing fruit clusters to singles and removing fruit that is likely to rub on the limbs. Thinning also eliminates fruit that appears damaged by early season insects or diseases. Heavy mite feeding early in the season ( late June and early July) not only can reduce tree growth and yield, but also can drastically affect fruit bud formation, and thereby reduce yields the following year. Also, based on personal communications with Hollabaugh Bros., Inc. in Biglerville, PA ( an Eastern U. S. grower visited on the IR 4/ EPA/ USDA Field Tour, June 2001), fruit thinning and mite outbreaks may occur simultaneously, but most likely mite outbreaks will occur in late July or early August, while fruit thinning is typically conducted in early summer ( June)..... Thus, even though the conduct of hand thinning and miticide use may not typically coincide, a post application exposure assessment for thinning is included, but is considered to represent a conservative exposure scenario. In addition to the hand thinning assessment, a post application assessment for hand harvesting is also included, given the relatively short proposed PHI for apricots, nectarines, peaches, plums and prunes ( three days)....... As mentioned above, there are no chemicalspecific post application exposure data available for bifenazate related to the proposed uses. In order to assess the highest potential post application exposures...... an estimate of dislodgeable foliar residues ( DFR) on DAT 0 was used for the proposed uses. This DFR estimate is anticipated to represent the highest post application exposures for the proposed use of bifenazate. In order to determine the time frame at which workers may enter treated sites to perform cultural activities, DFR estimates and corresponding MOEs were calculated using HED's default dissipation rate of 10% of foliar residues per day.

The estimated MOEs are 210 and therefore do not exceed HED's level of concern. Table 11 is a summary of the post application occupational exposures.

Tuberous and Corm Vegetables and Succulent Pea: Post application activities in tuberous and corm vegetable and succulent pea fields may result in exposure to workers. The highest TCs listed in SOP # 3.1 for the proposed crop sites are for irrigation activities and scouting in tuberous and corm vegetables ( 1500 cm2/ hr) and hand harvesting succulent peas ( 2500 cm2/ hr). The estimated MOEs resulting from these activities are 170 and therefore do not exceed HED's level of concern. Table 11 is a summary of the post application occupational exposures.

Table 11. Post Application Worker Exposure Assessments for Bifenazate Exposure Scenario AR ( lb ai/ acre) DFR on Day of Treatment1 ( µ g/ cm2) Transfer Coefficient ( cm2/ hr) Average Daily Dose2 ( mg/ kg/ day) Short term Dermal MOE on Day of Treatment tree fruit crops; hand thinning 3,000 0.384 210 tree fruit crops; hand harvesting 0.50 1.12 3,000 0.384 210 succulent pea; hand harvesting 0.75 1.682 2500 0.48 170 1 Surrogate DFR = application rate ( lb ai/ acre) x 20% available as dislodgeable residue x 4.54E8 µ g/ lb x 2.47E 8 acres/ cm2; DAT 0 = 0 days after treatment 2 ADD = DFR ( µ g/ cm2) x TC ( cm2/ hr) x 8 hrs/ day x 0.001 mg/ µ g x 1/ BW x % dermal absorption; BW= 70kg for adults; dermal absorption = 100% as NOAEL based on 21 day dermal study. Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 23 of 24 7.3 REIs Bifenazate is classified in Acute Toxicity Category IV for acute dermal, acute inhalation, primary eye irritation and primary skin irritation. It is not a dermal sensitizer. Therefore, the interim Worker Protection Standard ( WPS) REI of 12 hours is adequate to protect agricultural workers from post application exposures to bifenazate. The proposed labels include a REI of 12 hours.

8.0 DEFICIENCIES 8.1 Toxicology Succulent Pea and Tuberous and Corm Vegetable ( crop subgroup 1c) and Stone Fruit Label Amendment   The HIARC determined that a 28 day inhalation toxicity study is required to address concerns via this route of exposure ( TXR No. 0014658); a waiver from the 28 day inhalation study is granted for the following reasons: ( 1) bifenazate technical is of low volatility; ( 2) is Toxicity Category IV for acute inhalation; and ( 3) the extrapolated MOEs for anticipated inhalation exposures resulting from the proposed bifenazate uses are more than 10x the target MOE of 100 ( HED SOP 2002.01).

