UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: November 6, 2015 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

Subject: Pyriproxyfen. Human Health Risk Assessment for the Petition to Increase the 

Established Tolerance in/on Tea with a U.S. Registration for Imported Pyriproxyfentreated Tea. 

PC Code: 129032 DP Barcode: 427112 

Decision No.: 497260 Registration Nos.: Not Applicable 

Petition No.: 4E8326 Regulatory Action: Amended Tolerance (Increase) 

Assessment Single Chemical/ Registration Case No.: 7424 

Type: Aggregate 

TXRNo.: Not Applicable CAS No.: 95737-68-1 

MRID No.: Not Applicable 40 CFR: § 180.510 

From: Bonnie Cropp-Kohlligian, Environmental Sc entis~~ ~ - \~lly-- Austin Wray, Ph.D., Toxicologist ~ /Ll---;z 

Risk Assessment Branch IV ...:;;... ____ _ 

Health Effects Division (HED) (7509P) 

Through: Elissa Reaves, Ph.D., Branch Chief 

Risk Assessment Branch IV 

Health Effects Division (7509P) 

To: Carmen Rodia/Richard Gebken (RM I 0) 

Invertebrate-Vertebrate Branch 2 

Registration Division (RD) (7505P) 

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Table of Contents 

1.0 Executive Su1nmary ... ................................................................................... ........................ 4 

2.0 HED Recomn1endations .... .... ...................... ..................... ........ .............. ....... ................ ... ..... 6 

2.1 Data Deficienci es ........................ .... ......... ......... ............ ............... ...................................... 7 

2.2 Tolerance Considerations .. .... ......... ..... .... .... ..... .... .... ............... .... ....... ... .... .......... ... ... ........ 7 

2.2. l Enforcement Analytical Method ................................................................... ... ........... 7 

2.2.2 International Harmonization ....................................................................................... 7 

2.2.3 Recommended Tolerances .......................................................................................... 7 

2.2.4 Revisions to Petitioned-For Tolerances ...................................................................... 8 

2.3 Label Recomn1endations .................. ................................................................................. 8 

3.0 Introduction ..................................... ............. ............. .... ........ .... .............. .... ...... ....... ............. 8 

3. 1 Chemical Identity ....... .... .... ......... ..................... ..... .... .......................... .............................. 8 

3 .2 Physical/Chemical Characteristics .......... ............. .... ..... ....... ........... ....... .......... ... .......... .... 8 

3.3 Pesticide Use Pattern .................................................................................... .......... ........... 9 

3.4 Anticipated Exposure Pathways ................................................................... ............. ... .. 9 

3.5 Considerations of Environmental Justice .......................................................................... 9 

4.0 Hazard Characterization and Assessment ........................................................................... I 0 

4.1 Toxicology Studies Available for Analysis ........ ........................... .................................. 10 

4.2 Absorption, Distribution, Metabolism and Excretion ...................... ............................... 10 

4.2.1 Dermal Absorption .... .... ............. .... .... ..................................................... ... ....... ... ..... I I 

4.3 Toxicological Effects .. ............ .............. ........ ......... ........ .... .............................................. 11 

4.4 Safety Factor fo r Infants and Children (FQPA Safety Factor) ........................................ 13 

4.4.1 Completeness of the Toxicology Database .................... ........................................... 13 

4.4.2 .Evidence of Neurotoxicity ....................................................... ... .............................. 13 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........... 13 

4.4.4 Residual Uncertainty in the Exposure Database ....................................................... 14 

4.5 Toxicity Endpoint and Point of Departure ....... ........ ........................................... ............ 14 

4.5.1 Dose-Response Assessment.. ....... ..... ..................... ........ ............................... ... ......... 14 

4.5 .2 Recommendations for Combining Exposure Routes ................................................ 15 

4.5.3 Classification of Carcinogenic Potential ................................................................... 15 

4.5.4 Summary of Points of Departure Used in Risk Assessment.. ................................... 16 

5.0 Dietary Exposure and Risk Assessment ............................................................................. 19 

5.1 Metabolite/ Degradate Residue Profile ......................................................................... 19 

5.1. l Summary of Plant and Livestock Metabolism Studies .............................. ............. .. 19 

5.1.2 Comparison of Metabolic Pathways ......................................................................... 19 

5.1.3 Summary of Environmental Degradation ......... .... ................ ... ................. ................ 19 

5.1.4 Residues of Concern Summary and Rationale ............. ...................................... ....... 20 

5.2 Food Residue Profile ....................................................................................................... 20 

5.3 Water Residue Profile .................................................................................................. 21 

5.4 Dietary Exposure and Risk Assessment.. ..................................................................... 22 

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5.4.1 Acute Dietary and Drinking Water Analysis............................................................ 22

5.4.2 Chronic Dietary and Drinking Water Analysis......................................................... 22

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ..................................... 22

6.1 Residential Handler Exposure ......................................................................................... 23

6.2 Residential Post-Application Exposure........................................................................... 23

6.3 Residential Bystander Post-application Inhalation Exposure.......................................... 25

6.4 Spray Drift ....................................................................................................................... 25

7.1 Residential Risk Estimates for Use in Aggregate Assessments...................................... 26

7.0 Aggregate Exposure and Risk Assessment......................................................................... 26

7.1 Short-Term Aggregate Risk............................................................................................. 26

7.2 Intermediate-Term Aggregate Risk ................................................................................. 27

7.3 Long-Term Aggregate Risk............................................................................................. 27

8.0 Cumulative Risk.................................................................................................................. 28

9.0 Occupational Exposure and Risk Characterization............................................................. 29

10.0 References ....................................................................................................................... 29

Appendix A. Toxicology Profile and Executive Summaries....................................................... 30

A.1 Toxicology Data Requirements.................................................................................... 30

A.2 Toxicity Profiles........................................................................................................... 31

A.3 Toxicological Endpoints .............................................................................................. 40

A.4 Executive Summaries.................................................................................................. 42

Appendix B: Proposed Metabolic Pathway for Pyriproxyfen ...................................................... 57

Appendix C. Studies Reviewed for Ethical Conduct................................................................... 58
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1.0 Executive Summary

This assessment supports the petition to increase the currently established tolerance for residues 

of pyriproxyfen in/on tea to cover residues in/on pyriproxyfen-treated tea imported from Japan. 

It addresses the exposures and human health risks associated with exposures from currently 

registered uses of pyriproxyfen and the proposed tolerance increase in/on tea. It also assesses 

potential enhanced sensitivity of infants and children from dietary and/or residential exposure as 

required under the Food Quality Protection Act (FQPA) of 1996. 

Pyriproxyfen [2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine] is a broad spectrum pyridinebased insect growth regulator used to control a variety of insects in agriculture and nonagricultural areas. It acts by suppressing embryogenesis within the insect egg and inhibiting 

metamorphosis and adult emergence of target insects. It has numerous food, feed and non-food 

crop agricultural uses, as well as, commercial, and residential uses. Commercial uses include 

applications in and around food handling establishments and other commercial structures. 

Residential uses include applications both inside the home and outside on gardens, lawns, 

ornamentals, patios, and other outdoor structures. It is also directly applied to pets. End use 

formulations include emulsifiable concentrates, soluble concentrates, liquid ready-to-use, 

pressurized liquids, granules, dust, pellets, microencapsulates, and impregnated material. It is 

applied by both professional pest control operators and homeowners. It is applied to agricultural 

fields with aerial and ground equipment. It is applied to indoor sites with surface, space, and 

directed crack and crevice sprayers, aerosol generators, and foggers. For outdoor sites, liquid 

formulations are applied as surface sprays or directed perimeter treatment around buildings and 

structures. The granular formulation may be applied as a broadcast outdoor treatment to 

commercial and residential areas using aerial or ground equipment. 

Permanent tolerances are established under 40 CFR §180.510(a)(1) for residues of pyriproxyfen 

in/on numerous crops (no livestock commodities) ranging from 0.02 ppm to 100 ppm; including 

a tolerance in/on tea at 0.02 ppm resulting from the domestic use of pyriproxyfen as an ant bait

(EPA Reg. No. 59639-114). A tolerance is also established under 40 CFR §180.510(a)(2) at 0.10 

ppm for all food commodities for the use of pyriproxyfen in food handling establishments. 

Sumitomo Chemical Company, LTD through their agent, Valent U.S.A. Corporation, has 

submitted a petition (PP# 4E8326) to increase the currently established tolerance in/on tea from 

0.02 to 15 ppm to cover residues in/on pyriproxyfen-treated tea. The proposed use is on tea 

grown in Japan treated with Pluto MC (not registered in the U.S.), described as a 9% 

microcapsule formulation of pyriproxyfen. The maximum application rate is one application at 

1000L/10a (where a equals 100 m2) of a 1000x dilution of the end-use product (reviewer 

calculated use rate is 0.8 lb ai/A) and a 30-day pre-harvest interval (PHI).
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Hazard Identification

Pyriproxyfen was absorbed, metabolized, and rapidly excreted, primarily in the feces, in the rat 

metabolism study. There were no effects of sex or dose on absorption or elimination; however, 

the extent of metabolism and prevalence of metabolites was sex-dependent. The liver and kidney 

are the principal targets for pyriproxyfen after repeated dose exposures in mice, rats and dogs. 

Rodents and dogs also experienced slight anemia from chronic and subchronic exposures. The 

review of the acute and subchronic neurotoxicity studies indicates that pyriproxyfen is not a 

neurotoxic chemical. There was no evidence of prenatal or postnatal sensitivity or increased 

susceptibility in developmental studies in rats and rabbits, and in reproduction studies in rats. In 

the 2-generation reproduction toxicity study, offspring toxicity (lower pup body weight during 

lactation days 14 to 21) occurred in the presence of lower body weight in parental animals at the 

same dose level. Pyriproxyfen did not target the reproductive system. An immunotoxicity study 

showed no adverse effects on the immune system. No significant systemic toxicity was observed 

in either the 21-day dermal toxicity study in rats or in the 28-day inhalation study at exposure 

levels up to 1000 mg/kg/day and 1 mg/L, respectively. Pyriproxyfen has low acute toxicity by 

oral, dermal, inhalation and ocular routes of exposure (all studies either Toxicity Category III or 

IV). Pyriproxyfen is not a skin irritant (Toxicity Category IV) and was negative in the dermal 

sensitization study in guinea pigs. With respect to carcinogenicity, pyriproxyfen has been 

classified as a "Group E" chemical (no evidence for carcinogenicity to humans) based on the 

absence of carcinogenicity in mice and rats. Pyriproxyfen is negative for mutagenic activity in a 

battery of mutagenicity studies conducted with both the parent and/or metabolites. 

Dose Response Assessment

The toxicology database for pyriproxyfen is complete. The acute and subchronic neurotoxicity 

studies were negative and the immunotoxicity study was negative. There is no evidence of 

quantitative or qualitative susceptibility of the young following in utero prenatal exposure in rat 

and rabbit developmental studies and pre/postnatal exposure in the rat 2-generation reproduction 

study. Therefore, the FQPA Safety Factor (SF) is reduced to 1X.

An acute reference dose (aRfD) was not established for females 13-50 years old or the general 

population, because acute oral effects attributed to a single-dose exposure could not be identified 

in the toxicology database, including the acute neurotoxicity study and the developmental 

toxicity studies. A chronic reference dose (cRfD) of 0.35 mg/kg/day was determined on the 

basis of depressed body weight gain, anemia, and increased total cholesterol and phospholipid 

levels concurrent with increased relative liver weight at 141.28 mg/kg/day in two co-critical rat 

toxicity studies (subchronic and chronic). Since the FQPA SF has been reduced to 1X, the 

chronic population-adjusted dose (cPAD) is equal to the cRfD.

The short-term incidental oral endpoint of 100 mg/kg/day was based on lower body weight, 

depressed body weight gain and food consumption, and increased water consumption at the 

maternal lowest observed adverse effect level (LOAEL) of 300 mg/kg/day in a rat developmental 

toxicity study. The intermediate-term incidental oral endpoint of 35.1 mg/kg/day was based on 

systemic toxicity at the LOAEL of 141.28 mg/kg/day in two co-critical rat toxicity studies 

(subchronic and chronic).
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Short- and intermediate-term dermal endpoints were not selected since there was no systemic 

toxicity up to the limit dose of 1,000 mg/kg/day in the 21-day dermal toxicity study in rats. 

Likewise, short- and intermediate-term inhalation endpoints were not selected based on the lack 

of biologically adverse effects at 1.0 mg/L in the 28-day inhalation toxicity study in rats. Longterm dermal and inhalation endpoints were set at 35.1 mg/kg/day based on systemic toxicity in

the two co-critical (subchronic and chronic) rat feeding studies. A dermal absorption factor 

(DAF) of 30% was employed for oral to dermal route extrapolation. For long-term inhalation 

assessments, absorption from inhalation exposure was assumed to be equivalent to oral exposure. 

HED classified pyriproxyfen as a "Group E" chemical, no evidence for carcinogenicity to 

humans, based on the absence of evidence of carcinogenicity in male and female rats as well as 

in male and female mice. Therefore, a cancer risk assessment is not required.

Exposure/Risk Assessment and Risk Characterization

A dietary (food and water) exposure and risk assessment was conducted based on the proposed 

tolerance increase in/on tea to cover residues in/on pyriproxyfen-treated tea. No new drinking 

water, residential or occupational exposure scenarios are associated with the proposed tolerance

increase. However, for this assessment, the previous residential exposure assessment conducted 

in accordance with HED’s 2012 Residential SOPs, was further updated to be consistent with 

current HED policies. An unrefined chronic dietary (food and drinking water) risk assessment 

for pyriproxyfen showed that dietary (food and drinking water) exposure estimates are below 

HED’s level of concern for the general population and all population subgroups. Residential and 

aggregate risks are not of concern.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, listed in Appendix C, have 

been determined to require a review of their ethical conduct. Some of these studies are also 

subject to review by the Human Studies Review Board. All of the studies used have received the 

appropriate review. 

2.0 HED Recommendations

Pending a minor revision to Section F of the petition and submission of a reference standard for 

pyriproxyfen, HED has no objection to granting an increase of the currently established tolerance 

for residues of pyriproxyfen in/on tea from 0.02 to 15 ppm to cover residues in/on pyriproxyfentreated tea as specified in Section 2.2.3.
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2.1 Data Deficiencies

There are no data deficiencies; however, an acceptable analytical reference standard is required 

for pyriproxyfen since none is currently available in EPA’s National Pesticide Standards 

Repository (email communication between T. Cole and B. Cropp-Kohlligian, 8/25/2015). 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

A gas chromatography with nitrogen-phosphorus detection (GC/NPD) method (RM-33P-1-3a or 

9.66 V 1) is available for pyriproxyfen tolerance enforcement. The method has undergone an 

adequate radiovalidation, independent laboratory validation trial, petition method validation trial, 

and has been forwarded to the FDA for inclusion in PAM Vol. II. The level of detection (LOD) 

and level of quantitation (LOQ) are 0.01 and 0.02 ppm, respectively.

2.2.2 International Harmonization

No Codex, Canadian or Mexican maximum residue limit (MRL) for residues of pyriproxyfen are 

established in/on tea commodities. Japan and the European Commission have established MRLs

for residues of pyriproxyfen in/on tea at 15 ppm. 

2.2.3 Recommended Tolerances

Using all of the submitted crude dried tea magnitude of the residue data in the Organization for 

Economic Cooperation and Development (OECD) calculation procedures resulted in a calculated 

tolerance level of 20 ppm. While details regarding the calculation procedures for the petitionedfor tolerance level (15.0 ppm) were not provided in the petition, HED believes that this 

calculation is the result of excluding the trial with the highest residues (Nara, Japan/2008) likely 

due to concerns about detectable residues in the untreated control for that trial. HED considered 

the results of this trial to be viable for tolerance determination and did not exclude it, given that 

the residues in the control sample (0.10 ppm) were well below the residues in the test sample 

(11.4 ppm) for the subject trial. However, HED is recommending for the petitioned-for tolerance 

level of 15 ppm to harmonize with the Japanese MRL in/on tea. 

HED recommends that 40 CFR §180.510 be amended to increase the currently established 

tolerance for residues of pyriproxyfen in/on tea from 0.02 ppm to 15 ppm. HED has determined 

that the correct commodity definition should remain tea and the recommended tolerance level 

will cover incurred residues of pyriproxyfen in/on all tea commodities resulting from both 

currently registered domestic use and the proposed non-domestic use of pyriproxyfen. 

See Table 2.2.3.1.
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Table 2.2..3.1 Tolerance Summary for Pyriproxyfen

Commodity as Proposed 

by Petitioner

Proposed Tolerance 

(ppm)

Recommended Tolerance 

(ppm)

Correct Commodity 

Definition; Comments

Tea 15.0 151 Tea

1 The CFR should not include any further notation for this tolerance. Although the recommended tolerance level 

is not based on domestic use of pyriproxyfen, there is a U.S. registration for the use of pyriproxyfen as an ant 

bait (EPA Reg. No. 59639-114).

