UN ITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASH I NGTON, D.C. 20460



### MEMORANDUM

Date: November 6, 2015 OFF I CE OF C H EM ICAL SAFETY
AND POLLUT I ON PREVE N TION



### Subject: Pyriproxyfen. Human Health Ri s k Assessment fo r the Petition t o In c r ease the
Estab li shed Tolerance in/on Tea wit h a U.S. Registration for Imp orted Pyriproxyfentreated Tea.



### PC Code: 1 29032 

### DP Barcode: 427112


### Deci s ion No.: 497260 

### Regi s tration Nos. : Not Applicab l e 

### Petition No

. : 4E8326 

### Regu l atory Action: Amended Tolerance (Increase) 

### Assessment Single C hemical / 

### Regi s tration Case No.: 7424 

### Type: Aggregate


### TXRNo.: Not App li cab l e 

### CAS No.: 95737-68-1


### MRID No.: Not Applicable 

### 40 CFR: 

### § 1 80.510



### From: Bonni e Crop p-Kohlligian

, Env ironm ental

# Sc**entis~~ ~**  -

# \~lly-- Austin Wray

, Ph.D.

, Toxicolog i st

### ~ 

# /Ll---;z

Ri sk Assess m e nt Branch IV ...:;;...

____ _ Health Effects Division (HED) (7509 P)



### Through: E li ssa R eaves , Ph .D., Branch Chief
Risk Assessme nt Branch IV
Health Effects Division (7509P)



### To: Carmen Rodia/Richard Gebken 

### (RM I 0)
In vertebra t e- Vertebrate Bran ch 2 Registration Division ( RD) (7505P)

Page I of 58Pyriproxyfen ( 129032) Hum an Health Ri s k Assessment DP # : 427112



### Tabl e o f Co ntent s 1 .0 Executiv e Su1nmary

. .. . .... .. .. .. .. .. . ....... . ... . ... .. .. .. .. .................. .............. . .. .. .. ..... . ... .. .. . .. . .. .. . .. ..... 4
2. 0 H E D R ecomn1endations

.. .. .. .. .. .. ... . . . ... ... . ... .. .. ... . ... . ..... .. .. .. .. . . . ... .. . ... . . .. . ... . ... . .. . . . . .. .. . .. . .. .. . .. .. . .. 6


### 2 .1 D ata D e fic i e nci es

..................... ... .. .. ......... .. .. .. ... .. ........ .. .. . ... . . .. ..... .. .................................... 7
2 .2 T olerance Co n s id e rations

.. .. .. .. .. ..... .. ... . ... .. .. .. ... . . .. .. .. .. .. .. . . . .. .... .. .. . ... . .. . .. .. .. . .... . .. .. . .. . .. .. . ..... 7



### 2.2. l Enfo r ce m e nt A n a l yt ical Method

.............................................................. . .. .. . .. .. . .. . ..... 7



### 2.2.2 International H armonizat ion

.......................................................... . ... .. . ................. .. ... 7



### 2.2

. 3 Recommended To l erances

.......... ........................ ..... .. ...... ....................... . ............ . ...... 7



### 2.2.4 Revisions to Petiti o ned-F o r To l e ran ces

............. .. .. . ..... .. .. . .. .. . .. .. ................... . ............. 8



### 2.3 Labe l R eco mn1 e nd a tion s

. .. .. .. .. ..... . ... .. .. .. ... . ... .. .. .. . . .. ... .. .. .. . .. .. ............................................ 8
3 .0 In troductio n

. . .. . . . .. .. .... . ... . .. .. .. .. ... . . . ... ....... . ... .. .. . . ... . . .. .. .. .. ... . .. .. .. .. ...... . .. ..... . . .. . ... .. .. . .. .. . .. .. . ....... 8


### 3. 1 Chemica l I d e n ti ty

.. . .. .. .. .. .. .. .. .. .. ... ................ . .. .. . . . .. .. .. .. .. .. . .. . .. . . . .. ...... . .. . .... . . . . . . ................... 8
3

. 2 Physical/Ch e m i ca l C haract er i s ti cs

........ .. ... . ... ...... .. .. .. ... ..... .. ......... .. .. ..... . ....... .. . .. .. . .. . .. .. . ... 8


### 3.3 Pesticide Use Pattern

. .. ....... .................................................................. . .. ..... . .... . .. .. ........... 9


### 3.4 Ant i ci p ated Exposu r e P a thwa ys

.......................... ...... . . ......................... . .. . .. .. . ............ . .. .. 9 

### 3.5 Considerations of Enviro nm e ntal Ju s ti ce

.......................................................................... 9
4.0 H azard C h arac t er i zation and Assess m ent

........................................................................... I 0


### 4.1 Toxic o l ogy S tudi es Ava ilabl e for Analys i s

...... .. . ......... . ..... . ...... . ... . .. .. . ............................ 

### 1 0
4.2 Absorption, Distribution, Metaboli s m and Excretion

......... . . .. . .. .. .. .. ............................... 

### 10

4.2.1 D e rmal Abso rption

. ... . ... .. . ..... ... .. .. .. .. .. .. .......... . .. .. ..... . .. .. .. .. . ...... .... . . . . .. . . . .. . .. . . . .. .. . .. .. . .. I I



### 4.3 Toxico l ogical Effects

.. ...... ... . .. .. ........ . ... ...... .. .. .. ... .. .. .... .. .. .. .. . ........................................... 

### 11
4.4 Safety Factor fo r I nfant s and C hildr e n (FQ P A Safety Factor)

........................................ 

### 1 3

4.4.1 Co mpl eteness of the Toxicology Database

.............. ... . .. .. .. .. .. ................................... 

### 1 3

4.4.2

. Ev id e n ce of Neurotoxicity

. ... .. .. .. ................. . . ...... . ............ ..... .. . .. ... .... . ...................... 

### 1 3

4.4.3 Evidence of Se n sitivity / Susceptibility in th e De velop in g or You n g Animal

........... 

### 13

4.4.4 R es idu al Unce rt a int y in the Expos ur e D a t a ba se

... . .. .. ... . .. . ........................... . ............ 

### 1 4

4.5 Tox i city E ndpoint and Point of D e partur e

..... .. ... . .. .. .. .. .. .. .................... . ... . . .. .. . .. .. .. . .. . .... . . 

### 14
4.5.1 Do se- R espo n se Assessment..

. . . .. .. ... .. .. .. .. ... ... . . . . ... .. .. .. .. .. .. . ....................... . .. .. . .. .. . .. . .. . 

### 1 4

4.5

. 2 R ecom m e nd a ti ons for Comb inin g Expos ur e R o u tes

......... . ... .................. ..... . ....... . ... 

### 1 5

4.5.3 Classifica ti on of Carc in oge ni c Potential

................................................................... 

### 15

4.5.4 Summary of P oints of D eparture Used in Ri sk Assess m ent..

................................... 16

5

. 0 Dietary Exposure and Risk Assessment

. ........ . .... . .. .. .. . . .. .. ............................... . ..... .. .. . ........ 

### 19
5 .1 Metab o lit e / Degradate R es idu e P ro fil e

. ... .. ...... .. ...... .. .. .. .. . ................. . ............. ........... .. 

### 1 9

5

. 1

. l Summary o f Pl a nt and Livestock Metabolism Studies

.. .......................... .. .. . .. . .. .. . .. .. 

### 1 9

5

. 1

. 2 Comparison of M e tabolic Pathw ays

......................................................................... 

### 1 9

5

. 1

. 3 S umm a r y of E n v ir o nm enta l D egradat i o n

....... .. .. .. .. ....... . ...... . .. ........ . ...... .. .. . . . . .... . ..... 

### 19

5. 1.4 R esidue s of Concern Su mmar y and Rationale

.. . . . ........ ................. ..... . ............... .. . .... 20

5.2 Food R es i due Profile

....................................................................................................... 20


### 5

. 3 Water Residue Profile

.................................................................................................. 

### 21 5.4 Dietary Exposure and Ri sk Assess m e nt..

..................................................................... 22
Page 2 of 58Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 3 of 58 

### 5.4.1 Acute Dietary and Drinking Water Analysis

................................ ............................ 22

5.4.2 Chronic Dietary and Drinking Water Analysis

................................ ......................... 22

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ ..... 22 6.1 Residential Handler Exposure

................................ ................................ ......................... 23 6.2 Residential Post

- Application Exposure

................................ ................................ ........... 23 6.3 Residential Bystander Post

- application Inhalation Exposure

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

................................ ................................ ................................ ....................... 25 7.1 Residential Risk Estimates for Use in Aggregate Assessments

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

................................ ................................ ......... 26 7.1 Short

- Term Aggregate Risk

................................ ................................ ............................. 26 7.2 Intermediate

- Term Aggregate Risk

................................ ................................ ................. 27 7.3 Long

- Term Aggregate Risk

................................ ................................ ............................. 27 8.0 Cumulative Risk

................................ ................................ ................................ .................. 28 9.0 Occu pational Exposure and Risk Characterization

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

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

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

................................ ................................ .................... 30 A.2 Toxicity Profiles

................................ ................................ ................................ ........... 31 A.3 Toxicological Endpoints

................................ ................................ .............................. 40 A.4 Executive Summaries

................................ ................................ ................................ .. 42 Appe ndix B: Proposed Metabolic Pathway for Pyriproxyfen

................................ ...................... 57 Appendix C. Studies Reviewed for Ethical Conduct

................................ ................................ ... 58Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 4 of 58 

### 1.0 E xecutive Summary

This assessment supports the p etition to increase the currently established tolerance for residues of pyriproxyfen in/on tea to cover residues in/on pyriproxyfen

- treated tea imported from Japan. It addresses the exposures and human health risks associated with exposures from currently registered uses of pyriproxyfen and the proposed tolerance increase in/on tea. It also assesses potential enhanced sensitivity of infants and children from dietary and/or residential exposure as required under the Food Quality Protection Act (FQPA) of 1996.

Pyriproxyfen [2

- [1

- methyl

- 2

- (4

- phenoxyphenoxy)ethoxy]pyridine] is a broad spectrum pyridine

based insect growth regulator used to control a variety of insects in agriculture and non

agricultural areas. It acts by suppressing embryogenesis within the insect egg and inhibiting metamorphosis and adult emergence of target insects. It has numerous f ood, feed and non

- food

crop agricultural uses, as well as, commercial, and residential uses. Commercial uses include applications in and around food handling establishments and other commercial structures. Residential uses include applications both insid e the home and outside on gardens, lawns, ornamentals, patios, and other outdoor structures. It is also directly applied to pets. E nd use formulations include emulsifiable concentrates, soluble concentrates, liquid ready

- to

- use, pressurized liquids, gran ules, dust, pellets, microencapsulates, and impregnated material. It is applied by both professional pest control operators and homeowners. It is applied to agricultural fields with aerial and ground equipment. It is applied to indoor sites with surface , space, and directed crack and crevice sprayers, aerosol generators, and foggers. For outdoor sites, liquid formulations are applied as surface sprays or directed perimeter treatment around buildings and structures. The granular formulation may be appli ed as a broadcast outdoor treatment to commercial and residential areas using aerial or ground equipment.

Permanent tolerances are e stablished under 40 CFR §180.510(a)(1) for residues of pyriproxyfen in/on numerous crops (no livestock commodities) rangin g from 0.02 ppm to 100 ppm; including a tolerance in/on tea at 0.02 ppm resulting from the domestic use of pyriproxyfen as an ant bait (EPA Reg. No. 59639

- 114). A tolerance is also established under 40 CFR §180.510(a)(2) at 0.10 ppm for all food commodities for the use of pyriproxyfen in food handling establishments.