8.2 Residue Chemistry Succulent Pea and Tuberous and Corm Vegetable ( crop subgroup 1c)

  Revised Sections B and F   succulent shelled pea ( Regions 1 or 2 ( n= 1), 5 ( n= 3), 11( n= 1), and 12 ( n= 1)) and edible podded pea ( n= 3; Regions at the discretion of the petitioner) field trial data ( storage stability data validating the relevant intervals should also be submitted)

Stone Fruit Label Amendment   Section F   storage stability data for hops ( 175 days; 7 day interval from homogenization to analysis should also be validated)

  grape field trial data ( Region 1 ( n= 1))

  confirmation concerning the identification of D9569 as the major residue in milk ( see page 13)

8.3 Occupational/ Residential Succulent Pea and Tuberous and Corm Vegetable ( crop subgroup 1c) and Stone Fruit Label Amendment   none Attachment 1: Structures RDI: Branch ( 26 July 2006) T. Bloem: S10945: PY1:( 703) 605 0217: 7509P: RAB1 Bifenazate ( 000586) Human Health Risk Assessment D323893 Page 24 of 24 Attachment 1: chemical structures chemical name chemical structure bifenazate ( D2341)

hydrazinecarboxylic acid, 2( 4 methoxy[ 1,1' biphenyl] 3 yl), 1 methylethyl ester O NH N H O CH 3 O CH 3 CH 3 D3598 diazinecarboxylic acid, 2( 4 methoxy[ 1,1' biphenyl] 3 yl), 1 methylethyl ester O N N O CH 3 O CH 3 CH 3 D4642 diazinecarboxylic acid, 2( 4 methoxy[ 1,1' biphenyl] 3 yl), 1 methylethyl ester 2 oxide OCH3 N N O CH 3 O CH 3 OH D9963 4 methoxy[ 1,1' biphenyl] 3 ol OCH3 OH D1989 1,1' biphenyl, 4 methoxy OCH3 D9569 [ 1,1' biphenyl] 4,4' diol OH HO A1530 1,1' biphenyl, 4 ol OH A1530 sulfate OSO3H D9472 OH OH D23 14; biphenyl hydrazine; ( 4 methoxy[ 1,1' biphenyl] 3 yl) hydrazine OCH3 NH NH2


[Federal Register Volume 84, Number 30 (Wednesday, February 13, 2019)]
[Notices]
[Pages 3796-3797]
[FR Doc No: 2019-02139]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-P-3597]

Determination That LOTRIMIN (Clotrimazole) Topical Solution, 1%,
Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or Agency) has
determined that LOTRIMIN (clotrimazole) topical solution, 1%, was not
withdrawn from sale for reasons of safety or effectiveness. This
determination means that FDA will not begin procedures to withdraw
approval of abbreviated new drug applications (ANDAs) that refer to
this drug product, and it will allow FDA to continue to approve ANDAs
that refer to the product as long as they meet relevant legal and
regulatory requirements.

