Page 3 of 40

5.3 Water Residue Profile................................................................................................ 17

5.3.1 Estimated Drinking Water Concentrations.......................................................... 17

5.4 Dietary and Drinking Water Exposure and Risk.................................................... 17

5.4.1 Acute Dietary and Drinking Water Analysis ....................................................... 17

5.4.2 Chronic Dietary and Drinking Water Analysis ................................................... 17

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT .......................................... 18

6.1 Residential Bystander Postapplication Inhalation Exposure .................................... 19

6.2 Spray Drift...................................................................................................................... 19

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT............................................ 20

7.1 Short-, Intermediate-, and Long-Term Aggregate Risk ............................................ 20

8.0 CUMULATIVE RISK...................................................................................................... 24

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION.............................. 24

9.1 Exposure Scenarios....................................................................................................... 24

9.2 Handler Exposure.......................................................................................................... 25

9.3 Post Application Exposure............................................................................................ 25

9.3.1 Restricted Entry Interval ....................................................................................... 25

10. REFERENCES.................................................................................................................. 26

APPENDICES............................................................................................................................. 27

A TOXICOLOGY DATA SUMMARY............................................................................. 27

A.1 Guideline Data Requirements.................................................................................. 27

A.2 Toxicity Profiles......................................................................................................... 28

A.3 Toxicological Endpoints............................................................................................. 33

A.4 EXECUTIVE SUMMARIES (recently submitted studies)................................... 37

APPENDIX C. Physical/Chemical Properties.......................................................................... 40

APPENDIX D. Studies Reviewed for Ethical Conduct.......................................................... 40
Page 4 of 40

1.0 EXECUTIVE SUMMARY

The Interregional Research Project No. 4 (IR-4) submitted a petition for the establishment of 

permanent tolerances for residues of the insecticide pyriproxyfen [2-[1-methyl-2-(4-

phenoxyphenoxy)ethoxy]pyridine]. Permanent tolerance are currently established for a variety 

of commodities under 40 CFR 180.510(a)(1). Tolerances of 0.10 ppm are also established for all 

food commodities as a result of uses in food handling establishments under 40 CFR 

180.510(a)(2). Time-limited tolerances are also established under 40 CFR 180.510(b) for bean, 

succulent; celery and strawberry. 

The most recent human health risk assessment for pyriproxyfen was conducted by ARIA (DP#: 

360751, B. Hanson, 9/3/2009). 

Use Profile

Pyriproxyfen is an analogue of an insect juvenile hormone and interferes with the hormonal 

control of insect growth and development, thereby inhibiting egg hatch, larval embryogenesis, 

metamorphosis, and adult emergence. There are currently several end-use products of 

pyriproxyfen with food/feed uses that are registered to Valent USA Corporation:Distance, 

11.23% w/w, EPA Reg. No. 59639-96; Pyriproxyfen 0.86 EC Ag, 0.86 lb/gal EC, EPA Reg. No. 

59639-160; Pyriproxyfen 0.86 EC UPP, EPA Reg. No. 59639-163; Knack®IGR [0.86 lb/gal 

EC; EPA Reg. No. 59639-95], Esteem®35 WP, 35% WP, EPA Reg. No. 59639-115; and 

Esteem® Ant Bait, 0.5% w/w, EPA Reg. No. 59639-114: containing pyriproxyfen for use on a 

variety of crops. 

Permanent tolerances for pyriproxyfen have been established for a variety of commodities under 

40 CFR §180.510. 

Proposed New Uses

Under PP#1E7950, The Interregional Research Project Number 4 (IR-4) has submitted a petition 

for the establishment of permanent tolerances for residues of the insecticide pyriproxyfen [2-[1-

methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine] in conjunction with requests for amended 

Section 3 registrations of six pesticide formulations: Distance, 11.23% w/w, EPA Reg. No. 

59639-96; Pyriproxyfen 0.86 EC Ag, 0.86 lb/gal EC, EPA Reg. No. 59639-160; Pyriproxyfen 

0.86 EC UPP, EPA Reg. No. 59639-163; Knack®IGR [0.86 lb/gal EC; EPA Reg. No. 59639-

95], Esteem®35 WP, 35% WP, EPA Reg. No. 59639-115; and Esteem® Ant Bait, 0.5% w/w, 

EPA Reg. No. 59639-114: containing pyriproxyfen for use on the herb subgroup 19A. 

Maximum application rate is 0.087 lb a.i./A and the maximum seasonal application rate is 0.176 

lb a.i./A. A maximum of two applications is proposed along with a 1-day pre-harvest interval 

(PHI).

Hazard Identification

Pyriproxyfen is of low acute toxicity by oral, dermal, inhalation and ocular routes of exposure, 

since all studies are in 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. Based on 

repeated dose studies in mice, rats and dogs the liver and kidney are the principal target organs, 

with slight anemia occurring in rodent species. The review of the acute and subchronic 

neurotoxicity studies indicates pyriproxyfen is not a neurotoxic chemical. There was no 
Page 5 of 40

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 (decreased body weight on pups during lactation days 14 to 21) 

occurred in the presence of decreased body weight in parental animals at the same dose level. 

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. In a 28-day 

inhalation study, the LOAEL of 1 mg/L based on salivation in females and sporadic decreased 

body weight gains in males was not considered biologically relevant. 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. Pyriproxyfen was absorbed, metabolized, and rapidly 

excreted, primarily in the feces, in the rat metabolism study. There were no effects of gender, 

dose, or label position on absorption or elimination in the rat metabolism study. 

Dose Response Assessment

The database for pyriproxyfen is now 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 factor is reduced to 1X.