2.2.4 Revisions to Petitioned-For Tolerances

The petitioned-for tolerance for residues of pyriproxyfen in/on tea (15.0 ppm) must be corrected 

to 15 ppm, consistent with current practices for setting tolerances, and section F of the petition 

should be revised accordingly. 

2.3 Label Recommendations

None.

3.0 Introduction

3.1 Chemical Identity

Table 3.1.1 Test Compound Nomenclature.

Pyriproxyfen

Common name Pyriproxyfen

Company experimental name S-71639, S-31183

IUPAC name 4-phenoxyphenyl (RS)-2-(2-pyridyloxy)propyl ether

CAS name 2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine

CAS # 95737-68-1

End-use products/(EP) Not Applicable

3.2 Physical/Chemical Characteristics 

Table 3.2.1 Physicochemical Properties of the Technical Grade Test Compound: Pyriproxyfen. 

Parameter Value Reference

Melting range 45-47°C Physical Chemical 

pH (20°C) 6.4 Characteristics Summary

Density (25°C) 1.24

Water solubility (mg/L at 25°C) 0.367

Solvent solubility (mg/L at 20°C) 76700 Hexane 

60100 Methanol

The Pesticide Manual

Vapor pressure (20°C) 1.0x10-7 mmHg Physical Chemical 

Dissociation constant (pKa) Not Available Characteristics Summary

Octanol/water partition coefficient (Log KOW) 5.37 @ 25°C

UV/visible absorption spectrum 288 and 330 nm

O O CH2 CH

CH3

O

N
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3.3 Pesticide Use Pattern

The proposed use is on tea grown in Japan treated with Pluto MC (not registered in the U.S.), 

described as a 9% microcapsule formulation of pyriproxyfen. The maximum application rate is 

one application at 1000L/10a (where a equals 100 m2) of a 1000x dilution of the end-use product 

(reviewer calculated use rate is 0.8 lb ai/A) and a 30-days pre-harvest interval (PHI).

3.4 Anticipated Exposure Pathways

Dietary (food and water), residential and occupational exposure are expected based on existing 

uses of pyriproxyfen. The proposed tolerance increase in/on tea to cover residues in/on 

pyriproxyfen-treated tea will contribute to dietary (food only) exposure. No new drinking water, 

residential or occupational exposure scenarios are associated with the proposed tolerance 

increase. The previous residential exposure assessment conducted in accordance with HED’s 

2012 Residential SOPs (DP# 404203), was further updated to be consistent with current HED 

policies. The short-, intermediate- and long-term aggregate exposure assessments were updated 

to incorporate the updated residential exposure and updated dietary exposure from the petitionedfor increase in the tolerance for residues of pyriproxyfen in/on tea. 

3.5 Considerations of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

(http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf). 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and/or the 

CDC under the National Health and Nutrition Examination Survey/What We Eat in America 

(NHANES/WWEIA), and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.
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4.0 Hazard Characterization and Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database is complete and acceptable for characterizing pyriproxyfen hazard and 

includes the following studies:

- 90 day oral toxicity study – rat, mouse, and dog

- 21 day dermal toxicity study – rat 

- 28 day inhalation study - rat

- Prenatal developmental toxicity study – rat and rabbit

- Multi-generation reproduction and fertility toxicity study – rat

- 1 year chronic toxicity study – dog

- 2 year chronic toxicity/carcinogenicity study – rat 

- 2 year carcinogenicity study – mouse

- Mutagenicity battery

- Acute and subchronic neurotoxicity study – rat 

- Metabolism pharmacokinetics study – rat 

- Immunotoxicity study

4.2 Absorption, Distribution, Metabolism and Excretion

Absorption was nearly identical in males and females provided a single oral dose of 2 mg/kg 

(low dose) or 1000 mg/kg (high dose). Based on urine concentration pyriproxyfen was not easily 

absorbed (<12%) and was excreted rapidly (88.9 – 92.9% within 2 days). Excretion was near 

complete (92.3 - 98.5%) after 7 days despite a dip in the rate of elimination after the second day. 

Fecal excretion was the dominant elimination pathway after both low (86.1 – 93.2%) and high 

dose (84.7 – 89%) exposures. Urine excretion was minor compared to fecal elimination, but was 

more prominent in the high dose (7.5 – 11.8%) than in low dose (4.9 – 5.7%). Release of 

pyriproxyfen in expired air was not a significant (<0.5%). 

Metabolism was affected both by dose and the sex of the animal. Feces contained up to 17

metabolites whereas 11 were identified in the urine. Parent compound was identified in both 

forms of excreta. Metabolism was more extensive in females with only 21.2 – 21.9% of the 

parent compound remaining in the excreta compared to 32.5 – 34.8% in males. Metabolism of 

pyriproxyfen occurred primarily through hydroxylation at the 4’-position of the terminal phenyl 

ring. Metabolism via this pathway was utilized more in females (49.3 – 53.6%) than in males 

(32.1 – 43.3%) regardless of dose. Hydroxylation at the 2’-position of the phenyl ring was not as 

extensive, but was favored more at low dose (1.8 – 2.8%) than at the high dose (0.2%). 

Hydroxylation at the 5”-position of pyridyl ring, another minor pathway, was also more 

prevalent at the low dose (1.4 – 7.8% compared to 0.9 – 1.4% at the high dose). Unlike 

hydroxylation of the phenyl ring, hydroxylation of the pyridyl ring was more prominent in males 

(1.4 – 7.8%) than in females (0.9 – 1.7%). Of the minor metabolic pathways, high dose animals 

preferred sulfuric acid conjugation accounting for 1.2 – 2.8% compared to 0.8 – 2.4% in low 

dose animals. Minor metabolites born from dephenylation (0.8 – 1.6%) and conjugation with 

glucuronic acid (0.2 – 11%) were comparable across sex and dose. A proposed metabolic 
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pathway for pyriproxyfen is illustrated in Appendix B.

4’-OH-pyriproxyfen was the dominant fecal metabolite at both doses accounting for 23.3 –

38.4% in males and 46.4 – 47.2% in females. At the low dose other major metabolites were 

5”,4’-OH-pyriproxyfen (7.2% in males and 1.2 % in females) and 2’-OH-pyriproxyfen (1.8% in 

males and 2.8% in females). At high doses these metabolites were not as common, accounting 

for only 0.2 – 0.4% of the administered dose. Instead the major fecal metabolites were DPHpyriproxyfen and 4’-OH-pyriproxyfen-sulfate (combined 1.2 – 1.6%). Small quantities of these 

metabolites were present in low dose animals (<1.1%). The major urinary metabolite was 2-(2-

pyridyloxy) propionic acid (PYPAC) which accounted for 1 – 4.9%. The sulfuric acid 

conjugated compounds, 4’-OH-pyriproxyfen-sulfate and 5”,4’-OH-pyriproxyfen-sulfate, were 

also present at much lower concentrations (0.1 – 0.8% of the administered dose). Parent 

compound was only identified in urine of high dose animals (1.3% in males, and 2.7% in 

females). 4’-OH-pyriproxyfen was also identified in the urine at 1% in males and 5.6% in 

females; however, this metabolite and the parent compound were not observed in the urine of all 

animals and it is hypothesized that these metabolites originated from feces contamination and 

would otherwise not be present in the urine. 

No sex or dose related disparities were identified in the tissue distribution. Residual tissue 

concentration increased with dose but total accumulation never exceeded 0.3% of the 

administered dose 7 days after exposure. The residual carcass and fat were the primary sinks for 

pyriproxyfen amassing 0.065 – 0.148% and 0.024 – 0.042% of the administered dose, 

respectively. Minimal accumulation was observed in the liver (0.16 – 0.22%) and even less was 

present in the kidneys (0.002 – 0.003%). Between 0.006 and 0.013% was in circulation on seven 

days after exposure. The remaining tissues contained insignificant amounts of pyriproxyfen 

(<0.001%). 

4.2.1 Dermal Absorption

A dermal absorption study is not available for pyriproxyfen. However, a 21-day dermal rat 

toxicity study resulted in no toxicity up to the limit dose and; therefore, short- and intermediateterm dermal exposure assessments are not warranted. An oral endpoint was selected to be 

protective of the long-term dermal assessment. For the long-term dermal assessment, dermal 

penetration was estimated to be 30% by the extrapolation method of comparing the maternal 

toxicity LOAEL of 300 mg/kg/day in the rat developmental toxicity oral study and the dermal 

NOAEL of 1,000 mg/kg/day in the 21-day dermal study. These studies were both in the rat and 

approximately the same duration in exposure. Thus, a dermal-penetration factor of 30% was 

used for the route-to-route extrapolation in this long-term dermal risk assessment, since an oral 

study was selected for the endpoint.

4.3 Toxicological Effects

Pyriproxyfen is a broad spectrum pyridine insecticide. It mimics the insect juvenile hormone 

(JH) disrupting tightly controlled and temporally dependent growth and development pathways. 

In mammals, adults were more susceptible to pyriproxyfen exposure than developing young 

implying a mode of action not specific to developmental pathways. Primary targets for 
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pyriproxyfen were the liver (increased absolute and relative weight concurrent with elevated 

serum enzyme, cholesterol and phospholipid levels, hepatocyte enlargement, distended 

gallbladders), and the hematopoietic system (decreased red blood cell, hematocrit and 

hemoglobin counts) across all mammals examined. The kidneys (increased relative weight, 

tubular nephritis with dilation of renal tubules and focal mineralization, dilation of the renal 

pelvis, chronic interstitial nephritis) also appeared to be a target in rodent species; however, these 

histopathological lesions are also commonly observed in aging rodents and in many instances 

there were no associated clinical chemistry changes indicative of kidney toxicity. Systemic 

toxicity, manifest as reduced body weight (rat only), and depressed body weight gain and food 

consumption, often accompanied the liver, kidney, and hematological effects. Rats were more 

sensitive to oral exposure compared to mice or dogs; however, toxicity did not become more 

severe with exposure duration. The lack of progression was likely facilitated by the rapid 

elimination of the compound within 2 days of exposure that limited tissue accumulation and 

minimized damage to sensitive organs. 

Developing rats and rabbits and rat pups were not more sensitive or susceptible to pyriproxyfen 

exposure than the adults. Systemic toxicity (decreased body weight, body weight gain, food 

consumption), clinical signs of distress, decreased activity, and abortions in maternal rats and 

rabbits either preceded or co-occurred with the onset of developmental injury. Developmental 

effects from in utero (skeletal and visceral variations and reduced pup viability) and postnatal 

(decreased pup weight and renal pelvis dilation) exposure were only noted at the limit dose and 

could be attributed to compromised maternal health. There was no evidence of exposureinduced developmental anomalies in the fetal nervous system or of an exposure related 

deleterious influence on functional postnatal development in rats. Pyriproxyfen did not affect 

reproduction.

Other critical physiological systems were not uniquely sensitive to pyriproxyfen. Neurological 

effects (decreased motor activity after acute exposure) occurred in the absence of altered brain 

weight or histopathology (non-perfused tissues) at or above the limit dose. The respiratory 

system was unaffected in chronic and subchronic oral, dermal, and inhalation exposures and rats 

were tolerant of acute inhalation exposures to pyriproxyfen (Category III). The immune system 

was similarly unaffected after oral exposure up to the limit dose. Exceedingly high dermal doses 

are required to elicit dermal and systemic toxicity in subchronic exposures, and mortality 

(Category III) and irritation in acute exposures (Category IV). It is not a dermal sensitizer nor a 

strong eye irritant (Category IV). 

Neither pyriproxyfen nor its common metabolites (listed in section 4.2) demonstrated mutagenic 

behavior or carcinogenicity after long-term exposure. Pyriproxyfen is classified as a "Group E"

chemical indicating there is no evidence for carcinogenicity to humans based on the absence of 

carcinogenicity in mice and rats (TXR 0012966). 

The complete toxicity profile for pyriproxyfen is provided in Appendix A. 
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4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The 10X FQPA safety factor to account for potential increased susceptibility of infants and 

children is reduced to 1X for pyriproxyfen based on the following considerations:

1) The toxicology data base is complete and adequate for assessing increased infant and 

child susceptibility under FQPA 

2) There is no evidence of qualitative or quantitative susceptibility in developing rat and 

rabbit fetuses or in rat pups

3) There are no residual uncertainties in the exposure database

4) Exposure assessments are conservative and will not under-estimate exposure (see 

4.4.4 below)

4.4.1 Completeness of the Toxicology Database

The toxicity database is complete and adequate for assessing the susceptibility of infants and 

children to pyriproxyfen exposure (section 4.1). Qualitative and quantitative susceptibility at 

critical developmental life stages was addressed in two guideline developmental studies, two 

non-guideline developmental studies, and a 2-generation reproduction study. Additionally, a 

neurotoxicity battery and immunotoxicity study were available to assess unique susceptibly in 

these systems. 

4.4.2 Evidence of Neurotoxicity

The neurotoxicity battery provides no evidence to support a neurotoxic mode of action for 

pyriproxyfen. Decreases in motor activity were only observed above the limit dose (2000 

mg/kg/day) in the acute neurotoxicity (ACN) study and no neurotoxicity was observed in the 

subchronic neurotoxicity (SCN) study. Systemic effects in the SCN (reduced body weight, body 

weight gain, and food consumption) occurred in the absence of neurotoxic symptoms and no 

biologically relevant signs of neurotoxicity were observed in the other submitted studies 

indicating the nervous system is not the primary target of pyriproxyfen or its metabolites. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There are no indications from the pyriproxyfen database of sensitivity to infants and children. 

There was no evidence of prenatal or postnatal sensitivity or increased susceptibility in 

developmental studies in rats and rabbits, or in reproduction studies in rats. No evidence of 

developmental anomalies of the fetal nervous system was observed in prenatal developmental 

toxicity studies in either rats or rabbits at maternally toxic doses up to 1,000 mg/kg/day and 300 

mg/kg/day, respectively. There was no evidence of an effect on functional development during 

the postnatal period of a special developmental study in rats. In the 2-generation reproduction 

toxicity study, offspring toxicity (lower pup body weight relative to controls during lactation 

days 14 to 21) occurred in the presence of lower body weight in parental animals at the same 

dose level (i.e., comparable toxicity in adults and offspring). In the two non-guideline studies 

that evaluated perinatal and prenatal development, there was no evidence of quantitative or 

qualitative increased susceptibility. In one study, when pregnant rats were treated from gestation 
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day 17 to lactation day 20, the resulting toxicity was comparable between adults (clinical signs, 

depressed body weight gain and food consumption) and offspring (lower body weight and 

dilation of the renal pelvis) at the same dose. In the other study, when rats were exposed to 

pyriproxyfen prior to and during the early stages of pregnancy, no developmental toxicity was 

seen at the limit dose. 

4.4.4 Residual Uncertainty in the Exposure Database 

There are no residual uncertainties in the hazard or exposure databases. The dietary, drinking 

water, and residential exposure assessment included herein are considered conservative; the 

dietary assessment assumed 100% crop treated, DEEM 7.81 default processing factors, 

tolerance-level residues; the drinking water assessment was based on screening-level estimates 

of drinking water concentrations (EDWCs) generated by Tier 1 models; and the residential 

assessment did not take into account the daily dissipation of pyriproxyfen residues.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose-Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (food and water), occupational, 

and residential exposure scenarios are summarized below. A detailed description of the studies 

used as a basis for the selected endpoints is presented in Appendix A. 

An acute reference dose (aRfD) was not established for females 13-49 years old or the general 

population, because acute oral effects attributed to a single-dose exposure could not be identified 

in the toxicology database, including the developmental toxicity studies. Acute toxicity in the 

ACN study was observed only at doses that were not relevant to human exposure (i.e. above the 

limit dose) and were not considered in selecting endpoints for acute dietary assessments. 

The cRfD of 0.35 mg/kg/day was determined on the basis of depressed body weight gain, 

anemia, and increased relative liver weight with elevated serum cholesterol and phospholipid 

levels.in two co-critical rat toxicity studies (subchronic and chronic). The NOAEL from the 

chronic study, 35.1 mg/kg/day, was selected to set the chronic endpoint. Since the FQPA Safety 

Factor (SF) has been reduced to 1X, the chronic population-adjusted dose (cPAD) is equal to the 

cRfD.

Short-term incidental oral endpoint (NOAEL 100 mg/kg/day) was selected from the rat 

developmental based on decreased body weight, body weight gain, and food consumption, and 

increased water consumption at the maternal LOAEL of 300 mg/kg/day. The intermediate-term 

incidental oral endpoint (NOAEL = 35.1 mg/kg/day) was determined based on systemic toxicity 

described above (LOAEL = 141.28 mg/kg/day) in two co-critical rat toxicity studies (subchronic 

and chronic).