FOR FURTHER INFORMATION CONTACT: Stacy Kane, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 51, Rm. 6236, Silver Spring, MD 20993-0002,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION: In 1984, Congress enacted the Drug Price
Competition and Patent Term Restoration Act of 1984 (Pub. L. 98-417)
(the 1984 amendments), which authorized the approval of duplicate
versions of drug products under an ANDA procedure. ANDA applicants
must, with certain exceptions, show that the drug for which they are
seeking approval contains the same active ingredient in the same
strength and dosage form as the ``listed drug,'' which is a version of
the drug that was previously approved. ANDA applicants do not have to
repeat the extensive clinical testing otherwise necessary to gain
approval of a new drug application (NDA).
    The 1984 amendments include what is now section 505(j)(7) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(7)), which
requires FDA to publish a list of all approved drugs. FDA publishes
this list as part of the ``Approved Drug Products With Therapeutic
Equivalence Evaluations,'' which is known generally as the ``Orange
Book.'' Under FDA regulations, drugs are removed from the list if the
Agency withdraws or suspends approval of the drug's NDA or ANDA for
reasons of safety or effectiveness or if FDA determines that the listed
drug was withdrawn from sale for reasons of safety or effectiveness (21
CFR 314.162).
    A person may petition the Agency to determine, or the Agency may
determine on its own initiative, whether a listed drug was withdrawn
from sale for reasons of safety or effectiveness. This determination
may be made at any time after the drug has been withdrawn from sale but
must be made prior to approving an ANDA that refers to the listed drug
(Sec.  314.161 (21 CFR 314.161)). FDA may not approve an ANDA that does
not refer to a listed drug.
    LOTRIMIN (clotrimazole) topical solution, 1%, is the subject of NDA
017613, held by Schering-Plough Healthcare Products Inc., and initially
approved on February 3, 1975. LOTRIMIN is indicated for the topical
treatment of candidiasis due to Candida albicans and tinea versicolor
due to Malassezia furfur.
    LOTRIMIN (clotrimazole) topical solution, 1%, is currently listed
in the ``Discontinued Drug Product List'' section of the Orange Book.
In a letter dated August 31, 2005, Schering Corporation requested
withdrawal of NDA 017613 for LOTRIMIN (clotrimazole). In the Federal
Register of November 7, 2007 (72 FR 62858), FDA announced that it was
withdrawing approval of NDA 017613, effective December 7, 2007.
    Arent Fox LLP submitted a citizen petition dated September 21, 2018
(Docket No. FDA-2018-P-3597), under 21 CFR 10.30, requesting that the
Agency determine whether LOTRIMIN (clotrimazole) topical solution, 1%,
was withdrawn from sale for reasons of safety or effectiveness.
    After considering the citizen petition and reviewing Agency records
and based on the information we have at this time, FDA has determined
under Sec.  314.161 that LOTRIMIN (clotrimazole) topical solution, 1%,
was not withdrawn for reasons of safety or effectiveness. The
petitioner has identified no data or other information suggesting that
LOTRIMIN (clotrimazole) topical solution, 1%, was withdrawn for reasons
of safety or effectiveness. We have carefully reviewed our files for
records concerning the withdrawal of LOTRIMIN (clotrimazole) topical
solution, 1%, from sale. We have also independently evaluated relevant
literature and data for possible postmarketing adverse events. We have
found no information that would indicate that this drug product was
withdrawn from sale for reasons of safety or effectiveness.
    Accordingly, the Agency will continue to list LOTRIMIN
(clotrimazole) topical solution, 1%, in the ``Discontinued Drug Product
List'' section of the Orange Book. The ``Discontinued Drug Product
List'' delineates, among other items, drug products that have been
discontinued from marketing for reasons other than safety or
effectiveness. FDA will not begin procedures to withdraw approval of
approved ANDAs that refer to this drug product. In addition, FDA will
continue to approve ANDAs for this drug product as long as they meet
all other legal and regulatory requirements for the approval of ANDAs.
If the Agency determines that labeling for this drug product should be
revised to meet

current standards, the Agency will advise ANDA applicants to submit
such labeling.

    Dated: February 8, 2019.
Lowell J. Schiller,
Acting Associate Commissioner for Policy.
[FR Doc. 2019-02139 Filed 2-12-19; 8:45 am]
 BILLING CODE 4164-01-P


[Federal Register: November 25, 2008 (Volume 73, Number 228)]
[Rules and Regulations]
[Page 71526-71527]
[DOCID:fr25no08-3]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 39

[Docket No. FAA-2008-0834; Directorate Identifier 2007-SW-78-AD;
Amendment 39-15746; AD 2008-24-06]
RIN 2120-AA64

Airworthiness Directives; Agusta S.p.A. Model A109A and A109A II
Helicopters

AGENCY: Federal Aviation Administration (FAA), Department of
Transportation (DOT).

ACTION: Final rule.

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SUMMARY: This amendment supersedes an existing airworthiness directive
(AD) for the specified Agusta S.p.A. (Agusta) model helicopters. This
AD results from a revised mandatory continuing airworthiness
information (MCAI) issued by an aviation authority to identify and
correct an unsafe condition on an aviation product. The aviation
authority of Italy, with which we have a bilateral agreement, reports
that the previous MCAI should not apply to newly redesigned and
improved tail rotor blades. This AD requires the same inspections as
the current AD but limits the applicability to only three part-numbered
tail rotor blades. This AD requires actions that are intended to
prevent fatigue failure of a tail rotor blade (blade), loss of a tail
rotor, and subsequent loss of control of the helicopter.

DATES: This AD becomes effective on December 30, 2008.
    The incorporation by reference of certain publications is approved
by the Director of the Federal Register as of December 30, 2008.

ADDRESSES: You may examine the AD docket on the Internet at http://
regulations.gov or in person at the Docket Operations office, U.S.
Department of Transportation, M-30, West Building Ground Floor, Room
W12-140, 1200 New Jersey Avenue, SE., Washington, DC between 9 a.m. and
5 p.m. Monday through Friday, except Federal holidays.
    You may get the service information identified in this AD from
Agusta, Via Giovanni Agusta, 520 21017 Cascina Costa di Samarate (VA),
Italy, telephone 39 0331-229111, fax 39 0331-229605/222595, or at
http://customersupport.agusta.com/technical_advice.php.
    Examining the AD Docket: The AD docket contains the notice of
proposed rulemaking (NPRM), the economic evaluation, any comments
received, and other information. The street address and operating hours
for the Docket Operations office (telephone<PHONE_NUMBER>) are in the
ADDRESSES section of this AD. Comments will be available in the AD
docket shortly after they are received.