Sumitomo Chemical Company, LTD through their agent, Valent U.S.A. Corporation, has submitted a petition (PP# 4E8326) to increase the currently established tolerance in/on tea from 0.02 to 15 ppm to cover residues in/on pyriproxyfen

- treated tea. The proposed use is on tea grown in Japan treated with Pluto MC (not registered in the U.S.) , described as a 9% microcapsule formulation of pyriproxyfen. The maximum application rate is one application at 1000L/10a (where a equals 100 m 2 

### ) of a 1000x dilution of the end

- use product (reviewer calc ulated use rate is 0.8 lb ai/A) and a 30

- day pre

- harvest interval (PHI).Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 5 of 58 

### Hazard Identification

Pyriproxyfen was absorbed, metabolized, and rapidly excreted, primarily in the feces, in the rat metabolism study. There were no effects of sex or dose on absorption or elimination ; however, the extent of metabolism and prevalence of metabolites was sex

- dependent

. T he liver and kidney are the principal target s for pyriproxyfen after repeated dose exposure s in mice, rats and dogs. Rodents and dogs also exper ience d slight anemia from chronic and subchronic exposures . The review of the acute and subchronic neurotoxicity studies indicates that pyriproxyfen is not a neurotoxic chemical. There was no evidence of prenatal or postnatal sensitivity or increased

sus ceptibility in developmental studies in rats and rabbits, and in reproduction studies in rats. In the 2

- generation reproduction toxicity study, offspring toxicity ( lower pup body weight during lactation days 14 to 21) occurred in the presence of lower bod y weight in parental animals at the same dose level. Pyriproxyfen did not target the reproductive system. An immunotoxicity study showed no adverse effects on the immune system. No significant systemic toxicity was observed in either the 21

- day dermal to xicity study in rats or in the 28

- day inhalation study at exposure levels up to 1000 mg/kg/day and 1 mg/L, respectively

. Pyriproxyfen has low acute toxicity by oral, dermal, inhalation and ocular routes of exposure (all studies either Toxicity Category III or IV ) . Pyriproxyfen is not a skin irritant (Toxicity Category IV) and was negative in the dermal sensitization study in guinea pigs. With respect to carcinogenicity

, pyriproxyfen has been classified as a "Group E" chemical ( no evidence for carcinogenicity to humans ) based on the absence of carcinogenicity in mice and rats. Pyriproxyfen is negative for mutagenic activity in a battery of mutagenicity studies conducted with both the parent and/or metabolites.

Dose Response Assessment

The t oxicolog y database for pyriproxyfen is complete. The acute and subchronic neurotoxicity studies were negative and the immunotoxicity study was negative. There is no evidence of quantitative or qualitative susceptibility of the young following in utero pr enatal exposure in rat and rabbit developmental studies and pre/postnatal exposure in the rat 2

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

An acute reference dose (aRfD) was not established for females 13

- 50 y ears old or the general population, because acute oral effects attributed to a single

- dose exposure could not be identified in the toxicology database, including the acute neurotoxicity study and the developmental toxicity studies. A chronic reference dos e ( cRfD ) of 0.35 mg/kg/day was determined on the basis of depressed body weight gain, anemia, and increased total cholesterol and phospholipid levels concurrent with increased relative liver weight at 141.28 mg/kg/day in two co

- critical rat toxicity studie s (subchronic and chronic). Since the FQPA S F has been reduced to 1X, the chronic population

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

The short

- term incidental oral endpoint of 100 mg/kg/day was based on lower body weight, depressed body weight gain and food consumption, and increased water consumption at the maternal lowest observed adverse effect level ( LOAEL ) of 300 mg/kg/day in a rat developmental toxicity study . The intermediate

- term incidental oral endpoint of 35.1 mg/kg/day was based on system ic toxicity at the LOAEL of 141.28 mg/kg/day in two co

- critical rat toxicity studies (subchronic and chronic).Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 6 of 58 

### 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 t he 21

- day dermal toxicity study in rats. Likewise, s hort

- 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. L ong

term dermal and inh alation endpoint s w ere set at 35.1 mg/kg/day based on systemic toxicity in the two co

- critical (subchronic and chronic) rat feeding studies

. A dermal absorption factor (DAF) of 30% was employed for oral to dermal route extrapolation

. For long

- term inhala tion assessments, absorption from i nhalation exposure was assumed to be equivalent to oral exposure

.
HED classified pyriproxyfen as a "Group E" chemical, no evidence for carcinogenicity to humans , based on the absence of evidence of carcinogenicity in male and female rats as well as in male and female mice. Therefore, a cancer risk assessment is not required.

Exposure/Risk Assessment and Risk Characterization

A dietary (food and water) exposure and risk assessment was conducted based on the proposed tolerance increase in/on tea to cover residues in/on pyriproxyfen

- treated tea . No new drinking water, residential or occupational exposure scenarios are associated with the proposed tolerance increase

. However, for this assessment, t he previous residenti al exposure assessment conducted in accordance with HED’s 2012 Residential SOPs

, was further updated to be consistent with current HED policies. An unrefined chronic dietary (food and drinking water) risk assessment for pyriproxyfen showed that dietary (f ood and drinking water ) exposure estimates are below HED’s level of concern for the general population and all population subgroups. Residential and

a ggregate risks are not of concern.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, listed in Appendix C , have been determined to require a review of their ethical conduct. So me 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 R ecommendations

Pending a minor revision to Section F of the petition and submission of a reference sta ndard for pyriproxyfen

, HED has no objection to granting an increase of the currently established tolerance for residues of pyriproxyfen in/on tea from 0.02 to 15 ppm to cover residues in/on pyriproxyfen

treated tea as specified in Section 2.2.3.Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 7 of 58 

### 2.1 Data Deficiencies

There are no data deficiencies; however, a n acceptable analytical reference standard is required for pyriproxyfen since none is currently available in EPA’s National Pesticide Standards Repository (email communication between T. Cole and B. Cropp

- Kohlligian, 8/25/2015).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

A g as chromatography with nitrogen

- phosphorus detection (GC/NPD) method ( RM

- 33P

- 1

- 3a or 9.66 V 1 ) is available for pyriproxyfen tolerance enforcement. The method has undergone an adequate radiovalidation, independent laboratory validation trial, petition method validation trial, and has been forwarded to the FDA for inclusion in PAM Vol. II. T he level o f detection (LOD) and level of quantitation (LOQ) are 0.01 and 0.02 ppm, respectively.

2.2.2 International Harmonization

No Codex, Canadian or Mexican maximum residue limit (MRL) for residues of pyriproxyfen are established in/ on tea commodities . Japan and the European Commission have established MRL s for residues of pyriproxyfen in/on tea at 15 ppm

.

2.2 .3 Recommended Tolerances

Using all of the submitted crude dried tea magnitude of the residue data in the Organization for Economic Cooperation and Development (OECD) calculation procedures resulted in a calculated tolerance level of 20 ppm. While details regarding the calculation procedures for the petitioned

for tolerance level (15.0 ppm) were not provided in the petition, HED believes that this

ca lculation is the result of excluding the trial with the highest residues (Nara, Japan/2008) likely due to concerns about detectable residues in the untreated control for that trial. HED considered the results of this trial to be viable for tolerance deter mination and did not exclude it, given that the residues in the control sample (0.10 ppm) were well below the residues in the test sample (11.4 ppm) for the subject trial. However, HED is recommending for the petitioned

- for tolerance level of 15 ppm to ha rmonize with the Japanese MRL in/on tea.

HED recommends that 40 CFR §180.510 be amended to increase the currently established tolerance for residues of pyriproxyfen in/on tea from 0.02 ppm to 15 ppm. HED has determined that the correct commodity defini tion should remain tea and the recommended tolerance level will cover incurred residues of pyriproxyfen in/on all tea commodities resulting from both currently registered domestic use and the proposed non

- domestic use of pyriproxyfen. See Table 2.2.3.1

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

Page 8 of 58 T able 2.2..3.1 Tolerance Summary for Pyriproxyfen Commodity as Proposed by Petitioner Proposed Tolerance (ppm) Recommended Tolerance (ppm) Correct Commodity

Definition; Comments
Tea 15.0 15 1 Tea
1 The CFR should not include any furthe r notation for this tolerance. Although the recommended tolerance level is not based on domestic use of pyriproxyfen, there is a U.S. registration for the use of pyriproxyfen as an ant bait (EPA Reg. No. 59639

- 114).



### 2.2.4 Revisions to Petitioned

- For Tole rances

The petitioned

- for tolerance for residues of pyriproxyfen in/on tea (15.0 ppm) must be corrected to 15 ppm, consistent with current practices for setting tolerances, and section F of the petition should be revised accordingly.

2.3 Label Recommendations None

.

3.0 I ntroduction

3. 1 Chemical Identity

Table 3.1.1 Test Compound Nomenclature.

Pyriproxyfen

Common name Pyriproxyfen Company experimental name S

- 71639, S

- 31183

IUPAC name 4

- phenoxyphenyl (RS)

- 2

- (2

- pyridyloxy)propyl ether

CAS name 2

- [1

- methyl

- 2

- (4

- phenoxyphenoxy)ethoxy]pyridine

CAS # 95737

- 68

- 1

End

- use products/(EP) Not Applicable



### 3.2 Physical/Chemical Characteristics

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

Parameter Value Reference Melting range 45

- 47°C Physical Chemical Characteristics Summary pH (20°C) 6.4 Density (25°C) 1.24 Water solubility ( m g/L at 25°C) 0.367 Solvent solubility (mg/L at 20°C) 76700 Hexane 60100 Methanol The Pesticide Manual

Vapor pressure (20°C) 1.0x10

- 7 mmHg Physical Chemical Characteristics Summary Dissociation constant (pK a ) N ot Available Octanol/water partition coefficient ( Log K OW ) 5.37 @ 25°C UV/visible absorption spectrum 288 and 330 nmPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 9 of 58 

### 3.3 Pesticide Use Pattern

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

, described as a 9% microcapsule formulation of pyriproxyfen. The maximum application rate is one application at 1000L /10a (where a equals 100 m 2 

### ) of a 1000x dilut ion of the end

- use product (reviewer calculated use rate is 0.8 lb ai/A) and a 30

- days pre

- harvest interval (PHI).

3.4 Anticipated Exposure Pathways

Dietary (food and water), residential and occupational exposure are expected based on existing uses of p yriproxyfen. The proposed tolerance increase in/on tea to cover residues in/on pyriproxyfen

- treated tea will contribute to dietary (food only) exposure. No new drinking water, residential or occupational exposure scenarios are associated with the proposed tolerance increase. T he previous residential exposure assessment conducted in accordance with HED’s 2012 Residential SOPs (DP# 404203), was further updated to be consistent with current HED policies

. The short

- , intermediate

- and long

- term aggre gate exposure assessments were updated to incorporate the updated residential exposure and updated dietary exposure from the petitioned

for increase in the tolerance for residues of pyriproxyfen in/on tea.

3.5 Considerations of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Lo w

- Income Populations,” ( http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf )

. As a part of every pesticide risk a ssessment, 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 w ater consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and/or the CDC under the National Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age , season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, n on

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 10 of 58 

### 4.0 H azard Ch aracterization and Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database is complete and acceptable for characterizing pyriproxyfen hazard and includes the following studies:

- 90 day oral toxicity study

– rat, mouse, and dog

- 21 day dermal toxicity study

– rat

- 28 day inhalation study

- rat

- Prenatal developmental toxicity study

– rat and rabbit

- Multi

- generation reproduction and fertility toxicity study

– rat

- 1 year chronic toxicity study

– dog

- 2 year chronic toxicity/carcinogeni city study

– rat

- 2 year carcinogenicity study

– mouse

- Mutagenicity battery

- Acute and subchronic neurotoxicity study

– rat

- Metabolism pharmacokinetics study

– rat

- Immunotoxicity study

4.2 Absorption, Distribution, Metabolism and Excretion

Absorption was nearly identical in males and females provided a single oral dose of 2 mg/kg (low dose) or 1000 mg/kg (high dose). Based on urine concentration pyriproxyfen was not easily absorbed (<12%) and was excreted rapidly (88.9

– 92.9% within 2 days ). Excretion was near complete (92.3

- 98.5%) after 7 days despite a dip in the rate of elimination after the second day. Fecal excretion was the dominant elimination pathway after both low (86.1

– 93.2%) and high dose (84.7

– 89%) exposures. Urine excr etion was minor compared to fecal elimination, but was more prominent in the high dose (7.5

– 11.8%) than in low dose (4.9

– 5.7%). Release of pyriproxyfen in expired air was not a significant ( < 0.5%).