Short- and intermediate-term dermal endpoints were not selected since there was no systemic 

toxicity up to the limit dose of 1,000 mg/kg/day in the 21-day dermal toxicity study in rats. The 

long-term dermal endpoint was based on the systemic toxicity no-observed adverse-effect level 
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(NOAEL) of 35.1 mg/kg/day from the two co-critical (subchronic and chronic) rat feeding 

studies. An estimated dermal absorption factor of 30% was used for route-to-route extrapolation.

Short- and intermediate-term inhalation endpoints were not selected based on the lack of 

biologically adverse effects at 1.0 mg/L in the 28-day inhalation toxicity study in rats. The longterm inhalation endpoint was based on the systemic toxicity oral NOAEL of 35.1 mg/kg/day 

from the two co-critical (subchronic and chronic) rat feeding studies. Absorption from inhalation

exposure was assumed to be 100% for route-to-route extrapolation.

A UF 100x was applied to all dietary, residential, and occupational endpoints to account for 

interspecies extrapolation (10x) and intraspecies variation (10x).

HED classified pyriproxyfen as a "Group E" chemical, no evidence for carcinogenicity to 

humans, based on the absence of evidence of carcinogenicity in male and female rats as well as 

in male and female mice (TXR 0012966). Therefore, a cancer risk assessment is not required. 

It is recognized that the studies in the pyriproxyfen database, including some of those used for 

endpoint selection, have not been updated to reflect current policy and may be considered 

conservative. The currently selected PODs are protective of the effects observed in the 

pyriproxyfen database and any updates would not impact the overall findings of the risk 

assessment given the current risk picture for pyriproxyfen. 

4.5.2 Recommendations for Combining Exposure Routes

When there are potential residential exposures to the pesticide, risk assessment must consider 

exposures from three major sources: oral, dermal and inhalation exposures. If the toxicity 

endpoints and PODs for dermal, oral, and inhalation routes of exposure are similar the exposure 

or risk estimates from these exposure routes need to be combined. A common toxicity endpoint 

(decreases in body weight and alterations in clinical pathology parameters) was identified for the 

oral, dermal (oral equivalent) and inhalation (oral equivalent) routes; therefore, these routes can 

be combined for the appropriate populations for long-term aggregate risk assessment. Short- and 

intermediate-term exposures were not combined because no dermal or inhalation hazards were 

identified for these durations. 

4.5.3 Classification of Carcinogenic Potential

In accordance with the Agency’s 1986 Guidelines for Carcinogenic Risk Assessment, the 

RfD/Peer Review Committee classified pyriproxyfen as a "Group E" chemical - negative for 

carcinogenicity to humans (TXR 0012966). This classification is based on the lack of evidence 

of carcinogenicity in mice and rats. 
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4.5.4 Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints selected for dietary (Table 4.5.4.1), non-occupational (Table 

4.5.4.1), and occupational (Table 4.5.4.2) risk assessment are provided below.

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Pyriproxyfen for Use in Dietary and 

Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/F

QPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(All 

Populations)

An appropriate endpoint attributable to a single oral dose was not identified in the toxicology 

database, including the developmental and reproduction toxicity studies.

Chronic 

Dietary (All 

Populations)1

NOAEL = 35.1 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD 

= 0.35 

mg/kg/day

cPAD = 0.35 

mg/kg/day

Subchronic (41321716 ) and chronic 

(43210503) – rat (co-critical)

LOAEL = 141.28 mg/kg/day based on 

depressed and body weight gain, anemia, 

and increased relative liver weight with 

elevated cholesterol and phospholipid 

levels.

Short-Term 

Incidental, 

Oral (1-30 

days)

NOAEL = 100 

mg/kg/day

UFA= 10x

UFH=10x

LOC for 

MOE = 100

Rat developmental toxicity (44985002)

Maternal LOAEL = 300 mg/kg/day 

based on decreased body weight, body 

weight gain, and food consumption, and 

increased water consumption

IntermediateTerm 

Incidental, 

Oral (1-6 

months)1

NOAEL = 35.1 

mg/kg/day

UFA= 10x

UFH=10x

LOC for 

MOE = 100

Subchronic (41321716 ) and chronic 

(43210503) – rat (co-critical)

LOAEL = 141.28 mg/kg/day based on 

depressed body weight gain, anemia, 

and increased relative liver weight with 

elevated cholesterol and phospholipid 

levels.

Short-, and 

IntermediateTerm Dermal 

(1-30 days 

and 1-6 

months)

Based on the systemic toxicity NOAEL of 1,000 mg/kg/day (limit dose) in the 21 day dermal 

toxicity study in rats, quantification of dermal risks is not required. In addition, no 

developmental concerns (toxicity) were seen in either rats or rabbits.
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Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Pyriproxyfen for Use in Dietary and 

Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/F

QPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Long-Term

Dermal (6 

monthslifetime)1

NOAEL = 35.1 

mg/kg/day

DAF = 30%2

UFA= 10x

UFH=10x LOC for 

MOE = 100

Subchronic (41321716 ) and chronic 

(43210503) – rat (co-critical)

LOAEL = 141.28 mg/kg/day based on 

depressed body weight gain, anemia, and 

increased relative liver weight with 

elevated cholesterol and phospholipid 

levels.

Short-, and 

IntermediateTerm 

Inhalation (1-

30 days and 1-

6 months)

Based on the absence of biologically relevant toxicity at 1.0 mg/L, the quantification of 

inhalation risks is not required. In addition, no developmental concerns (toxicity) were seen in 

either rats or rabbits.

Long-Term 

Inhalation (6 

monthslifetime)1

NOAEL = 35.1 

mg/kg/day

UFA= 10x

UFH=10x LOC for 

MOE = 100

Subchronic (41321716 ) and chronic 

(43210503) – rat (co-critical)

LOAEL = 141.28 mg/kg/day based on 

depressed body weight gain, anemia, and 

increased relative liver weight with 

elevated cholesterol and phospholipid 

levels.

Cancer (oral, 

dermal, 

inhalation)

In accordance with the Agency’s 1986 Guidelines for Carcinogenic Risk Assessment, the 

RfD/Peer Review Committee classified pyriproxyfen as a "Group E" chemical - negative for 

carcinogenicity to humans. This classification is based on the lack of evidence of 

carcinogenicity in mice and rats (TXR 0012966). 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. DAF = dermal absorption factor 

1The NOAEL and LOAEL for the co-critical studies were based on the female endpoints from the chronic and subchronic rat studies, respectively. Females demonstrated greater or equivalent sensitivity to oral pyriproxyfen 

exposure relative to males; therefore, selection of two female endpoints accounted for effects observed in the males 

while maintaining consistency between the NOAEL and LOAEL.

2DAF estimated by comparing the rat developmental LOAEL of 300 mg/kg/day to the 21-day rat dermal study 

NOAEL of 1000 mg/kg/day (No NOAEL) = 300/1000=30%.
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Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Pyriproxyfen for Use in Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/F

QPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Short-, and 

IntermediateTerm Dermal 

(1-30 days 

and 1-6 

months)

Based on the systemic toxicity NOAEL of 1,000 mg/kg/day (limit dose) in the 21 day dermal 

toxicity study in rats, quantification of dermal risks is not required. In addition, no 

developmental concerns (toxicity) were seen in either rats or rabbits.

Long-Term

Dermal (6 

monthslifetime)

NOAEL = 35.1 

mg/kg/day

DAF = 30%*

UFA= 10x

UFH=10x LOC for 

MOE = 100

Subchronic (41321716 ) and chronic 

(43210503) – rat (co-critical)

LOAEL = 141.28 mg/kg/day based on 

depressed body weight gain, anemia, and 

increased relative liver weight with 

elevated cholesterol and phospholipid 

levels.

Short-, and 

IntermediateTerm 

Inhalation (1-

30 days and 1-

6 months)

Based on the absence of biologically relevant toxicity at the LOAEL of 1.0 mg/L, the 

quantification of inhalation risks is not required. In addition, no developmental concerns 

(toxicity) were seen in either rats or rabbits.

Long-Term 

Inhalation (6 

monthslifetime)

NOAEL = 35.1 

mg/kg/day

UFA= 10x

UFH=10x LOC for 

MOE = 100

Subchronic (41321716 ) and chronic 

(43210503) – rat (co-critical)

LOAEL = 141.28 mg/kg/day based on 

depressed body weight gain, anemia, and 

increased relative liver weight with 

elevated cholesterol and phospholipid 

levels.

Cancer 

(dermal, 

inhalation)

In accordance with the Agency’s 1986 Guidelines for Carcinogenic Risk Assessment, the 

RfD/Peer Review Committee classified pyriproxyfen as a "Group E" chemical - negative for 

carcinogenicity to humans. This classification is based on the lack of evidence of 

carcinogenicity in mice and rats (TXR 0012966). 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). DAF = dermal absorption factor 

*DAF estimated by comparing the rat developmental LOAEL of 300 mg/kg/day to the 21-day rat dermal study 

NOAEL of 1000 mg/kg/day (No NOAEL) = 300/1000=30%.
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5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Livestock Metabolism Studies

Adequate metabolism studies for pyriproxyfen are available on apples, cotton, and tomatoes. 

Based on these studies, the Metabolism Assessment Review Committee (MARC) determined 

that the residue of concern in plants is pyriproxyfen (DP#: 250953). 

Adequate ruminant and poultry metabolism studies are available for pyriproxyfen. HED 

determined that should future crop uses increase the maximum theoretical dietary burden 

(MTDB) to the point that tolerances are needed in livestock commodities, the residue of concern 

will be pyriproxyfen and the free and sulfate forms of 4'-OH-PYR.

An adequate confined rotational crop study was conducted for pyriproxyfen. Based on a 30-day 

plant back interval (PBI) and a treatment rate of 0.18 lb ai/A, no pyriproxyfen residues above 

0.01 ppm were found in any of the following crop matrices: lettuce leaf; radish tops and roots; 

and wheat grain, forage, straw and chaff. Accordingly, HED concluded that a 30-day PBI for 

non-labeled crops is appropriate.

5.1.2 Comparison of Metabolic Pathways

HED determined that the residue of concern in plants is pyriproxyfen. HED determined that 

should future crop uses increase the MTDB to the point that tolerances are needed in livestock 

commodities, the residue of concern in livestock will be pyriproxyfen and the free and sulfate 

forms of 4'-OH-PYR.

5.1.3 Summary of Environmental Degradation

Pyriproxyfen is expected to possess low mobility in soil (average Koc = 19260), and is not 

expected to be persistent in the open environment. Pyriproxyfen is stable to hydrolysis and 

anaerobic degradation (t1⁄2 = 250 days), but is susceptible to photolytic transformation in water (t1⁄2

= 6.4 days) and aerobic degradation (t1⁄2 = 9 days). Pyriproxyfen has low volatility and low water 

solubility. Pyriproxyfen shows moderate bioconcentration in fish (465 to 2,390x), with a rapid 

depuration rate. 
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5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4.1 provides a summary of the HED MARC decisions regarding residues of concern 

for pyriproxyfen (DP# 250953).

Table 5.1.4.1 Summary of Metabolites and Degradates to be included in the Risk Assessment and 

Tolerance Expression.

Matrix

Residues included in 

Risk Assessment

Residues included in 

Tolerance Expression

Plants Primary Crop Pyriproxyfen Pyriproxyfen

Rotational Crop Pyriproxyfen Pyriproxyfen

Livestock Ruminant

Pyriproxyfen and the free and 

sulfate forms of 4'-OH-PYR

Pyriproxyfen and the free and 

sulfate forms of 4'-OH-PYR

Poultry

Pyriproxyfen and the free and 

sulfate forms of 4'-OH-PYR

Pyriproxyfen and the free and 

sulfate forms of 4'-OH-PYR

Drinking Water Pyriproxyfen Not Applicable

5.2 Food Residue Profile

No residue data on plucked (undried) tea leaves were submitted; however, these data are not 

required for imported tea. No residue data on instant tea were submitted; however, the HED 

ChemSAC has recently decided that these data are no longer required (ChemSAC meeting 

8/26/15). 

Adequate magnitude of the residue data were submitted for residues of pyriproxyfen in dried tea 

grown/processed in Japan to support the proposed tolerance increase. Ten field trials were 

conducted in Japan during the 2004, 2005 and 2008 growing seasons. At each trial location, 

treated plots received one foliar application of end-use product Pluto MC, described as a 9% 

microcapsule formulation of pyriproxyfen. The application rate was 1000L/10a (where a equals 

100 m2) of a 1000x dilution of the end-use product (reviewer calculated use rate is 0.8 lb ai/A) 

28-30 days prior to harvest. To provide decline data, separate sub-plots at each trial location 

were also treated with one application of Pluto MC at 0.8 lb ai/A 21-22, 42-45 or 60 days prior to 

harvest. All samples were collected on the same day. The report described this scheme as a 

“reverse decline study.” No adjuvant was used in any of the trials. 

Only one untreated and one treated field trial sample of buds/leaves were collected from six of 

the trial locations (i.e., Fukuoka/2005, Shizuoka/2008, Nara/2008, Fukuoka/2008, 

Miyazaki/2008 and Kagoshima Osumi/2008). Two untreated and two treated field trial samples 

of buds/leaves were collected from four of the trial locations (i.e., Fukuoka/2004, Mie/2004, 

Mie/2008 and Kagoshima/2008). Harvested tea buds/leaves were processed by a tea 

manufacturing machine to crude dried tea. Each sample of crude dried tea was analyzed at two 

different laboratories, the Mitsukaido Laboratories, Institute of Environmental Toxicity and the 

In-house Analysis Institute of Sumika Technoservice Corporation.

Details for processing the harvested tea buds/leaves into crude dried tea samples were not 

provided in the submission. However, in Japan crude dried tea, or aracha, is typically a type of 

green tea produced by repeated steaming, rolling and drying steps to form needle shaped tea 
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leaves for distribution to wholesalers, not consumers. Parts of the leaves are then sorted, sized, 

graded, and blended to produce sencha tea for the consumer.

Residues of pyriproxyfen in crude dried tea, processed from buds/leaves treated at the proposed 

use rate and collected at PHIs of 28-30 days, ranged from 0.10 ppm to 11.4 ppm. [Note: Since 

only one sample was collected from trial locations having the lowest and highest values, the 

values for the individual sample and per-trial averages were the same.] Residue decline data 

show that the levels of pyriproxyfen decrease in crude dried tea with increasing PHIs. Data were 

collected with adequate data-collection methods. Adequate storage stability data are available to 

support sample storage durations and conditions. See Table 5.2.1 below.

Table 5.2.1 Summary of Residues from Tea Trials Conducted in Japan with Pyriproxyfen.

Commodity Total Application 

Rate1

PHI2

(days)

Residue Levels (ppm)

n Min.3 Max.3 LAFT3 HAFT3 Median4 Mean4 Standard 

Deviation4

Crude dried 

tea

x1000

1000L/10a

(0.8 lb ai/A)

21-22 8 0.89 14.9 0.89 14.9 6.905 7.30 4.11

28-30 10 0.10 11.45 0.10 11.45 4.045 4.38 3.46

42-45 10 0.02 8.57 0.02 8.57 2.015 2.56 2.66

60 3 <0.01 0.03 <0.01 0.03 0.01 0.02 0.01

1 Reported use rate: End-use product registered in Japan is PLUTO MC, a microcapsule formulation which contains 9.0% 

(w/w) of pyriproxyfen. Dilute end-use product 1000x and apply 1000L/10a; where a equals 100 m2. All trials were 

reportedly conducted at this same use rate without any deviation.

Reviewer calculated use rate: 0.8 lb ai/A. 

2 All trials were conducted using a single application and included residue decline trials, referred to in the study report as 

“reverse decline trials.” At each test location, a separate single application was made to a separate section of the test plot at 

various times prior to harvest (reflecting different PHIs), but all test plot samples of buds/leaves were harvested on the same 

day and processed by a tea manufacturing machine to crude dried tea. 

3 Since only one sample was collected from trial locations having the lowest and highest values, the values for the Min. 

individual sample and lowest average field trial (LAFT) are the same and the values for the Max. individual sample and

highest average field trial (HAFT) are the same.

4 Calculation used the higher of the two samples from trial locations Fukuoka/2004, Mie/2004, Mie/2008 and 

Kagoshima/2008. 

5 Detectable residues were found in the control sample from the trial location having the highest test sample residue value 

(Nara, Japan/2008); however, the residues in the control sample (0.10 ppm) were well below the residues in the test sample 

(11.4 ppm). The test sample value is considered viable for inclusion in the tolerance determination.

