Page 1 of 59 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: 09/ 29/ 2005 MEMORANDUM SUBJECT: Tau fluvalinate: Revised HED Chapter of the Reregistration Eligibility Decision Document ( RED). PC Code: 109302, Case #: 2295, DP Barcode: D321911.

Regulatory Action: Phase 2 Reregistration Action Risk Assessment Type: Single Chemical Aggregate FROM: Susan Stanton, Environmental Scientist Reregistration Branch 3 Health Effects Division ( 7509C)

AND John Doherty, Toxicologist Jose Morales, Chemist Robert Travaglini, Chemist Reregistration Branch 3 Health Effects Division ( 7509C)

THROUGH: Catherine Eiden, Chief Reregistration Branch 3 Health Effects Division ( 7509C)

TO: Kylie Rothwell, Chemical Review Manager Reregistration Branch III SRRD ( 7508C)

The attached risk assessment for tau fluvalinate has been revised to correct errors noted in the registrant's 30 day error comments on EPA's preliminary risk assessment, submitted by Wellmark International on May 31, 2005. Page 2 of 59 Table of Contents 1.0 Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.0 Ingredient Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.1 Summary of Registered/ Proposed Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.2 Structure and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2.3 Physical and Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.0 Metabolism Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.1 Comparative Metabolic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.2 Nature of the Residue in Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.2.1. Description of Primary Crop Metabolism . . . . . . . . . . . . . . . . . . . . . . . 11 3.2.2 Description of Livestock Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation . . . . . . . . . . 12 3.3 Environmental Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.4 Toxicity Profile of Major Metabolites and Degradates . . . . . . . . . . . . . . . . . . . 13 3.5 Summary of Residues for Tolerance Expression and Risk Assessment . . . . . . . . 13 3.5.1 Tabular Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.5.2 Rationale for Inclusion of Metabolites and Degradates . . . . . . . . . . . . . 13 4.0 Hazard Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4.1 Hazard Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4.2 FQPA Hazard Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.2.1 Adequacy of the Toxicity Data Base . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.2.2 Evidence of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.2.3 Developmental Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.2.4 Reproductive Toxicity Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.2.5 Additional Information from Literature Sources . . . . . . . . . . . . . . . . . . 26 4.2.6 Pre and/ or Postnatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 <IP_ADDRESS> Determination of Susceptibility . . . . . . . . . . . . . . . . . . . 26 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility . . . . . . . . . . . . . . . . 26 4.3 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 27 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.3.2 Evidence that supports not requiring Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 <IP_ADDRESS> Rationale for the UF DB ( when a DNT is recommended) . 28 4.4 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . . . . . . . . . . . 28 4.4.1 Acute Reference Dose ( aRfD)  General Population . . . . . . . . . . . . . . . . 29 4.4.2 Acute Reference Dose ( aRfD)  Females age 13 49 . . . . . . . . . . . . . . . . 30 4.4.3 Chronic Reference Dose ( cRfD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Page 3 of 59 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term) . . . . . . . . . . . . 31 4.4.5 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.4.6 Dermal Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . . . 31 4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . 31 4.4.8 Margins of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.4.9 Recommendation for Aggregate Exposure Risk Assessments . . . . . . . . 32 4.4.10 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.5 Special FQPA Safety Factor . . . . . . . . . 33 4.6 Endocrine disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 5.0 Public Health Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.1 Incident Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.2 Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 6.0 Exposure Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 6.1 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 6.1.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 6.1.2 Acute and Chronic Dietary Exposure and Risk . . . . . . . . . . . . . . . . . . . 37 6.2 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . 39 6.3.1 Residential Handler Exposure/ Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 6.3.2 Residential Post Application Exposure/ Risk . . . . . . . . . . . . . . . . . . . . . 40 6.3.3 Other ( Spray Drift, etc.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 7.0 Aggregate Risk Assessments and Risk Characterization . . . . . . . . . . . . . . . . . . . . . 40 7.1 Acute Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.2 Short Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.3 Intermediate Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.4 Long Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.5 Cancer Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 8.0 Cumulative Risk Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 9.0 Occupational Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 9.1 Short/ Intermediate/ Long Term Handler Risk . . . . . . . . . . . . . . . . . . . . . . . . . . 42 9.2 Short/ Intermediate/ Long Term Postapplication Risk . . . . . . . . . . . . . . . . . . . . . 49 10.0 Data Needs and Label Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 10.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 10.2 Residue Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 10.3 Occupational and Residential Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 References: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Page 4 of 59 1.0 Executive Summary The Health Effects Division ( HED) of EPA's Office of Pesticide Programs has evaluated the toxicity and exposure data bases for the pesticide active ingredient tau fluvalinate and has conducted a human health risk assessment in support of the Reregistration Eligibility Decision ( RED) for this active ingredient.

Use Information Tau fluvalinate is an insecticide/ miticide in the pyrethroid class of pesticides. It acts as an axonic poison by interfering with the sodium channels of both the peripheral and central nervous systems, stimulating repetitive nervous discharges, leading to paralysis. It is registered for a single food use ( beehives/ honey) and several non food uses, including ornamentals ( outdoor and containergrown greenhouse, interior plantscapes, dip for cuttings), building surfaces/ perimeters, ant mounds and certain crops ( carrots and Brassica/ cole crops) grown for seed. Tau fluvalinate has very limited annual domestic usage, with the majority of this usage in commercial greenhouses and on outdoor field and container grown ornamentals.

Toxicology The available toxicity data on tau fluvalinate are adequate to assess the chemical's hazard potential. Tau fluvalinate is a pyrethroid insecticide of the type II class. It is moderately acutely toxic, having been classified in Toxicity Category II by the oral route of exposure and Category III by the dermal route. It is not a primary irritant to either the eye ( Toxicity Category III) or skin ( Toxicity Category IV) and is not a dermal sensitization agent. The principle systemic effects seen in subchronic and chronic studies include reductions in body weight/ body weight gain ( dogs and rats), liver weight changes ( dogs and rats) and chronic nephritis ( mouse).

Tau fluvalinate is a pyrethroid insecticide that acts on the nervous system in insects. The mammalian studies demonstrate typical clinical signs associated with pyrethroid neurotoxicity, including excessive grooming, bulging eyes, abnormal stance, ruffled fur, hyperactivity, salivation, ataxia, muscle spasms, tremors, gait abnormalities, startle response hyperreaction and more. Some evidence of nerve degeneration was seen at higher doses in the acute neurotoxicity study.

As a type II pyrethroid, tau fluvalinate causes the " pyrethroid reaction", a specific type of dermal irritation following contact. The " pyrethroid reaction" may be one manifestation of the chemical's ability to act on nerve endings. The " pyrethroid reaction" is unlike the primary dermal irritation assessed in acute or subchronic dermal irritation studies. It occurs during animal feeding studies when dermal contact is made with the feed and may result in early termination of such studies for humane reasons due to the severity of skin lesions and subsequent infection. Thus, more definitive subchronic and chronic studies were done by gavage. In humans, the pyrethroid reaction is characterized by tingling sensations and/ or itching, often severe, upon contact with the chemical.

The rat developmental toxicity study did not demonstrate developmental toxicity at the highest dose tested. The rabbit developmental toxicity demonstrated some signs of skeletal variations Page 5 of 59 ( curved tibia and fibula) but at the same dose where maternal toxicity was seen. There were no effects of tau fluvalinate on reproductive performance. The offspring were noted to have tremors in one generation and to have slight body weight decrease in another generation, but these effects occurred at a dose that was also toxic to the parents. There is no quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses after in utero and/ or postnatal exposure to tau fluvalinate in the developmental and reproduction studies. Dose response relationships are well characterized and clear NOAELs/ LOAELs have been identified for the critical effects. Therefore, the special FQPA safety factor can be reduced to 1X, since the degree of concern is low and there are no residual uncertainties for pre and/ or postnatal toxicity.

No evidence of carcinogenicity was seen in mice or rats, and there is no concern for mutagenicity. Tau fluvalinate was negative for mutagenic effects in a battery of tests, including reverse mutation in Salmonella typhimurium, sister chromatid exchange in CHO cells, mouse lymphoma mutagenic assay, mammalian cells in culture transformation assay and unscheduled DNA synthesis in rat hepatocytes.

Residue Chemistry Tau fluvalinate is registered for a single food use in beehives. The available residue chemistry data are adequate to assess human dietary exposure to tau fluvalinate from the consumption of honey from treated hives. The residue of concern in honey for both tolerance enforcement and risk assessment is tau fluvalinate per se. A GC/ ECD method is available for the enforcement of tolerances for residues of tau fluvalinate in honey.

Environmental Fate The available environmental fate data for tau fluvalinate are adequate to assess the residues of concern in drinking water. Tau fluvalinate is highly immobile and practically insoluble in water, indicating a low potential for significant residues in drinking water. None of the major degradates found in environmental fate studies are of toxicological concern. Therefore, the residue of concern in drinking water is tau fluvalinate, per se.

Residential Exposure Although tau fluvalinate is labeled for use in residential areas, a residential exposure assessment was not conducted, since there is little potential for residential exposure from these uses. There are no homeowner applications allowed and, therefore, no potential for residential handler exposure. Also, there are no wide area, broadcast applications of tau fluvalinate in residential areas and, therefore, little potential for post application residential exposure. The current residential uses ( building surfaces/ perimeters and ant mounds) are largely spot applications that are not likely to result in significant post application exposure of adults or children. Page 6 of 59 Aggregate Risk Acute and chronic ( long term) aggregate risk assessments were conducted for tau fluvalinate. These assessments considered dietary ( food + water) exposure only, since the current uses of taufluvalinate are not expected to result in significant residential exposure.

Tier 1acute and chronic dietary exposure analyses using both DEEM FCID   and Lifeline indicate that aggregate exposure to tau fluvalinate from food and drinking water is well below HED's levels of concern for this pesticide. Estimated chronic exposures are less than 1% of the cPAD for the general U. S. population and all population subgroups. Estimated acute exposures are 5% of the aPAD or less for all population subgroups at the 95th percentile of exposure.

Occupational Exposure Inhalation exposure of pesticide handlers is likely during the use of tau fluvalinate in a variety of occupational environments. Since no chemical specific handler exposure data are available for tau fluvalinate, short and intermediate term inhalation exposures were assessed using data from the Pesticide Handlers Exposure Database ( PHED) Version 1.1. PHED data were used with other HED standard values for areas treated per day, body weight and the level of personal protective equipment ( PPE) and engineering controls to assess handler exposures to taufluvalinate Using these assumptions, the calculated occupational handler exposures for all exposure scenarios at all levels of protection, including baseline ( i. e., no respirator), do not exceed HED's level of concern ( i. e., MOEs > 100). Estimated inhalation exposures for handlers wearing respirators, as required by current labels, are well below HED's level of concern ( MOEs > 900). Post application inhalation exposure of workers to tau fluvalinate is expected to be minimal, except in greenhouses, where potential inhalation exposure is mitigated by the ventilation requirements of the Worker Protection Standard.

Dermal exposure to tau fluvalinate is expected to be largely self limiting due to the irritation that occurs on contact with the pesticide as a result of the characteristic " pyrethroid reaction". Therefore, dermal handler and post application exposures were not assessed. HED believes the issue of dermal exposure can be best addressed by labeling to avoid contact with skin and instructions to wash the affected area immediately following contact. Currently approved end use product labels include adequate precautionary labeling.

Conclusions Tau fluvalinate is an insecticide/ miticide with very limited annual domestic usage. Under the conditions of its current use, human health risks to workers handling the pesticide or to the general population, including infants and children, are well below HED's level of concern.

2.0 Ingredient Profile Tau fluvalinate is an insecticide/ miticide in the pyrethroid class of pesticides. It acts as an axonic poison by interfering with the sodium channels of both the peripheral and central nervous systems, stimulating repetitive nervous discharges, leading to paralysis. It is registered for a single food Page 7 of 59 use ( beehives/ honey) and several non food uses, including ornamentals ( outdoor and containergrown greenhouse, interior plantscapes, dip for cuttings), building surfaces/ perimeters, ant mounds and certain crops ( carrots and Brassica/ cole crops) grown for seed.

Tau fluvalinate products are registered in the U. S. to Wellmark International. Currently registered end use formulations include Mavrik Aquaflow ( EPA Reg. No. 2724 478), a flowable formulation containing 2 lbs. tau fluvalinate per gallon, and Zoecon RF 318 Apistan Strip ( EPA Reg. No. 2724 406), an impregnated plastic formulation containing 10.25% tau fluvalinate by weight. Mavrik is registered for use on ornamentals ( outdoor and container grown, greenhouse, interior plantscapes, dip for cuttings), building perimeters and ant mounds; as well as on carrots and Brassica/ cole crops grown for seed under FIFRA § 24 ( c) Special Local Need registrations in California. The Apistan Strip is registered to control varroa mites in beehives.

2.1 Summary of Registered/ Proposed Uses TABLE 2.1 Summary of Registered Uses of Tau fluvalinate Use Site Product Maximum Application Rate Application Method Maximum No. of Applications Greenhouses ( nonfood plants), containerized nursery stock Mavrik Aquaflow 2724 478 10.0 fl. oz. product ( 0.16 lb. a. i.)/ 100 gal./ 20,000 sq. ft. Broadcast, fogger, bench 4/ month Interior plantscapes Mavrik Aquaflow 2724 478 10.0 fl. oz. product ( 0.16 lb. a. i.)/ 100 gal.