Metabolism was affected both by dose and the sex of the animal. Feces contained up to 17 metabolites whereas 11 were identified in the urine. Parent compound was identified in both forms of excreta. Metabolism was more extensive in females with only 21.2

– 21.9% of the parent compound remaining in the excreta compared to 32.5

– 34.8% in males. Metabolism of pyriproxyfen occurred primarily through hydroxylation at the 4’

- position of the terminal phen yl ring. Metabolism via this pathway was utilized more in females (49.3

– 53.6%) than in males (32.1

– 43.3%) regardless of dose. Hydroxylation at the 2’

- position of the phenyl ring was not as extensive, but was favored more at low dose (1.8

– 2.8%) than at the high dose (0.2%). Hydroxylation at the 5”

- position of pyridyl ring, another minor pathway, was also more prevalent at the low dose (1.4

– 7.8% compared to 0.9

– 1.4% at the high dose). Unlike hydroxylation of the phenyl ring, hydroxylation of the pyridyl ring was more prominent in males (1.4

– 7.8%) than in females (0.9

– 1.7%). Of the minor metabolic pathways, high dose animals preferred sulfuric acid conjugation accounting for 1.2

– 2.8% compared to 0.8

– 2.4% in low dose animals. Minor metabo lites born from dephenylation (0.8

– 1.6%) and conjugation with glucuronic acid (0.2

– 11%) were comparable across sex and dose. A proposed metabolicPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 11 of 58 

### pathway for pyriproxyfen is illustrated in Appendix B.

4’

- OH

- pyriproxyfen was the dominant fecal metabol ite at both doses accounting for 23.3

– 38.4% in males and 46.4

– 47.2% in females. At the low dose other major metabolites were 5”,4’

- OH

- pyriproxyfen (7.2% in males and 1.2 % in females) and 2’

- OH

- pyriproxyfen (1.8% in males and 2.8% in females). At hig h doses these metabolites were not as common, accounting for only 0.2

– 0.4% of the administered dose. Instead the major fecal metabolites were DPH

pyriproxyfen and 4’

- OH

- pyriproxyfen

- sulfate (combined 1.2

– 1.6%). Small quantities of these metabolites w ere present in low dose animals ( < 1.1%). The major urinary metabolite was 2

- (2

- pyridyloxy) propionic acid (PYPAC) which accounted for 1

– 4.9%. The sulfuric acid conjugated compounds, 4’

- OH

- pyriproxyfen

- sulfate and 5”,4’

- OH

- pyriproxyfen

- sulfate, were also present at much lower concentrations (0.1

– 0.8% of the administered dose). Parent compound was only identified in urine of high dose animals (1.3% in males, and 2.7% in females). 4’

- OH

- pyriproxyfen was also identified in the urine at 1% in males and 5. 6% in females; however, this metabolite and the parent compound were not observed in the urine of all animals and it is hypothesized that these metabolites originated from feces contamination and would otherwise not be present in the urine.

No sex or d ose related disparities were identified in the tissue distribution. Residual tissue concentration increased with dose but total accumulation never exceeded 0.3% of the administered dose 7 days after exposure. The residual carcass and fat were the primary sinks for pyriproxyfen amassing 0.065

– 0.148% and 0.024

– 0.042% of the administered dose, respectively. Minimal accumulation was observed in the liver (0.16

– 0.22%) and even less was present in the kidneys (0.002

– 0.003%). Between 0.006 and 0.013% w as in circulation on seven days after exposure. The remaining tissues contained insignificant amounts of pyriproxyfen ( < 0.001%).

4.2.1 Dermal Absorption

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

- day dermal rat toxici ty study resulted in no toxicity up to the limit dose and ; therefore

, short

- and intermediate

term dermal exposure a ssessments 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/da y in the 21

- day dermal study. T hese 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 en dpoint.

4.3 Toxicological Effects

Pyriproxyfen is a broad spectrum pyridine insecticide. It mimics the insect juvenile hormone (JH) disrupting tightly controlled and temporally dependent growth and development pathways. In mammals, adults were more sus ceptible to pyriproxyfen exposure than developing young implying a mode of action not specific to developmental pathways. Primary targets forPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 12 of 58 

### pyriproxyfen were the liver (increased absolute and relative weight concurrent with elevated

serum enzyme , choles terol and phospholipid levels , hepatocyte enlargement , distended gallbladders ), and the hematopoietic system (decreased red blood cell, hematocrit and hemoglobin counts) across all mammals examined. T he kidneys (increased relative weight, tubular nephriti s with dilation of renal tubules and focal mineralization, dilation of the renal pelvis, chronic interstitial nephritis) also appeared to be a target in rodent species ; however, these histopathological lesions are also commonly observed in aging rodents an d in many instances there were no associated clinical chemistry changes indicative of kidney toxicity. Systemic toxicity, manifest as reduced body weight (rat only)

, and depressed body weight gain and food consumption, often accompanied the liver, kidney, and hematological effects. Rats were more sensitive to oral exposure compared to mice or dogs ; however, t oxicity did not become more severe with exposure duration. The lack of progression was likely facilitated by the rapid elimination of the compound w ithin 2 days of exposure that limited tissue accumulation and minimized damage to sensitive organs.

Developing rats and rabbits and rat pups were not more sensitive or susceptible to pyriproxyfen exposure than the adults. Systemic toxicity (decreased b ody weight, body weight gain, food consumption), clinical signs of distress, decreased activity, and abortions in maternal rats and rabbits either preceded or co

- occurred with the onset of developmental injury. Developmental effects from in utero (skeletal and visceral variations and reduced pup viability) and postnatal (decreased pup weight and renal pelvis dilation) exposure were only noted at the limit dose and could be attributed to compromised maternal health. There was no evidence of exposur e

induced developmental anomalies in the fetal nervous system or of an exposure related deleterious influence on functional postnatal development in rats. Pyriproxyfen did not affect reproduction.

Other critical physiological systems were not uniquely se nsitive to pyriproxyfen. Neurological effects (decreased motor activity after acute exposure) occurred in the absence of altered brain weight or histopathology (non

- perfused tissues) at or above the limit dose. The respiratory system was unaffected in ch ronic and subchronic oral, dermal, and inhalation exposures and rats were tolerant of acute inhalation exposures to pyriproxyfen (Category III). The immune system was similarly unaffected after oral exposure up to the limit dose. Exceedingly high dermal doses are required to elicit dermal and systemic toxicity in subchronic exposures, and mortality (Category III) and irritation in acute exposures (Category IV). It is not a dermal sensitizer nor a strong eye irritant (Category IV).

Neither pyriproxyfen nor its common metabolites (listed in section 4.2) demonstrated mutagenic behavior or carcinogenicity after long

- term exposure. Pyriproxyfen is classified as a "Group E" chemical indicating there is no evidence for carcinogenicity to humans based on the absence of carcinogenicity in mice and rats (TXR 0012966)

.
The complete toxicity profile for pyriproxyfen is provided in Appendix A.Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 13 of 58 

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

The 10X FQPA safety factor to ac count for potential increased susceptibility of infants and children is reduced to 1X for pyriproxyfen based on the following considerations:

1) The toxicology data base is complete and adequate for assessing increased infant and child susceptibility under F QPA 2) There is no evidence of qualitative or quantitative susceptibility in developing rat and rabbit fetuses or in rat pups 3) There are no residual uncertainties in the exposure database 4) Exposure assessments are conservative and will not under

- estimate expos ure (see 4.4.4 below)

4.4.1 Completeness of the Toxicology Database

The toxicity database is complete and adequate for assessing the susceptibility of infants and children to pyriproxyfen exposure (section 4.1). Qualitative and quantitative susceptibility at critical developmental life stages was addressed in two guideline developmental studies, two

non

- guideline developmental studies, and a 2

- generation reproduction study. Additionally, a neurotoxicity battery and immun o tox icity study were available to assess unique susceptibly in these systems.

4.4.2 Evidence of Neurotoxicity

The neurotoxicity battery provides no evidence to support a neurotoxic mode of action for pyriproxyfen. Decreases in motor activity w ere only observed above the limit dose (2000 mg/kg/day) in the acute neurotoxicity (ACN) study and no neurotoxicity was observed in the subchronic neurotoxicity (SCN) study. Systemic effects in the SCN (reduced body weight, body weight gain, and food cons umption) occurred in the absence of neurotoxic symptoms and no biologically relevant signs of neurotoxic ity were observed in the other submitted studies indicating the nervous system is not the primary target of pyriproxyfen or its metabolites.

4.4.3 Ev idence of Sensitivity/Susceptibility in the Developing or Young Animal

There are no indications from the pyriproxyfen database of sensitivity to infants and children. There was no evidence of prenatal or postnatal sensitivity or increased susceptibility in developmental studies in rats and rabbits, or in reproduction studies in rats. No evidence of developmental anomalies of the fetal nervous system was observed in prenatal developmental toxicity studies in either rats or rabbits at maternally toxic dose s up to 1,000 mg/kg/day and 300 mg/kg/day, respectively. There was no evidence of an effect on functional development during the postnatal period of a special developmental study in rats. In the 2

- generation reproduction toxicity study, offspring toxicit y ( lower pup body weight relative to controls during lactation days 14 to 21) occurred in the presence of lower body weight in parental animals at the same dose level (i.e., comparable toxicity in adults and offspring). In the two non

- guideline studies th at evaluated perinatal and prenatal development, there was no evidence of quantitative or qualitative increased susceptibility. In one study, when pregnant rats were treated from gestationPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 14 of 58 

### day 17 to lactation day 20, the resulting toxicity was comparable between adults (clinical signs, depressed body weight gain and food consumption) and offspring ( lower body weight and dilation of the renal pelvis) at the same dose. In the other study, when rats were exposed to pyriproxyfen prior to and during the early stages of pregnancy, no developmental toxicity was seen at the limit dose.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the hazard or exposure databases. The dietary, drinking water, and resident ial exposure assessment included herein are considered conservative; the dietary assessment assumed 100% crop treated, DEEM  

### 7.81 default processing factors, tolerance

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

- level estimates of drinking water concentrations (EDWCs) generated by Tier 1 models ; and the residential assessment did not take into account the daily dissipation of pyriproxyfen residues.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose

- Response Assessment

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

, occupational

, and residential exposure scenarios are summarized below. A detailed description of the studies used as a basis for the selected endpoints is presented in Appendi x A.

An acute reference dose (aRfD) was not established for females 13

- 49 years old or the general population, because acute oral effects attributed to a single

- dose exposure could not be identified in the toxicology database, including the developmenta l toxicity studies. Acute toxicity in the ACN study was observed only at doses that were not relevant to human exposure (i.e. above the limit dose) and were not considered in selecting endpoints for acute dietary assessments.

The cRfD of 0.35 mg/kg/day was determined on the basis of depressed body weight gain, anemia, and increased relative liver weight with elevated serum cholesterol and phospholipid levels. in two co

- critical rat toxicity studies (subchronic and chronic). The NOAEL from the chronic study, 35.1 mg/kg/day, was selected to set the chronic endpoint. Since the FQPA Safety Factor (SF) has been reduced to 1X, the chronic population

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

Short

- term incidental oral endpoint (NOAEL 100 mg/kg/day) was selected from the rat developmental based on decreased body weight, body weight gain, and food consumption, and increased water consumption at the maternal LOAEL of 300 mg/kg/day. The intermediate

- term incidental oral endpoint (NOAEL = 35.1 mg/kg/day) was determined based on systemic toxicity described above (LOAEL = 141.28 mg/kg/day) in two co

- critical rat toxicity studies (subchronic and chronic).

Short

- and inter mediate

- 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 levelPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 15 of 58 

### (NOAEL) of 35.1 mg/kg/day from the two co

- critical (subchronic and chronic) rat feeding studies. An estimated dermal absorption factor of 30% was used for route

- to

- route extrapolation.

Short

- and intermediate

- term inhalation endpoints were n ot selected based on the lack of biologically adverse effects at 1.0 mg/L in the 28

- day inhalation toxicity study in rats. The long

term inhalation endpoint was based on the systemic toxicity oral NOAEL of 35.1 mg/kg/day from the two co

- critical (subchron ic and chronic) rat feeding studies. Absorption from inhalation

exposure was assumed to be 100% for route

- to

- route extrapolation.

