### EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: K able Davis, (703) 306

- 0415

Makhteshim

- Agan of North America, Inc. (d/b/a ADAMA)

5 E8362

EPA has received a pesticide petition ( 5 E8362 ) from Makhteshim Agan of North America (d/b/a ADAMA)

, 3120 Highwoods Blvd. , Raleigh, NC 27604 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346 a(d), to amend 40 CFR part 180 by establishi ng a tolerance for residues of tau

- fluvalinate in or on the raw agricultural commodity wine grape at 1.0 parts per million (ppm)

. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) o f the FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant and Livestock metabolism. The qualitative nature of the residue of tau

- fluvalinate in plants is adequately understood based on acceptable plant metabolism studies with alfalfa and apples

. HED had previously concluded (G. Herndon memo of 2/13/92 concerning PP# OF0384 7) that these plant metabolism studies were acceptable. These studies demonstrate that the residue of concern is fluvalinate per se. Fluvalinate is metabolized to decarboxy

- fluvalinate (minor pathway) or is cleaved to forn1 anilino acid and phenoxyb enzyl alcohol (major pathway), each 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. HED noted that an additional p lant metabolism study would be required to support the registration of any other uses of fluvalinate (or tau

- fluvalinate) on food/feed crops. Therefore

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. HED had previously concluded that the qualitative nature of the residue in animals was adequately understood based on the results of acceptable ruminant and poultry metabolism studies ( B. Cutchin memo of 6/16/95 concerning PP#OF0334 7). The residue of concern in livestock commodities was determined to be fluvalinate per se.

2. Analytical method. Acceptable methods are available for enforcement and data collection purposes for both plan t 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

- flu valinate residues of concern in or on plant and animal commodities. Th e stated limits of quantitation are 0.01 ppm for plant commodities (except oil) and animal commodities, and 0.02 ppm for oil. In addition, the FDA multi

- residue methods2

p ublished in the PAM Volume I, section 302 and 303, showed an acceptable recovery (>80% ) for
tau

- fluvalinate.

3. Magnitude of residues. The crop residue studies that have been submitted include 16 field trials in northern and southern regions of Europe. These crop field trial data support the geographic regions that will export tau

- fluvali nate treated grapes and wine. At harvest, residues in grape ranged from 0.01

. to 0.58 mg/kg , which demonstrate that the proposed tolerance for grapes should not be exceeded when tau

- fluvalinate is used according to labeled directions.

B. Toxicological Pr

ofile

1. Acute toxicity. Tau

- fluvalinate 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 II I) or skin (Toxicity Category IV) and is not a dermal sensitization agent. The principle systemic effects observed in sub

- chronic and chronic studies include reductions in body weight/body weight gain (dogs and rats), liver weight changes (dogs and rats) a nd chronic nephritis (mouse).

2. Genotoxicty. No evidence of carcinogenicity was demonstrated 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.

3. Reproductive and developmental toxicity

. The rat devel opmental toxicity study did not demonstrate developmental toxicity at the highest dose tested. The rabbit d evelopmental toxicity demonstrated some signs of skeletal variations (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 NOAELs/LOAELs have been identified for the critical effects.

4. Chronic and Subchronic toxicity. Based on a weight

- of

- evidence approach, a conservative NOAEL for neurotoxic effects has been identified for tau

- fluvalinate. This approac h 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, a bnormal 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. These signs were observed during the first 3 hours after dosing and subsided within 6 hours. 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).These two studies were evaluated in parallel because the clinical signs of neurotoxicity in the rat chronic study are transi ent

. T hese 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 prolonged3

nervous system stimulation/agitation. Furthermore, the results of the 90

- day subchronic neurotoxicity study are consistent with the results of the rat chronic feeding study, demonstrating marked evidence of neurotoxicity at a similar low dose. T he 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 t o be seen at 1.0 mg/kg/day in the chronicstudy, 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. T this conservative determination is protective for all population subgroups. This NOAEL was applied to acute and chronic dietary exposures and short

- term and intermediate

- term in halation exposures

5

. Animal metabolism. The metabolism of the chemical in animals for this use is adequately understood. Rat/Mouse: 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 feces and urine, respectively, after 4 days with most excreted within 24 hours. An aniline metabolite was identified in the urine but several other metabolites were not f urther 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 2 4 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 fece s. 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. Spec ifically, 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 an d converted to the lactone of anilino acid, or may form haloaniline or diacid

.
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 vari ous PBA conjugates.

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 mat rices.

6

. Metabolite toxicology

. Makhteshim

- Agan of North America Inc., has determined that there are no metabolites of toxicological concern and therefore, no metabolites need to be included in the tolerance expression and require regulation. Based on the available data for tau

fluvalinate, it has been determined that the residue of concern is tau

- fluvalinate, per se.