5.3 Water Residue Profile

No new drinking water exposure scenarios are associated with the proposed tea tolerance 

increase for pyriproxyfen-treated imported tea. The following information concerning the 

environmental fate and drinking water assessment of pyriproxyfen for existing uses of 

pyriproxyfen was provided by EFED (DP#: 397089, J. Hetrick, 7/25/2012). 

Tier 1 FIRST and GENEEC modeling was conducted to assess estimated drinking water 

concentration (EDWC) of pyriproxyfen in surface and ground water source drinking water. No 

monitoring surface or ground water monitoring data are available for pyriproxyfen. The drinking 

water assessment considers only parent pyriproxyfen. Tier 1 FIRST modeling predicts that 

pyriproxyfen concentrations in surface source drinking water are not expected to exceed 1.952 

μg/L for the daily peak and 0.111 μg/L for the annual average based on the proposed application 

rates for herbs. Tier 1 GENEEC modeling predicts that pyriproxyfen concentrations in ground 

source drinking water are not expected to exceed 0.000804 μg/L for the daily peak and annual 
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average. Based on previous drinking water assessments for pyriproxyfen use on watercress, 

using the Tier 1 Rice Model, the maximum EDWC for pyriproxyfen in surface source drinking 

water are not expected to exceed 2.98 μg/L for peak and annual average concentrations. In 

ground water, the EDWCs for pyriproxyfen are not expected to exceed 0.006 μg/L for peak and 

annual average concentrations. This assessment shows that past drinking water assessments for 

pyriproxyfen provide a higher EDWC. EFED recommended using 2.98 μg/L for the EDWC. 

The drinking water assessment is considered conservative since it was based on estimates of 

drinking water concentrations generated by the Tier 1 Rice Model. 

5.4 Dietary Exposure and Risk Assessment

5.4.1 Acute Dietary and Drinking Water Analysis

There was no appropriate endpoint for assessing acute dietary exposure; therefore, no acute 

dietary risk assessment was performed. 

5.4.2 Chronic Dietary and Drinking Water Analysis

An unrefined chronic aggregate dietary (food and drinking water) exposure and risk assessment 

was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity 

Intake Database (DEEM-FCID) Version 3.16. This software uses 2003-2008 food consumption 

data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition 

Examination Survey, What We Eat in America, (NHANES/WWEIA). The chronic dietary 

exposure and risk estimates (food and drinking water) were estimated at 3.7% of the cPAD for the 

U.S. population and 12% of the cPAD for the most highly-exposed population subgroup (children 

1-2 years old) and are below HED’s level of concern (<100% cPAD). See Table 5.4.2.1 below.

Table 5.4.2.1 Summary of Chronic Dietary Exposure and Risk for Pyriproxyfen.

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

General U.S. Population

0.35

0.012957 3.7

All Infants (< 1 year old) 0.018036 5.2

Children 1-2 years old 0.042557 12

Children 3-5 years old 0.033637 10

Children 6-12 years old 0.019280 5.5

Youth 13-19 years old 0.011080 3.2

Adults 20-49 years old 0.010408 3.0

Adults 50-99 years old 0.009331 2.7

Females 13-49 years old 0.010095 2.9

1Highest exposure identified in bold.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

No new residential exposure scenarios are associated with the proposed tea tolerance increase for 

pyriproxyfen-treated imported tea. Pyriproxyfen is the active ingredient in many currently 

registered residential products for flea and tick control (home environment and pet treatments) as 

well as products for ant and roach control (indoor and outdoor applications). Formulations 

include carpet powders, foggers, aerosol sprays, liquids (shampoos, sprays, and pipettes for pet 
Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 23 of 58

treatments), granules, bait (indoor and outdoor), and impregnated materials (pet collars). 

A detailed review of information pertaining to residential exposure to pyriproxyfen is available 

in a previous memo (DP#: 404203). In this 2012 ORE memo, HED updated the residential 

exposure assessment to reflect updates to residential exposure standard operating procedures 

(SOPs). 

6.1 Residential Handler Exposure

There is the potential for short-term residential handler dermal and inhalation exposure from the 

registered uses of pyriproxyfen; however, since no short-term dermal or inhalation PODs were 

identified, a quantitative assessment was not conducted. 

6.2 Residential Post-Application Exposure 

Based on the registered use patterns, the following post-application scenarios were assessed in 

the 2012 ORE memo:

 Hand-to-Mouth: 

o Short- and intermediate-term hand-to-mouth exposures for Children 1 to <2 years

old from treated carpets and flooring and petting treated animals (shampoos, 

sprays, spot-on treatments and collars).

o Long-term hand-to-mouth exposures for Children 1 to <2 years old from treated 

carpets and flooring and petting treated animals from pet collars (note efficacy of 

carpet powders is 365 days and efficacy of pet collars up to 395 days).

 Dermal: 

o Long-term dermal exposures from treated carpets, flooring, and pets (note 

efficacy of carpet powders is 365 days and efficacy of pet collars up to 395 days). 

For this assessment, HED further updated the residential pet assessments by assessing long-term 

dermal and hand-to-mouth for all direct pet applications which is consistent with current HED 

policies.

HED acknowledges that pet owners could retreat the home environment and/or a pet near the end 

of the efficacy period identified on the product labels. However, there are no chemical-specific 

residue data for pyriproxyfen to determine the dissipation rate of residues or whether residues 

may be additive upon retreatment. Therefore, a Tier 1, screening level assessment was 

performed based on Day 0 residues without accounting for daily residue dissipation. HED 

anticipates that this assessment is protective as pyriproxyfen residues would be expected to 

dissipate from Day 0 residue values.
Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

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Table 6.2.1 Summary of Risk Estimates for Existing Residential Uses of Pyriproxyfen

Formulation 

Use

Maximum 

Application 

Ratea

Route of Exposure Short-Term 

MOE

IntermediateTerm MOELong-Term 

MOEb

Combined 

MOEs 

(Long-term 

only)

Household/Pet Flea and Tick Control

Carpet 

powder - flea 

and tick 

treatment

1x10-6lb ai/ft2

Incidental oral 

(Hand-to-Mouth) 35000 12000 12000

4000

Dermal

Child

1 to < 2 

yrs old N/A N/A 6100

Adults 5800 N/A

Fogger 4.99x10-7

lb 

ai/ft2

Incidental oral 

(Hand-to-Mouth) 87000 31000 N/A

N/A

Dermal N/A N/A N/A

Pet spray 

mist

1.3x10-5lb 

ai/application

Incidental oral 

(Hand-to-Mouth) 980000 340000 700000

22000

Dermal

Child

1 to < 2 

yrs old N/A N/A

23000

Adults 59000 N/A

Pet spot-on 

for cats

1.7x10-4lb 

ai/application

Incidental oral 

(Hand-to-Mouth) 76000 27000 27000

860

Dermal

Child

1 to < 2 

yrs old N/A N/A

890

Adults 2300 N/A

Pet spot-on 

for dogs

2.1x10-4lb 

ai/application

Incidental oral 

(Hand-to-Mouth) 120000 44000 44000

1400

Dermal

Child

1 to < 2 

yrs old N/A N/A

1400

Adults 3700 N/A

Pet collars 4.63x10-4

lb 

ai/collar

Incidental oral 

(Hand-to-Mouth) 28000 9800 9800

320

Dermal

Child

1 to < 2 

yrs old N/A N/A 330

Adults 830 N/A

Pet 

shampoos

1.13x10-4lb 

ai/application

Incidental oral 

(Hand-to-Mouth) 230,000 27000 27000

2500

Dermal

Child

1 to < 2 

yrs old N/A N/A

2700

Adults 6800 N/A

Ant and Roach Control

Granular Bait 0.225 lb ai/A Incidental oral 

(Hand-to-Mouth) 290,000 100,000 N/A N/A

a. Identified from 2002 assessment (DP#: 281982, T. Swackhammer, 5/2/2002).

b. Long-term assessments conducted for products with efficacy of up to 1 year – pet collars and indoor carpet powder as well as all direct pet 

application products.
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6.3 Residential Bystander Post-application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html). The 

Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the Agency will use this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for pyriproxyfen. 

6.4 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for pyriproxyfen. The Agency has been working with the Spray Drift Task 

Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), EPA Regional Offices, and State Lead Agencies for pesticide regulation 

and other parties to develop the best spray drift management practices (see the agency’s Spray 

Drift website for more information).1 The Agency has also developed a policy on how to 

appropriately consider spray drift as a potential source of exposure in risk assessments for 

pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during 

the Registration Review process which ensures that all uses for that pesticide will be considered 

concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures for 

Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift.

 

1 Available at http://www.epa.gov/opp00001/factsheets/spraydrift.htm
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7.1 Residential Risk Estimates for Use in Aggregate Assessments

Table 6.4.1 reflects the residential risk estimates for use in the aggregate risk assessment for 

pyriproxyfen.

Table 6.4.1. Recommendations for the Residential Exposures for the Pyriproxyfen Aggregate Assessment.1

Lifestage Route of Exposure Residential Post-application MOE

Short-term

Adults N/A N/A

Child 1 to <2 years old Incidental oral from pet collar use 28000

Intermediate-Term

Adults N/A N/A

Child 1 to <2 years old Incidental oral from pet collar use 9800

Long-Term

Adults Dermal from pet collar use 830

Child 1 to <2 years old Dermal + Incidental oral from pet collar use 320

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

7.0 Aggregate Exposure and Risk Assessment

In accordance with the FQPA, when there are potential residential exposures to a pesticide, 

aggregate risk assessment must consider exposures from three major routes: oral, dermal, and 

inhalation. There are three sources for these types of exposures: food, drinking water, and 

residential uses. In an aggregate assessment, exposures from relevant sources are added together 

and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks 

themselves can be aggregated. When aggregating exposures and risks from various sources, 

HED considers both the route and duration of exposure. There are previously registered 

residential uses of pyriproxyfen; therefore, aggregate risks need to be assessed. The aggregate 

risks for pyriproxyfen are not of concern. 

7.1 Short-Term Aggregate Risk

In aggregating short-term risk, HED considered background chronic-dietary exposure (food + 

drinking water) and short-term, residential non-dietary oral exposures (hand-to-mouth exposures 

by toddlers following applications around the home and on pets for flea and tick control-carpet 

powder and pet shampoo). Since HED did not select a short-term dermal endpoint, a dermalexposure assessment is not included in the short-term aggregate assessment. The total short-term 

dietary and residential aggregate (incidental oral) MOE is 2200. As this MOE is greater than 

100, the short-term aggregate risk does not exceed HED’s level of concern. Table 7.1.1

summarizes the short-term aggregate exposure to pyriproxyfen residues for Children 1 to <2 

years old which is the highest-risk population subgroup (lowest MOE > 100).
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Table 7.1.1 Short-Term Term Aggregate Risk Calculations

Population

Pet Collar Use

LOC for 

Aggregate 

Risk1

Dietary

MOE2

MOE Oral 

Residential 

Exposure3

MOE 

Dermal 

Residential 

Exposure4

MOE 

Inhalation 

Residential 

Exposure5

Aggregate 

MOE (food, 

water, and 

residential)6

Children 1 to < 2 

years old

100 2350 28000 NA NA 2200

1 Target MOE= 100 (10x for intra and 10x for inter-species)

2 MOE dietary = [(short-term oral NOAEL)/(chronic dietary exposure)]. Oral study NOAEL= 100 mg/kg/day

3 MOE oral = [(short-term oral NOAEL)/(hand-to-mouth residential exposure)]. Oral study NOAEL= 100

mg/kg/day. (MOE from Table 6.4.1).

4 MOE dermal = Not applicable

5 MOE inhalation = Not applicable

6 MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) ]

7.2 Intermediate-Term Aggregate Risk

In aggregating intermediate-term risk, HED considered background chronic dietary exposure 

(food + drinking water) and intermediate-term, residential non-dietary oral exposures (by 

toddlers following flea and tick control applications around the home and on pets for products 

with labeled efficacies of more than 30 days-carpet powder and pet shampoo). Since HED did 

not select an intermediate-term dermal endpoint, a dermal-exposure assessment is not included in 

the intermediate-term aggregate assessment. The total intermediate-term dietary and residential 

aggregate MOE is 760. As this MOE is greater than 100, the chronic aggregate risk does not 

exceed HED’s level of concern. Table 7.2.1 summarizes the intermediate-term aggregate 

exposure to pyriproxyfen residues for Children 1 to <2 years old which is the highest-risk 

population subgroup (lowest MOE > 100).

Table 7.2.1. Intermediate-Term Term Aggregate Risk Calculations

Population

Pet Collar Use

LOC for 

Aggregate 

Risk1

Dietary

MOE2

MOE Oral 

Residential 

Exposure3

MOE 

Dermal 

Residential 

Exposure4

MOE 

Inhalation 

Residential 

Exposure5

Aggregate 

MOE (food, 

water, and 

residential)6

Children 1 to < 2 

years old

100 825 9800 NA NA 760

1

 Target MOE= 100 (10x for intra and 10x for inter-species)

2 MOE dietary = [(intermediate-term oral NOAEL)/(chronic dietary exposure)]. Oral study NOAEL= 35.1 

mg/kg/day

3 MOE oral = [(intermediate-term oral NOAEL)/(hand-to-mouth residential exposure)]. Oral study NOAEL= 35.1 

mg/kg/day. (MOE from Table 6.4.1).

4 MOE dermal = Not applicable

5 MOE inhalation = Not applicable

6 MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral)]

7.3 Long-Term Aggregate Risk

In aggregating chronic risk, HED considered background chronic dietary exposure (food + 

drinking water) and long-term, residential non-dietary oral and dermal exposures (by toddlers 
Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 28 of 58

following flea and tick control applications around the home and on pets for products with 

labeled efficacies of more than 6 months-carpet powder and pet collar). Since HED did not 

select a long-term oral endpoint for pyriproxyfen, the chronic aggregate risk was performed 

using the chronic dietary endpoint. A long-term post-application residential assessment was 

performed for toddlers only since they are anticipated to have the higher exposures than adults 

from treated home environments and pets due to their behavior patterns. The total chronic 

dietary and residential aggregate MOE is 230. As this MOE is greater than 100, the chronic 

aggregate risk does not exceed HED’s level of concern. Table 7.3.1 summarizes the chronic 

aggregate exposure to pyriproxyfen residues for Children 1 to <2 years old which is the highestrisk population subgroup (lowest MOE > 100).

Table 7.3.1. Long-Term Term Aggregate Risk Calculations

Population

Pet Collar Use

LOC for 

Aggregate 

Risk1

Dietary

MOE2

MOE Oral 

Residential 

Exposure3

MOE 

Dermal 

Residential 

Exposure4

MOE 

Inhalation 

Residential 

Exposure5

Aggregate 

MOE (food, 

water, and 

residential)6

Children 1 to < 2 

years old

100 825 9800 330 NA 230

1 Target MOE= 100 (10x for intra and 10x for inter-species)

2 MOE dietary = [(long-term oral NOAEL)/(chronic dietary exposure)]. Oral study NOAEL= 35.1 mg/kg/day

3 MOE oral = [(long-term oral NOAEL)/(long-term incidental oral exposure)]. Oral study NOAEL= 35.1 

mg/kg/day. (MOE from Table 6.4.1).

4 MOE dermal = [(long-term dermal NOAEL)/(long-term dermal4 exposure)]. Oral study NOAEL= 35.1 

mg/kg/day. (MOE from Table 6.4.1).

5 MOE inhalation = Not applicable

6 MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE dermal)]

8.0 Cumulative Risk

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, 

or revoke a tolerance, the Agency consider “available information” concerning the cumulative 

effects of a particular pesticide's residues and “other substances that have a common mechanism 

of toxicity.”

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to pyriproxyfen and any other substances, and pyriproxyfen does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that pyriproxyfen has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.
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9.0 Occupational Exposure and Risk Characterization

The proposed use of pyriproxyfen is on tea grown in Japan. There are no occupational exposure 

scenarios associated with the proposed tolerance increase and an occupational exposure and risk 

characterization is not required.

10.0 References

Pyriproxyfen. Petition to Increase the Established Tolerance in/on Tea with a U.S. Registration for Imported 

Pyriproxyfen-treated Tea. Summary of Analytical Chemistry and Residue Data. B. Cropp-Kohlligian, D426704, 

9/8/2015

Pyriproxyfen. Chronic Dietary (Food and Drinking Water) Exposure Assessment for the Petition to Increase the 

Established Tolerance in/on Tea with a U.S. Registration for Imported Pyriproxyfen-treated Tea. B. CroppKohlligian, D427113, 9/8/2015

Pyriproxyfen: Occupational and Residential Assessment to Support the New Use on the Herb Subgroup 19A and 

the Expansion of Existing Crop Group Uses to Numerous Crop Subgroups. I. Nieves, D404203, 8/22/2012

Tier I Drinking Water Assessment for New Use of Insect Growth Inhibitor 2-[1-methyl-2- (4-

phenoxyphenoxy)ethoxy]pyridine Pyriproxyfen on Herb Subgroup 19A. J. Hetrick, D397089, 7/25/2012

Pyriproxyfen. Results of the Metabolism Assessment Review Committee Meeting Held on 10-Nov-1998. W. 