A UF 100x was applied to all dietary, residential, and occupational endpoints to account for interspecies extrapolation (10x ) and intraspecies variation (10x).

HED classified pyriproxyfen as a "Group E" chemical, no evidence for carcinogenicity to humans , based on the absence of evidence of carcinogenicity in male and female rats as well as in male and female mice (TXR 0012966 ) . Therefore, a cancer risk assessment is not required.

It is recognized that the studies in the pyriproxyfen database, including some of those used for endpoint selection, have not been updated to reflect current policy and may be considered

conservat ive. The currently selected PODs are protective of the effects observed in the pyriproxyfen database and any updates would not impact the overall findings of the risk assessment given the current risk picture for pyriproxyfen.

4.5.2 Recommendations for Combining Exposure Routes

When there are potential residential exposures to the pesticide, risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. If the toxicity endpoints and PODs for dermal, oral, and i nhalation routes of exposure are similar the exposure or risk estimates from these exposure routes need to be combined. A common toxicity endpoint (decreases in body weight and alterations in clinical pathology parameters) was identified for the oral, der mal (oral equivalent) and inhalation (oral equivalent) routes ; therefore, these routes can be combined for the appropriate populations for long

- term aggregate risk assessment. Short

- and intermediate

- term exposures were not combined because no dermal or i nhalation hazards were identified for these durations.

4.5.3 Classification of Carcinogenic Potential

In accordance with the Agency’s 1986 Guidelines for Carcinogenic Risk Assessment, the RfD/Peer Review Committee classified pyriproxyfen as a "Group E" chemical

- negative for carcinogenicity to humans (TXR 0012966). T his classification is based on the lack of evidence of carcinogenicity in mice and rats.Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 16 of 58 

### 4.5.4 Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints sele cted for dietary (Table 4.5.4.1), non

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

Table 4.5.4. 1 Summary of Toxicological Doses and Endpoints for Pyriproxyfen for Use in Dietary and

Non

- Occupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/F

QPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (All Populations) An appropriate endpoint attributable to a single oral dose was not identified in the toxicology

database, including the developmental and reproduction toxicity studies.

Chronic Dietary (All Populations) 1 NOAEL = 35.1

mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Chronic RfD

= 0.35 mg/kg/day

cPAD = 0.35 mg/kg/day Subchronic (41321716 ) and chronic

(43210503)

– rat (co

- critical)

LOAEL = 141.28 mg/kg/day based on depressed and body weight gain, anemia, and increased relative liver weight with elevated cholesterol and phospholipid levels.

Short

- Term Incidental, Oral (1

- 30 days) NOAEL = 100

mg/kg/day UF A = 10x

UF H =10x LOC for

MOE = 100 Rat developmental toxicity (44985002)

Maternal LOAEL = 300 mg/kg/day based on decreased body weight, body weight gain, and food consumption, and increased water consumption

Intermediate

Term Incidental, Oral (1

- 6 months) 1 NOAEL = 35.1

mg/kg/day UF A = 10x

UF H =10x LOC for

MOE = 100 Subchronic (41321716 ) and chronic

(43210503)

– rat (co

- critical)

LOAEL = 141.28 mg/kg/day based on de pressed body weight gain, anemia, and increased relative liver weight with elevated cholesterol and phospholipid levels.
Short

- , and Intermediate

Term Dermal (1

- 30 days and 1

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

toxicity study in rats, quantification of dermal risks is not required. In addition, no developmental concerns (toxicity) were seen in either rats or rabbits.Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 17 of 58 Table 4.5.4. 1 Summary of Toxicological Doses and Endpoints for Pyriproxyfen for Use in Dietary and

Non

- Occupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/F

QPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Long

- Term Dermal (6 months

lifetime) 1 NOAEL = 35.1

mg/kg/day

DAF = 30% 2 UF A = 10x

UF H =10x LOC for

MOE = 100 Subchronic (41321716 ) and chronic

(43210503)

– rat (co

- critical)

LOAEL = 141.28 mg/kg/day based on de pressed body weight gain, anemia, and increased relative liver weight with elevated cholesterol and phospholipid levels.
Short

- , and Intermediate

Term Inhalation (1

- 30 days and 1

- 6 months) Based on the absence of biologically relevant toxicity at 1.0 mg/L, the quantification of

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

Long

- Term Inhalation (6 months

lifetime) 1 NOAEL = 35.1

mg/kg/day UF A = 10x

UF H =10x LOC for

MOE = 100 Subchronic (41321716 ) and chronic

(43210503)

– rat (co

- critical)

LOAEL = 141.28 mg/kg/day based on depressed body weight gain, anemia, and increased relative liver weight with elevated cholesterol and phospholipid levels.

Cancer (oral, dermal, inhalation) In accordance with the Agency’s 1986 Guidelines for Carcinogenic Risk Assessment, the

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

- negative for carcinogenicity to humans . This classification is based on the lack of evidence of carcinogenicity in mice and rats (TXR 0012966)

.

Point of Departure (POD) = A data point o r an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = low est observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD =

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

1 The NOAEL and LOAEL for the co

- critical studies were based on the female endpoints from the chronic and sub

chronic rat studies, respectively. Females demonstrated greater or equivalent sensitivity to oral pyriproxyfen exposure relative to males; therefore , selection of two female endpoints accounted for effects observed in the males while maintain ing consistency between the NOAEL and LOAEL.

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

- day rat dermal study NOAEL of 1000 mg/kg/day (No NOAEL) = 300/1000=30%.Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 18 of 58 Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Pyriproxyfen for Use in Occupational

Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/F

QPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Short

- , and Intermediate

Term Dermal (1

- 30 days and 1

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

toxicity study in rats, quantif ication of dermal risks is not required. In addition, no developmental concerns (toxicity) were seen in either rats or rabbits.

Long

- Term Dermal (6 months

lifetime) NOAEL = 35.1

mg/kg/day

DAF = 30%* UF A = 10x

UF H =10x LOC for

MOE = 100 Subchronic (41321716 ) and chronic

(43210503)

– rat (co

- critical)

LOAEL = 141.28 mg/kg/day based on depressed body weight gain, anemia, and increased relative liver weight with elevated cholesterol and phospholipid levels.
Short

- , and Intermediate

Term Inhalation (1

- 30 days and 1

- 6 months) Based on the absence of biologically relevant toxicity at the LOAEL of 1.0 mg/L, the

quantification of inhalation risks is not required. In addition, no developmental concerns (toxicity) were seen in either rats or rabbits.

Long

- Term Inhalation (6 months

lifetime) NOAEL = 35.1

mg/kg/day UF A = 10x

UF H =10x LOC for

MOE = 100 Subchronic (41321716 ) and chronic

(43210503)

– rat (co

- critical)

LOAEL = 141.28 mg/kg/day based on depressed body weight gain, anemia, and increased rela tive liver weight with elevated cholesterol and phospholipid levels.

Cancer (dermal, inhalation) In accordance with the Agency’s 1986 Guidelines for Carcinogenic Risk Assessment, the

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

- negative for carcinogenicity to humans . This classification is based on the lack of evidence of carcinogenicity in mice and rats (TXR 0012966)

.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertaint y factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). DAF = dermal absorption factor *DAF estimated by comparing the rat developmental LOAEL of 3 00 mg/kg/day to the 21

- day rat dermal study NOAEL of 1000 mg/kg/day (No NOAEL) = 300/1000=30%.Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 19 of 58 

### 5.0 D ietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Livestock Metabolism Studies

Adequate metabolism studies for pyriproxyfen are available on apples, cotton, and tomatoes. Based on these studies, the Metabolism Assessment Review Committee (MARC) determined that the residue of concern in plants is pyriproxyfen (DP#: 250953).

Adequate r uminant and poultry metabolism studies are available for pyriproxyfen . HED determined that should future crop uses increase the maximum theoretical dietary burden (MTDB) to the point that tolerances are needed in livestock commodities, the residue of concern will be pyriproxyfen and the free and sulfate forms of 4'

- OH

- PYR.

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

- day plant back interval (PBI) and a treatment rate of 0.18 lb ai/A, no pyriproxyfen residue s 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 Meta bolic Pathways

HED determined that the residue of concern in plants is pyriproxyfen. HED determined that should future crop uses increase the MTDB to the point that tolerances are needed in livestock commodities, the residue of concern in livestock will be pyriproxyfen and the free and sulfate forms of 4'

- OH

- PYR.

5.1.3 Summary of Environmental Degradation

Pyriproxyfen is expected to possess low mobility in soil (average K oc 

### = 19260), and is not expected to be persistent in the open environment. Pyripro xyfen is stable to hydrolysis and anaerobic degradation (t 1⁄2 

### = 250 days), but is susceptible to photolytic transformation in water (t 1⁄2 

### = 6.4 days) and aerobic degradation (t 1⁄2 

### = 9 days). Pyriproxyfen has low volatility and low water solubility. Pyriproxyfe n shows moderate bioconcentration in fish (465 to 2,390x), with a rapid depuration rate.Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 20 of 58 

### 5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4.1 provides a summary of the HED M ARC decisions regarding residues of concern for pyriproxyfen (DP# 250953)

.

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

Tolerance Expression.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Pyriproxyfen Pyriproxyfen

Rotational Crop Pyriproxyfen Pyriproxyfen

Livestock Ruminant Pyriproxyfen and the free and sulfate forms of 4'

- OH

- PYR Pyriproxyfen and the free and sulfate forms of 4'

- OH

- PYR

Poultry Pyriproxyfen and the free and sulfate forms of 4'

- OH

- PYR Pyriproxyfen and the free and sulfate forms of 4'

- OH

- PYR Drinking Water Pyriproxyfen N ot Applicable



### 5.2 Food Residue Profile

No residue data on plucked (undried) tea leaves were submitted; however, these data are not required for imported tea. No residue data on instant tea were submitted; however, the HED ChemSAC has recently decided that these data are no longer required (ChemSAC meeting 8/26/15 ).

Adequate magnitude of the residue data were submitted for residues of pyriproxyfen in dried tea grown/processed in Japan to support the proposed tolerance increase. Ten field trials were conducted in Japan during the 2004, 2005 and 2008 growing seasons. At each trial location, treated plots received one foliar application of end

- use product Pluto MC, described as a 9% microcapsule formulation of pyriproxyfen. The application rate was 1000L/10a (where a equals 100 m 2 

### ) of a 1000x dilution of the end

- use pr oduct (reviewer calculated use rate is 0.8 lb ai/A) 28

- 30 days prior to harvest. To provide decline data, separate sub

- plots at each trial location were also treated with one application of Pluto MC at 0.8 lb ai/A 21

- 22, 42

- 45 or 60 days prior to harvest. All samples were collected on the same day. The report described this scheme as a “reverse decline study.” No adjuvant was used in any of the trials.

Only one untreated and one treated field trial sample of buds/leaves were collected from six of the trial locations (i.e., Fukuoka/2005, Shizuoka/2008, Nara/2008, Fukuoka/2008, Miyazaki/2008 and Kagoshima Osumi/2008). Two untreated and two treated field trial samples of buds/leaves were collected from four of the trial locations (i.e., Fukuoka/2004, Mi e/2004, Mie/2008 and Kagoshima/2008). Harvested tea buds/leaves were processed by a tea manufacturing machine to crude dried tea. Each sample of crude dried tea was analyzed at two different laboratories, the Mitsukaido Laboratories, Institute of Environ mental Toxicity and the
In

- house Analysis Institute of Sumika Technoservice Corporation.

Details for processing the harvested tea buds/leaves into crude dried tea samples were not provided in the submission. However, in Japan crude dried tea, or aracha, is typically a type of green tea produced by repeated steaming, rolling and drying steps to form needle shaped teaPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 21 of 58 

### leaves for distribution to wholesalers, not consumers. P arts of the leaves are then sorted, sized, graded, and blended to produce sencha tea for the consumer.

Residues of pyriproxyfen in crude dried tea, processed from buds/leaves treated at the proposed use rate and collected at PHIs of 28

- 30 days, ranged from 0.10 ppm to 11.4 ppm. [Note: Since only one sample was collected from trial loca tions having the lowest and highest values, the values for the individual sample and per

- trial averages were the same.] Residue decline data show that the levels of pyriproxyfen decrease in crude dried tea with increasing PHIs. Data were collected with a dequate data

- collection methods. Adequate storage stability data are available to support sample storage durations and conditions. See Table 5 .2.1 below.