Risk assessments were conducted for the specific exposure scenarios listed below. 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. Therefore, an acute risk assessment is not required. The cRfD of 0.35 mg/kg/day was 

determined on the basis of decreased body weight and changes in clinical chemistry parameters 

in two co-critical rat toxicity studies (subchronic and chronic). Since the FQPA Safety Factor 

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

The short-term incidental oral endpoint (NOAEL 100 mg/kg/day) was determined on the basis of

the rat developmental maternal LOAEL of 300 mg/kg/day, based on decreased body weight, 

body weight gain, and food consumption, and increased water consumption. The intermediateterm incidental oral endpoint (NOAEL 35.1 mg/kg/day) was determined based on systemic 

toxicity (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 

(NOAEL) of 35.1 mg/kg/day from the two co-critical (subchronic and chronic) rat feeding 

studies. 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. An inhalation-absorption 

factor of 100% was used for route-to-route extrapolation. 
Page 6 of 40

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

Risk assessments were conducted for dietary (food and water) and occupational exposure 

pathways based on the proposed new use of pyriproxyfen. No new residential uses are 

associated with the proposed use; however, the residential exposure assessment was updated 

with HED’s 2012 Residential SOPs, along with policy changes for body weight assumptions. 

An unrefined chronic dietary and drinking water risk assessment for pyriproxyfen showed that 

dietary and drinking water exposure estimates are below HED’s level of concern for the general 

population and all population subgroups. Since no short- or intermediate-term inhalation or 

dermal endpoints were identified, an occupational exposure assessment did not need to be 

conducted. 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 D, 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

2.1 Data Deficiencies/Conditions of Registration 

Submission of a revised Section F is required. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The registrant submitted adequate concurrent recovery data for a GC/NPD method (RM-33P-1-

3a or 9.66 V 1) used to determine residues of pyriproxyfen in/on the subject crops. 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.

The GC/NPD method RM-33P-1-3a is adequate for enforcement of the recommended tolerance 

levels for residues of pyriproxyfen in/on the subject crops. As tolerances for residues of 

pyriproxyfen in livestock commodities are not required at this time, enforcement methodology

for determining residues in livestock is not required at this time.
Page 7 of 40

2.2.2 International Harmonization

There is a Codex MRL for Citrus fruit of 0.50 ppm. The US will harmonize for citrus fruit at 

0.50 ppm. Also, there is a Canadian tolerance of 0.8 ppm for bell peppers, and 0.25 ppm for 

tomatoes. US will harmonize for vegetable, fruiting, group 8-10 at 0.80 ppm.

2.2.3 Recommended Tolerances

A revised Section F proposing fresh and dry Herb subgroup 19A tolerances of 30 and 100 ppm, 

respectively, is required (i.e. 3.3X processing factor). In addition, a tolerance for Fruit, citrus, 

group 10-10 should be revised to 0.5 ppm to harmonize with Codex and the tolerance for 

vegetable, fruiting, group 8-10 should be revised to 0.8 ppm to harmonize with the Canadian 

MRL for bell peppers.

HED has examined the residue chemistry database for pyriproxyfen. With regards to 

pyriproxyfen for PP#1E7950, pending submission and a revised Section F (see requirements 

under Proposed Tolerances), there are no residue chemistry issues that would preclude granting 

amended registrations for amended Section 3 registrations of six pesticide formulations: 

Distance, 11.23% w/w, EPA Reg. No. 59639-96; Pyriproxyfen 0.86 EC Ag, 0.86 lb/gal EC, 

EPA Reg. No. 59639-160; Pyriproxyfen 0.86 EC UPP, EPA Reg. No. 59639-163; Knack®IGR 

[0.86 lb/gal EC; EPA Reg. No. 59639-95], Esteem®35 WP, 35% WP, EPA Reg. No. 59639-

115; and Esteem® Ant Bait, 0.5% w/w, EPA Reg. No. 59639-114: containing pyriproxyfen for 

use on a variety of crops, and to expand currently registered foliar uses for bulb vegetables, 

fruiting vegetables, citrus fruits, pome fruits, caneberry, bushberry and berry, low growing 

except strawberry, to include the additional commodities specified under the following new crop 

groups/subgroups, respectively: Vegetable, bulb, subgroup 3-07, Vegetable, fruiting, group 8-

10, Fruit, citrus, group 10-10, Fruit, pome 11-10, Caneberry subgroup 13-07A, Bushberry 

subgroup 13-07B, Herb subgroup 19A group 13-07A, Berry, low growing, except, strawberry, 

subgroup 13-07H, and Herb subgroup 19A fresh and Herb Subgroup 13A dried or establishment 

of tolerances for residues of pyriproxyfen only in/on the following commodities:

Vegetable, bulb, subgroup 3-07....................................................0.70 ppm

Vegetable, fruiting, group 8-10.....................................................0.80 ppm

Fruit, citrus, group 10-10.............................................................0.50 ppm

Fruit, pome, group 11-10.............................................................0.20 ppm

Caneberry subgroup 13-07A..........................................................1.0 ppm

Bushberry subgroup 13-07B...........................................................1.0 ppm

Berry, low growing, except, strawberry, subgroup 13-07H.......................1.0 ppm

Herb subgroup 19A , fresh.............................................................30 ppm

 Herb subgroup 19A, dried............................................................100 ppm

The amended registrations are limited to expansions to add the commodities specified under the 

new crop groups/subgroups and do not include substantive changes to currently registered use 

patterns (i.e., maximum use rates, retreatment intervals, pre-harvest intervals, use of adjuvants, 

etc.). 
Page 8 of 40

With regards to pyriproxyfen for PP#1E7950, pending submission of a revised Section F (see 

requirements under Proposed Tolerances), there are no residue chemistry issues that would 

preclude granting Section 3 registrations of six pesticide formulations: Distance, 11.23% w/w, 

EPA Reg. No. 59639-96; Pyriproxyfen 0.86 EC Ag, 0.86 lb/gal EC, EPA Reg. No. 59639-160; 

Pyriproxyfen 0.86 EC UPP, EPA Reg. No. 59639-163; Knack®IGR [0.86 lb/gal EC; EPA Reg. 

No. 59639-95], Esteem®35 WP, 35% WP, EPA Reg. No. 59639-115; and Esteem® Ant Bait, 

0.5% w/w, EPA Reg. No. 59639-114: to permit a new use on Herb subgroup 19A or 

establishing tolerances for residues of pyriproxyfen only in/on the following commodities:

Herb subgroup 19A, fresh........................30 ppm

Herb subgroup 19A, dried........................100 ppm

2.2.4 Revisions to Petitioned-For Tolerances

Tolerance level is different than that proposed by the registrant. This is due to calculating the 

MRLs with the OECD MRL calculator.