FOR FURTHER INFORMATION CONTACT: Sharon Miles, Aviation Safety
Engineer, FAA, Rotorcraft Directorate, Regulations and Guidance Group,
Fort Worth, Texas 76193-0111, telephone<PHONE_NUMBER>, fax (817) 222-
5961.

SUPPLEMENTARY INFORMATION:

Discussion

    We issued an NPRM on July 27, 2008 to amend 14 CFR part 39 to
include a superseding AD that would apply to the specified Agusta model
helicopters. That NPRM was published in the Federal Register on August
6, 2008 (73 FR 45644) and proposed the same inspection requirements as
the current AD. It also proposed to limit the applicability to only
three part-numbered tail rotor blades.
    You may obtain further information by examining the MCAI and any
related service information in the AD docket.

Comments

    By publishing the NPRM, we gave the public an opportunity to
participate in developing this AD. However, we received no comment on
the NPRM or on our determination of the cost to the public. Therefore,
based on our review and evaluation of the available data, we have
determined that air safety and the public interest require adopting the
AD as proposed.

Relevant Service Information

    Agusta has issued Bollettino Tecnico No. 109-110, Revision A, dated
December 12, 2005 (BT). The actions described in the MCAI are intended
to correct the same unsafe condition as that identified in the service
information.

Differences Between This AD and the MCAI

    The MCAI states to comply with the manufacturer's BT. This AD
differs from the incorporated portions of the BT as follows:
    (1) We refer to the compliance time as hours time-in-service rather
than flight hours.
    (2) We do not require you to contact the manufacturer.

Costs of Compliance

    We estimate that this AD will affect about 40 helicopters of U.S.
registry. We also estimate that it will take about 2.5

work-hours to inspect the affected blades of each helicopter at an
average labor rate of $80 per work-hour. The cost of performing the
daily magnifying glass visual inspection is negligible. Based on these
figures, we estimate the cost of this AD on U.S. operators to be
$48,000, assuming 6 dye-penetrant inspections a year, negligible costs
for the magnifying glass inspection, and no cracked blades are found.

Authority for This Rulemaking

    Title 49 of the United States Code specifies the FAA's authority to
issue rules on aviation safety. Subtitle I, section 106, describes the
authority of the FAA Administrator. ``Subtitle VII: Aviation
Programs,'' describes in more detail the scope of the Agency's
authority.
    We are issuing this rulemaking under the authority described in
``Subtitle VII, Part A, Subpart III, Section 44701: General
requirements.'' Under that section, Congress charges the FAA with
promoting safe flight of civil aircraft in air commerce by prescribing
regulations for practices, methods, and procedures the Administrator
finds necessary for safety in air commerce. This regulation is within
the scope of that authority because it addresses an unsafe condition
that is likely to exist or develop on product(s) identified in this
rulemaking action.

Regulatory Findings

    We determined that this AD will not have federalism implications
under Executive Order 13132. This AD will not have a substantial direct
effect on the States, on the relationship between the national
government and the States, or on the distribution of power and
responsibilities among the various levels of government.
    Therefore, I certify this AD:
    1. Is not a ``significant regulatory action'' under Executive Order
12866;
    2. Is not a ``significant rule'' under the DOT Regulatory Policies
and Procedures (44 FR 11034, February 26, 1979); and
    3. Will not have a significant economic impact, positive or
negative, on a substantial number of small entities under the criteria
of the Regulatory Flexibility Act.
    We prepared an economic evaluation of the estimated costs to comply
with this AD and placed it in the AD docket.

List of Subjects in 14 CFR Part 39

    Air transportation, Aircraft, Aviation safety, Incorporation by
reference, Safety.

Adoption of the Amendment

0
Accordingly, under the authority delegated to me by the Administrator,
the FAA amends 14 CFR part 39 as follows:

PART 39--AIRWORTHINESS DIRECTIVES

0
1. The authority citation for part 39 continues to read as follows:

    Authority: 49 U.S.C. 106(g), 40113, 44701.