Table 5. 2.1 Summary of Residues from Tea Trials Conducted in Japan with Pyriproxyfen.

Commodity Total Application

Rate 1 PHI 2

(days) Residue Levels (ppm)

n Min. 3 Max. 3 LAFT 3 HAFT 3 Median 4 Mean 4 Standard Deviation 4

Crude dried

tea x1000

1000L/10a

(0.8 lb ai/A) 21

- 22 8 0.89 14.9 0.89 14.9 6.905 7.30 4.11

28

- 30 10 0.10 11.4 5 0.10 11.4 5 4.045 4.38 3.46
42

- 45 10 0.02 8.57 0.02 8.57 2.015 2.56 2.66
60 3 <0.01 0.03 <0.01 0.03 0.01 0.02 0.01

1 Reported use rate: End

- use product registered in Japan is PLUTO MC, a microcapsule formulation which contains 9.0% (w/w) of pyriproxyfen. Dilute end

- use product 1000x and apply 1000L/10a; where a equals 100 m 2 . All trials were reportedly conducted at this same u se rate without any deviation. Reviewer calculated use rate: 0.8 lb ai/A. 2 All trials were conducted using a single application and included residue decline trials, referred to in the study report as “reverse decline trials.” At each test location, a se parate single application was made to a separate section of the test plot at various times prior to harvest (reflecting different PHIs), but all test plot samples of buds/leaves were harvested on the sa me day and processed by a tea manufacturing machine to crude dried tea. 3 Since only one sample was collected from trial locations having the lowest and highest values, the values for the Min. individual sample and lowest average field trial (LAFT) are the same and the values for the Max. individual sample and highest average field trial (HAFT) are the same. 4 Calculation used the higher of the two samples from trial locations Fukuoka/2004, Mie/2004, Mie/2008 and Kagoshima/2008. 5 Detectable residues were found in the control sample from the trial location having the highest test sample residue value (Nara, Japan/2008); however, the residues in the control sample (0.10 ppm) were well below the residues in the test sample (11.4 ppm). The test sample value is considered viable for inclusion in the tolerance determi nation.



### 5.3 Water Residue Profile

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

- treated imported tea

. The following information concerning the environmental fate and drinking water ass essment of pyriproxyfen for existing uses of pyriproxyfen was provided by EFED (DP#: 397089, J. Hetrick, 7/25/2012).

Tier 1 FIRST and GENEEC modeling was conducted to assess estimated drinking water concentration (EDWC) of pyriproxyfen in surface and ground water source drinking water. No monitoring surface or ground water monitoring data are available for pyriproxyfen. The drinking water assessment considers only parent pyriproxyfen. Tier 1 FIRST modeling predicts that pyriproxyfen concentrations in surface source drinking water are not expected to exceed 1.952 μg/L for the daily peak and 0.111 μg/L for the annual ave rage 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 annualPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 22 of 58 

### average. Based on previous dri nking 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 μ g /L for peak and annual average concentrations. In ground water, t he EDWCs for pyriproxyfen are not expected to exceed 0.006 μg /L for peak and annual average concentrations. This assessment shows that past drinking water assessments for pyriproxyfen provide a higher EDWC. EFED recommend ed using 2.98 μg /L for the EDWC. The drinking water assessment is considered conservative since it was based on estimates of drinking water concentrations generated by the Tier 1 Rice Model.

5.4 Dietary Exposure and Risk Assessment

5.4.1 Acute Dietary and Drinking Water Analysis

There was no appropriate endpoint for assessing acute dietary exposure; therefore, no acute dietary risk assessment was performed.

5.4.2 Chronic Dietary and Drinking Water Analysis

An unrefined chronic aggregate dietary ( food and drinking water ) exposu re and risk assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16. This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’ s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). The chronic dietary exposure and risk estimates (food and drinking water) were estimated at 3.7% of the cPAD for the U.S. population and 12% of the cPAD for the m ost highly

- exposed population subgroup (children 1

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

Table 5.4.2.1 Summary of Chronic Dietary Exposure and Risk for Pyriproxyfen.
Population Subgroup cPAD (mg/kg/day) Chronic Exposure (mg/kg/day) %cPAD General U.S. Population

0.35 0.012957 3.7 All Infants (< 1 year old) 0.018036 5.2 Children 1

- 2 years old 0.042557 12 Children 3

- 5 years old 0.033637 10 Children 6

- 12 years old 0.019280 5.5 Youth 13

- 19 years old 0.011080 3.2 Adults 20

- 49 years old 0.010408 3.0 Adults 50

- 99 years old 0.009331 2.7 Females 13

- 49 years old 0.010095 2.9

1 Highest exposure identified in bold.



### 6.0 R esidential (Non

- Occupational) Exposure/ R isk Characterization

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

- treated imported tea

. Pyriproxyfen is the active ingredient in many currently registered residential products for flea and tick control (home en vironment 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 petPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 23 of 58 

### treatments), granules, bait (indoo r and outdoor), and impregnated materials (pet collars).

A detailed review of information pertaining to residential exposure to pyriproxyfen is available in a previous memo (DP#: 404203 )

. In this 2012 ORE memo, HED updated the residential

exposure asse ssment to reflect updates to residential exposure standard operating procedures (SOPs).

6.1 Residential Handler Exposure

There is the potential for short

- term residential handler dermal and inhalation exposure from the registered uses of pyriproxyfen; however, since no short

- term dermal or inhalation PODs were identified, a quantitative assessment was not conducted.

6.2 Residential Post

- A pplication Exposure

Based on the registered use patterns, the following post

- application scenarios were assessed in the 2012 ORE memo :

 Hand

- to

- Mouth:

o Short

- and intermediate

- term hand

- to

- mouth exposures for Children 1 to <2 year s old from treated carpets and flooring and petting treated animals (shampoos,

sprays, s pot

- on treatments and collars).

o Long

- term hand

- to

- mouth exposures for Children 1 to <2 year s old from treated carpets and flooring and petting treated animals from pet collars (note efficacy of carpet powders is 365 days and efficacy of pet collars up to 395 days).

 Dermal:

o Long

- term dermal exposures from treated carpets, flooring, and pets (note efficacy of carpet powders is 365 days and efficacy of pet collars up to 395 days).

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

- term dermal and hand

- to

- mouth for all direct pet applications which is consistent with current HED policies.

HED acknowledges that pet owners could retreat the home environment and/or a pet near the end of the efficacy period ide ntified on the product labels. However, there are no chemical

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

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

p erformed based on Day 0 residues without accounting f or daily residue dissipation. HED anticipates that this assessment is protective as pyriproxyfen residues would be expected to dissipate from Day 0 residue values.Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 24 of 58 Table 6.2.1 Summary of Risk Estima tes for Existing Residential Uses of Pyriproxyfen

Formulation Use Maximum

Application Rate a Route of Exposure Short

- Term MOE Intermediate

Term MOE Long

- Term

MOE b Combined

MOEs (Long

- term only)
Household/Pet Flea and Tick Control

Carpet powder

- flea and tick

treatment 1x10

- 6 lb ai/ft 2 Incidental oral (Hand

- to

- Mouth) 35000 12000 12000

4000

Dermal Child

1 to < 2

yr s old N/A N/A 6100

Adults 5800 N/A

Fogger 4.99x10

- 7 lb

ai/ft 2 Incidental oral

(Hand

- to

- Mouth) 87000 31000 N/A N/A Dermal N/A N/A N/A

Pet spray mist 1.3x10

- 5 lb

ai/application Incidental oral

(Hand

- to

- Mouth) 980000 340000 700000

22000

Dermal Child

1 to < 2

y rs old N/A N/A 23000

Adults 59000 N/A

Pet spot

- on for cats 1.7x10

- 4 lb

ai/application Incidental oral

(Hand

- to

- Mouth) 76000 27000 27000

860

Dermal Child

1 to < 2

y rs o ld N/A N/A 890

Adults 2300 N/A

Pet spot

- on for dogs 2.1x10

- 4 lb

ai/application Incidental oral

(Hand

- to

- Mouth) 120000 44000 44000

1400

Dermal Child

1 to < 2

y rs old N/A N/A 1400

Adults 3700 N/A

Pet collars 4.63x10

- 4 lb

ai/collar Incidental oral

(Hand

- to

- Mouth) 28000 9800 9800

320

Dermal Child

1 to < 2

y rs old N/A N/A 330

Adults 830 N/A

Pet shampoos 1.13x10

- 4 lb

ai/application Incidental oral

(Hand

- to

- Mouth) 230 ,000 27000 27000

2500

Dermal Child

1 to < 2

y rs old N/A N/A 2700

Adults 6800 N/A

Ant and Roach Control

Granular Bait 0.225 lb ai/A Incidental oral (Hand

- to

- Mouth) 290,000 100,000 N/A N/A

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

- term assessments conducted for products with efficacy of up to 1 year

– pet collars and indoor carpet powder as well as all direct pet application products

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

Page 25 of 58 

### 6.3 Residential Bystander Post

- applica tion Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from i ts Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html ) . The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review, the Agency will use this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studi es) or further analysis is required for pyriproxyfen

.

6.4 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application method s (e.g., groundboom and airblast) employed for pyriproxyfen. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 1 

### The Agency has also developed a policy on how to appropriately consider s pray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will b e considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This d ocument outlines the quantification of indirect non

- occupational exposure to drift.

1 Available at http://www.epa.gov/opp00001/factsheets/spraydrift.htmPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 26 of 58 

### 7.1 Residential Risk Estimates for Use in Aggregate Assessments

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

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

Lifestage Route of Exposure Residential Post

- application MOE

Short

- term Adult s N/A N/A Child 1 to <2 y ear s old Incidental oral from pet collar use 28000 Intermediate

- Term Adult s N/A N/A Child 1 to <2 y ear s old Incidental oral from pet collar use 9800 Long

- Term Adult s Dermal from pet collar use 8 30 Child 1 to <2 y ear s old Dermal + Incidental oral from pet collar use 320

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



### 7.0 A ggregate 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 f rom 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 duratio n of exposure. There are previously registered residential uses of pyriproxyfen ; therefore

, aggregate risks need to be assessed. The aggregate risks for pyriproxyfen are not of concern.

7.1 Short

- Term Aggregate Risk

In aggregating short

- term risk, HED considered background chronic

- dietary exposure (food + drinking water) and short

- term, residential non

- dietary oral exposures (hand

- to

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

- carpet powde r and pet shampoo). Since HED did not select a short

- term dermal endpoint, a dermal

exposure assessment is not included in the short

- term aggregate assessment. The total short

- term dietary and residential aggregate (incidental oral) MOE is 2 2 00. As this MOE is greater than 100, the short

- term aggregate risk does not exceed HED’s level of concern. Table 7.1. 1 summarizes the short

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

years o ld which is the highest

- risk population subgroup (lowest MOE > 100).Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 27 of 58 Table 7.1.1 Short

- Term Term Aggregate Risk Calculations

Population P et C ollar U se

LOC for Aggregate Risk 1 Dietary

MOE 2 MOE Oral

Residential Exposure 3 MOE

Dermal Residential Exposure 4 MOE

Inhalation Residential Exposure 5 Aggregate

MOE (food, water, and residential) 6

Children 1 to < 2

y ear s old 100 2350 28 000 NA NA 2 2 00

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

- species)

2 MOE dietary = [(short

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

3 MOE oral = [(short

- term oral NOAEL)/(hand

- to

- mouth residential exposure)]. Oral study NOAEL= 100 mg/kg/day. (MOE from Table 6.4.1 ).

4 MOE dermal = Not applicable

5 MOE inhalation = Not applicable

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



### 7.2 Intermediate

- Term Aggregate Risk

In aggregating intermediate

- term risk, HED considered background chronic dietary exposure (food + drinking water) and intermediate

- term, residential non

- dietary oral exposures (by toddlers following flea and tick c ontrol 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 in termediate

- term aggregate assessment. The total intermediate

- term dietary and residential aggregate MOE is 7 6 0. As this MOE is greater than 100, the chronic aggregate risk does not exceed HED’s level of concern. Table 7. 2.1 summarizes the intermediate

- t erm aggregate exposure to pyriproxyfen residues for Children 1 to < 2 years o ld which is the highest

- risk population subgroup (lowest MOE > 100).