Donovan and W. Dykstra, D250953, 11/19/1998
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food use for pyriproxyfen are in Table A.1. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Guideline Data Requirements

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation..............................................

870.2600 Dermal Sensitization .....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 28-Day Dermal..............................................................

870.3250 90-Day Dermal..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

no

yes

yes

yes

no

yes

870.3700 Developmental Toxicity (rodent) ...................................

870.3700 Developmental Toxicity (nonrodent) .............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100 Chronic Toxicity (rodent)...............................................

870.4100 Chronic Toxicity (nonrodent).........................................

870.4200 Oncogenicity (rat) ..........................................................

870.4200 Oncogenicity (mouse) ....................................................

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Bacterial reverse mutation assay ....................

870.5300 Mutagenicity—gene mutation test-mammalian ......................

870.53xx Mutagenicity—chromosome aberration test ..........................

870.53xx Mutagenicity—other .....................................................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100 Acute Delayed Neurotoxicity (hen)................................

870.6100 90-Day Neurotoxicity (hen) ...........................................

870.6200 Acute Neurotoxicity Screening Battery (rat)..................

870.6200 90-Day Neurotoxicity Screening Battery (rat) ...............

870.6300 Developmental Neurotoxicity .......................................

no

no

yes

yes

no

no

no

yes

yes

no

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

no

yes

yes

no

yes
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A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile - Pyriproxyfen 

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute Oral 42178302 LD50 > 5,000 

mg/kg IV 

870.1200 Acute Dermal 42178303 LD50 > 2000 mg/kg III 

870.1300 Acute Inhalation 42178304 LC50 > 1.3 mg/L III 

870.2400 Primary Eye Irritation 42178305 mild irritation IV 

870.2500 Primary Skin Irritation 42178306 non-irritating IV 

870.2600 Dermal Sensitization 42178307 not dermal 

sensitizer 
Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Pyriproxyfen

Guideline No./ 

Study Type/Animal 

Species and Strain

MRID No. or Study Authors 

(year)/ Classification /Doses

Results

870.3100 

90-Day oral toxicity 

rodents (mouse) 

43210504 (1990).

Acceptable/guideline 

0, 200, 1000, 5000 or 10000 

ppm (diet)

M: 0, 28.2, 149.4, 838.1 or 

2034.5 mg/kg/day 

F: 0, 37.9, 196.5, 963.9 or 

2345.3 mg/kg/day 

NOAEL = 149.4 mg/kg/day in males, 196.5 mg/kg/day 

in females LOAEL = 838.1 mg/kg/day in males, 963.9

mg/kg/day in females based on pathological changes in 

the kidney, increased absolute and relative (to body) 

liver weight, decreased red blood cell parameters (both 

sexes) and decreased body weight gain (M) 

870.3100 

90-Day oral toxicity 

rodents (rat) 

41321716 (1989) 

Acceptable/guideline 

0, 400, 2000, 5000 or 10000 

ppm (diet) 

M: 0, 23.49, 117.79, 309.05 or 

641.81 mg/kg/day 

F: 0, 27.68, 141.28, 356.30 or 

783.96 mg/kg/day 

NOAEL = 23.49 mg/kg/day in males, 27.68 mg/kg/day 

in females LOAEL = 117.79 mg/kg/day in males, 

141.28 based on increased total cholesterol and 

phospholipids (M),decreased red blood cell, 

hematocrit, and hemoglobin counts, increased relative 

(to body) liver weight (M), and negative trend in red 

blood cell volume (F) 

870.3150 

90-Day oral toxicity 

non-rodents (dog) 

42178307 (1988) 

Acceptable/guideline 

0, 100, 300 or 1000 mg/kg/day 

(capsule)

NOAEL = 100 mg/kg/day in males and females 

LOAEL = 300 mg/kg/day in males and females based 

on increased absolute and relative (to body) liver 

weight (both sexes) and hepatocyte enlargement (F) 

870.3200 

21-Day dermal 

toxicity(rat) 

43994102 (1993) 

Acceptable/guideline 

0, 100, 300 or 1000 mg/kg/day

 

NOAEL = 1000 mg/kg/day (males and females). 

LOAEL not established.

870.3200 

21-Day dermal 

toxicity(rat)

44037205 (1996)

Acceptable/guideline 

0, 100, 300 or 1000 mg/kg/day 

Systemic NOAEL = 1000 mg/kg/day (M&F). LOAEL 

not established.

Dermal NOAEL = 300 mg/kg/day. LOAEL = 1000 

mg/kg/day based on dermal irritation including 

acanthosis, dermal lymphoid cell infiltrate and dermal 

hemorrhage (M&F).
Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Pyriproxyfen

Guideline No./ 

Study Type/Animal 

Species and Strain

MRID No. or Study Authors 

(year)/ Classification /Doses

Results

870.3265 

28-Day inhalation 

toxicity (rat) 

42178308 (1988) 

Supplementary

0, 269, 482 or 1000 mg/m3 

0, 0.269, 0.482 or 1.000 mg/L

NOAEL = 0.482 mg/L (males and females) LOAEL =

1.000 mg/L based on salivation (both sexes), sporadic 

decreased body weight gain (M), and increased lactate 

dehydrogenase (M). Decreases in actual body weights 

were not observed. These minor changes are not 

considered biologically relevant.

870.3700a 

Prenatal 

developmental (rat) 

44985002 (1988) 

Acceptable/non-guideline 

0, 100, 300, 500 or 1000 

mg/kg/day via gavage

Parental NOAEL = 100 mg/kg/day. LOAEL = 300

mg/kg/day based on clinical signs, decreased body 

weight gains, increased water consumption (both sexes) 

and increased food consumption, changes in organ 

weights, and gross pathological changes (M) 

Developmental NOAEL = 1,000 mg/kg/day (HDT)

870.3700b 

Prenatal 

developmental 

(rabbit)

41321720, 42178311, 

43215401, 43215402, 

43215403 (1989) 

Acceptable/guideline 

0, 100, 300 or 1000 mg/kg/day 

via gavage

Maternal NOAEL = 100 mg/kg/day. LOAEL = 300 

mg/kg/day based on premature delivery/abortions, soft 

stools, emaciation, lusterless fur, decreased activity, 

and bradypnea. 

Developmental NOAEL = 300 mg/kg/day. LOAEL = 

1000 mg/kg/day based on decreased viable litters 

available for evaluation 

870.3700a 

Prenatal 

developmental (rat) 

42178312 (1988) 

Acceptable/guideline 

0, 100, 300 or 1000 mg/kg/day 

via gavage

Maternal NOAEL = 100 mg/kg/day. LOAEL = 300

mg/kg/day based on decreased body weight, body 

weight gain, and food consumption and increased water 

consumption. 

Developmental NOAEL = 300 mg/kg/day. LOAEL = 

1,000 mg/kg/day based on increased incidence of 

skeletal variations at gestation day 21 and unspecified 

visceral variations at post-natal day (PND) 56. 

870.3800 

Reproduction and 

fertility effects (rat) 

42178313 (1991) 

Acceptable/guideline 

0, 200, 1000, or 5000 ppm 

(diet)

M: 0, 18, 87, or 453 

mg/kg/day 

F: 0, 20, 96, or 498 mg/kg/day 

Parental/Systemic NOAEL = 87 mg/kg/day in males, 

96 mg/kg/day in females. LOAEL = 453 mg/kg/day in 

males, 498 mg/kg/day in females based on decreased 

body weight, body weight gain, and food consumption 

(both sexes), increased absolute and relative liver 

weight (both sexes), increased relative kidney weight in 

males and histopath lesions of kidney (chronic 

interstitial nephritis) and liver (clear cell focus 

associated with pale area at fissure of medium lobe) in 

males.

Reproductive NOAEL > 453 mg/kg/day in males, 498

mg/kg/day in females. LOAEL not established. 

Offspring NOAEL = 87 mg/kg/day in males, 96 

mg/kg/day in females. LOAEL = 453 mg/kg/day in 
Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Pyriproxyfen

Guideline No./ 

Study Type/Animal 

Species and Strain

MRID No. or Study Authors 

(year)/ Classification /Doses

Results

males, 498 mg/kg/day in females based on decreased 

body weight on lactation days 14 and 21. 

870.3800 

Reproduction and 

fertility effects (rat) 

44985001 (1988) 

Acceptable/non-guideline 

0, 30, 100, 300, or 500 

mg/kg/day via gavage

Maternal NOAEL = 100 mg/kg/day. LOAEL = 300

mg/kg/day based on clinical signs, decreased body 

weight gains, and decreased food consumption.

Offspring NOAEL = 100 mg/kg/day. LOAEL = 300 

mg/kg/day based on decreased body weight and 

increased incidence of dilation of the renal pelvis. 

870.4100b 

Chronic toxicity 

(dog)

42178309 (1991) 

Acceptable/guideline 

0, 30, 100, 300 or 1000 

mg/kg/day (capsule)

NOAEL = 100 mg/kg/day in males and 

females LOAEL = 300 mg/kg/day in males and 

females based on decreased body weight gain and 

increased relative liver weight (both sexes) and 

increased cholesterol and triglycerides and decreased 

red cell counts and hemoglobin in males 

870.4300 

Chronic/Carcinogenic

ity (rat) 

42178314, 43210501, 

43210502, 43210503 (1991) 

Acceptable/guideline 

0, 120, 600 or 3000 ppm (diet)

M: 0, 5.42, 27.31 or 138.0 

mg/kg/day F: 0, 7.04, 35.1 or 

182.7 mg/kg/day 

NOAEL = 138 mg/kg/day in males, 35.1 mg/kg/day in 

females LOAEL not established in males, 182.7

mg/kg/day in females based on decreases in body 

weight gain. No evidence of carcinogenicity 

870.4200

Carcinogenicity 

(mouse)

42178310 (1991) 

Acceptable/guideline 

0, 120, 600 or 3000 ppm (diet)

M: 0, 16.8, 84.0, or 420 

mg/kg/day 

F: 0, 21.9, 109.5, or 547 

mg/kg/day 

NOAEL = 84 mg/kg/day in males, 109.5 mg/kg/day in 

females LOAEL = 420 mg/kg/day in males, 547

mg/kg/day in females based on renal lesions in males 

and females. No evidence of carcinogenicity 

870.5100 

Bacterial Reverse 

Mutation Test 

44503506 (1995) 

Acceptable/guideline 

Tested up to 5000 ug/plate or 

cytotoxic levels, in presence 

and absence of activation, in S. 

typhimurium strains TA98, 

TA100, TA1535 and TA1537 

and E.coli strain WP2uvra 

Non-mutagenic with 2-OH-PY (metabolite of 

pyriproxyfen).
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Pyriproxyfen

Guideline No./ 

Study Type/Animal 

Species and Strain

MRID No. or Study Authors 

(year)/ Classification /Doses

Results

870.5100 

Bacterial Reverse 

Mutation Test 

44503507 (1993) 

Acceptable/guideline 

Tested up to 5000 ug/plate or 

cytotoxic levels, in presence 

and absence of activation, in S. 

typhimurium strains TA98, 

TA100, TA1535 and TA1537 

and E.coli strain WP2uvra

Non-mutagenic with 4'-OH-PY, 5"-OH-PYR, DPHPYR, POPA, and PYPAC (metabolites of 

pyriproxyfen). 

870.5100 

Bacterial Reverse 

Mutation Test 

44503508 (1995) 

Acceptable/guideline 

Tested up to 5000 ug/plate or 

cytotoxic levels, in presence 

and absence of activation, in S. 

typhimurium strains TA98, 

TA100, TA1535 and TA1537 

and E.coli strain WP2uvra

Non-mutagenic with 2,5-OH-PY (metabolite of 

pyriproxyfen). 

870.5100 

Bacterial Reverse 

Mutation Test 

42178315 (1988) 

Acceptable/guideline 

Tested up to 5000 ug/plate or 

cytotoxic levels, in presence 

and absence of activation, in S. 

typhimurium strains TA98, 

TA100, TA1535, TA1537, and 

TA1538 and E.coli strain 

WP2uvra 

Non-mutagenic with or without metabolic activation.

870.5300 

In vitro Mammalian 

Cell Gene Mutation 

Test

42178316 (1990) 

Acceptable/guideline 

Chinese hamster lung V79 

cells tested up to cytotoxic 

concentrations or limit of 

solubility, in presence and 

absence of activation.

Non-mutagenic at the HGPRT locus 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Pyriproxyfen

Guideline No./ 

Study Type/Animal 

Species and Strain

MRID No. or Study Authors 

(year)/ Classification /Doses

Results

870.5375 

In vitro Mammalian 

Chromosome 

Aberration Test 

(August 1998)

41321722 (1989) 

Acceptable/guideline 

Chinese hamster ovary (CHO) 

cell cultures in the absence or 

presence of activation.

Negative. Did not induce structural chromosome 

aberrations 

870.5550 

Unscheduled DNA 

Synthesis in 

Mammalian Cells in 

Culture 

42178317 (1988) 

Acceptable/guideline 

HeLa cells exposed up to 

cytotoxic levels, both in the 

presence or absence of S-9.

Negative. There was no evidence that unscheduled 

DNA synthesis, as determined by radioactive tracer 

procedures (nuclear silver grain counts) was induced 

870.6200a

Neurotoxicity 

screening battery

- Acute neurotoxicity 

(rat)

Crl:CD(SD) rats

48711901, 48711903, 

48711904 (2011)

Acceptable /guideline

0, 300, 1000 or 2000 mg/kg 

via gavage

The NOAEL is 1000 mg/kg bw/day. The LOAEL was 

2000 mg/kg bw/day, based on deceases in motor 

activity on Day 0 in males and unkempt appearance in 

females.

870.6200b

Neurotoxicity 

screening battery

- Subchronic 

neurotoxicity (rat)

Crl:CD(SD) rats

48711901, 48711902, 

48711905 (2011)

Acceptable /guideline

0,1500, 5000, or 15,000 ppm 

via diet 

M: 0, 108, 359, 1111 

mg/kg/day 

F: 0, 102, 407, 1212 

mg/kg/day

Neurotoxicity. NOAEL = 15,000 ppm (1111

mg/kg/day for males and 1212 mg/kg/day for females).

The LOAEL for neurotoxicity was not observed.

Systemic toxicity. NOAEL = 5000 ppm (359

mg/kg/day for males and 407 mg/kg/day for 

females).The LOAEL was 15,000 ppm (1111 

mg/kg/day for males and 1212 mg/kg/day females) 

based on lower mean body weights, body weight gains, 

and food consumption for both sexes. 

870.7485 

Metabolism and 

pharmacokinetics 

(rat)

42178318 (1988) 

42201402 (1988)

44036914 (1993)

Acceptable/guideline 

42178318: The major routes of excretion of 

radioactivity were via the urine and feces. The 

excretion of radioactivity into urine and feces was rapid 

and over a 7-day period, most (92-97%) of the test 

compound administered was excreted in the urine (5-

12%) and feces (81-92%) from the animals. Most (63-

83%) of the dose was eliminated in the urine and feces 

within 24 hours after dosing. Expired air was not 

detected. Radioactivity in tissue residues was very low 

in all tissues expect the fat. Recoveries of the 

administered doses in the tissues including carcass 

were not more than 0.3% indicating that the potential 

for bioaccumulation of sumilarv is minimal even after 

high dose or repeated low dose exposures. In the urine, 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Pyriproxyfen

Guideline No./ 

Study Type/Animal 

Species and Strain

MRID No. or Study Authors 

(year)/ Classification /Doses

Results

a total of 11 metabolites were detected and two of them 

(4’-OH-31183 sulfate and 4’-OH-POP sulfate) were 

identified. In the feces, an unmetabolized sumilarv (7-

37% of the dose) and a total of up to 17 metabolites 

were detected and 10 of them (6 unconjugated and 4 

sulfate conjugates) were identified. The four major 

fecal metabolites were 4’-OH-31183, 4’-OH-31183 

sulfate, 5, 4’-OH-31183 sulfate, and 4’-OH-POPA. The 

metabolites in the liver, kidney, blood, bile, and fat of 

rats were also examined. Based on the metabolites 

identified by TLC cochromotography with synthetic 

standards the major biotransformation reactions of 

sumilarv include: 1) Oxidation at 4’-postion, of the 

terminal phenyl group; 2) Oxidation at 5-psition of 

pyridine; 3) Cleavage of the ether linkage and 

conjugation of the resultant phenols with sulfuric acid. 