0.5 fl. oz./ 5 gal./ 1,000 sq. ft. Broadcast, fogger, bench Not Specified ( NS)

Woody and herbaceous ornamentals, plantscapes Mavrik Aquaflow 2724 478 10.0 fl. oz. product ( 0.16 lb. a. i.)/ 100 gal./ 20,000 sq. ft. Low pressure fan spray ( on base of stem or trunk) 24/ year Flower and foliage cuttings Mavrik Aquaflow 2724 478 5.0 fl. oz. product ( 0.08 lb. a. i.)/ 100 gal. Dipping NS Eugenia and pepper tree Mavrik Aquaflow 2724 478 10.0 fl. oz. product ( 0.16 lb. a. i.)/ 100 gal. Spray 2 at 14 day intervals Building perimeters ( outdoors) Mavrik Aquaflow 2724 478 3 tsp. product/ 5 gal./ 1,000 sq. ft. Low pressure fan spray to edge of structure 4/ month Ant Mound Drench Mavrik Aquaflow 2724 478 10.0 fl. oz. product ( 0.16 lb. a. i.)/ 100 gal.; 1 gal./ mound Drench NS TABLE 2.1 Summary of Registered Uses of Tau fluvalinate Use Site Product Maximum Application Rate Application Method Maximum No. of Applications Page 8 of 59 O O O N H C H 3 CH 3 CN Cl F 3 C SLN 24( c) CA960010: Carrots grown for seed Mavrik Aquaflow 2724 478 9.6 fl. oz. product ( 0.15 lb. a. i.)/ Acre Aerial, ground NS SLN 24( c) CA040022: Brassica/ cole crops grown for seed Mavrik Aquaflow 2724 478 9.6 fl. oz. product ( 0.15 lb. a. i.)/ Acre Aerial, ground NS Beehives Zoecon Apistan Strip RF 318 2724 406 1 strip for each 5 combs of bees or less in each bee chamber Impregnated strip: Placed in empty hives with gloved hands. Leave strip in hive for 6 to 8 weeks. Treat in the spring and fall. 5 strips/ year 2.2 Structure and Nomenclature Tau fluvalinate is an enriched isomer pesticide resulting from the partial purification of racemic fluvalinate. Fluvalinate, as initially synthesized, was a mixture of diasterioisomers. These were not cis/ trans isomers as is the case with some pyrethroids. The chemical structure of fluvalinate contains two chiral centers with two optical positions possible at each. Thus, racemic fluvalinate is a mixture of four optical isomers, designated as R 2R, R 2S, S 2R and S 2S. Only one of these isomers ( S 2R), however, is insecticidally active. In 1980, process changes permitted the synthesis of fluvalinate free of two of the insecticidally inactive isomers, resulting in a compound containing only two of the optical isomers ( one insecticidally active and one inactive) and twice the insecticidal activity of racemic fluvalinate. This enriched isomer form was termed " halfresolved or "(  RS, 2R) fluvalinate".

TABLE 2.2. Tau fluvalinate Nomenclature Chemical Structure Empirical Formula C26H22ClF3N2O3 Common name Tau fluvalinate IUPAC name ( RS)   cyano 3 phenoxybenzyl N( 2 chloro  ,  ,   trifluoro p tolyl) D valinate CAS name cyano( 3 phenoxyphenyl) methyl N[ 2 chloro 4( trifluoromethyl) phenyl] Dvalinate CAS Registry Number 102851 06 9 ( tau fluvalinate) 69409 94 5 ( unresolved fluvalinate) TABLE 2.2. Tau fluvalinate Nomenclature Page 9 of 59 Known Impurities of Concern None Chemical Class Pyrethroid End Use Products ( EPs):

2724 478 Flowable formulation containing 2 lbs. tau fluvalinate per gallon Mavrik Aquaflow 2724 406 Impregnated plastic formulation containing 10.25% tau fluvalinate by weight. Zoecon Apistan Strip RF 318 2.3 Physical and Chemical Properties Tau fluvalinate has low volatility and low water solubility. Based on these characteristics, significant human exposure via the inhalation route or from drinking water would not be expected.

TABLE 2.3. Physicochemical Properties Parameter Value Reference Boiling point 164

C at 0.07 mm Hg D165590, 3/ 4/ 92, F. Toghrol pH Not applicable; tau fluvalinate is practically insoluble in water Density, bulk density, or specific gravity 1.262 g/ mL at 25

C D165590, 3/ 4/ 92, F. Toghrol Water solubility 2.4 ppb at 25

C D272832 and D273228, 3/ 21/ 01, K. Dockter Solvent solubility at 25

C 55.31 g/ 100 mL, methanol 24.05 g/ 100 mL, octanol Miscible at all levels in isooctane, toluene, acetonitrile, 2 propanol, dimethylformamide, and 1 octanol D272832 and D273228, 3/ 21/ 01, K. Dockter D165590, 3/ 4/ 92, F. Toghrol Vapor pressure < 1.0 x 10 5 Pa (< 10 7 torr), 25

C D272832 and D273228, 3/ 21/ 01, K. Dockter Dissociation constant, pKa Not applicable due to the instability of tau fluvalinate under acidic and basic conditions, and its extremely low water solubility. Phase 4 Review, 1/ 16/ 91 Octanol/ water partition coefficient POW > 106, 25

C D272832 and D273228, 3/ 21/ 01, K. Dockter UV/ visible absorption spectrum Not available Page 10 of 59 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile Rat/ Mouse: There are both rat and mouse metabolism studies that demonstrate that taufluvalinate is absorbed and excreted.

In the mouse, approximately 59% and 30% of the applied radioactive dose is excreted into the feces and urine, respectively, after 4 days with most excreted within 24 hours. An anilino metabolite was identified in the urine but several other metabolites were not further characterized.

In the rat metabolism study, approximately 75% of the administered dose was recovered in the excreta 24 hours after dosing following a 1 mg/ kg dose. A higher dose of 200 mg/ kg resulted in only about 45% of the dose being excreted in 24 hours. At the high dose level, the fecal route appeared to be the dominant route of elimination with only about 20% of the dose being recovered in the urine. The parent compound ( 85%) and an anilino acid ( 2%) represented the major composition of the feces. For the 1 mg/ kg dose group, 30 40% of the administered dose was recovered in the urine with elimination half lives of 12 hours for males and 15 hours for females. Several urinary metabolites were identified, with the major urinary metabolites being 3 ( 4' hydroxyphenoxy) benzoic acid and 3 phenoxybenzoic acid ( 3 PBA). A proposed metabolic pathway reflects the hydrolysis and cleavage of the cyano group at the ester linkage, oxidation of the triflouromethyl group and hydroxylation of the phenoxy ring. Specifically, tau fluvalinate is initially biotransformed to 3 phenoxybenzyl alcohol which is then oxidized to 3 phenoxybenzoic acid ( 3 PBA) and 3( 4' hydroxyphenoxy) benzoic acid. Tau fluvalinate is also metabolized to anilino acid which may be hydroxylated and converted to the lactone of anilino acid, or may form haloaniline or diacid ( Memo from W. B. Greer, 8/ 26/ 93, Fluvalinate  Submission of a Rat Metabolism Study in Compliance with Reregistration Requirements with attached DER, approved 8/ 27/ 93).

Plants: The existing plant metabolism studies indicate that tau fluvalinate is metabolized to decarboxy fluvalinate ( minor pathway) or is cleaved to form anilino acid and phenoxybenzyl alcohol ( major pathway), both of which are conjugated to carbohydrates before incorporation into the carbon pool. The major metabolite found in plants was 3 PBA. Other metabolites accounted for less than 10% of the TRR.

Ruminants: In metabolism studies in ruminants most (~ 80%) of the TRR was found in the GI tract ( 50%), urine ( 25%) and feces ( 4.2%), with minor amounts found in milk, kidney, liver, muscle and fat. Tau fluvalinate, per se, comprised 81% and 84% of the TRR in the GI tract and in feces. The major metabolites found in urine were 3 PBA and 3 PBA/ glycine conjugate. Minor metabolites found in ruminant matrices included 4' OH fluvalinate and various PBA conjugates.

Summary: The available metabolism studies indicate that tau fluvalinate is metabolized in a similar way in rodents, plants and ruminants, with unmetabolized parent and 3 PBA ( or its conjugates) comprising the majority of the residue in most matrices. Page 11 of 59 3.2 Nature of the Residue in Foods The registered use of tau fluvalinate in beehives does not involve the direct application of taufluvalinate to honey, but rather the possible transfer of secondary residues from tracking by bees who have been in contact with the insecticide strips containing the pesticide. A beehive metabolism ( i. e., nature of the residue) study was not required for tau fluvalinate. Generally, HED considers all available metabolism data ( e. g., plant, livestock, other arthropods) and environmental fate data ( e. g., hydrolysis studies) in determining the residue of concern in honey from pesticide use in beehives ( Residue Data Requirements for Uses in Beehives, Chem SAC memo, 2/ 25/ 99). Based on the available data for tau fluvalinate, the Team has determined that the residue of concern in honey is tau fluvalinate, per se. The available data are discussed below.

3.2.1. Description of Primary Crop Metabolism Currently, there are no registered uses of tau fluvalinate on plant commodities. Previously registered uses on cotton and coffee have been cancelled and the associated tolerances, including tolerances for secondary residues in animal commodities, have been revoked. Metabolism studies on several crops ( including cotton, corn, tomatoes, lettuce, cabbage, bean, alfalfa and apples) were submitted by the registrant in connection with previously registered/ pending food uses. The studies on cotton, corn, tomatoes, lettuce, cabbage and bean were determined to be unacceptable for various reasons, including inadequate radiolabeling of the test material and/ or the need to further elucidate the unknown and unextractable portions of the TRR ( G. Herndon memo of 2/ 6/ 92). In its review of an IR 4 request to amend the tolerance for coffee, HED concluded that the available plant metabolism studies with alfalfa and apples were adequate to support the registered use of tau fluvalinate on coffee as well as then pending import tolerances for apples, kiwi, and oriental pears ( G. Herndon memo of 2/ 13/ 92 concerning PP# 0F03847). [ Note: The coffee use has been cancelled and the import tolerances are no longer being pursued]. The residue of concern was determined to be fluvalinate, per se. HED noted that an additional plant metabolism study would be required to support the registration of any other uses of fluvalinate ( or tau fluvalinate) on food/ feed crops The available plant metabolism studies indicate that tau fluvalinate is metabolized to decarboxyfluvalinate ( minor pathway) or is cleaved to form anilino acid and phenoxybenzyl alcohol ( major pathway), both of which are conjugated to carbohydrates before incorporation into the carbon pool.

3.2.2 Description of Livestock Metabolism There are currently no registered uses of tau fluvalinate on any livestock feed item. Therefore, data pertaining to the nature of the residue in livestock are not required. However, ruminant and poultry metabolism studies for tau fluvalinate were previously submitted by the registrant in support of the cotton use which has since been cancelled. Based on these studies, HED concluded that the qualitative nature of the residue in animals was adequately understood ( R. Cook memo of 12/ 10/ 90 concerning PP# 0F03347; and W. Cutchin memo of 6/ 16/ 95  Response to Inquiry. Current Status of Fluvalinate. DP Barcode: D209130). The residue of concern in livestock commodities was determined to be tau fluvalinate, per se. Page 12 of 59 Tau fluvalinate is metabolized in ruminant animals the following way: 50 percent in the gastrointestinal tract ( 81% tau fluvalinate); 25 percent in urine ( metabolism of tau fluvalinate to 3 phenoxybenzoic acid ( 3 PBA) followed by conjugation of 3 PBA with glycine); 4.2 percent in feces ( 84% tau fluvalinate); 0.18 percent in milk ( 46% 3 PBA glycine, 33% tau fluvalinate and 6 to 10% 3 PBA glycine bound to unextractable residues); 0.20 percent in kidney ( 6% taufluvalinate 34% 3 PBA, 2% PB alcohol, 18% 3 PBA glycine, 13% 4' OH 3 PBA glycine and 1.3% 3 PBA glucoside); and 0.19 percent in liver ( 48% tau fluvalinate, 3.7% 4' OH fluvalinate, 7.9% 3 PB Aldehyde, 7.8% 3 PBA glycine and 0.7% 3 PBA glucoside). Of the radiolabeled residue found in fat, 39 percent was identified as tau fluvalinate, 15% 3 PB Aldehyde; in muscle 40 percent was tau fluvalinate, 4% 4' OH fluvalinate and 12% 3 PB aldehyde.

3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation Tau fluvalinate is presently not registered for use on any annual crop; therefore, no residue chemistry data are required under these guideline topics.

3.3 Environmental Degradation Tau fluvalinate is highly immobile ( K d values between 853 and 1,708 with corresponding K oc values between 110,000 and 370,000, respectively) and practically insoluble in water ( 2.4 ppb at 25C), indicating a low potential for significant residues in drinking water. Nevertheless, taufluvalinate is registered for outdoor, non food uses ( including carrots and Brassica/ cole crops grown for seed, ornamentals and building perimeters) that could potentially result in residues in surface or ground water.

The major routes of degradation of tau fluvalinate in laboratory studies are by abiotic processes ( photodegradation in water and soil, and pH dependent hydrolysis) and biotic processes under aerobic conditions. Tau fluvalinate is expected to be rapidly degraded in both soil and aquatic environments under aerobic conditions but is expected to be stable under anaerobic conditions. Tau fluvalinate degraded rapidly by aqueous photolysis with a half life of 1 day but was slightly more stable to soil photolysis with a half life of 18 days. Tau fluvalinate degraded in an aerobic soil metabolism study with half lives of 8 and 15 days and had a half life of 63 days in a supplemental terrestrial field dissipation study. In an anaerobic aquatic metabolism study taufluvalinate degraded with half lives of 255 and 413 days in the whole system.

In water, the major degradates of tau fluvalinate seen in environmental studies were 3 Phenoxybenzaldehyde ( 3 PB Aldehyde), 2( 2 Chloro 4 carboxyl) anilino 3 methylbutanoic acid, 2[ 4 Carboxyl 2( chloro) anilino] 3 methylbutanoic acid ( Diacid), 2( 2 Chloro 4 trifluoromethyl) anilino 3 methylbutanoic acid, 2[ 2 Chloro 4( trifluoromethyl) anilino] 3 methylbutanoic acid ( Anilino acid), 2 Chloro 4 trifluoromethylaniline ( Haloaniline), and Cyanohydrin. In addition, 4 amino 3 chlorobenzoic acid and carbon dioxide were found as minor degradates in various studies.

