EPA Registration Division contact: Andrew Ertman; 703-308-9367

Interregional Research Project Number 4 (IR-4) 

PP No. 1E7950 

 EPA has received a pesticide petition (PP No. 1E7950) Interregional 

Research Project Number 4 (IR-4), IR-4 Project Headquarters, Rutgers, The State 

University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08540 

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 180.510 by establishing a tolerance 

for residues of Pyriproxyfen in or on the raw agricultural commodity Vegetable, bulb, 

group 3-07 at 0.70 ppm; Vegetable, fruiting, group 8-10 at 0.20 ppm; Fruit, citrus, group 

10-10 at 0.30 ppm; Fruit, pome, group 11-10 at 0.20 ppm; Caneberry subgroup 13-07A at 

1.0 ppm; Bushberry subgroup 13-07B at 1.0 ppm; Berry, low growing, except 

strawberry, subgroup 13-07H at 1.0 ppm; and Herb subgroup 19A at 50 ppm. The 

petitioner is also proposing revocation of the existing tolerance for residue of the 

insecticide chemical pyriproxyfen 2-[1-Methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine, in 

or on the raw agricultural commodities; Vegetable, bulb, group 3, except onion, bulb; 

Onion, bulb; Vegetable, fruiting, group 8; Okra; Fruit, citrus; Fruit, pome; Caneberry 

subgroup 13-A; Bushberry subgroup 13-B; Cranberry; Loganberry; Juneberry; 

Lingonberry; and Salal, because tolerances for the revised groupings are being requested. 

EPA has determined that the petition contains data or information 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 granting of the 

petition. Additional data may be needed before EPA rules on the petition. 

A. Residue Chemistry

1. Plant metabolism. Metabolism of 14C-pyriproxyfen labeled in the 

phenoxyphenyl ring and in the pyridyl ring has been 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 samples remained as parent. Comparing 

metabolites detected and quantified from cotton, 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, the residue of concern is best defined as the 

parent, pyriproxyfen. 

Ruminant and poultry metabolism studies demonstrated that transfer of administered 14Cresidues to tissues was low. Total 14C-residues in goat milk, muscle and tissues accounted 

for less than 2% of the administered dose, and were less than 1 ppm in all cases. In 

poultry, total 14C residues in eggs, muscle and tissues accounted for about 2.7% of the 

administered dose, and were less than 1 ppm in all cases except for gizzard. 

2. Analytical method. Practical analytical methods for detecting and measuring 
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levels of pyriproxyfen (and relevant metabolites) have been developed and validated 

in/on all appropriate agricultural commodities, respective processing fractions, milk, 

animal tissues, and environmental samples. The extraction methodology has been 

validated using aged radiochemical residue samples from metabolism studies. The 

methods have been validated in cottonseed, apples, soil, and oranges at independent 

laboratories. EPA has successfully validated the analytical methods for analysis of 

cottonseed, pome fruit, nutmeats, almond hulls, 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 classified as Category III for acute dermal and inhalation 

toxicity, and Category IV for acute oral toxicity, and skin/eye irritation. 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 with 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 performed in rats and 

rabbits, and multigenerational effects on reproduction were tested in rats. These studies 

have been reviewed and found to be acceptable to the Agency. 
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In the developmental toxicity study conducted 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 toxicity (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 present 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 visceral and skeletal variations was observed 

postnatally at 1000 mg/kg bw/day. The NOAEL for postnatal developmental toxicity was 

300 mg/kg bw/day. 

In the developmental toxicity study conducted with rabbits, technical pyriproxyfen was 

administered by gavage at levels of 0, 100, 300, and 1000 mg/kg bw/day during gestation 

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, pyriproxyfen 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 increased 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 females). 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 primarily of decreased body weight gain; increased 

liver weights; histopathological changes in the liver and kidney; 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 pyriproxyfen technical in rats, decreased body weight 

and increased water consumption were observed at 1000 mg/m3

. The NOAEL in this 

study was 482 mg/m3

. 

A 21-day dermal toxicity study in rats with pyriproxyfen technical did not produce any 

signs of dermal or systemic toxicity at 1000 mg/kg bw/day, the highest dose tested. In a 

21-day dermal study conducted with KNACK7

 Insect Growth Regulator the test material 
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produced a NOAEL of 1000 mg/kg bw/day (highest dose tested) for systemic effects, and 

a NOAEL for skin irritation of 100 mg/kg bw/day. 

5. Chronic toxicity. Pyriproxyfen technical has been tested 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 EPA in the Reference Dose Tracking Report 

include negative trend in mean red blood cell volume, increased hepatocyte cytoplasm 

and cytoplasm:nucleus ratios, and decreased sinusoidal spaces. 