No significant sex-or dose-related differences exist in 

the absorption, distribution, or metabolism of sumilarv 

for all dosing regimens. 

44036914: Absorption was nearly identical in males 

and females provided a single oral dose of 2 mg/kg 

(low dose) or 1000 mg/kg (high dose). Based on urine 

concentration pyriproxyfen was not easily absorbed 

(<12%) and was excreted rapidly (88.9 – 92.9% within 

2 days). Excretion was near complete (92.3 - 98.5%) 

after 7 days despite a dip in the rate of elimination after 

the second day. Fecal excretion was the dominant 

elimination pathway after both low (86.1 – 93.2%) and 

high dose (84.7 – 89%) exposures. Urine excretion 

was minor compared to fecal elimination, but was more 

prominent in the high dose (7.5 – 11.8%) than in low 

dose (4.9 – 5.7%). Release of pyriproxyfen in expired 

air was not a significant (<0.5%). 

Metabolism was affected both by dose and the sex of 

the animal. Feces contained ten metabolites whereas 

the urine only contained three. Parent compound was 

identified in both forms of excreta. Metabolism was 

more extensive in females with only 21.2 – 21.9% of 

the parent compound remaining in the excreta 

compared to 32.5 – 34.8% in males. Metabolism of 

pyriproxyfen occurred primarily through hydroxylation 

at the 4’-position of the terminal phenyl ring. 

Metabolism via this pathway was utilized more in 

females (49.3 – 53.6%) than in males (32.1 – 43.3%) 

regardless of dose. Hydroxylation at the 2’-position of 

the phenyl ring was not as extensive, but was favored 

more at low dose (1.8 – 2.8%) than at the high dose 

(0.2%). Hydroxylation at the 5”-position of pyridyl 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Pyriproxyfen

Guideline No./ 

Study Type/Animal 

Species and Strain

MRID No. or Study Authors 

(year)/ Classification /Doses

Results

ring, another minor pathway, was also more prevalent 

at the low dose (1.4 – 7.8% compared to 0.9 – 1.4% at 

the high dose). Unlike hydroxylation of the phenyl 

ring, hydroxylation of the pyridyl ring was more 

prominent in males (1.4 – 7.8%) than in females (0.9 –

1.7%). Of the minor metabolic pathways, high dose 

animals preferred sulfuric acid conjugation accounting 

for 1.2 – 2.8% compared to 0.8 – 2.4% in low dose 

animals. Minor metabolites born from dephenylation 

(0.8 – 1.6%) and conjugation with glucuronic acid (0.2 

– 11%) were comparable across sex and dose. 

4’-OH-pyriproxyfen was the dominant fecal metabolite 

at both doses accounting for 23.3 – 38.4% in males and 

46.4 – 47.2% in females. At the low dose other major 

metabolites were 5”,4’-OH-pyriproxyfen (7.2% in 

males and 1.2 % in females) and 2’-OH-pyriproxyfen 

(1.8% in males and 2.8% in females). At high doses 

these metabolites were not as common, accounting for 

only 0.2 – 0.4% of the administered dose. Instead the 

major fecal metabolites were DPH-pyriproxyfen and 

4’-OH-pyriproxyfen-sulfuric acid (combined 1.2 –

1.6%). Small quantities of these metabolites were 

present in low dose animals (<1.1%). The major 

urinary metabolite was PYPAC which accounted for 1 

– 4.9%. The sulfuric acid conjugated compounds, 4’-

OH-pyriproxyfen-sulfur and 5”,4’-OH-pyriproxyfensulfur, were also present at much lower concentrations 

(0.1 – 0.8% of the administered dose). Parent 

compound was only identified in urine of high dose 

animals (1.3% in males, and 2.7% in females). 4’-OHpyriproxyfen was also identified in the urine at 1% in 

males and 5.6% in females; however, this metabolite 

and the parent compound were not observed in the 

urine of all animals and it is hypothesized that these 

metabolites originated from feces contamination and 

would otherwise not be present in the urine. 

No sex or dose related disparities were identified in the 

tissue distribution. Residual tissue concentration 

increased with dose but total accumulation never 

exceeded 0.3% of the administered dose 7 days after 

exposure. The residual carcass and fat were the primary 

sinks for pyriproxyfen amassing 0.065 – 0.148% and 

0.024 – 0.042% of the administered dose, respectively. 

Minimal accumulation was observed in the liver (0.16 

– 0.22%) and even less was present in the kidneys 

(0.002 – 0.003%). Between 0.006 and 0.013% was in 

circulation. The remaining tissues contained 

insignificant amounts of pyriproxyfen (<0.001%). 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Pyriproxyfen

Guideline No./ 

Study Type/Animal 

Species and Strain

MRID No. or Study Authors 

(year)/ Classification /Doses

Results

870.7800

Immunotoxicity 

(mouse)

Female CD-I mice

48711906, 48711907 (2012)

Acceptable/guideline

0, 1000, 2000, or 5000 ppm (0, 

228, 449, 1139 mg/kg bw/day) 

via diet for 28 days

The systemic toxicity LOAEL is 5000 ppm (1139 

mg/kg/day), based on lower body weight gain and 

increase of absolute and relative body weight to liver 

weight. The NOAEL for systemic toxicity is 2000 ppm 

(449 mg/kg/day).

The LOAEL for immunotoxicity is not observed. The 

NOAEL for immunotoxicity is 5000 ppm (1139 

mg/kg/day).
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A.3 Toxicological Endpoints

A.3.1 Acute Reference Dose (aRfD) - General Population (Including Infants and Children) 

and Females Age 13-49

An appropriate endpoint attributable to a single oral dose was not available in the data base, 

including developmental toxicity in the developmental toxicity studies. Acute toxicity in the 

ACN study was observed at doses that were not relevant to human exposure (i.e. above the limit 

dose) and were not considered in selecting endpoints for acute dietary assessments. 

A.3.2 Chronic Reference Dose (cRfD) -

Study Selected: Subchronic toxicity and chronic toxicity (feeding) - rat

(co-critical)

MRID No.: 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic)

Executive Summary: See Appendix A, Guideline [§ 870.3100 and 870.4100] 

Dose and Endpoint for Risk Assessment: NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 

mg/kg/day based on decreased body weight gain, anemia, and increased relative liver weight with 

elevated cholesterol and phospholipid levels.

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation, 1x 

FQPA SF

Comments about Study/Endpoint: This endpoint from co-critical studies is an appropriate 

endpoint of duration and provides the lowest NOAEL in the database for chronic effects via the 

oral route.

A.3.3 Incidental Oral Exposure (Short-, Intermediate-, and Long-Term)

Short-Term

Study Selected: Developmental - rat

MRID No.: 44985002

Executive Summary: See Appendix A, Guideline [§ 870.3700a] 

Dose and Endpoint for Risk Assessment: Parental NOAEL = 100 mg/kg/day, Parental LOAEL 

= 300 mg/kg/day based on clinical signs, decreased body weight, body weight gain, and food 

consumption, and increased water consumption 

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation

Comments about Study/Endpoint: Since there is no evidence in the database suggesting the 

young are more sensitive than adults, the endpoint derived from a maternal endpoint is appropriate 

for the incidental oral exposure of young children. The endpoint from the rat developmental study 

provides the highest NOAEL for the short-term exposure assessment.

Chronic RfD = 35.1 mg/kg/day = 0.35 mg/kg/day

 100
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Intermediate-Term

Study Selected: Subchronic toxicity and chronic toxicity (feeding) - rat

(co-critical)

MRID No.: 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic)

Executive Summary: See Appendix A, Guideline [§ 870.3100 and 870.4100] 

Dose and Endpoint for Risk Assessment: NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 

mg/kg/day based on decreased body weight gain, anemia, and increased relative liver weight with 

elevated cholesterol and phospholipid levels.

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation

Comments about Study/Endpoint: Evaluation of effects across durations of exposure suggests 

toxicity increases with duration of exposure. Therefore the short exposure in the developmental 

study is not appropriate for assessing intermediate exposures. The endpoint from co-critical 

studies is the highest NOAEL in the database for the intermediate-term scenario via the oral 

route.

A.3.4 Dermal Absorption

A dermal absorption study is not available for pyriproxyfen. However, a 21-day dermal rat 

toxicity study resulted in no toxicity up to the limit dose and therefore short- and intermediateterm dermal exposure assessments are not warranted. An oral endpoint was selected to be 

protective of the long-term dermal assessment. For the long-term dermal assessment, dermal 

penetration was estimated to be 30% by the extrapolation method of comparing the maternal 

toxicity LOAEL of 300 mg/kg/day in the rat developmental toxicity oral study and the dermal 

NOAEL of 1,000 mg/kg/day in the 21-day dermal study. These studies were both in the rat and 

approximately the same duration in exposure. 

A.3.5 Dermal Exposure (Short-, Intermediate-, and Long-Term)

Short- and Intermediate-Term

Dermal toxicity in the 21-day dermal rat toxicity study was only apparent at the limit dose and 

systemic toxicity was not observed up to the limit dose. There are no developmental 

susceptibility or neurotoxicity concerns from the oral database, therefore a quantitative dermal 

assessment is not warranted.

Long-Term

Study Selected: Subchronic toxicity and chronic toxicity (feeding) - rat

(co-critical)

MRID No.: 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic)

Executive Summary: See Appendix A, Guideline [§ 870.3100 and 870.4100] 

Dose and Endpoint for Risk Assessment: NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 

mg/kg/day based on decreased body weight gain, anemia, and increased relative liver weight with 

elevated cholesterol and phospholipid levels.

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation
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Comments about Study/Endpoint: A long-term dermal study is not available; therefore, an oral 

study was used to assess the long-term dermal assessment. The combined chronic and subchronic 

rat oral endpoints were selected because they were of appropriate duration to estimate long-term 

exposure. A dermal absorption factor of 30% was incorporated into the oral endpoints to 

approximate the dermal dose required to elicit similar effects (see Appendix A.3.5 for more 

detailed explanation).

A.3.6 Inhalation Exposure 

Short- and Intermediate-Term

The minor changes (salivation, sporadic decreased body weight gain, and increased lactate 

dehydrogenase) observed at the highest concentration tested (1 mg/L) are not considered to be 

biologically relevant. There are no developmental susceptibility or neurotoxicity concerns from 

the oral database, therefore a quantitative inhalation assessment is not warranted.

Inhalation Exposure (Long Term)

Study Selected: Subchronic toxicity and chronic toxicity (feeding) - rat

(co-critical)

MRID No.: 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic)

Executive Summary: See Appendix A, Guideline [§ 870.3100 and 870.4100] 

Dose and Endpoint for Risk Assessment: NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 

mg/kg/day based on decreased body weight gain, anemia, and increased relative liver weight with 

elevated cholesterol and phospholipid levels.

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation

Comments about Study/Endpoint: A long-term inhalation study is not available. Therefore an 

oral study was used to assess the long-term inhalation assessment. This oral endpoint from the 

co-critical studies is the lowest NOAEL in the database for chronic effects via the oral route. The 

inhalation absorption is assumed to be 100% since an oral study is being used for the assessment.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity - Rat

In a subchronic oral toxicity study (MRID 41321716), S-31183 (95.3% a.i., Lot # PYG-87074) 

was administered to Crl:CD BR rats at doses of 0, 400, 2000, 5000, and 10000 ppm (equivalent 

to 0, 23.49, 117.79, 309.05, and 641.81 mg/kg/day in males and 0, 27.68, 141.28, 356.30, and 

783.96 mg/kg/day in females) for 90 days.

The LOAEL for systemic toxicity was 2000 ppm (117.79 and 141.28 mg/kg/day in males 

and females, respectively) based on higher mean total cholesterol and phospholipids, 

decreased mean red blood cell, hematocrit and hemoglobin counts, and significantly higher 

relative liver weight in male rats and a negative trend in mean red blood cell volume in 

females. The NOAEL for systemic toxicity in rats of either sex was 400 ppm (23.49 and 
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27.68 mg/kg/day in males and females, respectively).

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

subchronic oral toxicity study in rats (870.3100; OECD 408).

870.3100 90-Day Oral Toxicity - Mouse

When technical Sumilarv was administered to male and female CD-I mice at dietary levels of 0, 

200, 1000, 5000, or 10000 ppm (approximately mg/kg/day calculated equivalents: 0, 28.2, 149.4, 

838.1, and 2034.5 for males, and 0, 37.9, 196.5, 963.9, and 2345.4 for females), there was an 

increase in mortality in both sexes at the highest dose tested. In animals of both sexes that 

received the two highest doses, kidney lesions were present. Macroscopically, there was dilation 

of the renal pelvises, fluid filled renal pelvises, unequal kidney sizes, cysts and paleness. 

Microscopically, there was nephrosis with renal tubular dilation and dilation and mineralization 

of the renal pelvises.

In addition to these effects, there was a decrease in body weight gain in males at the two highest 

dose levels, significant decrease in red blood cells, hemoglobin, hematocrit, MCV and MCH, and 

increased liver to body weight ratios. Females at the 5000 ppm dose level had significant 

decreases in red blood cells, hemoglobin, and hematocrit, significantly increased liver weights, 

and significantly increased liver to body weight ratios. At 10000 ppm there was only one 

surviving female; therefore, the numbers were not sufficient for evaluation.

The LOAEL was 5000 ppm (838.1 and 963.9 mg/kg/day in males and females, respectively) 

based on renal pathology, statistically significant increases in liver weights and in 

liver:body weight ratios, and statistically significant decreases in red blood cell parameters 

and in body weight gain in males. The NOAEL was 1000 ppm (149.4 and 196.5 mg/kg/day 

in males and females, respectively).

The kidney pathology was not associated with any clinical findings. Urinalysis was 

unremarkable. With regard to serum chemistry, of the parameters that could be correlated with 

renal disease, only the blood urea nitrogen (BUN) was elevated in both sexes at 5000 ppm. No 

similar elevations in BUN were reported in the three surviving males and in the one surviving 

female at 10000 ppm.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

subchronic oral toxicity study in mice (870.3100; OECD 408).

870.3150 90-Day Oral Toxicity - Dog

In a subchronic toxicity study (MRID 42178307), S-31183 (97.2% a.i., Lot# PTG-86011) was 

administered in gelatin capsules to 4 beagle/sex at doses of 0, 30, 100, 300, and 1000 mg/kg/day for 90 

days.

The LOAEL was 300 mg/kg/day, based on significantly higher absolute liver weights and 

liver-to-body weight ratios in the males, and enlargement of hepatocytes observed in 

females at that concentration, compared with dogs on the control diet. The NOAEL was

100 mg/kg/day. 
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The changes in liver weights, organ-to-body weight ratios, and increase in size observed in the 

hepatocytes at 300 mg/kg/day are probably not due to hepatotoxicity, however; rather, these 

changes appear to be adaptations of liver to detoxifying the test substance, since these changes 

are observed in both groups at the highest dose tested. 

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

subchronic oral toxicity study in non-rodents (870.3150; OECD 409).

870.3200 21-Day Dermal Toxicity – Rat

In a repeated dose dermal toxicity study (MRID 44037205), pyriproxyfen (V071639) 0.83EC 

(11.1% a.i., Lot #SF05L41, Batch #VS-18B-43) was applied to the shaved skin of five Sprague 

Dawley-derived [CD-Crl:CD(SD)BR] rats/sex/dose at dose levels of 0, 100, 300, or 1000 

mg/kg/day for 6 hours/day, 5 days/week, for 3 weeks.

Rats in the 1000 mg/kg/day treatment group exhibited higher frequencies and more severe 

irritation of the treated skin than the control group rats. Symptoms of dermal irritation included 

moderate/marked epidermal acanthosis (5/5 males v. in controls), slight dermal lymphoid cell 

infiltrate (5/5 males, 2/5 females), and dermal hemorrhage (2/5 males, 3/5 females). Dermal 

irritation observed in the rats in the 100 or 300 mg/kg/day treatment groups were comparable to 

that observed in the controls. No systemic responses were observed. For all treatment groups, 

body weights, and body weight gains, and mean food consumption values were similar to the 

controls. There were not treatment-related differences in findings, organ weight, or macroscopic 

or microscopic organ morphology between rats in the treated and control groups.

The dermal LOAEL for this study is 1000 mg/kg/day, based on the presence of treatmentrelated dermal irritation in the treated skin of rats in this treatment group. The NOAEL is 

300 mg/kg/day. 

The systemic LOAEL was not established. The systemic NOAEL was 1000 mg/kg/day.

This study is classified Acceptable and satisfies the guideline requirement for a subchronic 

inhalation study (OCSPP 870.3200, OECD 410)

870.3465 28-Day Inhalation – Rat

In a 28-day inhalation study (MRID 42178308), groups of male and female Sprague-Dawley rats 

were exposed via inhalation at concentrations of 0, 269, 482, or 1000 mg/m3 for 4 hours/day for 

28 days. 

