EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Richard Gebken, 703-305-6701

INSTRUCTIONS: Please utilize this outline in p reparing the pesticide petition. In

cases where the outline element does no t apply, please insert “NA-Remove” and

maintain the outline. Please do not chan ge the margins, font, or format in your pesticide petition. Simply repla ce the instructions that appear in green, i.e., “[insert company name],” with the information specific to your action.

TEMPLATE:

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from Sumitomo Chemical Company (through their Agent Va lent U.S.A. Corporation), 1600 Riviera Avenue, Suite 200, Walnut Creek, CA 94596 pro posing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFD CA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.510 by raising the tole rance for residues of Pyri proxyfen in or on the raw agricultural commodity Tea from 0.02 ppm to 15 ppm. EPA has determined that the petition contains data or info rmation regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports gr anting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. Metabolism of 14 C-pyriproxyfen labeled in the phenoxyphenyl ring and in the pyridyl ring has b een studied in cotton, apples, tomatoes, lactating goats, and laying hens (and rats). The major metabolic pathways in plants is aryl hydroxylation and cleavage of the ether linkage, followed by further metabolism into more polar products by further oxidation and/or conjugation reactions. However, the bulk

of the radiochemical residue on RAC sa mples remained as parent. Comparing metabolites detected and quantified from cott on, apple, tomato, goat and hen (and rat) shows that there are no significant metabolites in plants which are not also present in the excreta or tissues of animals. Therefore, th e residue of concern is best defined as the parent, pyriproxyfen.

Ruminant and poultry metabolism studies demons trated that transfer of administered 14 Cresidues to tissues was low. Total 14 C-residues in goat milk, musc le and tissues accounted for less than 2% of the administered dose, and were less than 1 ppm in all cases. In poultry, total 14 C residues in eggs, muscle and ti ssues accounted for about 2.7% of the administered dose, and were less than 1 ppm in all cases except for gizzard.2

2. Analytical method. Practical analytical methods for detecting and measuring levels of pyriproxyfen (and relevant metabo lites) have been developed and validated in/on all appropriate agricultural commodities, respective processing fractions, milk, animal tissues, and environmental samp les. The extraction methodology has been validated using aged radiochemical resi due samples from metabolism studies. The methods have been validated in cottonseed, apples, soil, and ora nges at independent

laboratories. EPA has successfu lly validated the analytical methods for analysis of cottonseed, pome fruit, nutmeats, almond hu lls, and fruiting vegetables. The limit of detection of pyriproxyfen in the methods is 0.01 ppm which will allow monitoring of food with residues at the levels proposed for the tolerances.

3. Magnitude of residues. Residue data has been submitted which adequately support the requested tolerances.

B. Toxicological Profile

1. Acute toxicity. The acute toxicity of technical grade pyriproxyfen is low by all routes. The compound is classi fied as Category III for acute dermal and inhalation toxicity, and Category IV for acute oral toxici ty, and skin/eye irrita tion. Pyriproxyfen is not a skin sensitizing agent.

2. Genotoxicty. Pyriproxyfen does not present a genetic hazard. Pyriproxyfen was negative in the following tests for mutagenicity: Ames assay with and without S9, in

vitro unscheduled DNA synthesis in HeLa S3 cells, in vitro gene mutation in V79 Chinese hamster cells, and in vitro chromosomal aberration w ith and without S9 in Chinese hamster ovary cells.

3. Reproductive and developmental toxicity. Pyriproxyfen is not a developmental or reproductive toxicant. Developmental toxicity studies have been pe rformed in rats and rabbits, and multigenerational effects on reprodu ction were tested in rats. These studies

have been reviewed and found to be acceptable to the Agency.

In the developmental toxicity study conduc ted with rats, technical pyriproxyfen was administered by gavage at levels of 0, 100, 300, and 1000 mg/kg bw/day during gestation days 7-17. Maternal toxi city (mortality, decreased body weight gain and food consumption, and clinical signs of toxicity) was observed at doses of 300 mg/kg bw/day and greater. The maternal NOAEL was 100 mg /kg bw/day. A transient increase in

skeletal variations was observed in rat fetuses from females exposed to 300 mg/kg bw/day and greater. These effects were not pres ent in animals examined at the end of the postnatal period, therefore, the NOAEL for prenatal developmental toxicity was 100 mg/kg bw/day. An increased incidence of vis ceral and skeletal variations was observed postnatally at 1000 mg/kg bw/day. The NOAEL fo r postnatal developmental toxicity was 300 mg/kg bw/day.