3.4 Toxicity Profile of Major Metabolites and Degradates Page 13 of 59 Toxicology data for the major metabolite of tau fluvalinate, 3 PBA, indicate that this compound and its conjugates are not of toxicological concern. Specific data are not available for other metabolites; however, the major plant and animal metabolites are also metabolites in the rat, and, therefore, their toxicity was assessed when the parent was studied. In addition, none of the major plant or animal metabolites contains the intact ester linkage responsible for the neurotoxicity of tau fluvalinate.

3.5 Summary of Residues for Tolerance Expression and Risk Assessment 3.5.1 Tabular Summary Table 3.5. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Honey Parent Tau Fluvalinate Parent Tau Fluvalinate Rotational Crop N/ A Livestock Ruminant Poultry Drinking Water Parent Tau Fluvalinate Not Applicable 3.5.2 Rationale for Inclusion of Metabolites and Degradates The risk assessment team concluded that the residue of concern for risk assessment purposes in all commodities and drinking water consists of parent tau fluvalinate only. The team based its decision on the following evidence: ( 1) The major metabolite in plants and animals, 3 phenoxybenzoic acid ( 3 PBA), and its conjugates are not of concern based on toxicology data for PBA; ( 2) the major plant and animal metabolites are also metabolites in the rat, and, therefore, their toxicity was assessed when the parent was studied; and ( 3) none of the major plant or animal metabolites contains the intact ester linkage responsible for the neurotoxicity of tau fluvalinate.

The team's decision is consistent with HED's earlier determination regarding the toxicological significance of tau fluvalinate metabolites ( PP# 6G3401/ FAP# 6H5501  Fluvalinate on Various Fruits and Vegetable Crops  Response to Residue Chemistry Branch's Memorandum Dated August 21, 1986 Concerning the Toxicological Significance of Various Animal and Plant Metabolites; W. Greear; 3/ 7/ 87). In the 1987 memo, HED concluded that none of the major plant or animal metabolites of tau fluvalinate were of toxicological concern.

4.0 Hazard Characterization/ Assessment 4.1 Hazard Characterization Page 14 of 59 Tau fluvalinate is a pyrethroid insecticide of the type II class. Tau fluvalinate is moderately acutely toxic, being classified in Toxicity Category II for oral toxicity and Category III for dermal toxicity. Tau fluvalinate is not a primary irritant to either the eye ( Toxicity Category III) or skin ( Toxicity Category IV) and is not a dermal sensitization agent.

As a type II pyrethroid, tau fluvalinate causes the " pyrethroid reaction", a specific type of dermal irritation following contact. The " pyrethroid reaction" is unlike the primary dermal irritation assessed in acute or subchronic dermal irritation studies. The " pyrethroid reaction" occurs during feeding studies when dermal contact is made with the feed. The rats or mice develop skin lesions that can potentially become infected to such a degree that the animals need to be sacrificed for humane reasons. The " pyrethroid reaction" can limit the dose levels and duration of exposure to confound subchronic and particularly chronic exposure studies when dosing is by incorporation of the test material into the feed. A study in rats was conducted to establish that the dermal reactions do not come when tau fluvalinate is dosed by gavage and result from dermal contact with either the feed or the feces or emesis ( for dogs). Thus, more definitive subchronic and chronic studies were done by gavage.

Subchronic and chronic oral systemic toxicity. In dogs, systemic responses to treatment by gavage were limited to body weight decreases and liver weight increases as well as emesis and salivation. In the rat subchronic study, body weight and liver weight were established as systemic effects of treatment. In the chronic rat study, body weight decrease was the main response to treatment. In the mouse carcinogenicity study, no effects on body weight were noted, but the LOAEL was based on chronic nephritis. Clinical signs of pyrethroid toxicity were noted in the subchronic and chronic studies.

Subchronic dermal toxicity. A 21 day dermal toxicity study in rabbits demonstrated skin lesions at 100 to1000 mg/ kg/ day that may be related to secondary effects of the " pyrethroid reaction". In addition, there were systemic effects at 500 mg/ kg/ day and above, including decreased food consumption and body weight effects.

Subchronic inhalation toxicity. There is no study that assesses subchronic inhalation toxicity. Tau fluvalinate may have a special problem with regard to the unknown consequences resulting from the property of this chemical to cause the " pyrethroid reaction" once the respiratory tract is exposed to the chemical. In particular, persons with asthma and emphysema may be especially sensitive. Prevention of possible respiratory hazard associated with the " pyrethroid reaction" should be accomplished by requiring the use of respirators for those product uses where spray mists or other potentially respirable atmospheres containing tau fluvalinate occur.

Developmental and reproductive toxicity. The rat developmental toxicity study did not demonstrate developmental toxicity at the highest dose tested. The rabbit developmental toxicity demonstrated some signs of skeletal variations ( curved tibia and fibula) but at the same dose where there was maternal toxicity. There were no effects of tau fluvalinate on reproductive performance. The offspring were noted to have tremors in one generation and to have slight body weight decrease in another generation, but these effects occurred at a dose that was also toxic to the parents. Page 15 of 59 Neurotoxicity. Tau fluvalinate is a pyrethroid insecticide that acts on the Na conductance channel in both peripheral and central nervous systems. The " pyrethroid reaction" may be considered to be one manifestation of the ability of this chemical to act on nerve endings and cause its characteristic tingling sensations. The non guideline " acute" neurotoxicity study with 7 daily doses in males only resulted in several clinical signs related to nerve stimulation, and there was evidence of nerve fiber degeneration. The subchronic neurotoxicity study did not reveal nerve fiber degeneration but demonstrated excessive grooming and bulging eyes, signs of either nerve stimulation or agitation.

Carcinogenicity. Tau fluvalinate is not considered a likely human carcinogen since neither the rat nor the mouse carcinogenicity studies were determined to demonstrate a positive response for increased tumors.

Mutagenicity. There is no mutagenicity concern. Tau fluvalinate was not shown to be mutagenic or to have genetic toxicity in several studies including the Salmonella strains ( Ames test), sister chromatid exchange, chromosome aberrations in rats and unscheduled DNA synthesis.

Metabolism. There are both rat and mouse metabolism studies that demonstrate that taufluvalinate is absorbed and excreted. In the mouse, approximately 59% and 30% of the applied radioactive dose is excreted into the feces and urine, respectively, after 4 days, with most excreted within 24 hours. An anilino metabolite was identified in the urine but several other metabolites were not further characterized. In the rat, approximately 75% of the administered dose was recovered in the excreta 24 hours after dosing at a 1 mg/ kg dose. A higher dose of 200 mg/ kg resulted in only about 45% of the dose being excreted in 24 hours. At the high dose level, the fecal route appeared to be the dominant route of elimination with only about 20% of the dose being recovered in the urine. The parent compound ( 85%) and an anilino acid ( 2%) represented the major composition of the feces. For the 1 mg/ kg dose group, 30 40% of the administered dose was recovered in the urine with elimination half lives of 12 hours for males and 15 hours for females. Several urinary metabolites were identified, with the major urinary metabolites being 3 ( 4' hydroxyphenoxy) benzoic acid and 3 phenoxybenzoic acid.

Dermal absorption. There is no acceptable guideline study that demonstrates a dermal absorption factor. There is one study ( Accession No.: 250142, classified as unacceptable/ guideline, not ungradable) that demonstrated that only 4% of the applied dose was absorbed in a single male rat. Comparison of the LOAEL of 125 mg/ kg/ day ( based on " anorexia and general depression") from the rabbit developmental toxicity study with the LOAEL of 500 mg/ kg/ day ( based on systemic response of decreased food consumption) from the 21 day dermal toxicity study would suggest that a dermal absorption factor of 25% ( 125 mg/ kg/ day ÷ 500 mg/ kg/ day x 100) would be appropriate.

Endocrine disruption. There were no indications based on the animal studies submitted for registration purposes that indicate that tau fluvalinate affects either the estrogen, androgen or thyroid or other hormone systems. Page 16 of 59 Table 4.1a Acute Toxicity Profile  Tau fluvalinate Guideline No. Study Type MRID( s) ( Year) Results Toxicity Category 870.1100 Acute oral  rat 0094103 LD50 = 282 ( 218 365) mg/ kg  males 261 ( 194 353) mg/ kg  females. II 870.1200 Acute dermal  rabbit 41597301 ( 1998) LD50 > 2000 mg/ kg III 870.1300 Acute inhalation  rat  Not applicable ( 1).

870.2400 Acute eye irritation  rabbit 00144622 ( 1984) Slight conjunctival discharge observed one hour post instillation. Conjunctival swelling and redness noted for up to three days. III 870.2500 Acute dermal irritation  rabbit 00144623 ( 1984) PII = 0.8 IV 870.2600 Skin sensitization  guinea pig 41889714 ( 1990) Not a sensitizer. Not applicable ( 1)  The vapor pressure of technical tau fluvalinate is < 1 x 10  7 torr at 25

C ( i. e. is a viscous liquid). Refer to B. Greear memo dated 01/ 10/ 91.

Table 4.1b Subchronic, Chronic and Other Toxicity Profile  Tau fluvalinate Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3100 90 Day oral toxicity  rat. International Research and Development, Study # 322 047, 9/ 24/ 81 00094109 ( 1981) 92069032 ( 1990) Acceptable/ Guideline 0, 0.3, 1, 3, 30 or 50 mg/ kg/ day. ( Technical  " half resolved") Systemic: NOAEL = 3 mg/ kg/ day LOAEL = 30 mg/ kg/ day based on enlarged lymph nodes, deceased Hb, Hct and RBC counts and increased organ and ratio weights. Dermal (" pyrethroid reaction"): NOAEL = 1 mg/ kg/ day LOAEL = 3 mg/ kg/ day based on skin lesions.

870.3100 ( b) 90 day oral toxicity  mouse. Litton Bionetics, Inc., Study No.: 22088, 11/ 1/ 81 00094113 ( 1981) Supplementary 0, 1, 3, 30, 50 or 100 mg/ kg/ day. ( Technical " half resolved"). NOAEL  could not be established due to the " pyrethroid reaction"  skin lesions, with their sequella ( increased WBC counts, enlarged lymph nodes, infected eyes, and splenic changes) in all dosed groups. At higher doses decreased body weight and other blood effects and ovary weight and ovary cysts. Table 4.1b Subchronic, Chronic and Other Toxicity Profile  Tau fluvalinate Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 17 of 59 870.3200 21/ 28 Day dermal toxicity  rabbit Elars BioResearch Lab, Inc, Study No.: 1675 P, October 10, 1981. 00094115 ( 1981) 92069034 ( 1990) Acceptable/ Guideline Systemic: NOAEL = 100 mg/ kg/ day LOAEL = 500 mg/ kg/ day based on decreased food consumption. Dermal: ( site of application) Minimal effects at 100 mg/ kg/ day. Indications of " pyrethroid reaction at higher doses ( biting and scarring).

Non Guideline 90 Day dermal toxicity  rat. IRDC, Study No.: 322049 322058, Jan 1, 1982. 00126175 ( 1982). 249604 ( 1982) " Minimum" ( Non Guideline) Study summary does not give a NOAEL or LOAEL but discusses mechanism of skin lesion development. States that the dermal exposure, and not oral exposure, results in " pyrethroid reaction". Study is not appropriate for dermal exposure endpoint.

870.3465 90 Day inhalation toxicity No study available.

870.3700a Prenatal developmental  rats Argus Research Labs, Study No.: 1819 011, 2/ 6/ 98. 44743301 ( 1998) Acceptable/ Guideline. 0, 5, 10 or 15 mg/ kg/ day. Maternal NOAEL = 5 mg/ kg/ day LOAEL = 10 mg/ kg/ day based on decreased body weight and food consumption. Developmental NOAEL =  15 mg/ kg/ day. No effects seen at highest dose tested.

870.3700b Prenatal developmental  rabbits Hazleton Laboratories, Study No.: 777 137, 12/ 23/ 81 0094112 ( 1981) 92069038 ( 1990) Acceptable/ Guideline 0, 5, 25 or 125 mg/ kg/ day. Maternal NOAEL = 25 mg/ kg/ day LOAEL = 125 mg/ kg/ day based on anorexia and general depression. Developmental NOAEL = 25 mg/ kg/ day LOAEL = 125 mg/ kg/ day based on skeletal anomalies, curved tibia and fibula.

870.3800 Reproduction and fertility effects  rats Huntingdon Research Center, Study No.; MCI 56/ 8694, 7/ 2/ 86. 44596601 ( 1986) Acceptable/ Guideline 0/ 0, 0.76/ 0.84, 1.90/ 2.08 or 9.53/ 10.51 mg/ kg/ day for males/ females. Parental/ Systemic NOAEL = 1.90/ 2.08 mg/ kg/ day LOAEL = 9.53/ 10.51 mg/ kg/ day based on clinical signs ( skin ulcerations.). Reproductive: LOAEL > 9.53/ kg/ day Offspring: NOAEL = 1.90/ 2.08 mg/ kg/ day LOAEL = 9.53/ 10.51 mg/ kg/ day based on tremors during lactation in both litters, decrease in pup weight in F2 generation ( 12%, p < 0.05) and slightly lower litter size.

870.4100a Chronic toxicity  rat Refer to 870.4300 combined chronic feeding/ carcinogenicity study. Table 4.1b Subchronic, Chronic and Other Toxicity Profile  Tau fluvalinate Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 18 of 59 870.4100b Chronic toxicity ( dog) Covance Laboratory, Study No.: 6398 117, 12/ 17/ 98. 44743201 ( 1998) Acceptable/ Guideline 0, 3, 12 and 50 mg/ kg/ day. NOAEL = 3 mg/ kg/ day LOAEL = 12 mg/ kg/ day based on decreased body weight and body weight gain and increased liver weight in females.