The LOAEL was 1000 mg/m3 based on increased salivation. Sporadic decrease in body 

weight were also reported and a statistically significant increase was also reported in the 

lactate dehydrogenase (LDH) level. This increase was not considered biologically relevant. 

The NOAEL was 482 mg/m3(equivalent to 138 and 162 mg/kg/day in males and females 

respectively).

This study is classified Acceptable and satisfies the guideline requirement for a subchronic 
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inhalation study (OCSPP 870.3200, OECD 413)

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 42178312, 41321719), pyriproxyfen technical (97.2% 

purity) was administered to groups of 36 pregnant Sprague-Dawley rats/ dose by gavage at dose 

levels of 0, 100, 300, or 1000 mg/kg/day from days 7 through 17 of gestation in a volume of 

5ml/kg of corn oil. The study was conducted in two segments. In one, the dams were killed on 

gestation day 21 and fetuses were evaluated. In the other, the dams delivered naturally and pups 

were weaned at postnatal day 21. Pups were killed serially at postnatal day 21 (after assessment 

of reflexes and sensory response), at 8 weeks of age (following open field testing, rotor testing, 

and examination of learning ability in a water maze), or after assessment of reproductive 

performance. 

The maternal NOAEL was 100 mg/kg/day, based on decreased body weight, body weight 

gain, and food consumption, and increased water consumption at the LOAEL of 300 

mg/kg/day. At 1000 mg/kg/day, increased incidences of mortality and clinical signs were 

also observed. 

The developmental NOAEL was 300 mg/kg/day, based upon an increased incidence of 

fetuses with poorly ossified sternebrae (6 fetuses from 4 litters v. 2 fetuses from 2 litters in 

the control), opening of foramen transversarium of the 7th cervical vertebrae (22 fetuses 

from 11 litters v. 0 fetuses in the control), and total number of skeletal variations (37 

fetuses from 17 litters v. 14 fetuses from 10 litters in the control) at gestation day 21 and 

renal pelvis dilation (7 young from 6 litters v. 0 young in the control) at postnatal day 56 at 

the developmental LOAEL of 1000 mg/kg/day. 

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

prenatal developmental toxicity study in rats (870.3700a; OECD 414).

870.3700b Prenatal Developmental Toxicity Study - Rabbit

A prenatal developmental toxicity study (MRID 42178311, 43215401, 43215402, 41321720) 

was conducted in pregnant JW-NIBS rabbits, in which pyriproxyfen (97.2% a.i.) was 

administered by gavage at doses of 100, 300, or 1000 mg/kg/day in distilled water on gestation 

days 6-18. 

The maternal NOAEL was 100 mg/kg/day. The maternal LOAEL was 300 mg/kg/day, 

based on occurrence of premature delivery/abortions, soft stools, emaciation, lusterless fur, 

decreased activity, and bradypnea/deep breathing. At 1000 mg/kg/day, these signs 

increased in incidence and frequency. 

The developmental NOAEL was 300 mg/kg/day, based on decreased viable litters available 

for examinations at the LOAEL of 1000 mg/kg/day. 
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This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

prenatal developmental toxicity study in rabbits (870.3700b; OECD 414).

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects - Rat

In a two-generation reproduction study (MRID 42178313), pyriproxyfen (95.3% purity) was 

administered to 26 Sprague-Dawley rats/sex/dose at dietary levels of 0, 200, 1000, or 5000 ppm 

(18, 87, or 453 mg/kg/day for males and 20, 96, or 498 mg/kg/day for females) for one litter per 

generation. 

The parental LOAEL was 5000 (453 mg/kg/day in males, 498 mg/kg/day in females), based 

on decreased body weight, body weight gain, and food consumption (both sexes) and 

increased liver weight in the F1 males and females, and histopathological lesions of liver 

and kidneys of F1 males. The parental NOAEL was 1000 ppm (87 mg/kg/day in males, 96 

mg/kg/day in females).

The reproductive NOAEL > 5000 ppm (453 mg/kg/day in males, 498 mg/kg/day in females). 

The reproductive LOAEL was not established. 

The offspring LOAEL was 5000 ppm (453 mg/kg/day in males, 498 mg/kg/day in females) 

based on decreased body weight on lactation days 14 and 21 in F1 and F2 pups. The 

offspring NOAEL was 1000 ppm (87 mg/kg/day in males, 96 mg/kg/day in females). 

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

reproductive toxicity study in rats (870.3800; OECD 416).

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

In a chronic toxicity/carcinogenicity study (MRID 42178314, 43210501) groups of male and 

female Sprague-Dawley rats were fed diets containing technical pyriproxyfen at doses of 0, 120, 

600, or 3000 ppm (equivalent to 0, 5.42, 27.31, or 138 mg/kg/day in males and 0, 7.04, 35.1, or 

182.7 mg/kg/day in females) for 104 weeks.

The LOAEL for females was 3000 ppm (182.7 mg/kg/day) based on a 16.9% decrease in 

body weight gain in females compared to controls while a LOAEL was not established for 

males. The NOAEL for females was 600 ppm (35.1 mg/kg/day) and the NOAEL for males 

was >3000 ppm (138 mg/kg/day). 

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

chronic toxicity/carcinogenicity study in rats (870.4100a/870.4200a; OECD 452/451).
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870.4100b Chronic Toxicity - Dog

In a chronic toxicity study (MRID 42178309), S-31183 (94.4% a.i., Lot# 87074) was 

administered in gelatin capsules to 4 beagle/sex at doses of 0, 30, 100, 300, and 1000 mg/kg/day 

for approximately one year.

In males receiving 300 mg/kg/day there was also significant increases in cholesterol levels 

throughout the study and increases in triglyceride levels at week 50. Mild anemia was also 

present in males at this dose level and was characterized by significant decrease in hemoglobin 

and red cell count when compared to controls. 

At 1000 mg/kg, death was reported in two of the four males and was attributed to hepatic failure. 

In the remaining males, there was as significant increase in prothrombin time, and in both sexes 

there were increases in hepatic enzyme levels and gross and microscopic hepatic lesions. 

Decreases in body weight gain were also reported for both sexes and there was an increase in 

relative and absolute liver weights at the high dose level.

The LOAEL was 300 mg/kg/day based on statistically and biologically significant decreases 

in body weight gain and increases in relative liver weights in both sexes. The NOAEL was 

100 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

chronic toxicity study in nonrodents (870.4100b; OECD 452).

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study - rat

See executive summary for 870.4100a.

870.4200b Carcinogenicity (feeding) - Mouse

In a carcinogenicity study in mice (MRID 42178310), technical pyriproxyfen (95.3%) was 

administered by diet to randomized groups of 50/sex/dose male and female CD-1 mice at levels 

of 0,120, 600, and 3000 ppm (16.8, 84.0, and 420 mg/kg/day in males and 21.0, 109.5, and 547

mg/kg/day in females) for 78 weeks. There was no increased tumor incidence in either sex that 

could be attributed to the test material. 

The LOAEL for systemic effects in both sexes was 3000 ppm (420 and 547 mg/kg/day in 

males and females, respectively) based on renal lesions in both sexes. The NOAEL for 

systemic effects in both sexes was 600 ppm (84.0 and 109.5 mg/kg/day in males and females, 

respectively).

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

carcinogenicity study in mice (870.4200b; OECD 451).
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A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100, Gene 

Mutation

MRID 44503506, 44503507, 

44503508, 42178315

Acceptable

Neither pyriproxyfen nor its metabolites induced mutations in 

S. typhimurium and E. coli at concentrations up to 5000 

ug/plate in either presence or absence of metabolic activation

Cytogenetics

Guideline 870.5300, 

Mammalian gene mutation 

assay

MRID 42178316

Acceptable

Negative for mutagenic response up to cytotoxic levels or 

insoluble concentrations both in the absence and presence of 

metabolic activation

Chromosome aberrations

Guideline 870.5375, 

Chromosome aberrations

MRID 41321722

Acceptable

Pyriproxyfen is not clastogenic in either presence or absence 

of metabolic activation

Unscheduled DNA Synthesis

Guideline 870.5550, 

Unscheduled DNA synthesis

MRID 42178317

Acceptable

Negative for a positive genotoxic responses

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study - Hen

Not required

870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID # 48711904), groups of non-fasted, 6 weeks old

Crl:CD(SD) rats, 12/sex/dose were given a single oral dose of Pyriproxyfen T.G. (99.5%, Lot # 

080506G) in corn oil at doses of 0, 300, 1000 or 2000 mg/kg bw and observed for 14 days. 

Neurobehavioral assessment functional observational battery and motor activity testing was 

performed on all animals at 8 hours post dosing. At study termination, all animals were 

euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 
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6/sex/group from both controls and 2000 mg/kg were subjected to histopathological evaluation 

of brain and peripheral nervous system tissues. 

A test substance-related unkempt appearance was noted for one male and six females in the 2000 

mg/kg group at the detailed physical examination. There were no treatment related effects on 

mortality, body weight, brain weight or gross and histologic pathology, neuropathology or FOB 

measurements. Motor activity testing revealed test substance-related, lower total and ambulatory 

counts at 1000 and 2000 mg/kg group males, compared with the control group on study Day 0 

only. Compared to the control group, mean motor activity counts were 20.9% and 21.4% lower 

(total) and 20.0% and 27.4% lower (ambulatory) for the 1000 and 2000 mg/kg group males, 

respectively, and were significant (p<0.032) for the 2000 mg/kg group. By study Days 7-14, 

mean total and ambulatory activity counts for males of both groups were unaffected by test 

substance. 

No microscopic effects supportive of clinical signs or changes in motor activity were observed, 

indicating that these effects could be due to either general malaise or transient changes in neural 

activity. 

Based on the effects seen in this study, the LOAEL was 2000 mg/kg bw/day based on 

deceases in motor activity on Day 0 in males and unkempt appearance in females. The 

NOAEL is 1000 mg/kg bw/day.

This neurotoxicity study is classified as Acceptable/Guideline and satisfies the guideline 

requirement for an acute neurotoxicity study in rats (870.6200; OECD 424).

870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity study (MRID # 48711905), Pyriproxyfen T.G. (99.5% a.i, Lot # 

080506G) was administered to 12 Crl:CD(SD) rats/sex/group at dose levels of 0,1500, 5000, or 

15,000 ppm (equivalent to 0, 108, 359, 1111 mg/kg bw/day for males and 0, 102, 407, 1212 

mg/kg bw/day for females) for 13 weeks. 

Neurobehavioral assessment (functional observational battery and motor activity testing) was 

performed in12 animals/sex/group at pretest (study week -1), study weeks 1, 3, 7, and 12, 

respectively. At study termination, 6 animals/sex/group were euthanized and perfused in situ for 

neuropathological examination. Of the perfused animals, 6/sex/group from both control and 

15,000 ppm group were subjected to histopathological evaluation of brain and peripheral nervous 

system tissues.

Homogeneity, stability, and concentration of the test substance in the diet were within the 

acceptable range of the performing laboratory. There were no test substance-related clinical 

findings noted at any concentration and all animals survived to the scheduled necropsy on 

Study Day 91. In the 15,000 ppm group, significantly (p<0.01) lower mean body weight gains 

were noted during Study Days 0-14 and 0-7 for the males and females, respectively. Mean body 

weight gains for males and females in this group generally remained lower (occasionally 

significant; p<0.01) than the control group throughout the remainder of the study and resulted in 
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significantly (p<0.01) lower mean cumulative body weight gains (Study Days 0-91). As a result, 

mean body weights for the 15,000 ppm group males and females were 12.1% to 16.4% and 8.1% 

to 10.8% lower, respectively, than the control group during Study Days 7-91 and 35-91, 

respectively; significance (p<0.05 or p<0.01) was achieved beginning on Study Days 7 and 35, 

respectively, and continued to be observed throughout the remainder of the study. Test 

substance-related, lower mean food consumption (g/animal/day) was noted in the 15,000 ppm 

group males and females throughout the treatment period (Study Days 0-91); differences were 

generally significant (p<0.05 or p<0.01) for males and occasionally significant (p<0.05 or 

p<0.01) for females. FOB and motor activity parameters were not significantly affected by test 

substance administration. Gross and histopathological examinations, as well as brain weights and 

measurements, were not affected by test substance administration. 

Based on the effects seen in this study, the LOAEL for neurotoxicity was not observed, with 

a NOAEL of 15,000 ppm (1111 mg/kg/day for males and 1212 mg/kg/day for females).

The LOAEL for systemic toxicity was 15,000 (1111 mg/kg/day for males and 1212 

mg/kg/day females) based on lower mean body weights, body weight gains, and food 

consumption for both sexes, with a NOAEL of 5000 ppm (359 mg/kg/day for males and 407 

mg/kg/day for females).

The study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

subchronic neurotoxicity study in rats (870.6200b). 

870.6300 Developmental Neurotoxicity Study

Not required

A.4.8 Metabolism

870.7485 Metabolism - Rat

In a metabolism study (MRID 42178318 and 42201402) rats were dosed with 14C labeled 

sumilarv at oral doses of 2 or 1000 mg/kg, and at repeated oral doses (14 daily doses) of 

unlabeled sumilarv at 2 mg/kg followed by administration of a single oral dose of labeled 

sumilarv at 2 mg/kg. The major routes of excretion of radioactivity were via the urine and feces. 

The excretion of radioactivity into urine and feces was rapid and over a 7-day period, most (92-

97%) of the test compound administered was excreted in the urine (5-12%) and feces (81-92%) 

from the animals. Most (63-83%) of the dose was eliminated in the urine and feces within 24 

hours after dosing. Expired air was not detected. Radioactivity in tissue residues was very low in 

all tissues expect the fat. Recoveries of the administered doses in the tissues including carcass 

were not more than 0.3% indicating that the potential for bioaccumulation of sumilarv is minimal 

even after high dose or repeated low dose exposures. In the urine, a total of 11 metabolites were 

detected and two of them (4’-OH-31183 sulfate and 4’-OH-POP sulfate) were identified. In the 

feces, an unmetabolized sumilarv (7-37% of the dose) and a total of up to 17 metabolites were 

detected and 10 of them (6 unconjugated and 4 sulfate conjugates) were identified. The four 

major fecal metabolites were 4’-OH-31183, 4’-OH-31183 sulfate, 5, 4’-OH-31183 sulfate, and 
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4’-OH-POPA. The metabolites in the liver, kidney, blood, bile, and fat of rats were also 

examined. Based on the metabolites identified by TLC cochromotography with synthetic 

standards the major biotransformation reactions of sumilarv include: 1) Oxidation at 4’-postion, 

of the terminal phenyl group; 2) Oxidation at 5-psition of pyridine; 3) Cleavage of the ether 

linkage and conjugation of the resultant phenols with sulfuric acid. No significant sex-or doserelated differences exist in the absorption, distribution, or metabolism of sumilarv for all dosing 

regimens.

870.7485 Metabolism - Rat

In a metabolism study (MRID 44036914), male and female Sprague-Dawley rats (7 week old) 

were given a single oral gavage dose of pyriproxyfen [4-phenosyphenyl (RS)-2-(2-pyridylosy) 

propyl ether], which was labeled at the 2 and 6 positions of the pyridyl ring with 14C ([pyridyl2,6-

14C]pyriproxyfen), at a rate of 2 mg/kg (low-does) or 1000 mg/kg (high-dose).

The radiocarbon was rapidly eliminated from the body within 7 days after administration in both 

groups. From 88.9% to 92.9% of the dosed 14C was excreted into urine, feces, and expired air in 

the first two days, and 92.3-98.5% of the dosed 14C was excreted within 7 days after 

administration. 14C -Excretion into expired air was less than 0.5% for all groups. Fecal excretion 

was predominant, being 84.7-93.2% of the dose. 14C -Residues in tissues on the 7th day after 

administration were less than 0.3% of the dosed 14C, being the highest in fat (low-dose: 0.014-

0.015 ug equivalents of pyriproxyfen/g wet tissue (ppm), high dose: 6.0-6.3 ppm). 14C-Residues 

levels in blood, blood cell, kidney, and liver were 0.002 – 0.009 ppm for the low dose group, and 

1.2 – 4.5 ppm for the high dose group. 14C -Residue levels in other tissues were low being less 

than 0.003 ppm and 3 ppm for the low and high dose groups, respectively. There were no 

significant sex-or dose-related differences in 14C -excretion and 14C -distribution.