In the developmental toxicity study conducte d with rabbits, techni cal pyriproxyfen was administered by gavage at levels of 0, 100, 300, and 1000 mg/kg bw/day during gestation3

days 6-18. Maternal toxicity (clinical signs of toxicity including one death, decreased body weight gain and food consumption, and abortions or premature deliveries) was observed at oral doses of 300 mg/kg bw/day or higher. The maternal NOAEL was 100 mg/kg bw/day. No developmental effects were observed in the rabbit fetuses. The NOAEL for developmental toxicity in rabbits was 1000 mg/kg bw/day.

In the rat reproduction study, pyrip roxyfen was administered in the diet at levels of 0, 200, 1000, and 5000 ppm through two generations of rats. Adult systemic toxicity (reduced body weights, liver and kidney histopathology, and in creased liver weight) was produced at the 5000 ppm dose (453 mg/kg bw /day in males, 498 mg/kg bw/day in females) during the pre-mating period. The systemic NOAEL was 1000 ppm (87 mg/kg bw/day in males, 96 mg/kg bw/day in fe males). No effects on reproduction were produced at 5000 ppm, the highest dose tested.

4. Subchronic toxicity. Subchronic oral toxicity studies conducted with pyriproxyfen technical in the rat, mouse and dog indicate a low level of toxicity. Effects observed at high dose levels consisted primar ily of decreased body weight gain; increased liver weights; histopathologica l changes in the liver and ki dney; decreased red blood cell counts, hemoglobin and hematocrit; altered blood chemistry parameters; and, at 5,000 and 10,000 ppm in mice, a decrease in survival rates. The NOAELs from these studies were 400 ppm (23.5 mg/kg bw/day for males, 27.7 mg/kg bw/day for females) in rats, 1000 ppm (149.4 mg/kg bw/day for males, 196.5 mg /kg bw/day for females) in mice, and 100 mg/kg bw/day in dogs.

In a four week inhalation study of pyriproxyf en technical in rats, decreased body weight and increased water consumption were observed at 1000 mg/m 3 . The NOAEL in this study was 482 mg/m 3

.

A 21-day dermal toxicity study in rats with pyriproxyfen technica l did not produce any signs of dermal or systemic toxicity at 1000 mg/kg bw/day, the highest dose tested.

An immunotoxicity study has been conduc ted in mice at doses up to 5000 ppm (1139 mgkg/day). No immunotoxicity was observed.

Acute and subchronic neurotox icity studies were also conducted. At a dose of 2000 mg/kg/day, decreased motor activity was obs erved in the acute study. The NOAEL is 1000 mg/kg/day. No neurotoxicity was observe d in the subchronic study, even at doses as high as 15,000 ppm (1111 mg/kg/day for ma les and 1212 mg/kg/day for females). Taken together, these studies indicate that pyriproxyfen is not neurotoxic.

5. Chronic toxicity. Pyriproxyfen technical has been te sted in chronic studies with dogs, rats and mice. EPA has established a reference dose (RfD) for pyriproxyfen of 0.35 mg/kg bw/day, based on the NOAEL in female rats from the two year chronic/oncogenicity study. Effects cited by EP A in the Reference Dose Tracking Report include negative trend in mean red blood ce ll volume, increased hepatocyte cytoplasm and cytoplasm:nucleus ratios, a nd decreased sinusoidal spaces.4

Pyriproxyfen is not a carcinogen. Studies with pyriproxyfen have shown that repeated high dose exposures produced changes in the liver, kidney and red blood cells, but did not produce cancer in test animals. No oncogenic respons e was observed in a rat two-year chronic feeding/oncogenicity study or in a seventy-eight week study on mice. The oncogenicity classification of pyriproxyfen is "E" (no evidence of carcinogenicity for humans).

Pyriproxyfen technical was administered to dogs in capsules at doses of 0, 30, 100, 300 and 1000 mg/kg bw/day for one year. Dogs expo sed to dose levels of 300 mg/kg bw/day or higher showed overt clinical signs of toxicity, elev ated levels of blood enzymes and liver damage. The NOAEL in this study was 100 mg/kg bw/day.

