Absorption, Distribution and Excretion
Male and female rats were given a single oral dose of ... ((14)C)pyriproxyfen /labeled on the phenoxyphenyl moiety/ <4-phenoxyphenyl(R,S)-2-(2-pyridyloxy)propyl ether> at 2 (low dose) or 1000 (high dose) mg/kg. (14)C was rapidly excreted into feces and urine, with the former route predominating (about 90% of the dose). Peak (1)4C concentrations in blood, kidney, liver, and other tissues except for fat occurred 2-8 hr after administration, being 0.4, 0.4, 2.5, and <0.2 g of pyriproxyfen equivalents/g of tissue (ppm), respectively. Peak (14)C concentration in fat occurred 12-24 hr after administration, being 0.3-0.5 ppm. (14)C tissue residues on the seventh day were below 0.02 and 10 ppm for the low and high doses, respectively. ... No marked sex-related differences were observed for (14)C excretion or (14)C tissue residues. However, a slight sex-related variation was found for the extent of metabolic reactions.
... Rats were orally dosed with (14)C-labeled pyriproxyfen at 2 or 1,000 mg/kg and at repeated oral doses (14 daily doses) of unlabeled pyriproxyfen at 2 mg/kg followed by admin of a single oral dose of labeled pyriproxyfen at 2 mg/kg. Most radioactivity was excreted in the feces (81-92%) and urine (5-12%) over a 7-day collection period. ... /Radioactivity/ was not detected /in expired air/. Tissue radioactivity levels were very low (< 0.3%) except for fat. Examination of urine, feces, liver, kidney, bile, and blood metabolites yielded numerous (>20) identified metabolites when compared to synthetic standards.

---

Metabolism / Metabolites
The metabolic fate of pyriproxyfen (4-phenoxyphenyl (RS)-2-(2-pyridyloxy)propyl ether, Sumilarv) was examined in rats and mice given single oral doses of (pyridyl-2,6-(14)C)- or (phenoxyphenyl-(14)C)pyriproxyfen at doses of 2 and 1000 mg/kg. The carbon-14 was excreted almost completely into urine and feces within 7 days after dosing and fecal excretion of carbon-14 predominated in both animals. Excretion of carbon-14 into feces and urine was, respectively, 84-97% and 4-12% of the dose in rats and 64-91% and 9-38% in mice. Major metabolic reactions of pyriproxyfen were (1) hydroxylation at the 4-position of the terminal phenyl ring, (2) hydroxylation at the 2-position of the terminal phenyl ring, (3) hydroxylation at the 5-position of the pyridyl ring, (4) dephenylation, (5) cleavage of ether linkages, and (6) conjugation of the resultant phenols with sulfate or glucuronate. Although there was generally no marked difference in the metabolic profile of pyriproxyfen between the two species, significant sex-related differences were found in metabolic reactions 1, 3, and 6 in the rat but not in the mouse.
Levels of cytochrome P450 and b5 were investigated in microsomal enzymes of houseflies from the gut and fat body of the third instar larvae of a pyriproxyfen-resistant strain (YPPF) and two pyriproxyfen-susceptible strains (YS and SRS). In comparison to the YS and SRS strains, YPPF microsomes had higher levels of total cytochrome P450s in both the gut and fat body. Furthermore, microsomes from the gut and fat body of YPPF larvae were found to have a much greater ability to hydroxylate aniline than YS larvae. In vitro metabolism studies of pyriproxyfen indicated that the metabolic rates were much higher in both the gut and fat body of YPPF larvae than of YS and SRS larvae. The major metabolites of pyriproxyfen in houseflies were identified to be 4'-OH-pyriproxyfen and 5"-OH-pyriproxyfen. Cytochrome P450 inhibitors, piperonyl butoxide (PB) and 2-propynyl 2,3,6-trichlorophenyl ether (PTPE), decreased the metabolic rates significantly in all three strains. This study confirmed that microsomal cytochrome P450 monooxygenases play an important role in the pyriproxyfen resistance of the housefly. Furthermore, it suggests that the fat body must be as important as the gut for the metabolism of pyriproxyfen in resistant housefly larvae.
... Rats were orally dosed with (14)C-labeled pyriproxyfen at 2 or 1,000 mg/kg and at repeated oral doses (14 daily doses) of unlabeled pyriproxyfen at 2 mg/kg followed by admin of a single oral dose of labeled pyriproxyfen at 2 mg/kg. ...Examination of urine, feces, liver, kidney, bile, and blood metabolites yielded numerous (>20) identified metabolites when compared to synthetic standards. The major biotransformation reactions of pyriproxyfen include: (i) Oxidation of the 4' - position of the terminal phenyl group; (ii) Oxidation at the 5' - position of pyridine; (iii) Cleavage of the ether linkage and conjugation of the resultant phenols with sulfuric acid.