Table 7. 2.1. Intermediate

- Term Term Aggregate Risk Calculations

Population P et C ollar U se

LOC for Aggregate Risk 1 Dietary

MOE 2 MOE Oral

Residential Exposure 3 MOE

Dermal Residential Exposure 4 MOE

Inhalation Residential Exposure 5 Aggregate

MOE (food, water, and residential) 6

Children 1 to < 2

y ear s old 100 825 9800 NA NA 7 6 0

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

- species)

2 MOE dietary = [(intermediate

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

3 MOE oral = [(intermediate

- term oral NOAEL)/(hand

- to

- mouth residential exposure)]. Oral study NOAE L= 35.1 mg/kg/day. (MOE from Table 6.4.1 ).

4 MOE dermal = Not applicable

5 MOE inhalation = Not applicable

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



### 7.3 Long

- Term Aggregate Risk

In aggregating chronic risk, HED considered background chronic dietary exposure (food + drinking water) and long

- term, residential non

- dietary oral and dermal exposures (by toddlersPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 28 of 58 

### following flea and tick control applications around the home and on pets f or 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

- ap plication 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 aggregat e MOE is 2 3 0. As this MOE is greater than 100, the chronic aggregate risk does not exceed HED’s level of concern. Table 7. 3.1 summarizes the chronic aggregate exposure to pyriproxyfen residues for Children 1 to < 2 years o ld which is the highest

risk popu lation subgroup (lowest MOE > 100).

Table 7. 3.1. Long

- Term Term Aggregate Risk Calculations

Population P et C ollar U se

LOC for Aggregate Risk 1 Dietary

MOE 2 MOE Oral

Residential Exposure 3 MOE

Dermal Residential Exposure 4 MOE

Inhalation Residential Exposure 5 Aggregate

MOE (food, water, and residential) 6

Children 1 to < 2

y ear s old 100 825 9800 330 NA 2 3 0

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

- species)

2 MOE dietary = [(long

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

3 MOE oral = [(long

- term oral NOAEL)/(long

- term incidental oral exposure)]. Oral study NOAEL= 35.1 mg/kg/day. (MOE from Table 6.4.1 ).

4 MOE dermal = [(long

- term dermal NOAEL)/(long

- term dermal4 exposure)]. Oral study NOAEL= 35.1 mg/kg/day. (MOE from Table 6.4.1).

5 MOE inhalation = Not applicable

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



### 8.0 C umulative Risk

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

o r revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to pyriproxyfen and any other substances, and pyriproxyfen does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that pyriproxyfen has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to dete rmine 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 cumul ating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

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

Page 29 of 58 

### 9.0 O ccupational Exposure and Risk Characterization

The proposed use of pyriproxyfen is on tea grown in Japan. There are no occupational exposure scenarios associated with the proposed tolerance increase and an occupational exposure and risk characterization is not required.

10.0 R eferences

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

- treated Tea. Summary of Analytical Chemistry and Residue Data . B. Cropp

- Kohlligian, D 426704

, 9/ 8 / 20 15

Pyriproxyfen. Chronic Dietary (Food and Drink ing Water) Exposure Assessment for the Petition to Increase the Established Tolerance in/on Tea with a U.S. Registration for Imported Pyriproxyfen

- treated Tea . B. Cropp

Kohlligian, D 427113

, 9/8/ 20 15

Pyriproxyfen: Occupational and Residential Assessment to Support the New Use on the Herb Subgroup 19A and the Expansion of Existing Crop Group Uses to Numerous Crop Subgroups. I. Nieves, D404203, 8/22/2012

Tier I Drinking Water Assessment for New Use of Insect Growth Inhibitor 2

- [1

- methyl

- 2

- (4

- phenoxypheno xy)ethoxy]pyridine Pyriproxyfen on Herb Subgroup 19A

. J. Hetrick, D397089, 7/25/2012

Pyriproxyfen. Results of the Metabolism Assessment Review Committee Meeting Held on 10

- Nov

- 1998

. W. Donovan and W. Dykstra, D250953, 11/ 19/1998Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 30 of 58 

### Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.500) for food use for pyriproxyfen are in Table A. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used

.

Table A.1. Guideline Data Requirements

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

................................ ..................... yes yes yes yes yes yes yes

yes yes yes yes yes
870.3100 Oral Subchronic (rodent)

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

................................ ......... 870.3200 28

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes yes yes

no

no yes

yes yes

no yes
870.3700 Developmental Toxicity (rodent)

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

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

................................ ................................ . yes yes yes yes

yes yes
870.4100 Chronic Toxicity (rodent)

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

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

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

................................ .................... yes yes yes yes yes

yes yes yes
870.5100 Mutagenicity

— Bacterial reverse mutation assay

.................... 870.5300 Mutagenicity

— gene mutation test

- mammalian

...................... 870.53xx Mutagenicity

— chromosome aberration test

.......................... 870.53xx Mutagenicity

— other

................................ ..................... yes yes yes yes yes

yes yes yes 870.6100 Acute Delayed Neurotoxicity (hen)

................................ 870.6100 90

- Day Neurotoxicity (hen)

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

.................. 870.6200 90

- Day Neurotoxicity Screening Battery (rat)

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

................................ ....... no

no yes yes

no no

no yes yes

no
870.7485 General Metabolism

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

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

................................ ............................. yes

no yes yes

no yesPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 31 of 58 

### A. 2 Toxic ity Profiles

Table A.2.1. Acute Toxicity Profile

- Pyriproxyfen

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

870.1100 Acute Oral 42178302 LD50 > 5,000 mg/kg IV

870.1200 Acute Dermal 42178303 LD50 > 2000 mg/kg III

870.1300 Acute Inhalation 42178304 LC50 > 1.3 mg/L III

870.2400 Primary Eye Irritation 42178305 mild irritation IV

870.2500 Primary Skin Irritation 42178306 non

- irritating IV

870.2600 Dermal Sensitization 42178307 not dermal sensitizerPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 32 of 58 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Pyriproxyfen

Guideline No./ Study Type/Animal Species and Strain MRID No. or Study Authors

(year)/ Classification /Doses Results

870.3100

90

- Day oral toxicity rodents (mouse) 43210504 (1990).

Acceptable/guideline

0, 200, 1000, 5000 or 10000 ppm (diet)

M: 0, 28.2, 149.4, 838.1 or 2034.5 mg/kg/day F: 0, 37.9, 196.5, 963.9 or 2345.3 mg/kg/day NOAEL = 149.4 mg/kg/day in males, 196.5 mg/k g/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 ga in (M)

870.3100

90

- Day oral toxicity rodents (rat) 41321716 (1989)

Acceptable/guideline

0, 400, 2000, 5000 or 10000 ppm (diet)

M: 0, 23.49, 117.79, 309.05 or 641.81 mg/kg/day F: 0, 27.68, 141.28, 356.30 or 783.96 mg/kg/day NOAEL = 23.49 mg/kg/day in males, 27.68 mg/kg/day in females LOAEL = 117.79 mg/kg/day in males, 141.28 based on increased total cholesterol and phospholipids (M),decreased red blood cell, hematocrit, and hemoglobin counts, increased relative (to body) liver weight (M), and negative trend in red blood cell volume (F)

870.3150

90

- Day oral toxicity

non

- rodents (dog) 42178307 (1988)

Acceptable/guideline

0, 100, 300 or 1000 mg/kg/day (capsule) NOAEL = 100 mg/kg/day in males and females LOAEL = 300 mg/kg/day in males and females based on increased absolute and relative (to body) liver weight (bot h sexes) and hepatocyte enlargement (F)

870.3200

21

- Day dermal toxicity(rat) 43994102 (1993)

Acceptable/guideline

0, 100, 300 or 1000 mg/kg/day NOAEL = 1000 mg/kg/day (males and females). LOAEL not established.

870.3200

21

- Day dermal toxicity(rat) 44037205 (1996)

Acceptable/guideline

0, 100, 300 or 1000 mg/kg/day Systemic NOAEL = 1000 mg/kg/day (M&F). LOAEL not established.

Dermal NOAEL = 300 mg/kg/day. LOAEL = 1000 mg/kg/day based on dermal irritation including acanthosis, dermal lymphoid cell infiltrate and dermal hemorrhage (M&F).Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 33 of 58 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Pyriproxyfen

Guideline No./ Study Type/Animal Species and Strain MRID No. or Study Authors

(year)/ Classification /Doses Results

870.3265

28

- Day inhalation toxicity (rat) 42178308 (1988)

Supplementary

0, 269, 482 or 1000 mg/m 3 0, 0 .269, 0.482 or 1.000 mg/L NOAEL = 0.482 mg/L (males and females) LOAEL = 1.000 mg/L based on salivation (both sexes), sporadic decreased body weight gain (M), and increased lactate dehydrogenase (M). Decreases in actual body weights were not observed. These minor changes are not considered biologically relevant.

870.3700a

Prenatal developmental (rat) 44985002 (1988)

Acceptable/non

- guideline

0, 100, 300, 500 or 1000 mg/kg/day via gavage Parental NOAEL = 100 mg/kg/day. LOAEL = 300 mg/kg/day base d on clinical signs, decreased body weight gains, increased water consumption (both sexes) and increased food consumption, changes in organ weights, and gross pathological changes (M)

Developmental NOAEL = 1,000 mg/kg/day (HDT)
870.3700b

Prenatal developmental (rabbit) 41321720, 42178311,

43215401, 43215402, 43215403 (1989)

Acceptable/guideline

0, 100, 300 or 1000 mg/kg/day via gavage Maternal NOAEL = 100 mg/kg/day. LOAEL = 300 mg/kg/day based on premature delivery/abortions, soft stools, emac iation, 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/gu ideline

0, 100, 300 or 1000 mg/kg/day via gavage Maternal NOAEL = 100 mg/kg/day. LOAEL = 300 mg/kg/day based on decreased body weight, body weight gain, and food consumption and increased water consumption.

Developmental NOAEL = 300 mg/kg/day. LOAEL = 1,000 mg/kg/day based on increased incidence of skeletal variations at gestation day 21 and unspecified visceral variations at post

- natal day (PND) 56.
870.3800

Reproduction and fertility effects (rat) 42178313 (1991)

Acceptable/guideline

0, 200, 1000, or 5000 ppm (diet)

M: 0, 18, 87, or 453 mg/kg/day F: 0, 20, 96, or 498 mg/kg/day Parental/Systemic NOAEL = 87 mg/kg/day in males, 96 mg/kg/day in females. LOAEL = 453 mg/kg/day in males, 498 mg/kg/day in females based on decreased body we ight, body weight gain, and fo od consumption (both sexes), increased absolute and relative liver weight (both sexes) , increased relative kidney weight in males and histopath lesions of kidney (chronic interstitial nephritis) and liver (clear cell focus associated with pale area at fissure of medium lobe) in males

.
Reproductive NOAEL > 453 mg/kg/day in males, 498 mg/kg/day in females. LOAEL not established

.
Offspring NOAEL = 87 mg/kg/day in males, 96 mg/kg/day in females. LOAEL = 453 mg/kg/day inPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 34 of 58 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Pyriproxyfen

Guideline No./ Study Type/Animal Species and Strain MRID No. or Study Authors

(year)/ Classification /Doses Results

males, 498 mg/kg/day in females based on decreased body weight on lactation days 14 and 21.
870.3800

Reproduction and fertility effects (rat) 44985001 (1988)

Acceptable/non

- guideline

0, 30, 100, 300, or 500 mg/kg/day via gavage Maternal NOAEL = 1 00 mg/kg/day. LOAEL = 300 mg/kg/day based on clinical signs, decreased body weight gains, and decreased food consumption.