870.4200. Carcinogenicity  mouse. International Research and Development, Study No.: 322 048, 1/ 12/ 84. 00094889 ( 1981) 00128336 ( 1983) 00144628 ( 1984) 92069036 ( 1990) Acceptable/ Guideline for carcinogenicity, Supplementary ( Acceptable/ Non Guideline) for chronic feeding. 0, 2, 10 or 20 mg/ kg/ day. Dermal: NOAEL = 2 mg/ kg/ day LOAEL = 10 mg/ kg/ day based on dermal lesions. Systemic: NOAEL = 10 mg/ kg/ day LOAEL = 20 mg/ kg/ day based on chronic nephritis.

No evidence of carcinogenicity.

870.4300. Combined chronic feeding/ carcinogenicity  rats. International Research and Development, Study No.: 322 053, 8/ 27/ 84. 00128334 ( 1983) 00128335 ( 1982)

92069048 ( 1990) Acceptable/ Guideline 0, 0.25, 0.5 1, 2.5, 10 and 20 ( 10 and 20 for 17 weeks only) mg/ kg/ day. NOAEL = 0.5 mg/ kg/ day LOAEL = 1.0 mg/ kg/ day based on clinical signs of neurotoxicity ( abnormal stance, ruffling and transient hyperactivity, followed by hypoactivity in males and females) ( see section 4.4)

No evidence of carcinogenicity.

Gene Mutation 870.5100. Reverse mutation in salmonella T. Litton Bionetics, Study No.: 20988, October 20, 1980. 00094116 ( 1980) Acceptable. 1 to 10,000  g/ plate.. With or without metabolic activation. ( Fluvalinate) No evidence of mutagenic response.

Cytogenetics 870.5375. Sister chromatid exchange in CHO cells. Microbiological Associates, Study No.: T2258.334001, March 1, 1984. 00144626 ( 1984) Acceptable. 250 to 2000 nL/ mL ( Half resolved) No evidence of doubling of sister chromatid exchanges or changes in the sister chromatid frequency in presence or absence of metabolic activation. Table 4.1b Subchronic, Chronic and Other Toxicity Profile  Tau fluvalinate Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 19 of 59 Cytogenetics. 870. 5300. Mouse lymphoma mutagenic assay. Microbiological Associates, Study No.: 2258.701, March 2, 1984. 00144625 ( 1984) Acceptable. 0.013 to 1  L/ mL without activation and 0.0027 to 0.2  l/ mL with metabolic activation. ( Half resolved) No evidence of mutagenic activity in presence or absence of metabolic activation.

870.5300. Mammalian cells in culture transformation assay in mouse fibroblast. Litton Bionetics. Study No.: 20992, 11/ 18/ 80. 00094117 ( 1980) 00094118 ( 1980) Acceptable/ Nonguideline No evidence of transformation with or without metabolic activation.

Other Effects 870. 5550. Unscheduled DNA synthesis in rat hepatocytes. Microbiological Associates. Study No.: T2258.380, March 2, 1984. 00145614 ( 1984) Acceptable 0, 5, 10, 50 100 or 500 nl/ mL. ( Half resolved). No indication of induction of unscheduled DNA repair.

870.6200a Acute neurotoxicity screening battery 43433901 ( 1994) Acceptable/ Non Guideline.* 0, 10 , 60 or 100 mg/ kg * Upgraded in RED development Study does not follow 870.6200 guidelines: Females not included, motor activity not assessed and used multiple ( 7 day) dosing.

NOAEL = 10 mg/ kg/ day LOAEL = 60 mg/ kg/ day based on body weight decreases, clinical signs of neurotoxicity and sciatic nerve pathology.

870.6200b Subchronic neurotoxicity screening battery  rat Ricera, Inc. Study No.: 2504, 6/ 23/ 99. 44900601 ( 1999) Acceptable/ Guideline* 0, 2, 8 or 32 mg/ kg/ day.

* Upgraded in RED development NOAEL = Not established. LOAEL < 2 mg/ kg/ day based on clinical signs including excessive grooming in both sexes and bulging eyes in females.

* A study does not have to demonstrate a NOAEL to be classified as Acceptable/ Guideline.

870.6300 Developmental neurotoxicity No study available. Table 4.1b Subchronic, Chronic and Other Toxicity Profile  Tau fluvalinate Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 20 of 59 870.7485 Metabolism and pharmacokineticsrat Sandoz Agro, Inc. Study No.: 480605, Report No.: 13, 5/ 20/ 1992.

870.7485, Metabolism  mice. Zoecon Corp. Study No.: 3760 2 02 84, February 21, 1984. 43214101 ( 1993) 42322301 ( 1992)  rat study Acceptable/ Guideline.

072918 ( 1984)  mouse study Acceptable/ Non Guideline. There are both rat and mouse metabolism studies that demonstrate that tau fluvalinate is absorbed and excreted. In the mouse, approximately 59% and 30% of the applied radioactive dose is excreted into the urine and feces, respectively, after 4 days, with most excreted within 24 hours. An anilino metabolite was identified in the urine but several other metabolites were not further characterized. In the rat, approximately 75% of the administered dose was recovered in the excreta 24 hours after dosing at 1 mg/ kg body weight. A higher dose of 200 mg/ kg resulted in only about 45% of the dose being excreted in 24 hours. At the high dose level, the fecal route appeared to be the dominant route of elimination with only about 20% of the dose being recovered in the urine. The parent compound ( 85%) and an anilino acid ( 2%) represented the major composition of the feces. For the 1 mg/ kg dose group, 30 40% of the administered dose was recovered in the urine with elimination half lives of 12 hours for males and 15 hours for females. Several urinary metabolites were identified, with the major urinary metabolites being 3( 4' hydroxyphenoxy) benzoic acid and 3 phenoxybenzoic acid.

870.7600 Dermal penetration ( rat) MRID No.: 00126180 Unacceptable/ Guideline Single dose Approximately 4% of the dose applied to a single male rat was demonstrated to be absorbed with the resulting radioactivity being found in the feces as metabolites.

Special studies Special 90 day dermal study to investigate mechanism of dermal lesions ( see above under MRID No. 00126175).

4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base The toxicology database is adequate for the evaluation of risks to infants and children. Relevant studies include rat and rabbit developmental toxicity studies, a rat multi generation reproduction study and chronic/ carcinogenicity feeding studies in mice and rats. In addition, acceptable shortterm ( non guideline) and subchronic ( guideline) neurotoxicity studies are adequate to evaluate the neurotoxicity of tau fluvalinate. There is no developmental neurotoxicity study available in the database.

4.2.2 Evidence of Neurotoxicity Tau fluvalinate is a pyrethroid insecticide that acts on the nervous system in insects. The mammalian studies demonstrate typical clinical signs associated with pyrethroid neurotoxicity. Some evidence of nerve degeneration was seen at higher doses in the acute neurotoxicity study. Page 21 of 59 Acute Neurotoxicity Study.

In a non guideline special " acute" neurotoxicity study ( 1994, MRID No.: 43433901), 10 male Wistar rats/ dose group received 7 daily gavage doses of 0, 10 or 100 mg/ kg of tau fluvalinate ( 87.1% a. i.) in corn oil ( 10 mL/ kg). Due to severe toxicity, the high dose was discontinued and two additional groups of 10 male rats received 7 daily doses if 0 or 60 mg/ kg. Functional observational battery tests ( FOB) were conducted with clinical examinations pretreatment, on treatment days 1, 2, 4 and 7 and recovery days 7 and 14. Neural tissues were examined microscopically from 5 control and 5 rats treated with 60 mg/ kg after 7 days of treatment and from the remaining control and 60 mg/ kg animals after 14 days of treatment. Motor activity was not quantitated.

At 10 mg/ kg, a single incidence of ruffled fur ( days 2 and 3), salivation ( day 2) and hyperalgesia ( 4/ 10 vs 6/ 20 controls) were noted. Food consumption was 83% of control on days 1 to 4 of treatment. At 60 mg/ kg, significantly decreased food consumption was noted during dosing and recovery ( 86%, 77%, 74%, 84%, and 90% of controls on days 4 and 7 and on recovery days 1, 8 and 14, respectively). The food consumption was 31% and 26% of controls on days 1 4 and 4 7, respectively. Clinical/ behavioral effects seen as early as day 1 in all animals treated with 60 mg/ kg but not in controls included salivation, ruffled fur, dyspnea, muscle spasms and sedation. Other observations ( observed in 30 to 90% of the animals) included ataxia, coarse exertions tremor, hunched posture, gait abnormalities, serous reddish secretion from the nose, lids half closed, miosis, startle response hyperreaction, reduced grip strength, ( maximum 42.2% compared to controls) and reduced rearing count. Also observed were fear, diarrhea, vibrissa reflex hyperreaction and hyperalgesia. The clinical/ behavioral signs were transient and were not seen at the end of recovery period. Peripheral nerve fiber degeneration was observed in animals treated with 60 mg/ kg. The highest incidence and severity in nerve degeneration was seen in the sciatic nerve ( minimal to moderate lesions in 4 animals with minimal lesions in 2 controls). Following recovery, the incidence and severity of the lesions was decreased. The neurotoxicity LOAEL is 60 mg/ kg, based on clinical signs of toxicity ( observed as early as day 1) and peripheral nerve degeneration in male rats. The neurotoxicity NOAEL is 10 mg/ kg. Note: The slight decrease in food consumption and incidence of ruffled fur and salivation were not included in the NOAEL. It is unlikely that these occurred following a single dose.

This study is classified as ACCEPTABLE/ Non Guideline but does not satisfy the requirement for a series 870 6200 acute neurotoxicity study in the rat. This study is being reclassified from the original classification as SUPPLEMENTARY. The study is not eligible to be upgraded to an acceptable/ guideline 870 6200 study because females were not included, no motor activity assessments were made and the study included multiple daily dosing for 7 daily doses.

Subchronic Neurotoxicity Study.

In a subchronic oral neurotoxicity study ( 1999, MRID 44900601), groups of Wistar rats ( 10 rats/ sex/ group) were administered 0, 2, 8, or 32 mg/ kg/ day of Tau Fluvalinate ( Lot No. 56613870; Batch No. 96026; 88.3% active ingredient) by gavage for 90 days. An additional 5 rats/ sex in the control and high dose groups were maintained without treatment for a 28 day recovery period. Functional observational battery ( FOB) and motor activity ( MA) testing were Page 22 of 59 performed prior to administration, during weeks 1, 4, 8, and 13, and after the recovery period. Body weights and food consumption were recorded weekly for each animal. Neuropathologic examinations were performed on 6 animals from each of the control and high dose groups; brain weights were not obtained.

In the high dose groups, one male and one female were found dead during weeks 1 and 2, respectively intestinal lesions were found in both animals. In addition, one male and one female were sacrificed moribund due to self mutilation during weeks 4 and 8, respectively. Clinical signs of toxicity prior to death in these animals were similar to those described below. During the recovery period, one high dose male was found dead during week 1. Premature sacrifice or death of several other animals was considered incidental to treatment. Ophthalmologic examinations, gross necropsy and neuropathology of surviving animals were unremarkable. Approximately 4 hours post dosing, clinical signs reported weekly throughout the study in the high dose males and females included hunched posture ( 13 and 14), labored breathing ( 14 and 13), digging at cage ( 14 and 14), salivation ( 15 and 15), anogenital staining ( 15 and 15), dried material around the nose and/ or mouth ( 15 and 15), colored material around the eyes ( 13 and 14), lacrimation ( 13 and 14), and rough coat ( 15 and 15). Extremely decreased activity was observed in high dose males and females during the first half of the treatment period, whereas, excessive grooming ( 11 and 14) and bulging eyes ( 13 and 14) were more common in the second half of the treatment period. In addition, self mutilation was observed in 5 males and 6 females in the highdose group. In the mid dose males and females, clinical signs included hunched posture ( 2 and 8), digging ( 4 and 9), salivation ( 5 and 5) and excessive grooming ( 6 and 9). Many of these clinical signs in mid and high dose males and females were still present the following morning. In the low dose males and females, excessive grooming was observed in 5 and 6 animals, respectively, and bulging eyes were observed in 6/ 10 females. None of the control animals showed any of these signs with the exception of bulging eyes in 6/ 15 control females.

No treatment related effects on body weights, body weight gains, food consumption or neurobehavioral assessment were seen in the low and mid dose females or low dose males. High dose males had significantly ( p

0.01) lower body weights and body weight gains compared with the controls throughout the treatment and recovery periods. Absolute body weights of the high dose males were 80% of the control level for week 1 and declined to 67% of the control level by week 13. The most pronounced effect on body weight gain by the high dose males occurred as a weight loss for weeks 1 and 2; thereafter body weight gains were 4 36% of the control level. Absolute body weights and body weight gains of the mid dose males were not statistically different from the controls, however, body weight gains were 86 88% of the control levels for weeks 4 13. Mean absolute body weights of the high dose females were significantly ( p

0.05) less than the controls during weeks 1 3 and 5 ( 90 95% of controls). Body weight gains by the high dose females were significantly ( p

0.05 or 0.01) less than the controls for weeks 1 ( weight loss) and 3 6 ( 67 85% of controls). Food consumption by the high dose males was 49 92% of the control level during weeks 1 10 with statistical significance ( p

0.01) attained during weeks 1 5, 7, and 10. Food consumption by the high dose females was significantly ( p

0.01) less than the controls for weeks 1 and 3 ( 55% and 84%, respectively, of controls). No dose or treatmentrelated effects were noted in any group for fore and hind limb grip strength, landing foot splay, home cage observations, or sensorimotor and reflex responses. During handling, the incidence rate of animals with abnormal fur ( rough coat and piloerection) was increased in the high dose Page 23 of 59 males and females as noted during clinical observations. In the open field, abnormal posture was observed in 7.69 21.43% of high dose males and in 21.43 38.46% of high dose females compared with 0.0% of the controls at weeks 4 13. No other dose or treatment related abnormalities were observed in any group during open field evaluations. Mean distance traveled was significantly ( p

0.05 or 0.01) decreased in high dose males at weeks 1 and 8 to 61% and 73%, respectively, of the control values. For weeks 4 and 13, the distance traveled by the high dose males was slightly less than the controls: 82% and 90%, respectively. The mean distance traveled by the high dose females was significantly ( p

0.05 or 0.01) less than the controls throughout the treatment period ( 57 78% of control value). Correspondingly, mean resting time was significantly ( p

0.05 or 0.01) increased in high dose males and females to 122 129% and 118 135%, respectively, of the control levels. The LOAEL is 2 mg/ kg/ day based on clinical signs of toxicity, excessive grooming in males and females, and bulging eyes in females. The NOAEL is less than 2 mg/ kg/ day.