Pyriproxyfen technical was administered to mice at doses of 0, 120, 600 and 3000 ppm in diet for 78 weeks. The NOAEL for systemic e ffects in this study was 600 ppm (84 mg/kg bw/day in males, 109.5 mg/kg bw/day in females), and a LOAEL of 3000 ppm (420 mg/kg bw/day in males, 547 mg/kg bw/day in females) was established based on an increase in kidney lesions.

In a two-year study in rats, pyr iproxyfen technical was administ ered in the diet at levels of 0, 120, 600, and 3000 ppm. The NOAEL for syst emic effects in this study was 600 ppm (27.31 mg/kg bw/day in males, 35.1 mg/k g bw/day in females). A LOAEL of 3000 ppm (138 mg/kg bw/day in males, 182.7 mg/kg bw/day in females) was established based on a depression in body weight gain in females.

6. Animal metabolism. The absorption, tissue distribution, metabolism and

excretion of 14 C-labeled pyriproxyfen were studied in rats after single oral doses of 2 or 1000 mg/kg bw (phenoxyphenyl and pyridyl label) , and after a single oral dose of 2 mg/kg bw (phenoxyphenyl label only) following 14 daily oral doses at 2 mg/kg bw of unlabelled material. For all dose groups, most (88-96%) of the administered radiolabel

was excreted in the urine and feces within two days after radiolabeled test material dosing, and 92-98% of the admini stered dose was excreted within seven days. Seven days after dosing, tissue residues were generally low, accounting for no more than 0.3% of the

dosed 14 C. Radiocarbon concentrations in fat were the higher than in other tissues analyzed. Recovery in tissues over time indi cates that the potential for bioaccumulation is minimal. There were no significant sex or dose-related differences in excretion or

metabolism.

7. Metabolite toxicology

. Metabolism studies of pyriproxyfen in rats, goats and hens, as well as the fish bioaccumulation study demonstrate that the parent is very rapidly metabolized and eliminated. In the rat, most (88-96%) of the administ ered radiolabel was excreted in the urine and feces within two days of dosing, and 92-98% of the

administered dose was excreted within seve n days. Tissue residues were low seven days after dosing, accounting for no more than 0.3% of the dosed 14 C. Because parent and metabolites are not retained in the body, th e potential for acute toxicity from in situ formed metabolites is low. The potential for chronic toxicity is adequately tested by chronic exposure to the parent at the MT D and consequent chronic exposure to the internally formed metabolites.

Seven metabolites of pyriproxyfen, 4'-OH- pyriproxyfen, 5''-OH-pyriproxyfen, desphenyl-5

pyriproxyfen, POPA, PYPAC, 2- OH-pyridine and 2,5-diOH-pyrid ine, have been tested for mutagenicity (Ames) and acute oral to xicity to mice. All seven metabolites were tested in the Ames assay with and without S9 at doses up to 5000 micro-grams per plate or up to the growth inhibito ry dose. The metabolites di d not induce any significant increases in revertant colonies in any of th e test strains. Positive control chemicals

showed marked increases in revertant coloni es. The acute toxicity to mice of 4'-OHpyriproxyfen, 5''-OH-pyriproxyf en, desphenyl-pyriproxyfen, POPA, and PYPAC did not appear to markedly differ from pyriproxyfe n, with all metabolites having acute oral LD 50 values greater than 2000 mg/kg bw. The two pyridines, 2-OH-pyridine and 2,5-diOHpyridine, gave acute oral LD 50 values of 124 (male) and 166 (female) mg/kg bw, and 1105 (male) and 1000 (female) mg/kg bw, respectively.

8. Endocrine disruption

. Pyriproxyfen is specifically designed to be an insect growth regulator and is known to pr oduce juvenoid effects on arthro pod development. However,

this mechanism-of-action in ta rget insects and some other arthropods has li ttle to no relevance to the mammalian endocrine system. Specific Tier 1 screening and other tests uniquely designed to evaluate the potential effects of pyriproxyfen on endocrine systems

have been conducted and indica te that pyriproxyfen is not an endocrine disruptor. These studies are currently under ev aluation by the US EPA. Furthermore, the toxicology of pyriproxyfen has been extensively evaluated in acute, sub-chronic, and chronic toxicity, developmental, and reproductive toxicology st udies including detaile d histopathology of numerous endocrine-active tissues. The weig ht of evidence shows no evidence for

endocrine-mediated effects.