Sec.  39.13  [Amended]

0
2. The FAA amends Sec.  39.13 by adding the following new AD:

2008-24-06 Agusta S.p.A. Amendment 39-15746; Docket No. FAA-2008-
0834; Directorate Identifier 2008-SW-78-AD.

Effective Date

    (a) This airworthiness directive (AD) becomes effective on
December 30, 2008.

Other Affected ADs

    (b) This AD supersedes AD 99-27-12, Amendment 39-11493, Docket
No. 99-SW-91-AD (65 FR 346, January 5, 2000).

Applicability

    (c) This AD applies to Model A109A and A109A II helicopters,
with a tail rotor blade (blade), part number (P/N) 109-0132-02-11, -
15, and -121, with 400 or more hours time-in-service (TIS),
installed, certificated in any category.

Reason

    (d) Based on the Italian mandatory continued airworthiness
information (MCAI) AD, this action contains the same requirement as
superseded AD 99-27-12 but narrows the applicability from blade, P/N
``109-0132-02-all dash numbers,'' to specific P/Ns ``109-0132-02-11,
-15, and -121.'' Thus, this action does not apply to blades with any
other P/N, including newly designated blade, P/N 109-0132-02-125.
The actions specified by this AD are intended to continue the
requirements to prevent fatigue failure of a blade, loss of a tail
rotor, and subsequent loss of control of the helicopter.

Actions and Compliance

    (e) Required as indicated; unless already done, do the following
actions:
    (1) Before further flight, dye-penetrant inspect each blade for
a crack by following the Compliance Instructions, Part I, of Agusta
S.p.A. Bollettino Tecnico No. 109-110, Revision A, dated December
12, 2005 (BT). Thereafter, at intervals not to exceed 100 hours TIS,
dye-penetrant inspect each blade for a crack by following the
Compliance Instructions, Part III, of the BT. If you find a crack,
replace the cracked blade with an airworthy blade before further
flight.
    (2) Before the first flight each day, visually inspect each
blade for a crack using a 3 to 5 power magnifying glass by following
the Compliance Instructions, Part II, of the BT. If you find a
crack, replace the cracked blade with an airworthy blade before
further flight.

Differences Between This AD and the MCAI

    (f) The MCAI states to comply with the manufacturer's BT. This
AD differs from the incorporated portions of the BT as follows:
    (1) We refer to the compliance time as hours TIS rather than
flight hours.
    (2) We do not require you to contact the manufacturer.

Other Information

    (g) Alternative Methods of Compliance (AMOCs): The Manager,
Safety Management Group, Rotorcraft Directorate, FAA, has the
authority to approve AMOCs for this AD, if requested using the
procedures found in 14 CFR 39.19. Send information to ATTN: Sharon
Miles, Aviation Safety Engineer, Regulations and Guidance Group,
Fort Worth, Texas 76193-0111, telephone<PHONE_NUMBER>, fax (817)
222-5961.

Related Information

    (h) Mandatory Continuing Airworthiness Information (MCAI) ENAC
AD No. 2006-001, Revision 1, dated January 3, 2006, contains related
information.

Air Transport Association of America (ATA) Tracking Code

    (i) Air Transport Association of America (ATA) Code 6410: Main
Rotor Blades.

Material Incorporated by Reference

    (j) You must use the specified portions of Agusta S.p.A.
Bollettino Tecnico No. 109-110, Revision A, dated December 12, 2005,
to do the actions required.
    (1) The Director of the Federal Register approved the
incorporation by reference of this service information under 5
U.S.C. 552(a) and 1 CFR part 51.
    (2) For service information identified in this AD, contact
Agusta, Via Giovanni Agusta, 520 21017 Cascina Costa di Samarate
(VA), Italy, telephone 39 0331-229111, fax 39 0331-229605/222595, or
at http://customersupport.agusta.com/technical_advice.php.
    (3) You may review copies at the FAA, Office of the Regional
Counsel, Southwest Region, 2601 Meacham Blvd., Room 663, Fort Worth,
Texas, or at the National Archives and Records Administration
(NARA). For information on the availability of this material at
NARA, call<PHONE_NUMBER>, or go to: http://www.archives.gov/
federal-register/cfr/ibr-locations.html.

    Issued in Fort Worth, Texas, on November 7, 2008.
Mark R. Schilling,
Acting Manager, Rotorcraft Directorate, Aircraft Certification Service.
[FR Doc. E8-27611 Filed 11-24-08; 8:45 am]

BILLING CODE 4910-13-P