This study was previously classified as unacceptable/ guideline due to the lack of a NOAEL; however, the lack of a NOAEL does not automatically preclude an acceptable classification, and after reconsideration, the team has upgraded the study to Acceptable/ Guideline. The study satisfies the guideline requirement for a series 870.6200 subchronic neurotoxicity study in rats. In making its decision to upgrade this study, the team considered the results of the study together with the results of the rat chronic feeding study. The two studies taken together were deemed adequate to establish a NOAEL of 0.5 mg/ kg/ day for neurotoxic effects. See section 4.4 for more detailed information on the weight of the evidence approach used to select doses and endpoints for tau fluvalinate.

4.2.3 Developmental Toxicity Studies A. Rat Study.

In a developmental toxicity study ( 1998, MRID 44743301), Tau Fluvalinate ( 88.4% a. i., Lot # 56613870/ 96026) was administered by gavage at 0, 5, 10, or 15 mg/ kg/ day to pregnant Crl: CD ® BR VAF/ Plus ® rats ( 25/ dose) on gestation days ( GDs) 6 19. Dams were sacrificed on GD 20. No animals died during the study.

Decreases ( p

0.05 or 0.01) in body weights and body weight gains were observed in the 10 mg/ kg animals as follows: decreased mean body weights (  5%, GD 20); reduced body weights corrected for gravid uterine weight (  6%); decreased body weight gains (  17%, GDs 15 17); reduced body weight gains for the overall treatment interval (  17%, GDs 6 20) and for the overall study interval (  13%, GDs 0 20); decreased body weight gains corrected for gravid uterine weight for the overall treatment interval (  45%, GDs 6 20) and for the overall study interval (  26%, GDs 0 20). Decreases ( p

0.05 or 0.01) in absolute ( g/ day) and relative ( g/ kg/ day) food consumption were noted in the 10 mg/ kg animals at GDs 6 9 (  10 11%), GDs 15 19 (  11 13%), for the overall treatment interval (  9 10%, GDs 6 20), and for the overall study interval (  6 7%, GDs 0 20). At 15 mg/ kg, clinical observations were limited to increased incidences of chromorhinorrhea ( 14/ 375 possible observations in 8/ 25 animals, p

0.01) and urinestained abdominal fur ( 7/ 375 possible observations in 3/ 25 animals). When compared to concurrent controls, decreases ( p

0.05 or 0.01) in body weights and body weight gains were Page 24 of 59 observed in the 15 mg/ kg animals as follows: decreased mean body weights (  6 8%, GDs 18 20); reduced body weights corrected for gravid uterine weight (  8%); decreased gravid uterine weights (  12%, not statistically significant); decreased body weight gains (  33%, GDs 15 17); reduced body weight gains for the overall treatment interval (  27%, GDs 6 20) and for the overall study interval (  22%, GDs 0 20); decreased body weight gains corrected for gravid uterine weight for the overall treatment interval (  54%, GDs 6 20) and for the overall study interval (  34%, GDs 0 20). Decreases ( p

0.05 or 0.01) in absolute ( g/ day) and relative ( g/ kg/ day) food consumption were noted in the 15 mg/ kg animals beginning at GDs 6 9 and continuing throughout treatment (  8 17%), for the overall treatment interval (  12 15%, GDs 6 20), and for the overall study interval (  7 10%, GDs 0 20). No treatment related gross pathologic findings were noted. The number of corpora lutea, implantations, resorptions, percent males, and pre and postimplantation losses were similar between control and treated groups. The maternal LOAEL is 10 mg/ kg/ day based on decreased body weights, body weight gains, and food consumption. The maternal NOAEL is 5 mg/ kg/ day.

There were no treatment related developmental effects noted at any dose level. The developmental LOAEL was not observed. The developmental NOAEL is

15 mg/ kg/ day.

This developmental toxicity study is classified acceptable ( § 83 3[ a]) and does satisfy the guideline requirement for a developmental toxicity study in the rat.

B. Rabbit study.

In a developmental toxicity study ( 1981, MRID No. 00094112, and 1990, MRID No.: 92069054) Tau fluvalinate technical ( 93.1%, Run 23 R, Batch # 0281028) was administered in a corn oil vehicle by gavage at 0, 5, 25, or 125 mg/ kg/ day to pregnant New Zealand White rabbits ( 17 females/ dose) on gestation days ( GDs) 6 through 18. Dams were sacrificed on GD 29. One highdose female died on Day 16 following signs of labored respiration, cyanosis and depression. The cause of death of this female is not readily apparent but was not considered treatment related. One control animal and one high dose female were both sacrificed near the end of " term" after discovery of signs indicating abortion. No unusual gross pathology was observed in either animal.

Maternal survival was comparable between the control and treated groups. No treatment related findings were noted in the low or mid dose groups. In the high dose group ( 125 mg/ kg/ day), general depression ( 17/ 17) was observed at a greater incidence relative to controls ( 2/ 14). A transient ( statistically significant) mean body weight loss ( 13 14%) was noted for high dose females between Days 6 18. The greater incidences of depression and body weight loss in highdose females are considered compound related. The number of corpora lutea, implantations, resorptions, percent males, and pre and post implantation losses were similar between control and treated groups. The maternal LOAEL is 125 mg/ kg bw/ day, based on general depression and a decrease in body weight. The maternal NOAEL is 25 mg/ kg bw/ day.

No treatment related differences in fetal weights and lengths were observed. Accompanying the maternal toxicity in the high dose group were embryo or fetotoxic effects, higher incidence of resorption ( 40.2% vs. 22.6% in controls), and concurrent lower fetal viability ( 59.8% vs. 76.7% Page 25 of 59 in controls). These effects were not statistically significant, but were large and consistent, and are considered to be related to the administration of compound and a secondary effect of maternal toxicity. The number and incidence of visceral anomalies and variants were not statistically different between groups. The incidence of skeletal anomalies were increased in the high dose group as a result of fetuses in one litter having short and spatulate ribs ( 5 rabbits), short and curved femurs ( 5 rabbits), and a curved tibia and fibula ( 4 rabbits). A total of 10 litters and 55 fetuses were examined at the high dose. The developmental LOAEL is 125 mg/ kg/ day, based on higher incidence of resorption and concurrent lower fetal viability and evidence of skeletal variants. The developmental NOAEL is 25 mg/ kg/ day.

The developmental toxicity study in the rabbit is classified acceptable/ guideline ( 83 3[ a]) and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; OECD 414) in rabbits.

4.2.4 Reproductive Toxicity Study In a 2 generation reproduction study ( 1986, MRID 44596601), tau fluvalinate ( 93.1% a. i.) was continuously administered in the diet to Sprague Dawley rats ( P generation  28/ sex/ dose, 32/ sex/ dose at the high dose; F 1 generation  24/ sex/ dose) at dose levels of 0, 10, 25 or 125 ppm ( equivalent to [ M/ F] 0/ 0, 0.76/ 0.84, 1.90/ 2.08, and 9.53/ 10.51 mg/ kg/ day, respectively). Exposure to P animals began at 6 weeks of age and lasted for 10 weeks prior to mating and throughout mating, gestation, and lactation. F 1 pups selected to produce the F 2 generation were exposed to the same dosage as their parents at post natal day ( PND) 21 and continuously throughout the rest of the study. After approximately 12 weeks of treatment, F 1 offspring were paired to produce the F 2 litters that were necropsied at weaning. Mating to produce a second F 2b generation was not performed.

Systemic toxicity. There were no differences of toxicological concern in body weight, body weight gain, food consumption, female sexual development, reproductive performance, gross pathologic findings, absolute and body weight adjusted organ weights, and histological findings. At 125 ppm, treatment related clinical signs were limited to skin ulceration in P males ( 3/ 32 treated vs 0/ 28 controls), P females ( 1/ 32 treated vs 0/ 28 controls), and F 1 males ( 2/ 24 treated vs 0/ 24 controls). The P female and her litter were severely ulcerated and, therefore, were sacrificed. F 1 dams did not exhibit any treatment related clinical signs. No observations of toxicological significance were made at the mid ( 25 ppm) and low dose ( 10 ppm). The systemic toxicity LOAEL is 125 ppm ( 9.53/ 10.51 [ M/ F] mg/ kg/ day) based on clinical signs ( skin ulceration). The systemic toxicity NOAEL is 25 ppm ( 1.90/ 2.08 [ M/ F] mg/ kg/ day).

Offspring toxicity. There were no differences of toxicological concern in litter size, viability, developmental landmarks, gross pathologic findings, absolute and body weight adjusted organ weights, and histological findings. At 125 ppm, tremors were observed during the lactation period (

LD 14) in the F 1 litters ( 15/ 28 treated litters vs 0/ 28 controls) and F 2 litters ( 6/ 20 treated litters vs 1/ 24 controls). There was a toxicologically significant decrease in F 2 pup weight at PND 21 (  12%, p< 0.05). This decrease in pup weight, combined with a slightly lower litter size, caused a significant decrease (  16%, p< 0.05) in mean litter weight when compared to controls ( 286.9 g treated vs 342.1 g controls). No observations of toxicological significance were made Page 26 of 59 in the 10 or 25 ppm groups. The offspring toxicity LOAEL is 125 ppm ( 9.53/ 10.51 [ M/ F] mg/ kg/ day) based on decreased pup body weights and increased incidence of clinical signs ( tremors). The reproductive toxicity NOAEL is 25 ppm ( 1.90/ 2.08 [ M/ F] mg/ kg/ day).

The reproductive study is determined to be acceptable/ guideline ( § 83 4) and does satisfy the guideline requirement for a multi generational reproductive toxicity study in rats.

4.2.5 Additional Information from Literature Sources A literature search ( PubMed) revealed one paper ( J. Steroid Biochem. 35( 3 4): 409 414 ( 1990)) suggesting that pyrethroids as a class ( including tau fluvalinate) may have endocrine disrupting properties based on inhibition of [ 3H] methyltrienolone binding with human skin fibroblasts androgen receptors. Not all pyrethroids tested, however, were able to displace [ 3H] testosterone from sex hormone binding globulin. Although tau fluvalinate is not mentioned specifically, another publication ( Sheets et al, Toxicolo. Appl. Pharmacol. 126: 186 190 ( 1994)) discusses the inability of the neonatal rats to detoxify pyrethroids.

4.2.6 Pre and/ or Postnatal Toxicity <IP_ADDRESS> Determination of Susceptibility Neither the rat or rabbit developmental toxicity nor the rat multi generation reproduction studies demonstrated increased toxicity to the fetuses or offspring relative to the dams or parental generation, as indicated by the offspring having LOAELs greater than or equal to the parental LOAELs. In particular, the NOAEL and LOAEL for maternal toxicity in the rat developmental toxicity study were 5 and 10 mg/ kg/ day, whereas there was no developmental toxicity at 15 mg/ kg/ day, the highest dose tested. The NOAEL and LOAEL for both the maternal and developmental toxicity for the rabbit developmental toxicity study were 25 and 125 mg/ kg/ day. However, the developmental effects at 125 mg/ kg/ day or signs of lower fetal viability and evidence of skeletal variants were considered to accompany the lower body weight seen in the dams. Similarly, the NOAEL and LOAEL for the systemic effects in the parental groups was the same as the NOAEL and LOAEL for the offspring toxicity in the multi generation reproduction study. The degree of effects in the offspring was not considered severe enough to determine that there is a meaningful concern that the offspring are qualitatively more susceptible than the parents.

Thus, there is no evidence of increased qualitative or quantitative susceptibility of offspring to the toxic effects of tau fluvalinate in the available database.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility The team has concluded that there is a low degree of concern for residual uncertainties for preand post natal susceptibility. There is no evidence of increased susceptibility in the guideline developmental or reproductive studies. The team has selected an endpoint for risk assessment that provides a clear NOAEL for the primary effect of interest, neurotoxicity. It is the most conservative ( lowest) endpoint in the database and will be protective of other effects seen in the Page 27 of 59 database, and any potential effects seen in a DNT study. Further, although tau fluvalinate is a neurotoxicant and there is no developmental neurotoxicity study available, the team has determined that the potential for exposure of mothers, their fetuses and neonates to taufluvalinate is low based on the following:

1) Tau fluvalinate has very limited annual domestic usage, and the majority of this usage is in commercial greenhouses and on outdoor field and container grown ornamentals where pregnant women and babies are unlikely to be exposed.

2) Dietary exposures to tau fluvalinate are anticipated to be very low to insignificant, as the only registered food use of tau fluvalinate is in beehives ( honey). Honey is not used as an ingredient in infant formulas and is not considered an appropriate food for children less than 2 years old. In addition, the low solubility ( 2.4 ppb) of tau fluvalinate limits the likelihood of it getting into drinking water in appreciable quantities. The results of acute and chronic dietary exposure analyses conducted using DEEM FCID and Lifeline software confirm tau fluvalinate's low dietary exposure potential ( See section 6.1.2 below).

3) The potential for residential exposure is very low, based on the low annual usage on residential sites and the fact that there are no broadcast applications allowed in residential areas.

Based on tau fluvalinate's limited use and the low probability of exposure, the team has a low degree of concern for pre and/ or post natal increased sensitivity. Additional information supporting this conclusion, including specific production and usage data, is contained in the Confidential Appendix.