Offspring NOAEL = 100 mg/kg/day. LOAEL = 300 mg/kg/day based on decreased body weight and increased incidence of dilation of the ren al pelvis.
870.4100b

Chronic toxicity (dog) 42178309 (1991)

Acceptable/guideline

0, 30, 100, 300 or 1000 mg/kg/day (capsule) NOAEL = 100 mg/kg/day in males and females LOAEL = 300 mg/kg/day in males and females based on decreased body weight gain and increased relative liver weight (both sexes) and increased cholesterol and triglycerides and decreased red cell counts and hemoglobin in males
870.4300

Chronic/Carcinogenic ity (rat ) 42178314, 43210501,

43210502, 43210503 (1991)

Acceptable/guideline

0, 120, 600 or 3000 ppm (diet)

M: 0, 5.42, 27.31 or 138.0 mg/kg/day F: 0, 7.04, 35.1 or 182.7 mg/kg/day NOAEL = 138 mg/kg/day in males, 35.1 mg/kg/day in females LOAEL not established in males, 182.7 mg/kg/day in females based on decreases in body weight gain. No evidence of carcinogenicity

870.4200

Carcinogenicity (mouse) 42178310 (1991)

Acceptable/guideline

0, 120, 600 or 3000 ppm (diet)

M: 0, 16.8, 84.0, or 420 mg/kg/day F: 0, 21.9, 109.5, or 547 mg/kg/day NOAEL = 84 mg/kg/day in males, 109.5 mg/kg/day in females LOAEL = 420 mg/kg/day in males, 547 mg/kg/day in females based on renal lesions in males and females. No evidence of carcinogenicity

870.5100

Bacterial Reverse Mutation Test 44503506 (1995)

Acceptable/guideline

Tested up to 5000 ug/plate or cytotoxic levels, in presence and absence of activation, in S. typhimurium strains TA98, TA100, TA1535 and T A1537 and E.coli strain WP2uvra Non

- mutagenic with 2

- OH

- PY (metabolite of pyriproxyfen).Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 35 of 58 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Pyriproxyfen

Guideline No./ Study Type/Animal Species and Strain MRID No. or Study Authors

(year)/ Classification /Doses Results

870.5100

Bacterial Reverse Mutation Test 44503507 (1993)

Acceptable/guideline

Tested up to 5000 ug/plate or cytotoxic levels, in presence and absence of activation, in S. typhimurium strains TA98, TA100, TA1535 and TA1537 and E.coli strain WP2uvra Non

- mutagenic with 4'

- OH

- PY, 5"

- OH

- PYR, DPH

PYR, POPA, and PYPAC (metabolites of pyri proxyfen).

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.

t yphimurium strains TA98, TA100, TA1535, TA1537, and TA1538 and E.coli strain WP2uvra Non

- mutagenic with or without metabolic activation.

870.5300

In vitro Mammalian Cell Gene Mutation
Test 42178316 (1990)

Acceptable/guideline

Chinese hamster lung V79 cells tested up to cytotoxic concentrations or limit of solubility, in presence and absence of activation. Non

- mutagenic at the HGPRT locusPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 36 of 58 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Pyriproxyfen

Guideline No./ Study Type/Animal Species and Strain MRID No. or Study Authors

(year)/ Classification /Doses Results

870.5375

In vitro Mammalian Chromosome Aberration Test (August 1998) 41321722 (1989)

Acceptable/guideline

Chinese hamster ovary (CHO) cell cultures in the absence or presence of activation. Negative. Did not induce structural chromosome aberrations

870.5550

Unscheduled DNA Synthesis in Mammalian Cells in Culture 42178317 (1988)

Acceptable/guideline

HeLa cells exposed up to cytotoxic levels, both in the presence or absence of S

- 9. Negative. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures (nuclear silver grain counts) was indu ced

870.6200a

Neurotoxicity screening battery

- Acute neurotoxicity (rat)

Crl:CD(SD) rats 48711901, 48711903,

48711904 (2011)

Acceptable /guideline

0, 300, 1000 or 2000 mg/kg via gavage The NOAEL is 1000 mg/kg bw/day. T he LOAEL was 2000 mg/kg bw/day, based on deceases in motor activity on Day 0 in males and unkempt appearance in females.

870.6200b

Neurotoxicity screening battery

- Subchronic neurotoxicity (rat)

Crl:CD(SD) rats 48711901, 48711902,

48711905 (2011)

Acceptable /guideline

0,1500, 5000, or 15,000 ppm via diet M: 0, 108, 359, 1111 mg/kg/day F: 0, 102, 407, 1212 mg/kg/day Neurotoxicity. NOAEL = 15,000 ppm ( 1111 mg/kg/day for males and 1212 mg/kg/day for females). The LOAEL for neurotoxicity was not observed.

Systemic toxicity. NOAEL = 5000 ppm ( 359 mg/kg/day for males and 407 mg/kg/day for females). The LOAEL was 15,000 ppm (1111 mg/kg/day for males and 1212 mg/kg/day females) based on lower mean body weights, body weight gains, and food consumption for both sexes.

8 70.7485

Metabolism and pharmacokinetics (rat) 42178318 (1988)

42201402 (1988) 44036914 (1993) Acceptable/guideline 42178318: The major routes of excretion of radioactivity were via the urine and feces. The excretion of radioactivity into urine and feces was rapid and over a 7

- day period, most (92

- 97%) of the test compound administered was excreted in the urine (5

- 12%) and feces (81

- 92%) from the animals. Most (63

- 83%) of the dose was eliminated in the urine and feces within 24 hours after dosing. Expired air was not detected. Radioactivity in tissue residues was very low in all tissues expect the fat. Recoveries of the administer ed doses in the tissues including carcass were not more than 0.3% indicating that the potential for bioaccumulation of sumilarv is minimal even after high dose or repeated low dose exposures. In the urine,Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 37 of 58 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Pyriproxyfen

Guideline No./ Study Type/Animal Species and Strain MRID No. or Study Authors

(year)/ Classification /Doses Results

a total of 11 metabolites were detected and two of them (4’

- OH

- 31183 sulfate and 4’

- OH

- POP sulfate) were identified. In the feces, an unmetabolized sumi l a rv (7

- 37% of the dose) and a total of up to 17 metabolites were detected and 10 of them (6 unconjugated and 4 sulfate conjugates) were identified. The f our major fecal metabolites were 4’

- OH

- 31183, 4’

- OH

- 31183 sulfate, 5, 4’

- OH

- 31183 sulfate, and 4’

- OH

- POPA. The metabolites in the liver, kidney, blood, bile, and fat of rats were also examined. Based on the metabolites identified by TLC cochromotography wi th synthetic standards the major biotransformation reactions of sumilarv include: 1) Oxidation at 4’

- postion, of the terminal phenyl group; 2) Oxidation at 5

- psition of pyridine; 3) Cleavage of the ether linkage and conjugation of the resultant phenols wit h sulfuric acid. No significant sex

- or dose

- related differences exist in the absorption, distribution, or metabolism of sumilarv for all dosing regimens.

44036914: Absorption was nearly identical in males and females provided a single oral dose of 2 mg/kg (low dose) or 1000 mg/kg (high dose). Based on urine concentration pyriproxyfen was not easily absorbed (<12%) and was excreted rapidly (88.9

– 92.9% within 2 days). Excretion was near complete (92.3

- 98.5%) after 7 days despite a dip in the rate of elimination after the second day. Fecal excretion was the dominant elimination pathway after both low (86.1

– 93.2%) and high dose (84.7

– 89%) exposures. Urine excretion was minor compared to fecal elimination, but was more prominent in the high dose (7 .5

– 11.8%) than in low dose (4.9

– 5.7%). Release of pyriproxyfen in expired air was not a significant ( < 0.5%). Metabolism was affected both by dose and the sex of the animal. Feces contained ten metabolites whereas the urine only contained three. Parent compound was identified in both forms of excreta. Metabolism was more extensive in females with only 21.2

– 21.9% of the parent compound remaining in the excreta compared to 32.5

– 34.8% in males. Metabolism of pyriproxyfen occurred primarily through hydr oxylation at the 4’

- position of the terminal phenyl ring.

Metabolism via this pathway was utilized more in females (49.3

– 53.6%) than in males (32.1

– 43.3%) regardless of dose. Hydroxylation at the 2’

- position of the phenyl ring was not as extensive, b ut was favored more at low dose (1.8

– 2.8%) than at the high dose (0.2%). Hydroxylation at the 5”

- position of pyridylPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 38 of 58 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Pyriproxyfen

Guideline No./ Study Type/Animal Species and Strain MRID No. or Study Authors

(year)/ Classification /Doses Results

ring, another minor pathway, was also more prevalent at the low dose (1.4

– 7.8% compared to 0.9

– 1.4% at the high dose). Unlike hydroxy lation of the phenyl ring, hydroxylation of the pyridyl ring was more prominent in males (1.4

– 7.8%) than in females (0.9

– 1.7%). Of the minor metabolic pathways, high dose animals preferred sulfuric acid conjugation accounting for 1.2

– 2.8% compared to 0.8

– 2.4% in low dose animals. Minor metabolites born from dephenylation (0.8

– 1.6%) and conjugation with glucuronic acid (0.2

– 11%) were comparable across sex and dose.

4’

- OH

- pyriproxyfen was the dominant fecal metabolite at both doses accounting fo r 23.3

– 38.4% in males and 46.4

– 47.2% in females. At the low dose other major metabolites were 5”,4’

- OH

- pyriproxyfen (7.2% in males and 1.2 % in females) and 2’

- OH

- pyriproxyfen (1.8% in males and 2.8% in females). At high doses these metabolites were no t as common, accounting for only 0.2

– 0.4% of the administered dose. Instead the major fecal metabolites were DPH

- pyriproxyfen and 4’

- OH

- pyriproxyfen

- sulfuric acid (combined 1.2

– 1.6%). Small quantities of these metabolites were present in low dose anima ls ( < 1.1%). The major urinary metabolite was PYPAC which accounted for 1

– 4.9%. The sulfuric acid conju gated compounds, 4’

- OH

- pyriproxy fen

- sulfur and 5”,4’

- OH

- pyriproxyfen

sulfur, were also present at much lower concentrations (0.1

– 0.8% of the administe red dose). Parent compound was only identified in urine of high dose animals (1.3% in males, and 2.7% in females). 4’

- OH

pyriproxyfen was also identified in the urine at 1% in males and 5.6% in females; however, this metabolite and the parent compound were not observed in the urine of all animals and it is hypothesized that these metabolites originated from feces contamination and would otherwise not be present in the urine.

No sex or dose related disparities were identified in the tissue distribution. Residual tissue concentration increased with dose but total accumulation never exceeded 0.3% of the administered dose 7 days after exposure. The residual carcass and fat were the primary sinks for pyriproxyfen amassing 0.065

– 0.148% and 0.024

– 0.042% of the administered dose, respectively. Minimal accumulation was observed in the liver (0.16

– 0.22%) and even less was present in the kidneys (0.002

– 0.003%). Between 0.006 and 0.013% was in circulation. The remaining tissues contained insignificant amounts of pyriproxyfen (<0.001%).Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 39 of 58 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Pyriproxyfen

Guideline No./ Study Type/Animal Species and Strain MRID No. or Study Authors

(year)/ Classification /Doses Results

870.7800

Immunotoxicity (mouse)

Female CD

- I mice 48711906, 48711907 (2012)

Acceptable/guideline

0, 1000, 2000, or 5000 ppm (0, 228, 449, 1139 mg/kg bw/day) via diet for 28 days The systemic toxicity LOAEL is 5000 ppm (1139 mg/kg/day), based on lower body weight gain and increase of absolute and relative body weight to liver weight . The NOAEL for systemic toxicity is 2000 ppm (449 mg/kg/day).

The LOAEL for immunotoxicity is not observed. The NOAEL for immunotoxicity is 5000 ppm (1139 mg/kg/day).Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 40 of 58 

### A.3 Toxicological Endpoints

A.3.1 Acute Reference Dose (aRfD)

- General Population (Including Infants and Children) and Females Age 13

- 49

An appropriate endpoint attributable to a single oral dose was not available in the data base, including developmental toxicity in the developmental toxicity studies. Acute toxicity in the ACN study was observed at doses that were not relevant to human exp osure (i.e. above the limit dose) and were not considered in selecting endpoints for acute dietary assessments.