2.3 Label Recommendations

-Label for Distance (EPA Reg. No. 59639-96) must be amended to specify a maximum 

single application label rate for the sprench application method to herbs of 6 fluid ounces/10,000 

ft2or 3 fluid ounces /5000 ft2.

- Label for Esteem 35 WP (EPA Reg. No. 59639-115) Must require gloves unless the 

acute tox category is category IV for acute dermal and dermal/skin irritation.

-Label for Pyriproxyfen EC Ag (EPA Reg. No. 59639-160) The 4th bullet under the User 

Safety Recommendations should not be in that box and should be above that box since it's not a 

recommendation, but a requirement.

3.0 INGREDIENT PROFILE 

3.1 Chemical Identity

Table 2. 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) Knack®Insect Growth Regulator, Pyriproxyfen 0.86 EC Ag Insect Growth 

Regulator,Esteem®35 WP Insect Growth Regulator, Esteem® Ant 

3.2 Physical/Chemical Characteristics 

A table of the physiochemical properties of pyriproxyfen is provided in Appendix B. 

O O CH2 CH

CH3

O

N
Page 9 of 40

3.3 Pesticide Use Pattern

3.3.1 Registered Products

There are currently 173 active pyriproxyfen registrations including 165 Section 3 registrations 

and 6 special local needs (SLNs) or 24(c) registrations and 2 Experimental Use Permits (EUP). 

3.3.2 Proposed New Uses 

Under PP#1E7950, The Interregional Research Project Number 4 (IR-4) has submitted a petition 

for the establishment of permanent tolerances for residues of the insecticide pyriproxyfen [2-[1-

methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine] in conjunction with requests for amended 

Section 3 registrations of six pesticide formulations: Distance, 11.23% w/w, EPA Reg. No. 

59639-96; Pyriproxyfen 0.86 EC Ag, 0.86 lb/gal EC, EPA Reg. No. 59639-160; Pyriproxyfen 

0.86 EC UPP, EPA Reg. No. 59639-163; Knack®IGR [0.86 lb/gal EC; EPA Reg. No. 59639-

95], Esteem®35 WP, 35% WP, EPA Reg. No. 59639-115; and Esteem® Ant Bait, 0.5% w/w, 

EPA Reg. No. 59639-114: containing pyriproxyfen for use on the herb subgroup 19A. 

Maximum application rate is 0.087 lb a.i./A and the maximum seasonal application rate is 0.176 

lb a.i./A. A maximum of two applications is proposed along with a 1-day pre-harvest interval 

(PHI).

3.4 Anticipated Exposure Pathways

Dietary (food and water) exposures are expected based on existing uses of pyriproxyfen and the 

requested new use. An updated residential exposure assessment for short-term incidental oral 

and long-term dermal is required. 

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.eh.doe.gov/oepa/guidance/justice/eo12898.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. 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 postapplication 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. 
Page 10 of 40

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

A full suite of toxicity studies are now available for pyriproxyfen. The toxicology database is 

acceptable for characterizing pyriproxyfen hazard and includes the following studies:

Subchronic: 90-day Dietary in Rats, Mice, and Dogs; 21-day Dermal in Rats; 28-day Inhalation 

in Rats.

Chronic: 1-year Dietary in Dogs; Carcinogenicity Dietary Mice; 2-year Dietary Combined 

Chronic/Carcinogenicity in Rats.

Reproductive/Developmental: Developmental in Rats and Rabbits; Reproduction and Fertility 

Effects in Rats.

Neurotoxicity Battery: Acute and Subchronic in Rats

Mutagenicity and Genotoxicity in Bacterial & Mammalian Model Systems

Immunotoxicity: 28-day Dietary in Rats and Mice

Metabolism and Pharmacokinetic Studies in Rats 

 

4.2 Absorption, Distribution, Metabolism and Excretion

In the rat metabolism study, pyriproxyfen was absorbed was up to 12% based on urinary 

excretion estimates. Most radioactivity was excreted in the feces [81-92%] and urine [5-12%] 

over a 7 day collection period. Expired air containing radiolabeled CO2 was not detected in the 

rat metabolism study. Tissue radioactivity levels were very low [less than 0.3%] except for fat. 

Examination of urine, feces, liver, kidney, bile and blood metabolites yielded numerous [ > 20] 

identified metabolites.

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

Based on repeated dose studies in mice, rats and dogs the liver and kidney are the principal target 

organs, with slight anemia occurring in rodent species. Additionally, decreased body weight, 

body weight gain and/or food consumption were common findings in several studies. There was 

no systemic toxicity in a 21-day dermal toxicity study in rats up to the limit dose. In a 28-day 

inhalation study, the LOAEL of 1 mg/L based on salivation in females and sporadic decreased 

body weight gains in males was not considered biologically relevant.
Page 11 of 40

 

The recent submission and review of the acute and subchronic neurotoxicity studies indicates 

pyriproxyfen is not a neurotoxic chemical. There was no neurotoxicity observed in the acute and 

subchronic neurotoxicity studies up to the limit dose and no indication of toxicity to the central 

or peripheral nervous system in other subchronic or chronic toxicity studies. The salivation 

observed in the inhalation study was not observed in either the acute or subchronic neurotoxicity 

study. There were no treatment-related alterations in brain weight or histopathology (nonperfused tissues) following exposure to pyriproxyfen. 

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. 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 in a 

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

toxicity study, offspring toxicity (decreased body weight on pups during lactation days 14 to 21) 

occurred in the presence of decreased 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 

day 17 to lactation day 20, the resulting toxicity was comparable between adults (clinical signs, 

decreased body weight gain and food consumption) and offspring (decreased 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 in the early stages of pregnancy, no developmental toxicity was seen at 

the limit dose. 

In a battery of mutagenicity studies, pyriproxyfen was negative in the bacterial and mammalian 

gene mutation assays, an in vitro cytogenetic assay, as well as, in the Unscheduled DNA 

Synthesis (UDS) assay with HeLa cells. Based on these results, it is concluded that the 

mutagenic potential of pyriproxyfen is negative. An in vivo cytogenetic assay (e.g. mouse 

micronucleus study) has not been submitted. Since all in vitro mutagenicity studies are negative 

and there was no carcinogenic response in long term studies in rats and mice, the requirement for 

the in vivo cytogenetic assay is waived.