4.3 Recommendation for a Developmental Neurotoxicity Study The RARC met on 02/ 09/ 2005 and considered the factors that both support and do not support requiring a developmental neurotoxicity study as described below. After consideration of these factors as well as the exposure patterns, the RARC agreed that there would not be a sufficient exposure to justify requiring a developmental neurotoxicity study with tau fluvalinate ( Taufluvalinate Proposed Review and Risk Assessment Strategy Report of the Risk Assessment Review Committee ( RARC1), Feb. 9, 2005).

4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study Tau Fluvalinate is a pyrethroid insecticide with known effects on the nervous system in insects. In mammals manifestations of neurotoxicity resulting from interaction with the sodium channel ( and possibly other nerve membrane phenomena) can result. Since the fetus and neonatal mammals have a lower capacity for detoxifying the intact pyrethroid structure, there is a potential for neurotoxicity to result in fetuses if the intact pyrethroid passes the placenta or if intact pyrethroid can be transported to the newborn mammal via lactation. Although residues of intact pyrethroid in infant formula could result in exposure of newborns, there are currently no food uses of tau fluvalinate likely to result in such residues. Honey, the only food on which tau fluvalinate is used, is not a component of infant formula. Page 28 of 59 Tau fluvalinate was shown to cause peripheral nerve histological changes in the non guideline " acute" neurotoxicity study.

Developmental neurotoxicity studies have been requested for most other pyrethroids.

4.3.2 Evidence that supports not requiring Developmental Neurotoxicity study For the reasons described above in section <IP_ADDRESS> ( Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility) the team has determined that the potential for exposure of mothers, their fetuses and neonates to tau fluvalinate is low and not significant enough to justify requiring a developmental neurotoxicity study. Total domestic usage is very limited, and most of this use occurs on non food, non residential sites where exposure of pregnant women and infants would not be expected. Significant dietary exposure is not expected, based on tau fluvalinate's limited usage, low potential to contaminate drinking water and the fact that honey ( the only food use) is not a component of infant formula and not recommended for consumption by children under 2 years of age.

In addition, the conduct of a DNT study with tau fluvalinate would be confounded by the increased sensitivity of the rats to the " pyrethroid reaction". The severity of the dermal irritation that results from this reaction often requires early termination of the study. Such confounding would further affect the assessment of the neonatal pups who may be in dermal contact with the intact test material via proximity to spilled feed. The dams and pups would have to be dosed by gavage in an attempt to circumvent confounding of the study due to the " pyrethroid reaction".

<IP_ADDRESS> Rationale for the UFDB ( when a DNT is recommended)

Not applicable. A DNT study is not recommended.

4.4 Hazard Identification and Toxicity Endpoint Selection Comments about endpoint selection: Based on a weight of evidence approach, a conservative NOAEL for neurotoxic effects has been identified for tau fluvalinate. This approach is based on the results of 2 studies: the rat chronic feeding study and the rat subchronic neurotoxicity study. In the chronic study in the rat, clinical signs of neurotoxicity including: excessive salivation, pawing at bottom of the cage, lacrimation, abnormal stance, ruffling, and transient hyperactivity followed by hypoactivity were observed at 1.0 mg/ kg/ day; these effects were not seen at 0.5 mg/ kg/ day. In the subchronic study in the rat, excessive grooming and bulging eyes were noted in the animals at 2 mg/ kg/ day ( the lowest dose tested). We evaluated these two studies in parallel because the clinical signs of neurotoxicity in the rat chronic study are transient and mentioned in the report but not well documented. However, the team believes that these early onset neurotoxic effects are consistent with the typical clinical signs associated with pyrethroids and are most likely the result of preliminary nerve stimulation and/ or agitation. At the next highest dose tested in the chronic rat study ( 2.5 mg/ kg/ day), the development of tropic ( plantar) ulcers could possibly be indicative of amplified and prolonged nervous system stimulation/ agitation. Furthermore, the results of the 90 day subchronic neurotoxicity study are consistent with the Page 29 of 59 results of the rat chronic feeding study, demonstrating marked evidence of neurotoxicity at a similar low dose. The team believes that the results of these 2 studies taken together form the basis for a clear NOAEL of 0.5 mg/ kg/ day for neurotoxic effects, with minimal effects beginning to be seen at 1.0 mg/ kg/ day in the chronic study, thus establishing a conservative LOAEL. The selection of this LOAEL is further supported by the increasingly severe neurotoxic effects seen at the higher doses of 2 mg/ kg/ day and 2.5 mg/ kg/ day, respectively, in the shorter term subchronic study and longer term chronic feeding study. We believe that this conservative determination is protective for all population subgroups.

4.4.1 Acute Reference Dose ( aRfD)  General Population Studies Selected: Rat Chronic Feeding Study & Subchronic Neurtotoxicity Study in the rat ( See rationale Section 4.4)

MRID No: 92069048 & 44900601 Executive Summaries:

Rat Chronic Feeding Study: In a combined chronic / carcinogenicity study ( 1984, MRID 92069048), tau fluvalinate ( 92.1% a. i, Run 23R, Batch No. 0281028) was administered to Charles Rivers CD rats ( 85/ sex/ dose) by gavage at dose levels of 0, 0.25, 0.50, 1.0, or 2.5 mg/ kg bw/ day for 24 months.

In males and females from groups receiving 1.0 and 2.5 mg/ kg/ day, transient clinical signs of toxicity included excessive salivation and lacrimation, pawing of the bottom and sides of the cage, abnormal stance, ruffling, and transient hyperactivity followed by hypoactivity. These signs were observed during the first 3 hours after dosing and subsided within 6 hours. No treatment related effects on hematology, urinalysis, ophthalmology, clinical chemistry or organ weights were observed in male or female rats at any dose. Mean body weights were significantly decreased ( 13 15%) in females receiving 2.5 mg/ kg/ day. There were no effects of dosing on food consumption. There was an increase in plantar ulcers in females receiving 2.5 mg/ kg/ day when compared to controls. No other treatment related effects on gross or histopathology were observed at any dose. At the doses tested, there were no treatment related increases in tumor incidences in treated animals when compared with controls. The LOAEL is 1.0 mg/ kg/ day, based on abnormal stance, ruffling, and transient hyperactivity followed by hypoactivity in males and females. The NOAEL is 0.50 mg/ kg/ day .

This chronic/ carcinogenicity study in the rat is classified as acceptable/ guideline and satisfies the guideline requirement for a chronic/ carcinogenicity study [ OPPTS 870.4300); OECD 453] in the rat.

Subchronic Neurotoxicity Rat Study  See executive summary of this study in Section 4.2.2 Dose and Endpoint for Risk Assessment: NOAEL = 0.5 mg/ kg/ day based on excessive salivation and lacrimation, pawing of the bottom and sides of the cage, abnormal stance, ruffling, and transient hyperactivity followed by hypoactivity at 1.0 mg/ kg/ day ( LOAEL). Page 30 of 59 Uncertainty Factor( s): 100. Includes a 10X factor for interspecies extrapolation and a 10X factor for intraspecies variation.

Comments about Study/ Endpoint: See explanation above in Section 4.4. On February 9th, 2005, the RARC concurred that the results of the 90 day neurotoxicity study are consistent with the results of the chronic study and that the NOAEL from the rat chronic feeding study should be used for acute, chronic and inhalation endpoints. The acute, short term, intermediate term and long term effects of tau fluvalinate are not cumulative based on the characteristics and nature of typical pyrethroid effects. Furthermore, the RARC concurred that even though tau fluvalinate is a neurotoxicant, the low exposure precludes the need to require a DNT.

Acute RfD = 0.5 mg/ kg/ day ( NOAEL) = 0.005 mg/ kg/ day 100 ( UF)

4.4.2 Acute Reference Dose ( aRfD)  Females age 13 49 The acute RfD for females age 13 49 is the same as for the general population ( see above).

4.4.3 Chronic Reference Dose ( cRfD)

Studies Selected: Same as for acute dietary ( Rat Chronic Feeding Study & Subchronic Neurtotoxicity Studies ( See rationale Section 4.4).

MRID No: 92069048 & 44900601 Executive Summaries: See above.

Dose and Endpoint for Risk Assessment: NOAEL = 0.5 mg/ kg/ day based on excessive salivation and lacrimation, pawing of the bottom and sides of the cage, abnormal stance, ruffling, and transient hyperactivity followed by hypoactivity at 1.0 mg/ kg/ day ( LOAEL).

Uncertainty Factor( s): 100. Includes a 10X factor for interspecies extrapolation and a 10X factor for intraspecies variation.

Comments about Study: See section 4.4.1 Chronic RfD = 0.5 mg/ kg/ day ( NOAEL) = 0.005 mg/ kg/ day 100 ( UF) Page 31 of 59 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term)

Short/ Intermediate term oral endpoints are selected when incidental oral exposure could result from residential, recreational, and institutional pesticide use. Based on the limited usage of taufluvalinate and the nature of the currently registered uses, the potential for incidental oral exposure to tau fluvalinate is very low. Tau fluvalinate is registered for use in residential areas as a perimeter treatment around buildings and as an ant mound drench. Because of the localized nature of these uses, neither would be expected to result in significant incidental oral exposure. There are no broadcast or other wide area uses of tau fluvalinate permitted on residential, recreational or institutional sites. Based on these considerations, the team concluded that an incidental oral exposure endpoint was not required. The RARC concurred with the team's decision ( Tau fluvalinate: Proposed Review and Risk Assessment Strategy Report of the Risk Assessment Review Committee ( RARC1), Feb. 9, 2005)

4.4.5 Dermal Absorption There is no acceptable guideline study that demonstrates a dermal absorption factor. There is one study ( Accession No.: 250142, classified as unacceptable/ guideline, not ungradable) that demonstrated that only 4% of the applied dose was absorbed in a single male rat. Comparison of the LOAEL of 125 mg/ kg/ day ( based on " anorexia and general depression") from the rabbit developmental toxicity study with the LOAEL of 500 mg/ kg/ day ( based on systemic response of decreased food consumption) from the 21 day dermal toxicity study would suggest that a dermal absorption factor of 25% ( 125 mg/ kg/ day ÷ 500 mg/ kg/ day x 100) would be appropriate.

4.4.6 Dermal Exposure ( Short, Intermediate and Long Term)

No toxicity endpoint was selected for dermal exposure to products containing tau fluvalinate. Dermal exposure to products containing tau fluvalinate is expected to be largely self limiting due to the irritation that occurs as a result of the " pyrethroid reaction". The team determined ( and the RARC agreed) that the issue of dermal exposure can be best addressed by labeling to avoid contact with skin and instructions to wash the affected area immediately following contact. Currently approved end use product labels include adequate precautionary labeling.

4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term)

Studies Selected: Same as for acute and chronic dietary ( Rat Chronic Feeding Study & Subchronic Neurtotoxicity Studies ( See rationale Section 4.4).

MRID No: 92069048 & 44900601 Executive Summaries: See above.

Dose and Endpoint for Risk Assessment: NOAEL = 0.5 mg/ kg/ day based on excessive salivation and lacrimation, pawing of the bottom and sides of the cage, abnormal stance, ruffling, and transient hyperactivity followed by hypoactivity at 1.0 mg/ kg/ day ( LOAEL). Page 32 of 59 Comments about Study: See section 4.4.1. There is no subchronic inhalation study with taufluvalinate available for risk assessment. The potential for tau fluvalinate to affect the respiratory system in humans through its ability to cause the " pyrethroid reaction" has not been assessed in animal studies. Even if it were, the most appropriate species for assessing the potential human hazard due to possible respiratory effects may not be the rat, the species commonly used and recommended by the guidelines for subchronic inhalation studies. The potential for taufluvalinate to affect the respiratory system in humans is an important issue because humans with chronic respiratory conditions such as asthma or emphysema may have incidents triggered by exposure to tau fluvalinate. The RARC recommended that label restrictions be such that applicators and workers wear appropriate respirators when applying products that may result in spray mists or other inhalation hazards. Currently approved product labels require adequate protective clothing, including a NIOSH approved respirator for both indoor and outdoor applications.

4.4.8 Margins of Exposure The following margins of exposure ( MOEs) represent HED's level of concern for occupational and residential ( non dietary) exposure risk assessments:

Route of Exposure Occupational MOE ( all durations of exposure) Residential MOE ( all durations of exposure)

Dermal 100 ( this risk assessment is not required) 100 ( this risk assessment is not required)

Incidental Oral 100 ( this risk assessment is not required) 100 ( this risk assessment is not required)

Inhalation 100 100 ( this risk assessment is not required)

For occupational exposure ( all durations) risk assessments, an MOE of 100 is required. The MOE is based on 10x for intraspecies variation and 10x for interspecies extrapolation. For residential exposures, an MOE of 100 is required, and is based on 10x for intraspecies variation, 10x for interspecies extrapolation and a 1x special FQPA factor.

4.4.9 Recommendation for Aggregate Exposure Risk Assessments Exposures resulting from oral and inhalation exposure may be aggregated based on a common toxic endpoint: neurotoxicity. Neither an incidental oral endpoint nor a dermal endpoint was selected for risk assessment, and there is no need to aggregate exposures through these routes with oral ( dietary) and inhalation exposures.

4.4.10 Classification of Carcinogenic Potential Tau fluvalinate was not demonstrated to be carcinogenic in either the rat or mouse carcinogenicity studies, and none of the mutagenicity/ genetic toxicity studies were determined to be positive. Based on lack of carcinogenic effects in the rat and mouse carcinogenicity studies Page 33 of 59 and lack of a mutagenicity concern, tau fluvalinate can be classified as " not likely to be a human carcinogen".

Table 4.4. Summary of Toxicological Doses and Endpoints for Tau fluvalinate for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( females 13 49) No selection. No evidence that there is significant toxicity following a single exposure.