---

Biological Half-Life
... 918 days for pyriproxyfen in pepper fruits under cold storage conditions. ...

Toxicity Summary
IDENTIFICATION AND USE: Pyriproxyfen could be solid or liquid. Pyriproxyfen is a potent insect growth regulator affecting the hormonal balance in insects, thereby resulting in strong suppression of embryogenesis, metamorphosis, and adult formation. It is used to control agricultural, veterinary, and human health pests such as whiteflies and scale insects; flies, mosquitoes, and fleas. It is also used as veterinary medication. HUMAN EXPOSURE AND TOXICITY: The substance may have effects on the blood and liver. This may result in anemia, impaired functions and tissue lesions. Pyriproxyfen was reported to have some estrogenic activity in human ovarian carcinoma cells. In genotoxicity assays, an increase in unscheduled DNA synthesis was not induced both with and without activation in HeLa cells exposed up to insoluble doses ranging to 6.4 ug/mL (without activation) and 51.2 ug/mL (with activation). ANIMAL STUDIES: Groups of 21 male and 21 female rats were fed diets containing pyriproxyfen at concentrations of 0, 80, 400, 2,000 and 10,000 ppm for 6 months. No death was found in any group. Alopecia in the neck and/or back, and soft feces were noticed in both sexes fed 10,000 ppm. A marked decrease in body weight gain was observed in both sexes fed 10,000 ppm throughout the treatment period, accompanying a decrease in food-consumption and an increase in water-intake during the initial stage of treatment. In organ weight, increases in liver (in males fed 2,000 ppm and 10,000 ppm, and in females fed 10,000 ppm), kidney (in both sexes fed 10,000 ppm) and thyroid (in females fed 10,000 ppm) and a decrease in pituitary (in females fed 2,000 and 10,000 ppm) were observed. Gross pathology revealed a higher incidence of blackish-brown coloration of the liver, and a lower incidence of accentuated lobular pattern of the liver (in males fed 10,000 ppm). An enlargement of the liver was seen in a few animals of both sexes fed 10,000 ppm. Mice were immunized thrice with ovalbumin in 5% ethanol, with or without pyriproxyfen or alum. Large doses of pyriproxyfen (9 or 15 mM) significantly enhanced specific total IgG immune response. This enhancement was no longer present 24 hr after treatment with pyriproxyfen. Moreover, pyriproxyfen induced higher titers of IgG2a and enhanced tumor necrosis factor-alpha and gamma-interferon responses. In a gene mutation assay (Ames Test)/Reverse Mutation, findings were determined as negative for induction of gene mutation measured in 5 S. typhimurium strains and E. coli WP2 uvra at doses from 10 to 5,000 ug/plate with and without metabolic activation. The highest does was insoluble. A gene mutation assay in mammalian cells was found to be negative for mutagencity in CHO (Chinese hamster ovary) V79 cells with and without metabolic activation up to cytotoxic doses (300 ug/mL). In a structural chromosomal aberration assay in vitro, findings proved nonclastogenic in CHO cells both with and without metabolic activation up to cytotoxic doses (300 ug/mL). ECOTOXICITY STUDIES: The impacts of pyriproxyfen on Daphnia magna reproduction was studied using a series of male production screening assays. These assays demonstrate that pyriproxyfen increases male production in a concentration-dependent fashion with an EC50 of 156 pM (50.24 ng/L). Furthermore, pyriproxyfen decreases overall fecundity at all ages tested (7, 14, 21-d old female parthenogenic daphnids). Juvenile (3-d old) and reproductively mature (10-d old) female daphnids were also exposed to 155 pM pyriproxyfen for 2-12 d and reproduction measured for 16 d to compare the effects of short-term and prolonged exposures, and determine the potential for recovery. Results indicate that longer pyriproxyfen exposures (8-12 d) extend male production and decrease reproduction; however, daphnids exposed for only 2-4 d recover and produce a relatively normal abundance of neonates. In addition, juvenile daphnids are also very sensitive to pyriproxyfen, but the primary effect on juvenile daphnids is reduced reproduction and protracted development not male production. The effect of pyriproxyfen on early ovary synthesis was examined in the Gecarcinid land crab, Gecarcoidea natalis. Pyriproxyfen may have stimulated early ovary development and induced synthesis of yolk protein by mimicking methyl farnesoate and thus causing endocrine disruption. The impact of the juvenile hormone analog pyriproxyfen on honeybee larvae and resulting adults within a colony was studied. Pyriproxyfen-treated bees emerged earlier than control bees and the highest dose led to a significant rate of malformed adults (atrophied wings). Young pyriproxyfen-treated bees were more frequently rejected by nestmates from the colony, inducing a shorter life span. This could be linked to differences in cuticular hydrocarbon profiles between control and pyriproxyfen-treated bees. Finally, pyriproxyfen-treated bees exhibited fewer social behaviors (ventilation, brood care, contacts with nestmates or food stocks) than control bees. Larval exposure to sublethal doses of pyriproxyfen affected several life history traits of the honeybees.