The recent submission and review of an immunotoxicity study showed no adverse effects on the 

immune system (48711906, 48711907).

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 of low acute toxicity by oral, dermal, inhalation and ocular routes of exposure, 

since all studies are in 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. 

The complete toxicity profile for pyriproxyfen is provided in Appendix A. 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The FQPA factor has been reduced to 1X. There was no evidence of qualitative or quantitative 

susceptibility in the database and the database is now complete. 
Page 12 of 40

4.4.1 Completeness of the Toxicology Database

The toxicity database for pyriproxyfen is now complete. 

4.4.2 Evidence of Neurotoxicity

Acute and subchronic neurotoxicity studies have been recently submitted and reviewed by the 

Agency. Decreases in motor activity were only observed at a high dose in the acute 

neurotoxicity (ACN) study and no neurotoxicity observed in the subchronic neurotoxicity (SCN) 

study up to the limit dose (2,000 mg/kg/day). Specifically, in the ACN, the neurotoxicity 

NOAEL was 1000 mg/kg bw/day, while the LOAEL of 2000 mg/kg bw/day was based on 

deceases in motor activity on Day 0 in males and unkempt appearance in females. In the SCN, 

the neurotoxicity NOAEL was 1111 mg/kg/day for males and 1212 mg/kg/day for females. The 

LOAEL for neurotoxicity was not observed (>2,000 mg/kg/day). Based on the results on these 

recently reviewed neurotoxicity studies, there are no remaining concerns regarding neurotoxicity 

for pyriproxyfen.

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.

Specifically, there is no of evidence of quantitative or qualitative susceptibility of the young 

demonstrated by in utero prenatal exposure in rat and rabbit developmental studies and 

pre/postnatal exposure in the rat 2-generation reproduction study. 

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 generated by the PRZM-EXAMS and SCI-GROW 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) and occupational 

scenarios are summarized below. A detailed description of the studies used as a basis for the 

selected endpoints are presented in Appendix A. 

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 
Page 13 of 40

toxicity studies. Therefore, an acute risk assessment is not required. 

The cRfD of 0.35 mg/kg/day was determined on the basis of decreased body weight and changes 

in clinical chemistry parameters in two co-critical rat toxicity studies (subchronic and chronic). 

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 determined on the basis of the

rat developmental maternal LOAEL of 300 mg/kg/day, based on decreased body weight, body 

weight gain, and food consumption, and increased water consumption. The intermediate-term 

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

(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 

(NOAEL) of 35.1 mg/kg/day from the two co-critical (subchronic and chronic) rat feeding 

studies. 

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. An inhalation-absorption 

factor of 100% was used for route-to-route extrapolation.

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. 

4.5.2 Recommendations for Combining Exposure Routes

Aggregate exposure risk assessments will be limited to long-term dermal and incidental oral 

exposure, since no hazard was identified via the dermal and inhalation routes for the short-term 

and intermediate-term routes. 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. 

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. This classification is based on the lack of evidence of 

carcinogenicity in mice and rats.

4.5.4 Summary of Points of Departure Used in Risk Assessment
Page 14 of 40

Toxicological doses/endpoints selected for the paraquat risk assessment are provided in Table 3.

Table 3. Summary of Toxicological Dose and Endpoints for Pyriproxyfen Used in Human Health Risk 

Assessment.

Exposure

Scenario

Dose Used in 

Risk 

Assessment, UF

FQPA SF and Level 

of Concern for Risk 

Assessment Study and Toxicological Effects

Acute Dietary

females 13-50

years old and 

general population

NA NA An appropriate endpoint attributable to a 

single oral dose was not available in the 

data base, including the developmental and 

reproduction toxicity studies.

Chronic Dietary

all populations

NOAEL= 35.1 

mg/kg/day

UF = 100

FQPA SF = 1X 

cPAD = cRfD

 FQPA SF

= 0.35 mg/kg/day

Subchronic (41321716 ) and chronic 

(43210503) – rat (co-critical)

LOAEL = 141.28 mg/kg/day based on 

decreased body weight and alterations in 

clinical pathology parameters.

Short-Term 

Incidental, Oral (1-

30 days)

Residential

Oral Maternal 

NOAEL = 100 

mg/kg/day

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

Intermediate-Term 

Incidental, Oral (1-

6 months)

Residential

Oral NOAEL = 

35.1 mg/kg/day

LOC for MOE = 100 Subchronic (41321716 ) and chronic 

(43210503) – rat (co-critical)

LOAEL = 141.28 mg/kg/day based on 

decreased body weight and alterations in 

clinical pathology parameters.

Short-, and 

Intermediate-Term 

Dermal (1-30 days 

and 1-6 months)

(Occupational/

Residential)

NA NA 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)

(Occupational/

Residential)

Oral NOAEL= 

35.1 mg/kg/day

(dermal 

absorption rate = 

30%*)

LOC for MOE = 100 Subchronic (41321716 ) and chronic 

(43210503) – rat (co-critical)

LOAEL = 141.28 mg/kg/day based 

decreased body weight and alterations in 

clinical pathology parameters.

Short-, and 

Intermediate-Term 

Inhalation (1-30 

days and 1-6 

months)

(Occupational/

Residential)

NA NA 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 

Oral study 

NOAEL= 35.1 

LOC for MOE = 100 Subchronic (41321716 ) and chronic 

(43210503) – rat (co-critical)
Page 15 of 40

Table 3. Summary of Toxicological Dose and Endpoints for Pyriproxyfen Used in Human Health Risk 

Assessment.

Exposure

Scenario

Dose Used in 

Risk 

Assessment, UF

FQPA SF and Level 

of Concern for Risk 

Assessment Study and Toxicological Effects

months-lifetime)

(Occupational/

Residential)

mg/kg/day

(inhalation 

absorption rate = 

100%)

LOAEL = 141.28 mg/kg/day based on 

decreased body weight and alterations in 

clinical pathology parameters

Cancer (oral, 

dermal, inhalation)

Cancer 

classification 

("Group E") 

Risk Assessment not 

required

No evidence of carcinogenicity 

1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = 

lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, 

LOC = level of concern, MOE = margin of exposure, *dermal absorption 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%, 

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant/Livestock Metabolism Studies

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

Based on these studies, the residue of concern in plants is pyriproxyfen (DP#: 250953, W. 