C. Aggregate Exposure

1. Dietary exposure

. A Tier 1 dietary (food and wate r) exposure assessment was conducted by EPA to evaluate the potential ri sk due to chronic di etary exposure of the U.S. population and various subpopulations to residues of Pyriproxyfen from crops with existing tolerances (see Pyriproxyfen Huma n Health Risk Assessment, EPA Health Effects Division, September 3, 2009). Resi dues from use of Pyriproxyfen on the currently proposed crop are not included in the current assessment because the overall aggregate exposure contribution is considered negligible. These minor crop residues will be included in the aggregate exposure assessment at a later date. An acute risk

assessment was not conducted because an acute oral endpoint applicable to a single dose exposure could not be identified.

i. Food . Dietary exposures were calcul ated using DEEM-FCID version 2.0. Key assumptions for the Tier 1 assessment are tolerance-level residues on all commodities, 100% crop treated and default processing factors for processed commodities without processing data.

ii. Drinking water

. The dietary assessment also includes estimated drinking

water concentrations based on PRZM/EXAMS surface water models and the SCI-GROW groundwater model.

2. Non-dietary exposure

. Non-dietary (residential) aggregate exposures to Pyriproxyfen may occur as Pyriproxyfen is th e active ingredient in numerous registered6

products for flea and tick control. Formul ations include foggers, aerosol sprays, emulsifiable concentrates, and impregnated mate rials (pet collars). With the exception of the pet collar uses, consumer use of Pyriproxyf en typically results in acute and short-term intermittent exposures. No acute dermal, or inhalation dose or endpoint was identified in the toxicity data for Pyriproxyfen. Similarly, doses and endpoints were not identified for

short and intermediate term dermal or inha lation exposure to Pyriproxyfen. Therefore, only a chronic aggregate assessment was perf ormed to include non-dietary exposures to Pyriproxyfen.

D. Cumulative Effects

Section 408(b)(2)(D)(v) requires that the Agency must consider "available information" concerning the cumulative effects of a pa rticular pesticide's residues and "other

substances that have a common mechanism of toxicity." Available information in this context includes not only toxicity, chemistr y, and exposure data, but also scientific policies and methodologies for understandin g common mechanisms of toxicity and conducting cumulative risk assessments. At th is time, there is no available data to determine whether pyriproxyfen has a comm on mechanism of toxi city with other substances or how to include this pesticide in a cumulative risk assessment. For the purposes of this tolerance action, there is no assumption that pyriproxyfen has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population

. As no acute toxicity endpoint has been identified, no acute aggregate exposure assessment is required. The potential chronic di etary exposure from food and water to the U.S. Population will utilize 3.3% of the cPAD. The cPAD was defined using the NOEL from the subchronic an d chronic rat toxicity studies and includes an uncertainty factor of 100 to account for in tra- and inter-species variation (cPAD = 35.1 mg/kg/day). Aggregate exposures incl uding dietary residues in addition to residential non-dietary exposur es were below EPA’s level of concern (all MOEs < 100). Dietary exposures below 100% of the aPAD and Aggregate exposures above a MOE of 100 are generally considered to represent a reasonable certainty of no harm to exposed populations.

2. Infants and children . FFDCA section 408 provides that EPA shall apply an additional margin of safety, up to ten-fold, fo r added protection for infants and children in

the case of threshold effects unless EPA determin es that a different margin of safety will

be safe for infants and children. The toxico logical database for evaluating prenatal and postnatal toxicity for pyriproxyfen is complete with respect to current data requirements, and there are no special prenatal or postnatal toxicity concerns for infants and children.

Acute and subchronic neurotox icity studies and an immunot oxicity study are also in progress and will be submitted by agreed upon deadlines.

For the purposes of this petition, EPA ha s concluded that reliable data support reduction of the FQPA Safety Factor for prot ection of infants and children to 1X. No7

acute endpoint has been identified for infant s and children. Theref ore, no assessment of acute exposure from food or water to this su bgroup is required. The potential chronic dietary exposure from food and water to children 1-2 years old (the most highly exposed child/infant subgroup) will utili ze at most 10% of the cPAD. Aggregate exposures below 100% of the cPAD are generally considered to represent a reasonable certainty of no harm to exposed populations. Aggregation of dietary exposures with residential exposures (e.g. flea and tick treatments) also results in acceptable risks. Aggregate exposure MOEs for the most sensitive subpopul ation, children 1-2 years of age, are 430 or higher. MOEs greater than 100 indicate a reasonable certainty of no harm resulting from the associated exposures.

F. International Tolerances

The following are the only existi ng Codex MRLs for pyriproxyfen.