Toxicology data for the major metabolite of tau

- fluvalinate, 3

- PBA, indicate that this compound and its conjugates are not of toxicologi cal concern. Specific data are not available for other metabolites; however, the major plant and animal metabolites are also metabolites in the rat, and,4

therefore, their toxicity was assessed when the parent was studied. In addition, none of the major pla nt or animal metabolites contains the intact ester linkage responsible for the neurotoxicity of
tau

- fluvalinate.

7

. Endocrine disruption

. There were no indications based on the animal studies submitted for registration purposes that indicate that tau

- flu valinate affects either the estrogen, androgen or thyroid or other hormone systems

C. Aggregate Exposure

Dietary exposure. The dietary exposure and risk estimates resulting from intake of food and water with residues of tau

- fluvalinate were determined fo r the general U.S. population and all subpopulation groups. Nearly all of the estimated dietary exposure to tau

- fluvalinate is from drinking water. Estimated dietary exposure to tau

- fluvalinate from food represents between less than 0.01% to 0.06% (childre n, 1

- 2 yrs. old) of the total estimated exposure. No cancer dietary exposure assessment was conducted because studies indicate that there is no carcinogenic concern from tau

- fluvalinate exposure.

T he residue of concern for risk assessment purposes in all commodities and drinking water consists of parent tau

- fluvalinate only. This is based 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 responsibl e for the neurotoxicity of tau

- fluvalinate.

i. Food

. Acute Dietary Exposure

. The 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 e xposure (food + drinking 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

e xposures 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).

Chronic Dietary Exposure

. The chronic dietary exposure estimates using the DEE M

- FCID model were less than 1% of the cPAD for the U.S. population and all population subgroups. Tau

fluvalinate chronic dietary exposure (food + drinking 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 inf ants).

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.

ii. Drinking water. Since this will be an import tol erance use only, no changes to the current drinking water exposure an applicable.5

2. Non

- dietary exposure

. Since this will be an import tolerance use only, no changes to the current non dietary exposure an applicable.

D. Cumulative Effects

EPA co mpleted the Pyrethrins/Pyrethroid Cumulative Risk Assessment on October 4, 2011. This screening

- level cumulative risk assessment is highly conservative, overestimating actual risk. That is, the assessment assumes that people are exposed to the highest leve ls of residues in food, water, and in their homes, all on the same day. Even with these conservative and protective assumptions, the assessment shows that cumulative risks for both children and adults are not of concern for the currently registered uses of pyrethrins/pyrethroid pesticides. Further, the assessment shows that there is sufficient room in the pyrethroid cumulative risk cup to support consideration of additional individual pyrethroid pesticide uses.

E. Safety Determination

1. U.S. population

. No cancer aggregate risk assessment was conducted because tau

fluvalinate has not been shown to be carcinogenic.

The acute aggregate risk assessment considered exposures from food and water only, because there are no residential uses expected to contrib ute 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 represent the total acute aggregate risk for tau

fluvalinate. The acute agg regate risk estimates for the U.S. population and all subgroups are <6% of the aPAD and, therefore, below HED’s level of concern. There are no residential uses expected to contribute to short

- term or intermediate

- term exposures for this chemical, based on its current use patterns. Therefore, these aggregate assessments are not required.

A chronic aggregate risk assessment was performed for Registration Review based on potential exposure from food and drinking water. Short

- and intermediate

- term aggregate r isk assessments were performed based on potential exposure from food and drinking water, as well as spot, crack and crevice, and outdoor perimeter uses. The chronic dietary exposure, including drinking water, f or the general U.S. population wa s found to be 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). 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. In view of these previous assessments, ADAMA concludes that there is reasonable certainty that no harm will result from the proposed use of tau fluvalinate with t he additional use on wine grapes

. Concerning the aggregate assessment from all potential sources of exposure (food,water, residential), it has been demonstrated that the aggregate MOEs associated with the existing uses of tau fluvalinate do not exceed the Agency’s level of concern. There is reasonable certainty that no harm will result to the general population or to infants and c hi ld ren from the additional new

use of tau fluvalinate

.

2. Infants and children

. Section 408 of FFDCA provides that EPA may a pply an additional safety factor for infants and children to account for prenatal and postnatal toxicity and6

the completeness of the database. Based on the he toxicology database for tau fluvalinate

, EPA has determined the special FQPA SF is reduced to 1X.

This is grounded on following: 1 ) 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. 2) A clear NOAEL/LOAEL was established for the developmental rabbit study. 3) In the 2

- generation reproductive study in rats, the fetal anoma lies (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 t oxicity (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.

Based on this information ADAMA concludes tha t there is reasonable certainty that no harm will result to infants and children from aggregate exposure to tau fluvalinate residues associated with existing and proposed uses of tau fluvalinate on wine grapes

.

F. International Tolerances

There are no C ODEX maximum residue limits (MRLs) at this time. An EU MRL of 1.0 has been established for tau fluvalinate

.