Donovan and W. Dykstra, 11/19/1998). 

Ruminant and poultry metabolism studies have previously been submitted and reviewed in 

conjunction with a petition for cotton. 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 in support of the cotton petition. 

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 
Page 16 of 40

forms of 4'-OH-PYR.

5.1.3 Environmental Fate and Transport

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. 

5.1.4 Residues of Concern Summary and Rationale

Table 4 provides a summary of the MARC decisions regarding residues of concern for 

pyriproxyfen.

Table 4. 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 Pyriproxfen and the free and 

sulfate forms of 4'-OH-PYR

Pyriproxfen and the free and 

sulfate forms of 4'-OH-PYR

Poultry Pyriproxfen and the free and 

sulfate forms of 4'-OH-PYR

Pyriproxfen and the free and 

sulfate forms of 4'-OH-PYR

Drinking Water Pyriproxyfen NA

5.2 Food Residue Profile

5.2.1 Residues in Crops

The Interregional Research Project Number 4 (IR-4) has submitted greenhouse trial data for 

pyriproxyfen on basil. Four greenhouse trials were conducted in the United States during the 

2007 growing season in the North American Free Trade Agreement (NAFTA) Growing Zones 2 

(MD and TN; 2 trials), 3 (FL; 1 trial), and 9 (CO; 1 trial).

A summary of the residue data is presented in Table C.4. Following two foliar directed 

applications of the 0.86 lb ai/gal EC formulation of pyriproxyfen at 0.172-0.182 lb ai/A, residues 

(and per trial averages) of pyriproxyfen in/on fresh basil leaves and stems harvested at a 1-day 

PHI were 0.325-13.0 (0.413-12.5) ppm; corresponding residues (and per trial averages) in/on 

dried basil leaves and stems (one trial only) were 12.0-12.4 (12.2) ppm. The processing factor 

for drying basil is 3.3X (12.2/3.69).
Page 17 of 40

TABLE 5 Summary of Residue Data from Basil Greenhouse Trials with Pyriproxyfen.

Commodity Total

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Basil, fresh leaves and stems 0.172-0.182 1 4 0.325 13.0 0.413 12.5 4.81 5.64 5.12

Basil, dried leaves and stems 0.172 1 1 12.0 12.4 12.2 12.2 12.2 12.2 NA

1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. NA= Not applicable.

2

 LAFT = lowest average field trial; HAFT = highest average field trial.

5.3 Water Residue Profile

5.3.1 Estimated Drinking Water Concentrations 

The following information concerning the environmental fate and drinking water assessment 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 

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. Although the remainder of this memorandum describes 

the modeling and results for EDWCs based on the proposed use on herbs, EFED recommends 

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 and Drinking Water Exposure and Risk

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

A chronic dietary risk assessment was conducted using the DEEM-FCIDTM, Version 2.03, which 

incorporates consumption data from USDA’s CSFII, 1994-1996 and 1998. The chronic dietary 

exposure and risk estimates (food + 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 
Page 18 of 40

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

6, below.

Table 6. Summary of Dietary Exposure and Risk for Pyriproxyfen.

Population Subgroup

DEEM Chronic Dietary Analysis

Exposure (mg/kg/day) % cPAD

General U.S. Population 0.013105 3.7

All Infants (< 1 year old) 0.019055 5.4

Children 1-2 years old 0.042545 12

Children 3-5 years old 0.033830 9.7

Children 6-12 years old 0.019626 5.6

Youth 13-19 years old 0.011439 3.3

Adults 20-49 years old 0.010548 3.0

Adults 50+ years old 0.009321 2.7

Females 13-49 years old 0.010219 2.9

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

Pyriproxyfen is the active ingredient in many 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 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#: 281982, T. Swackhammer, 5/2/2002). Only a post-application 

incidental oral assessment was conducted, since HED did not select any short-term dermal or 

inhalation endpoints. HED has recently updated the residential standard operating procedures 

(SOPs) and body weights to be used in all human health risk assessments. Therefore, the 

existing residential use patterns have been reassessed for residential handler and post application 

exposures. 

Residential Handler

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. 

Residential Post-application

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

Hand-to-Mouth: 

o Short- and intermediate-term hand-to-mouth exposures for 1 to <2 year olds from treated carpets 

and flooring and petting treated animals (shampoos, sprays, spot-on treatments and collars).

o Long-term hand-to-mouth exposures for 1 to <2 year olds from treated carpets and flooring and 

petting treated animals (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). Since no short- or intermediateterm dermal endpoints were selected, no dermal assessment for these durations is included. 
Page 19 of 40

 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 chemicalspecific 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.

6.1 Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for pyriproxyfen at this time. In addition, no hazard has been 

identified for short- and intermediate-term inhalation exposures from pyriproxyfen. 

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

individuals nearby to 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. The Agency received the 

SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html) 

and is in the process of evaluating the SAP report. The Agency may, as appropriate, develop 

policies and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place or if inhalation PODs are selected in the future, the Agency may 

revisit the need for a quantitative post-application inhalation exposure assessment for 

pyriproxyfen.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for pyriproxyfen. 

The Agency has been working with the Spray Drift Task Force, 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 at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.
Page 20 of 40

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-, Intermediate-, and Long-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 2000. As this MOE is greater than 

100, the chronic aggregate risk does not exceed HED’s level of concern. Table 7.1.5

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

age which is the highest-risk population subgroup (lowest MOE > 100).
Page 21 of 40

Table 7.1.1. 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

1 to < 2 

year olds 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 N/A

N/A

Dermal N/A N/A N/A

Pet spot-on 

for cats

1.7x10-4lb 

ai/application

Incidental oral 

(Hand-to-Mouth) 76000 27000 N/A

N/A

Dermal N/A N/A N/A

Pet spot-on 

for dogs

2.1x10-4lb 

ai/application

Incidental oral 

(Hand-to-Mouth) 120000 44000 N/A

N/A

Dermal N/A N/A N/A

Pet collars 4.63x10-4

lb 

ai/collar

Incidental oral 

(Hand-to-Mouth) 28000 9800 9800

320

Dermal

1 to < 2 

year olds N/A N/A 330

Adults 830 N/A

Pet 

shampoos

1.13x10-4lb 

ai/application

Incidental oral 

(Hand-to-Mouth) 120,000 41,000 N/A

N/A

Dermal N/A N/A 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 previous assessment (DP#: 281982, T. Swackhammer, 5/2/2002).

b. Long-term assessments only conducted for products with efficacy of up to 1 year – pet collars and indoor carpet powder.
Page 22 of 40

Table 7.1.2: Non-Cancer Residential Combined (Multiple Exposure Scenarios) Exposure and Risk Estimates for

Pyriproxyfen.