Thirteen or more metabolites were found by HPLC and TLC analyses of feces and urine 

collected in the first two days. Ten of them were identified, accounting for 70-83% of the dosed 

14c. The metabolic pathways of pyriproxyfen in rats were proposed on the basis of identified 

metabolites. The major fecal metabolite was 4-(4’-hydroxyphenosyphenyl)-2-(2-

pyridyloxy)propyl ether, which had one hydroxyl group at the 4’-position of the terminal phenyl 

ring and accounted for 23-48% of the dosed 14C. Each of the other metabolic pathways, such as 

hydroxylation at the 2’-position of the terminal phenyl ring or at the 5’-postion of the pyridyl 

ring, dephenylation, cleavage of ether linkages, and conjugations of the resulting phenols with 

sulfuric acid or glucuronic acid, accounted for less than 10% of the dosed 14C. Pyriproxyfen was 

detected mainly in feces and its amount was 21-35% of the dosed 14C. The major urinary 

metabolite was 2-(2-pyridyloxy) propionic acid, accounting for 1-5% of the dose.

Comparison of metabolites in feces and urine, between male rats given a single oral low dose of 

pyriproxyfen labeled uniformly with 14C at the phenoxyphenyl ring [phenoxyphenyl14C]pyriproxyfen and those given the same dose of [pyridyl-2,6-

14C]pyriproxyfen, showed that 

metabolites resulting from cleavage of ether linkages accounted for 5.2% of the dosed 14C.
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870.7600 Dermal Absorption - Rat

A dermal absorption study is not available for pyriproxyfen. However, a 21-day dermal rat 

toxicity study resulted in no toxicity up to the limit dose and therefore short- and intermediateterm dermal exposure assessments are not warranted. An oral endpoint was selected to be 

protective of the long-term dermal assessment. For the long-term dermal assessment, dermal 

penetration was estimated to be 30% by the extrapolation method of comparing the maternal 

toxicity LOAEL of 300 mg/kg/day in the rat developmental toxicity oral study and the dermal 

NOAEL of 1,000 mg/kg/day in the 21-day dermal study. These studies were both in the rat and 

approximately the same duration in exposure. Thus, a dermal-penetration factor of 30% was 

used for the route-to-route extrapolation in this long-term dermal risk assessment, since an oral 

study was selected for the endpoint.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID # 48711907), Pyriproxyfen (99.5% ai, Batch # 080506G) 

was administered to four groups of female CD-I mice (n=10) in the diet at dose levels of 0, 1000, 

2000, or 5000 ppm (0, 228, 449, 1139 mg/kg bw/day) for at least 28 days. An additional positive 

group of 8 female mice were administered cyclophosphamide by gavage once daily at a dose of 

20 mg/kg/day for 5 consecutive days (study days 22-26). All animals were evaluated for 

mortality, clinical signs, body weight changes food and water consumptions. On study day 25, all 

animals were immunized with an i.v. injection of 0.2 mL of sheep red blood cells (2 x 109

SRBC/animal) in 0.9% saline. On study day 29, all mice were euthanized; the organ weights of 

the liver, spleen, adrenals and thymus were determined, and T-dependent antibody responses 

(TDAR) were determined by an antibody plaque-forming-cell (PFC) assay.

There were no test substance-related clinical signs of toxicity, morbidity, or mortality during the 

treatment period. Lower bodyweight gain compared to the controls, was observed in animals 

receiving 1000 or 5000 ppm (30% lower from controls). There were no test substance-related 

effects on food consumption. There were no treatment-related effects on macroscopic pathology 

of any treated group. There was a dose-related increase of absolute and relative body weight to 

liver weight and, with the exception of absolute liver weights at 1000 ppm, these differences 

were statistically significant from controls. There were no effects of treatment on spleen, thymus 

or adrenal weight.

The systemic toxicity LOAEL is 5000 ppm (1139 mg/kg/day), based on lower bodyweight 

gain and increase of absolute and relative body weight to liver weight. The NOAEL for 

systemic toxicity is 2000 ppm (449 mg/kg/day).

There were no statistically significant changes in the numbers of cells/spleen, PFC/106 viable 

cells or PFC/spleen for CD-I mice in any of the dosed groups when compared to the Control. 

Treatment with Cyclophosphamide at 20 mg/kg/day seven to three days prior to termination 

resulted in a significant reduction of the PFC response. The numbers of cells/spleen, PFC/106

viable cells and PFC/spleen (all p < 0.001) were all significantly reduced when compared to 
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the control.

The LOAEL for immunotoxicity is not observed. The NOAEL for immunotoxicity is 5000 

ppm (1139 mg/kg/day).

This immunotoxicity study is classified Acceptable/Guideline, and satisfies the guideline 

requirement for an immunotoxicity study (OPPTS 870.7800) in mice. 

A.4.10 Non-guideline studies

Reproduction and Fertility Effects – Rat

In a non-guideline study (MRID 44985001), pyriproxyfen (S-31183, 97.2% a.i., Lot# PTG86011) in corn oil was administered to pregnant Slc:SD rats (23-24/dose) on gestation day (GD) 

17 to lactation day (LD) 20 at doses of 0, 30, 100, 300, or 500 mg/kg/day. On day 4 postpartum, 

litters were standardized to a maximum of 8 pups/litter with 4/sex/litter, as nearly as possible; 

excess pups were sacrificed and examined for skeletal anomalies. Physical and sexual 

development of all F1 pups was monitored and on postnatal day (PND) 20, all pups were 

subjected to a sensory function test. At 3 weeks of age, all F1 pups (except the 2/sex/litter 

retained for learning tests and the 1 pup/sex/litter retained for reproductive ability) were 

necropsied, the organs were examined and weighed, and the pups were examined for visceral and 

skeletal anomalies. One F1 pup/sex/litter was subjected to an open field test, motor coordination 

test, learning ability test, and necropsied at 8 weeks of age. One F1 pup/sex/litter was raised to 

11 weeks of age and then paired for mating within the same dose group for a reproductive 

performance assessment.

At 300 and 500 mg/kg, clinical signs observed in the P females included diarrhea (3/24 and 

22/24 treated, respectively, vs 0/23 controls) and salivation (2/24 and 4/24 treated, respectively, 

vs 0/23 controls). Reductions (p<0.05 or 0.01) in body weight gains were noted in the P females 

on GD 19 (↓22 and 49%, respectively), 20 (↓17 and 57%, respectively), and 21 (↓17 and 64%, 

respectively). Body weight gains were increased in the P females at 500 mg/kg on LDs 4 through 

21 (↑58-1375%) and at 300 mg/kg on LD 21 (↑270%). Decreases in P food consumption were 

observed in the 300 and 500 mg/kg females as follows: on GDs 19 (↓20 and 39%, respectively), 

20 (↓13 and 44%, respectively), and 21 (↓10 and 50%, respectively) and LD 21 (↓11 and 17%, 

respectively).

At 500 mg/kg, two P animals died on day 5 of dosing after displaying clinical signs which 

included hypoactivity, rough hairs, hypothermia, and lacrimation on dosing day 4 or 5. Clinical 

signs in P females included: erythema and swelling of the periproctal region (8/24 treated); 

hypoactivity (4/24 treated); rough hair (3/24 treated); lacrimation (3/24 treated); and 

hypothermia (4/24 treated). None of these findings were observed in any control animal. 

Decreases in body weight gain and food consumption were observed in the P females on GD 22 

(↓109 and 63%, respectively). Increased absolute and relative liver weights were observed in the 

P females (absolute: ↑18%; relative: ↑17%). Gross findings observed at necropsy of the 500 

mg/kg females and no control animal (unless otherwise noted) included: atrophy of the thymus 

(4/23 treated); congestion of the liver (2/23); enlargement of the liver (1/23 treated); atrophy of 
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the spleen (4/23 treated); congestion of the kidney (1/23 treated); atrophy of the adrenal (5/23 

treated v. 1/23 controls); hemorrhage of the mucous membrane of the stomach (1/23); and ulcers 

of the stomach (2/23 treated). Percent preimplantation losses were increased in the F1 dams, as 

calculated by reviewers, at 500 mg/kg (↑208%).

When compared to concurrent controls, no treatment-related changes in P or F1 female body 

weights or F1 body weight gains were observed. No treatment-related differences in water 

consumption of the P females were observed. There were no differences of toxicological concern 

observed in the reproductive performs

The LOAEL for maternal toxicity is 300 mg/kg/day based on clinical signs, deceased body 

weight gains, and decreased food consumption. The NOAEL is 100 mg/kg.

At 300 and 500 mg/kg, body weights were decreased throughout the postnatal interval as 

follows: 300 mg/kg F1 males and females from PND – to weaning (↓9-17%); 500 mg/kg F1 

males and females from PND0 to weaning (↓15-23%). Body weights were also decreased during 

the learning ability phase (PNDs 28-56) in both males and females at 300 (↓5-13%) and 500 

mg/kg (↓7-15%). Upon visceral examination at PND 21, an increased fetal incidence [% fetal 

incidence (% litter incidence)] of dilation of the renal pelvis was observed at 300 [13.8 (30.4)] 

and 500 mg/kg [18.4(35.7)]. 

At 500 mg/kg, changes in mean litter size and viability indices were observed as follows: 

increased stillborn index (↑473%, calculated by reviewer); decreased day 4 viability in the 

females only (↓18%); decreased day 7 viability (↓12%, calculated by reviewer); decreased day 

21 viability (↓21-24%); decreased mean litter size over the entire PNDs 0-21 interval (↓12-29%, 

calculated by reviewer); decreased number of live pups (↓24-39%, calculated by reviewer PND 

0-21); and increased number of deaths for days 0-4 (↑350%, calculated by reviewer) and days 0-

21 (↑463%, calculated by reviewer). Upon visceral examination at PND 21, an increased fetal 

incidence of hyperemia and/or inflammatory cell infiltration in the propria of urinary bladder 

was observed microscopically (fetal incidence: 12.2%; litter incidence: 28.6%).

No changes in viability were noted in the pups selected for learning or reproductive phases; 

additionally, no differences in body weights were observed in the reproductive animals. No 

differences were noted in the physical or sexual development, behavioral aspects, locomotor 

activity, rotorod performance, or learning ability of the pups. There were not differences of 

toxicological concern in organ weights, external examination, or skeletal exam9ination at 3 

weeks, 8 weeks, or following the reproductive performance test. No treatment-related findings 

were observed in the cesarean section parameters for the F1 reproductive performance.

The LOAEL for reproductive toxicity in males and females is 300 mg/kg/day based on 

decreased body weight and increased incidence of dilation of the renal pelvis. The NOAEL 

is 100 mg/kg/day. 

This study is classified as Acceptable/Non-guideline.
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Developmental Toxicity – Rat

In a non-guideline study (MRID 44985002), pyriproxyfen (S-31183, 97.2% a.i., Lot# PTG86011) was administered by gavage in corn oil once daily to Slc:SD rats (24 rats/sex/dose) at 

dose levels of 0, 100, 300, 500, or 1000 mg/kg/day. In the parental animals, males were 

administered the test substance beginning at 6 weeks of age, were dosed for 9 weeks prior to 

mating, and for an additional 3 weeks until the end of the mating period; females were 

administered the test substance beginning at 9 weeks of age, for 2 weeks prior to the start of the 

mating, and continued to be dosed throughout mating and until gestation day (GD) 7. All live 

fetuses were weighed, sexed, and examined for external abnormalities. Approximately one-third 

of the fetuses per litter were subjected to a visceral examination, while all remaining fetuses were 

examined for skeletal anomalies.

At 300, 500, and 1000 mg/kg, clinical signs observed in males and females included: diarrhea in 

females (9/24. 22/24. And 24/24 treated, respectively, v. 0/24 controls); erythema and swelling 

of the periproctal region in females (1/24. 9/24, and 23/24 treated, respectively v. 0/24 controls). 

Reductions in body weight gains were noted in the males at 300 (↓8-11%, day 35-83), 500 (↓9-

21%, day 21-83), and 1000 mg/kg (↓25-41%, day 7-83); additionally, decreases in body weight 

gains were observed throughout the pre-mating interval in females at 300 (↓19-27%), 500 (↓26-

79%), and 1000 mg/kg (↓27-194%). Increases in food consumption observed in males were as 

follows: at 300 mg/kg, increases were noted on day 0, days 10-21, and days 35-62 (↑7-17%); at 

500 mg/kg, increases were observed on day 0 and on days 10-62 (↑5-24%); and at 1000 mg/kg, 

increases were noted on days 14-62 (↑8-34%). Increased water consumption was observed in 

males at 300 (↑13-41%, days 3-62), 500 (↑24-72%, days 3-62) and 1000 mg/kg (↑60-117%, days 

3-63). During the gestation interval, increases in water consumption were observed in the 300 

(↑15-25%, GDs 3-8), 500 (↑29-63%, GD 1-12), and 1000 mg/kg (↑48-135%, GDs 1-12) females.

In the males dosed at >300 mg/kg, it was stated that histopathological changes in the kidneys 

included regenerative changes of the tubules, dilation of the tubules, and accumulation of 

neutrophils or degenerated cells within the dilated and regenerated tubules; however, no 

incidence data were reported and only photographs of these findings were provided. Differences 

in absolute and relative organ weights in the >300 mg/kg males were as follows: decrease 

absolute (300 mg/kg: ↓11%; 500 mg/kg: ↓22%; and 1000 mg/kg: ↓42%) and relative (500 

mg/kg: ↓11%; and 1000 mg/kg: ↓26%) thymus weights: increased absolute (300 mg/kg: ↑23%; 

500 mg/kg: ↑24%; and 1000 mg/kg: ↑27%) and relative (300 mg/kg: ↑31%; 500 mg/kg: ↑41%; 

and 1000 mg/kg: ↑62%)liver weights; increased absolute (300 mg/kg: ↑9%; and 1000 mg/kg: 

↑8%) and relative (300 mg/kg: ↑16%; 500 mg/kg: ↑22%; and 1000 mg/kg: ↑38%) kidney 

weights; and increased absolute (300 mg/kg: ↑28%; 500 mg/kg: ↑36%; and 1000 mg/kg: ↑62%) 

and relative (300 mg/kg: ↑37%; 500 mg/kg: ↑56%; and 1000 mg/kg: ↑108%) adrenal weights. At 

necropsy, gross findings were observed in the 300, 500, and 1000 mg/kg males and not in the 

controls included: atrophy of the thymus (1/24. 1/23, and 12/24 treated, respectively); 

enlargement of the liver (18/24. 21/23, and 22/24 treated, respectively); dark-red color of the 

liver (21/24, 23/23, and 24/24 treated, respectively); enlargement of the kidney (1/24, 6/23, and 

16/24 treated, respectively); pitted surface of the kidney (8/24, 22/23, and 22/24 treated, 

respectively); and enlargement of the adrenal (12/24, 18/23, and 24/24 treated, respectively).

At 500 and 1000 mg/kg, clinical signs observed in the males included diarrhea (20/24 and 24/24 
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treated, respectively, vs 0/24 controls) and erythema and swelling of the periproctal region 

(22/24 and 24/24 treated, respectively, vs 0/24 controls). Decreased male body weights were 

observed at 500 mg/kg (↓6-12%, day 28-83) and at 1000 mg/kg (↓9-21%, day 3-83). Increases in 

water consumption were observed during pre-mating days 3-13 in the 500 and 1000 mg/kg 

females (↑60-82% and ↑100-137%, respectively). There were no differences of toxicological 

concern observed in the reproductive performance or Cesarean section parameters.

At 1000 mg/kg, two females died on days 5 or 7 of administration after displaying clinical signs 

including severe diarrhea, hypoactivity, and wasting. At necropsy, liver congestion, atrophy of 

the spleen and thymus, adrenal and liver enlargement and stomach ulcers were noted in either 1 

or both of these females that died prematurely. Lacrimation was observed in 3/24 males vs 0/24 

controls. In females, hypoactivity (4/24 treated vs 0/24 controls) and wasting (6/24 treated vs 

0/24 controls) were observed. In males, a single extreme decrease in body weight gains was 

observed on day 3 (↓108%). At necropsy, protrusion of the liver parenchyma on the 

diaphragmatic side was observed in 1/24 males vs 0/24 controls.

The LOAEL for parental toxicity in males and females is 300 mg/kg/day based on clinical 

signs, decreased body weight gains, and increased water consumption in both sexes, and 

increased food consumption, changes in organ weights, and gross pathological findings in 

males only. The NOAEL for both sexes is 100 mg/kg/day.

No developmental toxicity was observed at any dose level tested.

The developmental LOAEL was not observed. The developmental NOAEL was >1000 

mg/kg/day (limit dose). 

This study is classified as Acceptable/Non-guideline.
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Appendix B: Proposed Metabolic Pathway for Pyriproxyfen
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Appendix C. Studies Reviewed for Ethical Conduct

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task 

Force members Health Canada, U.S. Environmental Protection Agency, and the National 

Agricultural Chemicals Association, released February, 1995.

Agricultural Re-entry Task Force (ARTF) data base (SOP #3.1)