Acute Dietary ( general population) NOAEL = 0.5 mg/ kg/ day. UF = 100 aRfD = 0.005 mg/ kg/ day 1X aPAD = aPAD/ FQPA SF aPAD = 0.005/ 1 = 0.005 mg/ kg/ day LOAEL = 1 mg/ kg/ day. Clinical signs in the rat chronic feeding study coupled with a LOAEL of 2 mg/ kg/ day based on excessive grooming and bulging eyes in the subchronic neurotoxicity study.

Chronic Dietary ( all populations) NOAEL = 0.5 mg/ kg/ day UF = 100 cRfD = 0.005 mg/ kg/ day 1X cPAD = cRfD/ FQPA SF cPAD = 0.005/ 1 = 0.005 mg/ kg/ day LOAEL = 1 mg/ kg/ day. Clinical signs in the rat chronic feeding study coupled with a LOAEL of 2 mg/ kg/ day based on excessive grooming and bulging eyes in the subchronic neurotoxicity study.

Incidental Oral  all durations. No selection since there are no residential, recreational or institutional uses likely to result in incidental oral exposure to tau fluvalinate. As per e mail from K. Rothwell ( February 4, 2005) there is no residential turf use.

Dermal  all intervals No endpoint selection. Dermal exposure should be self limiting because of the dermal reactions resulting from contact with product. The issue of dermal exposure can be best addressed by labeling to avoid contact with skin and instructions to wash the affected area immediately following contact.

Inhalation  all intervals Short Term ( 1  30 days) NOAEL = 0.5 mg/ kg/ day. 1X MOE = 100 LOAEL = 1 mg/ kg/ day. Clinical signs in the rat chronic feeding study coupled with a LOAEL of 2 mg/ kg/ day based on excessive grooming and bulging eyes in the subchronic neurotoxicity study.

Cancer ( oral, dermal, inhalation) Classification: tau fluvalinate has not been reviewed by CARC or HIARC for carcinogenicity classification. However, since no evidence of carcinogenicity was seen in rat and mouse carcinogenicity studies with tau fluvalinate, and the available mutagenicity/ genetic toxicity data base do not indicate a concern, tau fluvalinate may be classified as " not likely to be a human carcinogen".

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable * Refer to Section 4.5 4.5 Special FQPA Safety Factor The team evaluated the potential for increased susceptibility of infants and children from exposure to tau fluvalinate as required by the Food Quality Protection Act ( FQPA) of 1996 according to Page 34 of 59 the 2002 OPP 10x Guidance Document. The team concluded that the special FQPA SF can be removed ( 1X) since there are no/ low concerns and no residual uncertainties for pre and/ or postnatal toxicity based on the following evidence:

° In the developmental rat study, maternal toxicity ( decreased body weight and food consumption) was observed at 10 mg/ kg/ day. However, fetal anomalies were not seen at the highest dose tested ( 15 mg/ kg/ day) indicating that there is no quantitative or qualitative pre and/ or postnatal toxicity resulting from exposure to tau fluvalinate.

° A clear NOAEL/ LOAEL was established for the developmental rabbit study.

° In the 2 generation reproductive study in rats, the fetal anomalies ( tremors during lactation in both litters, decrease in pup weight in F2 generation and slightly lower litter size) were seen only at the highest dose tested ( 9.53/ 10.51 mg/ kg/ day for males/ females), and they were observed in the presence of maternal toxicity ( skin ulcerations). The effects in the offspring, although not also seen in the parents, demonstrated a clear NOAEL and LOAEL and are considered a qualitative increase in susceptibility of low concern.

The tau fluvalinate risk assessment team evaluated the quality of the exposure data; and, based on these data, recommended that the special FQPA SF be reduced to 1X. The recommendation is based on the following:

° The dietary food exposure assessment utilizes tolerance level residues and 100% crop treated information for all commodities. By using these screening level assumptions, chronic exposures/ risks will not be underestimated.

° The dietary drinking water assessment utilizes values generated by models and associated modeling parameters which are designed to provide conservative, health protective, highend estimates of water concentrations.

4.6 Endocrine disruption EPA is required under the 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 recommendations of its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis 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 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). Page 35 of 59 In the available toxicity studies on tau fluvalinate submitted for registration purposes, there was no estrogen, androgen, and/ or thyroid mediated toxicity. When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, taufluvalinate may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

5.0 Public Health Data Reference: Review of Fluvalinate Incident Reports, DP Barcode D300199, Jerome Blondell, 03/ 14/ 2005 5.1 Incident Reports Databases for the OPP Incident Data System ( IDS), Poison Control Centers, the California Department of Pesticide Regulation, the National Pesticide Telecommunications Network ( NPTN) and the National Institute of Occupational Safety and Health's Sentinel Event Notification System for Occupational Risks ( NIOSH SENSOR) were consulted for incident data involving the insecticidal active ingredient tau fluvalinate.

From the available incident data it is apparent that tau fluvalinate exposure can lead to mild or moderate irritation of eyes and skin. Commonly reported systemic effects include headache, nausea and breathing difficulty. Many of the incidents reported in California were related to the pesticide's use in greenhouses. In addition, beekeepers nationwide have reported dermal or other allergic type reactions. In a comparison of Poison Control Centers' data for tau fluvalinate and other pesticides, tau fluvalinate was found to be as likely to cause minor symptoms as other pesticides in the database but much less likely to cause serious effects requiring hospitalization or critical care.

5.2 Other Tau fluvalinate is not included in the Agricultural Health Survey ( AHS) Applicator questionnaire and is not on the current National Health and Nutrition Examination Survey ( NHANES) list.

6.0 Exposure Characterization/ Assessment 6.1 Dietary Exposure/ Risk Pathway 6.1.1 Residue Profile Reference: Tau Fluvalinate. RED  Reregistration Eligibility Decision Document. Residue Chemistry Considerations. Case No. 2295; D300204; J. Morales; 02/ 22/ 05 A tolerance is established at 40 CFR § 180.427 ( a) under the name " Fluvalinate" for " residues of ( alpha RS , 2R) fluvalinate [( RS) alpha cyano 3 phenoxybenzyl ( R) 2[ 2 chloro 4 ( trifluoromethyl) anilino] 3 methylbutanoate" in/ on honey at 0.05 ppm. " Fluvalinate" is the common name for the racemic mixture of the 4 isomers of cyano( 3 phenoxyphenyl) methyl N[ 2 Page 36 of 59 chloro 4( trifluoromethyl) phenyl] valinate ( CAS name). " Tau fluvalinate" is the term for the half resolved mixture ( 2 of the 4 isomers). The tolerance expression should be revised to reflect the correct common name and the CAS name as follows: " Tolerances are established for residues of the insecticide tau fluvalinate [ cyano( 3 phenoxyphenyl) methyl N[ 2 chloro 4 ( trifluoromethyl) phenyl] D valinate] ...".

The nature of the residue in honey is adequately understood. Currently tolerances are expressed in terms of tau fluvalinate, per se. The current tolerance expression is adequate. Adequate data are available to reassess the established tolerance for honey at the same level. However, based on the available data, the established tolerance may be reduced from 0.05 ppm to 0.02 ppm.

A GC/ ECD method is available for the enforcement of tolerances for residues of tau fluvalinate in honey; this method has been forwarded to FDA for publication in PAM Vol. II. This method has a limit of detection of 0.01 ppm.

Acceptable methods are available for enforcement and data collection purposes for both plant and animal commodities. The Pesticide Analytical Manual ( PAM) Volume II lists Method I, a GC method with electron capture detection ( ECD), for the enforcement of tolerances for tau fluvalinate residues of concern in/ on plant and animal commodities. The stated limits of quantitation are 0.01 ppm for plant commodities ( except oil) and animal commodities, and 0.02 ppm for oil. These methods are not currently required to support reregistration of tau fluvalinate, as there are no registered uses on any plant or animal commodities.

The FDA PESTDATA database dated 11/ 01 ( PAM Volume I, Appendix I) indicates that taufluvalinate is completely recovered ( average recovery > 80%) using multiresidue methods Sections 302 ( Luke method; Protocol D) and 303 ( Mills, Onley, Gaither method; Protocol E, nonfatty). Recovery using Section 304 ( Mills Method; Protocol F, fatty food) was variable ( 47 96%).

The reregistration requirements for magnitude of the residue in/ on honey have been satisfied. Residues of tau fluvalinate were below the limit of detection (< 0.01 ppm) in all samples of honey from the brood and super layers, except one, taken 0, 28, 42, and 70 days following placement of 10% Impr strips in beehives; the strips were removed after 42 days, and the honey supers were not removed during treatment. One honey sample from the brood layer bore detectable residues at 0.015 ppm. Residues were also found to be < 0.01 ppm in honey from hives treated at exaggerated rates ( 2 4x) with longer exposure times.

The above data actually represent an exaggerated rate since honey supers remained in place during treatment ( current registration specifies that honey supers be removed during treatment); however, these were the data used to establish the current honey tolerance.

All previously registered uses of tau fluvalinate ( or tau fluvalinate) on food/ feed crops have been canceled. Page 37 of 59 6.1.2 Acute and Chronic Dietary Exposure and Risk Reference: Tau fluvalinate Acute and Chronic Dietary Exposure Assessments for the Reregistration Eligibility Decision; S. Stanton; 03/ 11/ 2005; DP Barcode D300203.

Acute and chronic dietary risk assessments were conducted using the Dietary Exposure Evaluation Model ( DEEM FCID   ) , Version 2.00/ 2.02, and the Lifeline Model Version 2.0, which use food consumption data from the USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998.

Acute Dietary Exposure Results and Characterization The Tier 1 acute analysis assumed 100% crop treated and reassessed tolerance level residues of 0.02 ppm in honey. Drinking water was incorporated directly in the dietary assessment using the 1 in 10 year annual peak concentration for surface water generated by the PRZM EXAMS model ( See Section 6.2, " Water Exposure/ Risk Pathway" for information on the drinking water estimates used in the analysis).

The resulting acute dietary exposure estimates using the DEEM FCID model were less than 6% of the aPAD for the U. S. population and all population subgroups. Tau fluvalinate acute dietary exposure ( food + water) at the 95th percentile was estimated at 0.000069 mg/ kg/ day for the U. S. population ( 1.4% of the aPAD) and 0.000257 mg/ kg/ day ( 5.1% of the aPAD) for the most highly exposed population subgroup ( All Infants). Estimated acute exposures at the 95th percentile using the Lifeline model were consistent with the DEEM FCID results ( 1.2% of the aPAD for the U. S. population and 3.9% of the aPAD for infants).

Nearly all of the estimated acute dietary exposure to tau fluvalinate is from drinking water. Estimated acute dietary exposure to tau fluvalinate from honey represents between < 0.01% and 0.06% ( children, 1 2 yrs. old) of the total estimated exposure.

Chronic Dietary Exposure Results and Characterization The Tier 1 chronic analysis assumed 100% crop treated and reassessed tolerance level residues of 0.02 ppm in honey. Drinking water was incorporated directly in the dietary assessment using the 1 in 10 year annual mean concentration for surface water generated by the PRZM EXAMS model ( See Section 6.2, " Water Exposure/ Risk Pathway" for information on the drinking water estimates used in the analysis).

The resulting chronic dietary exposure estimates using the DEEM FCID model were less than 1% of the cPAD for the U. S. population and all population subgroups. Tau fluvalinate chronic dietary exposure ( food + water) was estimated at 0.000014 mg/ kg/ day for the U. S. population ( 0.3% of the cPAD) and 0.000045 mg/ kg/ day ( 0.9% of the cPAD) for the most highly exposed population subgroup ( All Infants). Estimated chronic exposures using the Lifeline model were consistent with the DEEM FCID results ( 0.2% of the cPAD for the U. S. population and 0.8% of the cPAD for infants). Page 38 of 59 Nearly all of the estimated chronic dietary exposure to tau fluvalinate is from drinking water. Estimated chronic dietary exposure to tau fluvalinate from honey represents < 0.01% of the total estimated exposure for the U. S. population and all population subgroups.

Table 6.1. Summary of Dietary Exposure and Risk for Tau fluvalinate Population Subgroup Acute Dietary ( 95th Percentile) 1 Chronic Dietary DEEM FCID   Lifeline DEEM FCID   Lifeline Dietary Exposure ( mg/ kg) % aPAD Dietary Exposure ( mg/ kg) % aPAD Dietary Exposure ( mg/ kg/ day) % cPAD Dietary Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.000069 1.4 0.000060 1.2 0.000014 < 1 0.000010 < 1 All Infants (< 1 year old) 0.000257 5.1 0.000197 3.9 0.000045 < 1 0.000038 < 1 Children 1 2 years old 0.000109 2.2 0.000126 2.5 0.000021 < 1 0.000020 < 1 Children 3 5 years old 0.000098 2.0 0.000103 2.0 0.000020 < 1 0.000017 < 1 Children 6 12 years old 0.000068 1.4 0.000062 1.2 0.000013 < 1 0.000010 < 1 Youth 13 19 years old 0.000056 1.1 0.000046 < 1.0 0.000010 < 1 0.000007 < 1 Adults 20 49 years old 0.000064 1.3 0.000051 1.0 0.000013 < 1 0.000008 < 1 Adults 50+ years old 0.000058 1.2 0.000051 1.0 0.000014 < 1 0.000009 < 1 Females 13 49 years old 0.000064 1.3 0.000056 1.1 0.000013 < 1 0.000009 < 1 1Acute exposure is reported at the 95th percentile since it was a Tier 1 dietary assessment. Estimated exposures at the 99th and 99.9th percentiles were also well below HED's level of concern, with the highest estimated exposure at the 99.9th percentile ( infants using the DEEM FCID software) representing only 13% of the aPAD.

6.2 Water Exposure/ Risk Pathway Reference: Tier II Estimated Environmental Concentration for the Use of Tau Fluvalinate for Apiary Uses, Carrots for Seed ( 24 C SLNs), Building Perimeters, Nurseries, Ornamentals, Indoor Landscapes and Honey for the Human Health Drinking Water Risk Assessment; Mark Corbin; D304067; 02/ 03/ 2005.