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 response 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 exposed to dose levels of 300 mg/kg bw/day 

or higher showed overt clinical signs of toxicity, elevated 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 effects 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, pyriproxyfen technical was administered in the diet at levels 

of 0, 120, 600, and 3000 ppm. The NOAEL for systemic effects in this study was 600 

ppm (27.31 mg/kg bw/day in males, 35.1 mg/kg 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 14C-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 administered 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 14C. Radiocarbon concentrations in fat were the higher than in other tissues 

analyzed. Recovery in tissues over time indicates 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 
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metabolized and eliminated. In the rat, most (88-96%) of the administered radiolabel was 

excreted in the urine and feces within two days of dosing, and 92-98% of the 

administered dose was excreted within seven days. Tissue residues were low seven days 

after dosing, accounting for no more than 0.3% of the dosed 14C. Because parent and 

metabolites are not retained in the body, the 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 MTD and consequent chronic exposure to the 

internally formed metabolites. 

Seven metabolites of pyriproxyfen, 4'-OH-pyriproxyfen, 5''-OH-pyriproxyfen, desphenylpyriproxyfen, POPA, PYPAC, 2-OH-pyridine and 2,5-diOH-pyridine, have been tested 

for mutagenicity (Ames) and acute oral toxicity 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 inhibitory dose. The metabolites did not induce any significant 

increases in revertant colonies in any of the test strains. Positive control chemicals 

showed marked increases in revertant colonies. The acute toxicity to mice of 4'-OHpyriproxyfen, 5''-OH-pyriproxyfen, desphenyl-pyriproxyfen, POPA, and PYPAC did not 

appear to markedly differ from pyriproxyfen, with all metabolites having acute oral LD50

values greater than 2000 mg/kg bw. The two pyridines, 2-OH-pyridine and 2,5-diOHpyridine, gave acute oral LD50 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 produce juvenoid effects on arthropod development. 

However, this mechanism-of-action in target insects and some other arthropods has little 

to no relevance to the mammalian endocrine system. Specific tests uniquely designed to 

evaluate the potential effects of pyriproxyfen on mammalian endocrine systems are 

currently underway and have not been completed. Overall, however, the toxicology of 

pyriproxyfen has been extensively evaluated in acute, sub-chronic, and chronic toxicity, 

developmental, and reproductive toxicology studies including detailed histopathology of 

numerous endocrine-active tissues. The results of these studies show no evidence of any 

endocrine-mediated effects and no pathology of the endocrine organs. The battery of tests 

included in support of this petition fully characterizes potential endocrine-related in vivo

effects and clearly defines NOAEL/LOAEL values. 

C. Aggregate Exposure

1. Dietary exposure. A Tier 1 dietary (food and water) exposure assessment was 

conducted by EPA to evaluate the potential risk due to chronic dietary exposure of the 

U.S. population and various subpopulations to residues of Pyriproxyfen from crops with 

existing tolerances (see Pyriproxyfen Human Health Risk Assessment, EPA Health 

Effects Division, September 3, 2009). Residues from use of Pyriproxyfen on the 

currently proposed minor use crops were 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. 
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i. Food. Dietary exposures were calculated 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 the active ingredient in numerous registered 

products for flea and tick control. Formulations include foggers, aerosol sprays, 

emulsifiable concentrates, and impregnated materials (pet collars). With the exception of 

the pet collar uses, consumer use of Pyriproxyfen 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 inhalation exposure to Pyriproxyfen. Therefore, 

only a chronic aggregate assessment was performed 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 particular pesticide's residues and "other 

substances that have a common mechanism of toxicity." Available information in this 

context includes not only toxicity, chemistry, and exposure data, but also scientific 

policies and methodologies for understanding common mechanisms of toxicity and 

conducting cumulative risk assessments. At this time, there is no available data to 

determine whether pyriproxyfen has a common mechanism of toxicity 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 dietary 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 and chronic rat toxicity studies and includes 

an uncertainty factor of 100 to account for intra- and inter-species variation (cPAD = 

35.1 mg/kg/day). Aggregate exposures including dietary residues in addition to 

residential non-dietary exposures 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. 
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2. Infants and children. FFDCA section 408 provides that EPA shall apply an 

additional margin of safety, up to ten-fold, for added protection for infants and children in 

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

be safe for infants and children. The toxicological 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 neurotoxicity studies and an immunotoxicity study are also in 

progress and will be submitted by agreed upon deadlines. 

For the purposes of this petition, EPA has concluded that reliable data support 

reduction of the FQPA Safety Factor for protection of infants and children to 1X. No 

acute endpoint has been identified for infants and children. Therefore, no assessment of 

acute exposure from food or water to this subgroup 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 utilize 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 subpopulation, 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 existing Codex MRLs for pyriproxyfen.