Combined 

Exposure 

Scenario

Lifestage Exposure Scenario Route of 

Exposure

Combined Within 

Scenario MOEs Combined Across Scenarios MOE

ST IT LT ST IT LT

Flea 

Scenario

Adult

Post-application: 

Indoor Carpet -

Broadcast

Dermal N/A N/A 5800

N/A N/A 730

Post-application: 

Pet – Collar Dermal N/A N/A 830

Child

Post-application: 

Indoor Carpet -

Broadcast

Dermal N/A N/A

4000

16000 5400 300

Hand to 

Mouth 35000 12000

Post-application: 

Pet –Collar

Dermal N/A N/A

Hand to 320

Mouth 28000 9800

Table7.1.3: Recommendations for the Residential Exposures for the Pyriproxyfen Aggregate Assessment.1

Lifestage Route of Exposure Residential Post-application MOE2

Short-term

Adult Male N/A N/A

Child Incidental oral 16000

Intermediate-Term

Adult Male N/A N/A

Child Incidental oral 5400

Long-Term

Adult Male Dermal 730

Child Dermal + Incidental oral 300

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

2 Residential Post-application MOE = Combined flea treatment multiple scenario MOE (indoor carpet powder + pet treatment). 

For adults, the only applicable exposure route is long-term dermal. For children, the applicable exposure routes are short- and 

intermediate-term incidental oral and combined long-term incidental oral + dermal.

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

exceed HED’s level of concern. Table 7.1.5 summarizes the intermediate-term aggregate 

exposure to pyriproxyfen residues for Children 1-2 years of age which is the highest-risk 

population subgroup (lowest MOE > 100).
Page 23 of 40

Table 7.1.4 Short-Term Term Aggregate Risk Calculations

Population

Short- or Intermediate-Term Scenario

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 1-2 

years old

100 2350 16000 NA NA 2000

1

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

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

mg/kg/day

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

NOAEL= 35.1 mg/kg/day. (MOE from Table 7.1.3).

4 MOE dermal = Not applicable

5 MOE inhalation = Not applicable

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

Table 7.1.5 Intermediate-Term Term Aggregate Risk Calculations

Population

Short- or Intermediate-Term Scenario

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 1-2 

years old

100 825 5400 NA NA 720

1

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

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

mg/kg/day

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

NOAEL= 35.1 mg/kg/day. (MOE from Table 7.1.3).

4 MOE dermal = Not applicable

5 MOE inhalation = Not applicable

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

Table 7.1.6 Long-Term Term Aggregate Risk Calculations

Population

Short- or Intermediate-Term Scenario

LOC for 

Aggregate 

Risk1

Dietary

MOE2

MOE Oral 

+ Dermal 

Residential 

Exposure3

MOE

Dermal 

Residential 

Exposure4

MOE

Inhalation 

Residential 

Exposure5

Aggregate 

MOE (food, 

water, and 

residential)6

Adult Male

Adult Female

Children 1-2 

years old

100 825 300 NA NA 220

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 + dermal = [(long-term oral NOAEL)/(long-term incidental oral + dermal exposure)]. Oral study 

NOAEL= 35.1 mg/kg/day. (MOE from Table 7.1.3).

4 MOE dermal = Not applicable

5 MOE inhalation = Not applicable

6 MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE dermal) + (1/MOE inhalation)]
Page 24 of 40

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 

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 220. As this MOE is greater than 100, the chronic 

aggregate risk does not exceed HED’s level of concern. Table 7.1.6 summarizes the chronic 

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

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 paraquat 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/.

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

9.1 Exposure Scenarios

Based upon the proposed use pattern, HED believes the most highly exposed occupational 

pesticide handlers will be 1) mixer/loaders using open-pour loading of liquid formulation, 2) 

mixer/loaders using open-pour loading of wettable powders, 3) mixer/loaders using open pour 

loading of granules, 4) applicators using open-cab ground-boom sprayers, 5) applicators using 

open-cab airblast sprayers, 6) aerial applicators/ spray, 7) aerial applicators/ broadcast granule, 

8) applicators using ground broadcast granules, 9) applicators using the “spoon” method for 

distributing granules. 

The label directed use of personal-protective equipment (PPE) is as follows:

For the ant bait – applicators and other handlers must wear long pants, longsleeved shirt, shoes plus socks and waterproof gloves.
Page 25 of 40

For the wettable powder – applicators and other handlers must wear long-sleeved 

shirt, long pants and shoes plus socks.

For Knack®insect growth regulator – applicators and other handlers must wear 

coveralls over short-sleeved shirt and short pants or long-sleeved shirt and long pants, chemicalresistant gloves such as barrier laminate or Viton = 14 mils, chemical-resistant footwear plus 

socks, chemical-resistant headgear for overhead exposure, chemical resistant apron when 

cleaning equipment, mixing, or loading.

For Pyriproxyfen 0.86 EC Ag Insect Growth Regulator – Applicators and other 

handlers must wear long-sleeved shirt, long pants, socks, shoes and chemical-resistant gloves 

(such as barrier laminate or butyl rubber = 14 mils). 

Based upon the proposed use patterns, HED expects pesticide handler exposures to be short-term 

(1-30 days). Since there are no short-term or intermediate-term dermal or inhalation 

toxicological endpoints identified and since HED does not expect long-term exposures, exposure 

and risk assessments are not necessary for the proposed uses and are therefore not presented 

here. 

