EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Kable Davis, (703) 306-0415

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

5E8362

EPA has received a pesticide petition (5E8362) 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. 346a(d), to amend 40 

CFR part 180 by establishing 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) of 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 phenoxybenzyl 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 plant 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 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 or 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. In addition, the FDA multi-residue methods 
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published 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-fluvalinate 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 Profile

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 III) 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) and 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 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 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 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. 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 

transient. 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 
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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. 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 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 shorterterm subchronic study and longer-term chronic feeding study. Tthis conservative determination is 

protective for all population subgroups. This NOAEL was applied to acute and chronic dietary 

exposures and short-term and intermediate- term inhalation 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 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. Taufluvalinate is also metabolized to anilino acid which may be hydroxylated and 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 various 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 matrices.

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 taufluvalinate, 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 toxicological concern. Specific data are not available for other 

metabolites; however, the major plant and animal metabolites are also metabolites in the rat, and, 
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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.

7. 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

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 for 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% (children, 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.

The 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 responsible 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. Taufluvalinate acute dietary exposure (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 

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).

Chronic Dietary Exposure. The 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. Taufluvalinate 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 infants).

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 tolerance use only, no changes to the current 

drinking water exposure an applicable.
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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 completed 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 levels 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 taufluvalinate 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 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 represent the total acute aggregate risk for taufluvalinate. 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. 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 risk 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, 

for the general U.S. population was 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 the 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 children from the additional new 

use of tau fluvalinate.

2. Infants and children. Section 408 of FFDCA provides that EPA may apply an 

additional safety factor for infants and children to account for prenatal and postnatal toxicity and 
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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 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.

Based on this information ADAMA concludes that 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 CODEX maximum residue limits (MRLs) at this time. An EU MRL of 1.0 has been 

established for tau fluvalinate.