Tau fluvalinate is highly immobile ( K d values between 853 and 1,708 with corresponding K oc values between 110,000 and 370,000, respectively) and practically insoluble in water ( 2.4 ppb at 25C), indicating a low potential for significant residues in drinking water. Nevertheless, tau Page 39 of 59 fluvalinate is registered for outdoor, non food uses ( including carrots and Brassica/ cole crops grown for seed, ornamentals and building perimeters) that could potentially result in residues in surface or ground water.

The estimated drinking water concentrations from surface water sources were calculated using PRZM ( Pesticide Root Zone Model) and EXAMS ( Exposure Analysis Modeling System). Based on the modeling results, the 1 in 10 year annual mean ( chronic, non cancer) concentration in surface water is estimated to be 0.65 ppb. The 1 in 10 year annual peak ( acute) concentration is estimated to be 1.31 ppb. The estimated ground water concentrations were calculated using the Tier I SCI GROW ( Screening Concentration In Ground Water) model. The estimated acute and chronic drinking water concentration from ground water sources is 0.0025 ppb. The higher PRZM EXAMS estimated drinking water concentrations for surface water were used for the acute and chronic dietary analyses. The modeling results are summarized below:

Table 6.2. Summary of Estimated Surface and Ground Water Concentrations for Taufluvalinate

Exposure Duration Tau fluvalinate Surface Water Conc., ppb a Ground Water Conc., ppb b Acute 1.31 0.0025 Chronic ( non cancer) 0.65 0.0025 a From the Tier II PRZM EXAMS  Index Reservoir model. Input parameters are based on multiple ( 12) applications to woody ornamentals in Oregon at the maximum application rate of 0.34 lb. a. i./ A, the upper 90th percentile aerobic soil metabolic half life of 22.2 days, a photolysis half life of 1 day and the average K oc value of 244,000. b From the SCI GROW model assuming 12 applications to woody ornamentals at the maximum use rate of 0.34 lb. ai/ A, the median K oc of 270,000, and the average aerobic soil metabolic halflife of 11.5 days.

6.3 Residential ( Non Occupational) Exposure/ Risk Pathway Although tau fluvalinate is labeled for use in residential areas, a residential exposure assessment was not conducted, since there is little potential for exposure from these uses. Tau fluvalinate may be applied in residential areas to building surfaces/ perimeters and ant mounds by commercial applicators only ( i. e., no homeowner applications are permitted).

° Building surfaces and perimeters: Perimeter applications are made to a band of soil and/ or vegetation 6 to 10 feet wide around and adjacent to the structure. Sites may include vegetation areas, soil, trunks of woody ornamentals and fence lines adjacent to or around the structure. Surface applications are made as crack and crevice treatments to structures such as porches, window and door frames, eaves and foundations.

° Ant mounds: Tau fluvalinate is applied as a drench to individual ant mounds. Page 40 of 59 Page 41 of 59 6.3.1 Residential Handler Exposure/ Risk A residential handler exposure assessment was not conducted, since there are no homeowner uses of tau fluvalinate and, therefore, no potential for such exposure. All applications in residential areas are made by commercial applicators.

6.3.2 Residential Post Application Exposure/ Risk The residential uses of tau fluvalinate are largely spot applications. There are no wide area treatments, such as broadcast applications on home lawns, that would result in significant postapplication exposure of adults or children. Therefore, a residential post application exposure assessment is not required.

6.3.3 Other ( Spray Drift, etc.)

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 the ground application method employed for tau fluvalinate. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and 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.

7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, HED must consider and aggregate ( add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e. g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

For most pesticide active ingredients, water monitoring data are considered inadequate to determine surface and ground water drinking water exposure estimates, so model estimates have been used to estimate residues in drinking water ( EDWCs). In order to determine if aggregate risks are of concern, HED has historically calculated drinking water levels of comparison, or DWLOCs. The DWLOC is the maximum amount of a pesticide in drinking water that would be acceptable in light of combined exposure from food and residential pathways. The calculated DWLOCs were then compared to the EDWCs provided by EFED to determine if a potential concern existed for dietary exposure to residues in drinking water. Page 42 of 59 In order to fully implement the requirements of FQPA, HED and EFED have been working toward refining the screening level DWLOC approach to conducting aggregate risk assessments that combine exposures across all pathways. As part of this process, EFED and HED have agreed that EDWCs can be used directly in dietary exposure assessments to calculate aggregate dietary ( food + water) risk. This is done by using the relevant model value as a residue for drinking water ( all sources) in the dietary exposure assessment. The principal advantage of this approach is that the actual individual body weight and water consumption data from the CSFII are used, rather than assumed weights and consumption for broad age groups. This refinement has been used in estimating the dietary exposure component in the tau fluvalinate aggregate risk assessments.

7.1 Acute Aggregate Risk The acute aggregate risk assessment considered exposures from food and water only, because there are no residential uses expected to contribute to acute exposures for this chemical. Since water exposure was incorporated directly into the DEEM FCID and Lifeline dietary exposure analyses, the acute dietary risk estimates reported in section 6.1.2 represent the total acute aggregate risk for tau fluvalinate. The acute aggregate risk estimates for the U. S. population and all subgroups are < 6% of the aPAD and, therefore, below HED's level of concern.

7.2 Short Term Aggregate Risk There are no residential uses expected to contribute to short term exposures for this chemical, based on its current use patterns. Therefore, a short term aggregate assessment is not required.

7.3 Intermediate Term Aggregate Risk There are no residential uses expected to contribute to intermediate term exposures for this chemical, based on its current use patterns. Therefore, an intermediate term aggregate assessment is not required.

7.4 Long Term Aggregate Risk The long term ( chronic) aggregate risk assessment considered exposures from food and water only, because there are no residential uses expected to contribute to chronic exposures for this chemical. Since water exposure was incorporated directly into the DEEM FCID and Lifeline dietary exposure analyses, the chronic dietary risk estimates reported in section 6.1.2 represent the total chronic aggregate risk for tau fluvalinate. The chronic aggregate risk estimates for the U. S. population and all subgroups are < 1% of the cPAD and, therefore, below HED's level of concern.

7.5 Cancer Risk A cancer aggregate risk assessment is not required, since there was no evidence of carcinogenicity in the toxicology studies submitted for tau fluvalinate. Page 43 of 59 8.0 Cumulative Risk Characterization/ Assessment Tau fluvalinate is a member of the pyrethroid class of pesticides. Although all pyrethroids alter nerve function by modifying the normal biochemistry and physiology of nerve membrane sodium channels, EPA is not currently following a cumulative risk approach based on a common mechanism of toxicity for the pyrethroids. Although all pyrethroids interact with sodium channels, there are multiple types of sodium channels, and it is currently unknown whether they have similar effects on all channels. In addition, we do not have a clear understanding of effects on key downstream neuronal function, e. g., nerve excitability, nor do we understand how these key events interact to produce their compound specific patterns of neurotoxicity. There is ongoing research by both the EPA's Office of Research and Development and the pyrethroid registrants to evaluate the differential biochemical and physiological actions of pyrethroids in mammals. This research is expected to be completed by 2007. When the results of this research are available, the Agency will make a determination of common mechanism of toxicity as a basis for assessing cumulative risk. For information regarding EPA's procedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

9.0 Occupational Exposure/ Risk Pathway Reference: Tau Fluvalinate. Occupational and Residential Exposure Chapter of the Reregistration Eligibility Decision Document ( RED); DP Barcode: D300202; R. Travaglini; 03/ 24/ 05 9.1 Short/ Intermediate/ Long Term Handler Risk Occupational handlers may be exposed through the following routes during mixing, loading and application of tau fluvalinate using aerial, groundboom, high/ low pressure handwand or fogging equipment and during flagging operations for spray applications:

° Dermal: Although dermal exposure is expected, no toxicity endpoint for dermal exposure to tau fluvalinate has been selected. Dermal exposure to tau fluvalinate is expected to be largely self limiting due to the irritation that occurs on contact with the pesticide as a result of the characteristic " pyrethroid reaction"; and HED believes the issue of dermal exposure can be best addressed by labeling to avoid contact with skin and instructions to wash the affected area immediately following contact. Currently approved end use product labels include adequate precautionary labeling and protective equipment requirements ( long sleeved shirt, long pants, chemical resistant gloves, shoes and socks and a NIOSH approved respirator) to mitigate risk from dermal exposure. Therefore, a full dermal exposure assessment was not conducted. However, a screening level assessment was conducted, based on the systemic NOAEL of 100 mg/ kg/ day from the 21/ 28 day dermal toxicity study in rabbits. In this study, minimal irritation effects were seen at the 100 mg/ kg/ day dose with indications of the " pyrethroid reaction" only at the higher doses ( 500 and 2000 mg/ kg/ day). Margins of Exposure ( MOEs) based on this endpoint exceeded 100 for all handler scenarios at the baseline level of protection ( long Page 44 of 59 sleeved shirts and long pants, but no gloves or respirator) and are, therefore, not of concern.

° Inhalation: Even though the volatility of this chemical is low, both short and intermediate term inhalation exposure may occur based on the use patterns for taufluvalinate Long term inhalation exposure is not anticipated. An endpoint for short and intermediate term inhalation exposure has been selected, based on the NOAEL of 0.5 mg/ kg/ day from the rat chronic feeding study. Excessive salivation and lacrimation, pawing of the bottom and sides of the cage, abnormal stance, ruffling, and transient hyperactivity followed by hypoactivity were seen at the LOAEL of 1.0 mg/ kg/ day in this study.

Tau fluvalinate Handler Exposure Scenarios: Pesticide handlers may be exposed to taufluvalinate in a variety of occupational settings based on its currently registered use patterns. These use patterns are summarized below, along with assumptions regarding the daily area or acreage treated by handlers:

Table 9.1a Summary of Tau fluvalinate Use Patterns Crop or Treated Area Max. Application Rate ( lbs ai/ acre; lbs./ gallon) Application Method Application Formulation Daily Area or Acreage Treated1 bee hives 10.25 % a. i./ strip placement impregnated 5 combs carrots/ brassica 0.15 aerial/ ground boom liquid 350/ 80 acres outdoor/ indoor ornamentals 0.0016 lbs ai/ gal. low pressure handwand liquid 40 gal./ day outdoor perimeter treatments ( structures, buildings, etc) 0.0016 lbs ai/ gal high pressure handwand liquid 1000 gal./ day greenhouses 0.0016 lbs ai/ gal high pressure handwand liquid 1000 gal./ day greenhouse fog treatment 0.0016 lbs ai/ gal fogger liquid 1000 gal./ day cut flowers/ cuttings 0.0008 dip liquid 1000 gal./ day ant mounds 0.0016 lbs ai/ gal low pressure handwand liquid 40 gal./ day 1 The daily areas treated were defined for each handler scenario ( in appropriate units) by determining the amount that can be reasonably treated in a single day ( e. g., acres, # or combs or gallons per day). When possible, the assumptions for daily areas treated were taken from the Health Effects Division Science Advisory Committee on Exposure SOP # 9: Standard Values for Daily Acres Treated in Agriculture, completed on July 5, 2000. Page 45 of 59 HED evaluated occupational inhalation exposures for uses on carrots/ brassica, outdoor/ indoor ornamentals, outdoor perimeter treatments ( structures, buildings, etc), greenhouses and ant mounds. HED did not evaluate the remaining uses ( beehives, greenhouse fog treatment and cut flowers/ cuttings), as explained below:

° In the case of the treated strips used in beehives, an outdoor use, HED believes that exposure to the tau fluvalinate impregnated in the strips will be minimal due to its low vapor pressure ( 10  7 Torr).

° In the case of cut flowers/ cuttings, HED feels that the high pressure handwand greenhouse scenario would be a comparable, protective estimate of exposure to tau fluvalinate through this use.

° In the case of greenhouse fog treatments, HED does not have data with which to estimate possible tau fluvalinate exposures through this use. To address these potential exposures, HED is requiring the registrant to submit occupational exposure data for greenhouse exposure scenarios ( OPPTS Guideline 875.2500).

HED identified 8 specific occupational handler exposure scenarios for the selected uses and evaluated each of these for short and intermediate term inhalation exposures to tau fluvalinate:

13. Mix/ load: Liquids to Support Aerial Application on carrots/ brassica, 14. Application: Aerial Spray Application on carrots/ brassica, 15. Application: Groundboom Spray Application on carrots/ brassica, 16. Flagger: To Support Aerial Application on carrots/ brassica, 17. Mix/ load/ application on non agricultural outdoor areas, structures, buildings etc. ( high pressure handwand), 18. Mix/ load/ application for greenhouses ( high pressure handwand), 19. Mix/ load/ application for outdoor ornamentals ( low pressure handwand), and 20. Mix/ load/ application for ant mounds ( low pressure handwand).

Data and Assumptions For Handler Exposure Scenarios:

Because no chemical specific data and/ or studies were submitted for this chemical, PHED V1.1 has been used to assess the exposure scenarios for tau fluvalinate. PHED was designed by a Task Force of representatives from the U. S. EPA, Health Canada, the California Department of Pesticide Regulation and member companies of the Crop Life America ( formerly the American Crop Protection Association). PHED is a software system consisting of two parts  a database of measured exposure values for workers involved in the handling of pesticides under actual field conditions and a set of computer algorithms used to subset and statistically summarize the selected data. Currently, the database contains values for over 1,700 monitored individuals ( i. e., replicates).

The assumptions used in calculating handler exposures and risks are listed below: Page 46 of 59

Application Rates: The application rates are the maximum allowable rates that were identified on the registered product labels for each use assessed in this document.

Acreage Treated: The daily acres treated are HED standard values ( Health Effects Division Science Advisory Committee on Exposure SOP # 9: Standard Values for Daily Acres Treated in Agriculture, completed on July 5, 2000).