9.2 Handler Exposure 

The term “handler” applies to individuals who mix, load, and apply the pesticide product. Since 

there are no short-term or intermediate-term dermal or inhalation toxicological endpoints 

identified and since HED does not expect long-term exposures, exposure and risk assessments 

are not necessary for the proposed uses.

9.3 Post Application Exposure 

For occupational handlers, there is no dermal toxicological endpoint; therefore, it is not 

necessary to estimate post-application exposure or risk to agricultural workers.

9.3.1 Restricted Entry Interval

Pyriproxyfen is classified as Toxicity Category III for acute dermal and inhalation toxicity and 

Category IV for acute oral, primary eye and skin irritation and it is not a skin sensitizer. The 

Worker Protection Standard interim REI is 12 hours for compounds in Toxicity Categories III 

and IV for the acute effects noted above. Therefore, a 12 hour REI is sufficient to protect 

agricultural workers re-entering treated areas.
Page 26 of 40

10. REFERENCES

Pyriproxyfen. Amended Use. Expansions of Existing Crop Group/Representative Commodity Uses to Numerous 

Crop Subgroups, Adding Use on Herb Subgroup 19A. Summary of Analytical Chemistry and Residue Data., G. 

Otakie, D397523, 5/31/12

Pyriproxyfen. Chronic Dietary (Food and Drinking Water) Exposure Assessment for thePetition Proposing 

Tolerances for Residues of Pyriproxyfen on Herb Subgroup 19A, and the Expansions of Existing Crop Group Uses 

to Numerous Crop Subgroups., T. Morton, D397522, 8/21/2012

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

the Expansion of the Following Crop Groups/Subgroups: Bulb Vegetable Group 3-07; Fruiting Vegetable Group 8-

10; Citrus Fruit Group 10-10; Pome Fruit Group 11-10; Caneberry subgroup 13-07A; Bushberry Subgroup 13-07B; 

and Low Growing Berry, Except Strawberry Subgroup 13-07H., 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
Page 27 of 40

APPENDICES

A TOXICOLOGY DATA SUMMARY

A.1 Guideline Data Requirements

Guideline 

No. Study Type Technical MRID No. Required Submitted

870.3100

870.3150

870.3200

870.3250

870.3465

Subchronic (Oral) Toxicity - Rodent...............................................................

Subchronic (Oral) Toxicity - Non-Rodent ......................................................

21/28-Day Dermal Toxicity ............................................................................

90-Day Dermal Toxicity

90-Day Inhalation Toxicity ............................................................................

N

Y

N

N

N

Y

Y

Y

N

Y

41321716

00072416

44037205

00113718

870.3700a

870.3700b

870.3800

Prenatal Developmental Toxicity - Rodent .....................................................

Prenatal Developmental Toxicity - Non-Rodent .............................................

Reproduction and Fertility Effects ..................................................................

Y

Y

Y

Y

Y

Y

00113714

43964701

00096338

43949902

43215403

00126783

00149748

00149749

870.4100a

870.4100b

870.4200a

870.4200b

870.4300

Chronic (Oral) Toxicity - Rodent....................................................................

Chronic (Oral) Toxicity - Non-Rodent (Dog) .................................................

Carcinogenicity - Rat.................................................................................

Carcinogenicity - Mouse

Combined Chronic Toxicity /Carcinogenicity- Rat

Y

Y

Y

Y

Y

Y

Y

N

Y

Y

43210503

00132472

43210503

00087924

40202403

40218001

00138637

870.6100a

870.6100b

870.6200a

870.6200b

870.6300

870.7800

Neurotoxicity - Acute Delayed Neurotox.- Hen..............................................

Neurotoxicity - Subchronic - Hen ..................................................................

Neurotoxicity - Acute - Rat.............................................................................

Neurotoxicity -Subchronic - Rat .....................................................................

Developmental Neurotoxicity..................

Immunotoxicity............................. .........................................................

N

N

Y

Y

N

Y

N

N

Y

Y

N

Y

47794201

47794202

48667301
Page 28 of 40

A.2 Toxicity Profiles

Table A.1.b Toxicity Profile of Pyriproxyfen Technical

Guideline No./Study Type MRID No. (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) 

Table A.1.a Acute Toxicity of Pyriproxyfen Technical

Guideline 

No. Study Type MRID # 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 
Page 29 of 40

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).

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) (nonguideline)

44985002 (1988) 

Acceptable/nonguideline 

0, 100, 300, 500 or 1000 mg/kg/day 

(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)

870.3700a 

Prenatal developmental (rat) (nonguideline) 

44985001 (1988) 

Acceptable/nonguideline 

0, 30, 100, 300, or 500 mg/kg/day 

(gavage)

Maternal NOAEL = 100 mg/kg/day. 

LOAEL = 300 mg/kg/day based on 

clinical signs, decreased body weight 

gains, and decreased food 

consumption.

Developmental NOAEL = 100 

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

based on decreased body weight and 

increased incidence of dilation of the 

renal pelvis. 
Page 30 of 40

870.3700b 

Prenatal developmental (rabbit)

41321720, 42178311, 43215401, 

43215402, 43215403 (1989) 

Acceptable/guideline 

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

(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 

(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) and increased liver weight (both 

sexes) and histopathological lesions of 

liver and kidneys (M) 

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 males, 

498 mg/kg/day in females based on 

decreased body weight on lactation 

days 14 and 21. 

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, 300 mg/kg/day in 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 
Page 31 of 40

870.4300 

Chronic/Carcinogenicity (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).