---

Toxicity Data
LC50 (rat) > 1,300 mg/m3/4h

---

Interactions
A number of pesticides are used in agricultural production with some having estrogenic activities, such as endocrine-disrupting chemicals that may affect wildlife and humans. This study aimed to detect the estrogenic effects of some mixed agricultural chemicals in agricultural production. The assay to measure estrogenic activity was evaluated by the cell proliferative activity of MtT/Se cells, which respond well to estrogen. To evaluate MtT/Se cells we went down to the molecular level of estrogen receptor (ER)-alpha and ER-beta expression. The proportion of ER-alpha to ER-beta was 3.55:1, as determined by semi-quantitative real-time PCR. These results showed that ER-alpha was dominant in MtT/Se cells on the transcriptional level, therefore implying that the estrogenic activity detected by these cells may be mainly mediated by ER-alpha. It was found that ... pyriproxyfen ... had estrogenic activity. Several pesticides are often present in agricultural products. Therefore, we evaluated the estrogenic activity of a mixture of two pesticides. The REC(10) levels of prothiofos/pyriproxyfen and thiabendazole/orthophenylphenol were increased up to 10-fold. We concluded that those two pesticide combinations showed a significantly higher estrogenic effect in comparison to the results of the respective pesticides when tested individually.

---

Non-Human Toxicity Values
LD50 Rat oral >5000 mg/kg
LD50 Rat percutaneous >2000 mg/kg
LC50 Rat inhalation >1300 mg/cu m/4 hr
LD50 Rabbit dermal >2,000 mg/kg

Pyriproxyfen is an aromatic ether that consists of propylene glycol having a 2-pyridyl group at the O-1 position and a 4-phenoxyphenyl group at the O-3 position. It has a role as a juvenile hormone mimic. It is an aromatic ether and a member of pyridines. It is functionally related to a 4-phenoxyphenol.
Pyriproxyfen is a pyridine-based pesticide which is found to be effective against a variety of arthropoda. It was introduced to the US in 1996, to protect cotton crops against whitefly. It has also been found useful for protecting other crops. It is also used as a prevention for fleas on household pets.

---

Mechanism of Action
Pyriproxyfen mimics insect juvenile growth hormone, halting development during metamorphosis and larval development. It also concentrates in female flea ovaries, causing non-viable eggs to be produced. When combined with an adulticide (e.g., permethrin, fipronil) all stages of the parasite are killed and re-infestation is less likely.

---

Therapeutic Uses
(VET): ... We report here 2 cases of pediculosis in random-source ponies. Infestation and clinical signs were not present during a 4-wk quarantine period or for 3 to 9 mo thereafter but became apparent coincident with the ponies' movement from pasture to indoor housing. These 2 geldings presented with pruritus associated with excoriating lesions on the neck, and infestation with Bovicola (Werneckiella) equi Denny, 1842 was diagnosed. Ponies were treated successfully with standard wound care and a spray containing 2.0% permethrin and 0.05% pyriproxyfen. These cases highlight the importance of recognizing the possibility of louse infestation, even in healthy, well-cared-for animals, and the need for personnel to be aware of early behavioral signs of infestation, such as rubbing and agitation.

C20H19NO3

321.37

321.136

95737-68-1

Pyriproxyfen-d6;2673269-99-1;Pyriproxyfen-d4;2446366-95-4

91753

White to off-white solid powder

1.2±0.1 g/cm3

462.0±35.0 °C at 760 mmHg

45-47°C

165.4±16.2 °C

0.0±1.1 mmHg at 25°C

1.581

4.84

0

4

7

24

338

0

NHDHVHZZCFYRSB-UHFFFAOYSA-N

InChI=1S/C20H19NO3/c1-16(23-20-9-5-6-14-21-20)15-22-17-10-12-19(13-11-17)24-18-7-3-2-4-8-18/h2-14,16H,15H2,1H3

2-[1-(4-phenoxyphenoxy)propan-2-yloxy]pyridine

Tiger 10EC; Sumilarv; Pyriproxyfen

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~311.17 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.78 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (7.78 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)