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, DPH-PYR, 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
Page 32 of 40

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 

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)

48711901, 48711903, 48711904 (2011)

Acceptable /guideline

0, 300, 1000 or 2000 mg/kg (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)

48711901, 48711902, 48711905 (2011)

Acceptable /guideline

0,1500, 5000, or 15,000 ppm (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.
Page 33 of 40

870.7485 

Metabolism and pharmacokinetics 

(rat)

42178318 (1988) 

Acceptable/guideline 

Rats were orally dosed with 14C-labeled 

pyriproxyfen at 2 or 1000 mg/kg and at 

repeated oral doses [14 daily doses] of 

unlabeled pyriproxyfen at 2 mg/kg 

followed by administration of a single 

oral dose of labeled pyriproxyfen at 2 

mg/kg. Most radioactivity was 

excreted in the feces [81-92%] and 

urine [5-12%] over a 7 day collection 

period. Expired air containing CO2 

was not detected. Tissue radioactivity 

levels were very low [less than 0.3%] 

except for fat. Examination of urine, 

feces, liver, kidney, bile and blood 

metabolites yielded numerous [ > 20] 

identified metabolites when compared 

to synthetic standards. The major 

biotransformation reactions of 

pyriproxyfen include: 1. Oxidation of 

the 4' - position of the terminal phenyl 

group; 2. Oxidation at the 5' - position 

of pyridine; 3. Cleavage of the ether 

linkage and conjugation of the resultant 

phenols with sulfuric acid. 

870.7800

Immunotoxicity (mouse)

48711906, 48711907 (2012)

Acceptable

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).

The LOAEL for immunotoxicity is not 

observed. The NOAEL for 

immunotoxicity is 5000 ppm (1139 

mg/kg/day).

A.3 Toxicological Endpoints

A.3.1 Acute Reference Dose (aRfD) - General Population (Including Infants and Children) 

and Females Age 13-49

Study Selected: None

MRID Nos.: NA

Comments about Study/Endpoint: An appropriate endpoint attributable to a single oral dose was 

not available in the data base, including developmental toxicity in the developmental toxicity 

studies.
Page 34 of 40

A.3.2 Chronic Reference Dose (cRfD) -

Study Selected: Subchronic toxicity and chronic toxicity (feeding) - rat

(co-critical)

MRID No41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic)

Dose and Endpoint for Establishing a cRfD: NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 

mg/kg/day based on decreased body weight and alterations in clinical pathology parameters.

Uncertainty Factor(s): 100x (10x for interspecies extrapolation and 10x for intraspecies 

variations).

Comments about Study/Endpoint/Uncertainty Factor: 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- Term)

Study Selected: rat developmental

MRID Nos.: 44985002

Executive Summary: 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)

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.

Incidental Oral Exposure (Intermediate-Term)

Study Selected: Subchronic toxicity and chronic toxicity (feeding) - rat

(co-critical)

MRID Nos.: 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic)

NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 mg/kg/day based on decreased body weight and 

alterations in clinical pathology parameters.

Uncertainty Factor(s): 100x (10x for interspecies extrapolation and 10x for intraspecies 

variations).

Chronic RfD = 35.1 mg/kg/day = 0.351 mg/kg/day

 100
Page 35 of 40

Comments about Study/Endpoint: Evaluation of effects across durations of exposure suggests 

toxicity increases with duration of exposure. Therefore the short-term endpoint is not 

appropriate for the intermediate duration of exposure. 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. 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.3.5 Dermal Exposure (Short-, Intermediate-, and Long-Term)

Short- and Intermediate-Term

Study Selected: NA

MRID Nos.: NA

Dose and Endpoint for Risk Assessment: No toxicity observed at the limit dose of a 21-day 

dermal rat toxicity study. 

Comments about Study/Endpoint: The 21-day dermal rat toxicity study did not result in toxicity 

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.

Dermal Exposure (Long Term)

Study Selected: Subchronic toxicity and chronic toxicity (feeding) - rat

(co-critical)

MRID No41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic)

Dose and Endpoint for Establishing a cRfD: NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 

mg/kg/day based on decreased body weight and alterations in clinical pathology parameters.

Uncertainty Factor(s): 100x (10x for interspecies extrapolation and 10x for intraspecies 

variations).
Page 36 of 40

Comments about Study/Endpoint/Uncertainty Factor: A long-term dermal study is not available. 

Therefore an oral study was used to assess the long-term dermal assessment. 

An oral endpoint was selected to be protective of the long-term dermal assessment. For the longterm 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.3.6 Inhalation Exposure (Short and Intermediate-Term)

Study Selected: 21-Day inhalation toxicity study in rats

MRID No.: 42178308

Executive Summary: NA

Dose and Endpoint for Risk Assessment: 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.

Comments about Study/Endpoint: The minor changes observed at the highest concentration 

tested are not considered to be biologically relevant. Therefore a quantitative inhalation 

assessment is not warranted for the short and intermediate-term durations.

Inhalation Exposure (Long Term)

Study Selected: Subchronic toxicity and chronic toxicity (feeding) - rat

(co-critical)

MRID No41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic)

Executive Summary: 

Dose and Endpoint for Establishing a cRfD: NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 

mg/kg/day based on decreased body weight and alterations in clinical pathology parameters.

Uncertainty Factor(s): 100x (10x for interspecies extrapolation and 10x for intraspecies 

variations).

Comments about Study/Endpoint/Uncertainty Factor: 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 co-critical studies is the lowest NOAEL in the database for chronic effects via 

the oral route. The inhalation absorption is 100% since an oral study is being used for the 

assessment.
Page 37 of 40

A.4 EXECUTIVE SUMMARIES (recently submitted studies)

A.4.1 Neurotoxicity

870.6200a Acute – Rat

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, 

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). 

870.6200b Subchronic – Rat

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. 
Page 38 of 40

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 

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). 

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 
Page 39 of 40

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 effect 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 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. 
Page 40 of 40

APPENDIX C. Physical/Chemical Properties

Physicochemical Properties of Technical Grade Paraquat Dichloride.

Parameter Value Reference

Melting point/range decomposes at ca. 340 °C Product Chemistry Chapter 

of the Paraquat Dichloride 

Update, 10/10/91

pH 6.4 at 20 °C

Density 1.5 g/cm3at 25 °C

Water solubility (20 °C) freely soluble in water:

618-620 g/L at pH 5.2, 7.2, and 9.2 

Solvent solubility (20 °C) <0.1 g/L in acetone, dichloromethane, 

toluene, ethyl acetate, and hexane;

143 g/L in methanol

Vapor pressure <<10-8kPa at 25 °C

Octanol/water partition coefficient, 

Log(KOW)

log KOW = -4.5 at 20 °C

Dissociation constant, pKa 0.95 (pure active ingredient) Product Chemistry Chapter 

of the Paraquat 

Reregistration Standard, 

11/25/85

APPENDIX D. 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)