A.3.2 Chronic Reference Dose (cRfD)

-

Study Selected : Subchronic toxicity and chronic toxicity (feeding)

- rat (co

- critical) MRID No. : 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic) Executive Summary : See Appendix A, Guideline [§ 870.3100 and 870.4100] Dose and Endpoint for Risk Assessment : NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 mg/kg/day based on decreased body weight gain, anemia, and increased relative liver weight with elevated cholesterol and phospholipid levels. Uncertainty Factors: 100

– 10x for interspecies variation and 10x for intraspecies variation, 1x FQPA SF Comments about Study/Endpoint : This endpo int from co

- critical studies is an appropriate endpoint of duration and provides the lowest NOAEL in the database for chronic effects via the oral route.

A.3.3 Incidental Oral Exposure (Short

- , Intermediate

- , and Long

- Term)

Short

- Term

Study Selected : Developmental

- rat MRID No. : 44985002 Executive Summary : See Appendix A, Guideline [§ 870.3 700a ] Dose and Endpoint for Risk Assessment : Parental NOAEL = 100 mg/kg/day, Parental LOAEL

= 300 mg/kg/day based on clinical signs, decreased body weight , body weight gain, and food consumption, and increased water consumption Uncertainty Factors: 100

– 10x for interspecies variation and 10x for intraspecies variation Comments about Study/Endpoint : Since there is no evidence in the database suggesting the young are more sensitive than adults, the endpoint derived from a maternal endpoint is appropriate for the incidental oral exposure of young children. The endpoint fr om the rat developmental study provides the highest NOAEL for the short

- term exposure assessment. Chronic RfD = 35.1 mg/kg/day = 0.35 mg/kg/day 100Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 41 of 58 

### Intermediate

- Term

Study Selected : Subchronic toxicity and chronic toxicity (feeding)

- rat (co

- critical) MRID No. : 41321716 (subchronic) 42178314, 4321050 1, 43210502, 43210503 (chronic) Executive Summary : See Appendix A, Guideline [§ 870.3100 and 870.4100] Dose and Endpoint for Risk Assessment : NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 mg/kg/day based on decreased body weight gain, anemia, and increased rela tive liver weight with elevated cholesterol and phospholipid levels. Uncertainty Factors: 100

– 10x for interspecies variation and 10x for intraspecies variation Comments about Study/Endpoint : Evaluation of effects across durations of exposure suggests toxicity increases with duration of exposure. Therefore the short exposure in the developmental study is not appropriate for assessing intermediate exposures. The endpoint from co

- critical studi es 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 intermediate

term dermal exposure a ssessments 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 estima ted 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/da y in the 21

- day dermal study. These studies were both in the rat and

app roximately the same duration in exposure.

A.3.5 Dermal Exposure (Short

- , Intermediate

- , and Long

- Term)

Short

- and Intermediate

- Term

Dermal toxicity in the 21

- day dermal rat toxicity study was only apparent at the limit dose and systemic toxicity was n ot observed up to the limit dose. There are no developmental susceptibility or neurotoxicity concerns from the oral database, therefore a quantitative dermal assessment is not warranted.

Long

- Term

Study Selected : Subchronic toxicity and chronic toxicity (feeding)

- rat (co

- critical) MRID No. : 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic) Executive Summary : See Appendix A, Guideline [§ 870.3100 and 870.4100] Dose and Endpoint for Risk Assessment : NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 mg/kg/day based on decreased body weight gain, anemia, and increased relative liver weight with elevated cholesterol and phospholipid levels. Uncertainty Factors: 100

– 10x for interspecies variation and 10x for intraspecies variationPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 42 of 58 

### Comments about Study/Endpoint : A long

- term dermal study is not available; therefore, an oral study was used to assess the long

- term dermal assessment. The combined chronic and subchro nic rat oral endpoints were selected because they were of appropriate duration to estimate long

- term
exposure. A dermal absorption factor of 30% was incorporated into the oral endpoints to approximate the dermal dose required to elicit similar effects (se e Appendix A.3.5 for more detailed explanation).

A.3.6 Inhalation Exposure

Short

- and Intermediate

- Term

The minor changes (salivation, sporadic decreased body weight gain, and increased lactate dehydrogenase) observed at the highest concentration test ed (1 mg/L) are not considered to be biologically relevant. There are no developmental susceptibility or neurotoxicity concerns from the oral database, therefore a quantitative inhalation assessment is not warranted.

Inhalation Exposure (Long Term)

Study Selected : Subchronic toxicity and chronic toxicity (feeding)

- rat (co

- critical) MRID No. : 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic) Executive Summary : See Appendix A, Guideline [§ 870.3100 and 870.4100] Dose and Endpoint fo r Risk Assessment : NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 mg/kg/day based on decreased body weight gain, anemia, and increased relative liver weight with elevated cholesterol and phospholipid levels. Uncertainty Factors: 100

– 10x for interspecies variati on and 10x for intraspecies variation Comments about Study/Endpoint : A long

- term inhalation study is not available. Therefore an oral study was used to assess the long

- term inhalation assessment. This oral endpoint from the

co

- critical studies is the lowest NOAEL in the database for chronic effects via the oral route. The inhalation absorption is assumed to be 100% since an oral study is being used for the assessment.

A.4 E xecutive Summaries

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

- Rat In a subchronic oral toxicity study (MRID 41321716), S

- 31183 (95.3% a.i., Lot # PYG

- 87074) was administered to Crl:CD BR rats at doses of 0, 400, 2000, 5000, and 10000 ppm (equivalent to 0, 23.49, 117.79, 309.05, and 641 .81 mg/kg/day in males and 0, 27.68, 141.28, 356.30, and 783.96 mg/kg/day in females) for 90 days.

The LOAEL for systemic toxicity was 2000 ppm (117.79 and 141.28 mg/kg/day in males and females, respectively) based on higher mean total cholesterol and pho spholipids, decreased mean red blood cell, hematocrit and hemoglobin counts, and significantly higher relative liver weight in male rats and a negative trend in mean red blood cell volume in females. The NOAEL for systemic toxicity in rats of either sex wa s 400 ppm (23.49 andPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 43 of 58 

### 27.68 mg/kg/day in males and females, respectively).

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a subchronic oral toxicity study in rats (870.3100; OECD 408).

87 0.3100 90

- Day Oral Tox icity

- Mouse When technical Sumilarv was administered to male and female CD

- I mice at dietary levels of 0, 200, 1000, 5000, or 10000 ppm (approximately mg/kg/day calculated equivalents: 0, 28.2, 149.4, 838.1, and 2034.5 for males, and 0, 37.9, 196.5, 963. 9, and 2345.4 for females), there was an increase in mortality in both sexes at the highest dose tested. In animals of both sexes that received the two highest doses, kidney lesions were present. Macroscopically, there was dilation of the renal pelvises, f

luid filled renal pelvises, unequal kidney sizes, cysts and paleness. Microscopically, there was nephrosis with renal tubular dilation and dilation and mineralization of the renal pelvises.

In addition to these effects, there was a decrease in body weight gain in males at the two highest dose levels, significant decrease in red blood cells, hemoglobin, hematocrit, MCV and MCH, and increased liver to body weight ratios. Females at the 5000 ppm dose level had significant decreases in red blood cells, hemoglo bin, and hematocrit, significantly increased liver weights, and significantly increased liver to body weight ratios. At 10000 ppm there was only one surviving female; therefore, the numbers were not sufficient for evaluation.

The LOAEL was 5000 ppm (838.1 and 963.9 mg/kg/day in males and females, respectively) based on renal pathology, statistically significant increases in liver weights and in liver:body weight ratios, and statistically significant decreases in red blood cell parameters and in body weight gain in males. The NOAEL was 1000 ppm (149.4 and 196.5 mg/kg/day in males and females, respectively)

.
The kidney pathology was not associated with any clinical findings. Urinalysis was unremarkable. With regard to serum chem istry, of the parameters that could be correlated with renal disease, only the blood urea nitrogen (BUN) was elevated in both sexes at 5000 ppm. No similar elevations in BUN were reported in the three surviving males and in the one surviving female at 1000 0 ppm.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a subchronic oral toxicity study in mice (870.3100; OECD 408).

870.3150 90

- Day Oral Toxicity

- Dog In a subchronic toxicity study (MRID 42178307), S

- 31183 (97.2% a.i., Lot# PTG

- 86011) was administered in gelatin capsules to 4 beagle/sex at doses of 0, 30, 100, 300, and 1000 mg/kg/day for 90 days



### .
The LOAEL was 300 mg/kg/day, based on significantly higher absolute liver weights and liver

- to

- body weight ratios in the males, and enlargement of hepatocytes observed in females at that concentration, compared with dogs on the control diet. The NOAEL was 100 mg/kg/day

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

Page 44 of 58 

### The changes in liver weights, organ

- to

- body weight ratios, and increase in size observed in the hepatocytes at 300 mg/kg/day are probably not due to hepatotoxicity, however; rather, these changes appear to be adaptations of liver to detoxi fying the test substance, since these changes are observed in both groups at the highest dose tested.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a subchronic oral toxicity study in non

- rodents (870.3150; OECD 409).

870.3200 21

- Day Dermal Toxicity

– Rat

In a repeated dose dermal toxicity study (MRID 44037205), pyriproxyfen (V071639) 0.83EC (11.1% a.i., Lot #SF05L41, Batch #VS

- 18B

- 43) was applied to the shaved skin of five Sprague Dawley

- derived [CD

- Crl:C D(SD)BR] rats/sex/dose at dose levels of 0, 100, 300, or 1000 mg/kg/day for 6 hours/day, 5 days/week, for 3 weeks.

Rats in the 1000 mg/kg/day treatment group exhibited higher frequencies and more severe irritation of the treated skin than the control grou p rats. Symptoms of dermal irritation included moderate/marked epidermal acanthosis (5/5 males v. in controls), slight dermal lymphoid cell infiltrate (5/5 males, 2/5 females), and dermal hemorrhage (2/5 males, 3/5 females). Dermal irritation observed in t he rats in the 100 or 300 mg/kg/day treatment groups were comparable to that observed in the controls. No systemic responses were observed. For all treatment groups, body weights, and body weight gains, and mean food consumption values were similar to the controls. There were not treatment

- related differences in findings, organ weight, or macroscopic or microscopic organ morphology between rats in the treated and control groups.

The dermal LOAEL for this study is 1000 mg/kg/day, based on the presence of tr eatment

related dermal irritation in the treated skin of rats in this treatment group. The NOAEL is 300 mg/kg/day.

The systemic LOAEL was not established. The systemic NOAEL was 1000 mg/kg/day. This study is classified Acceptable and satisfies the guideline requirement for a subchronic inhalation study (OCSPP 870.3200, OECD 410)

870.3465 28

- Day Inhalation

– Rat

In a 28

- day inhalation study (MRID 42178308), groups of male and female Sprague

- Dawley rats were exposed via inhalatio n at concentrations of 0, 269, 482, or 1000 mg/m3 for 4 hours/day for 28 days.

The LOAEL was 1000 mg/m 3 

### based on increased salivation. Sporadic decrease in body weight were also reported and a statistically significant increase was also reported in the lactate dehydrogenase (LDH) level. This increase was not considered biologically relevant. The NOAEL was 482 mg/m 3 

### (equivalent to 138 and 162 mg/kg/day in males and females respectively).

This study is classified Acceptable and satisfies the guideline requirement for a subchronicPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 45 of 58 

### inhalation study (OCSPP 870.3200, OECD 413)

A.4.2 Prenatal Developmental Toxic ity

870.3700a Prenatal Developmental Toxicity Study

– Rat

In a developmental toxicity study (MRID 42178312, 41321719), pyriproxyfen technical (97.2% purity) was administered to groups of 36 pregnant Sprague

- Dawley rats/ dose by gavage at dose levels of 0, 100, 300, or 1000 mg/kg/day from days 7 through 17 of gestation in a volume of 5ml/kg of corn oil. The study was conducted in two segments. In one, the dams were killed on gestation day 21 and fetuses were evaluated. In the other, the dams delivered na turally and pups were weaned at postnatal day 21. Pups were killed serially at postnatal day 21 (after assessment of reflexes and sensory response), at 8 weeks of age (following open field testing, rotor testing, and examination of learning ability in a wa ter maze), or after assessment of reproductive performance.

The maternal NOAEL was 100 mg/kg/day, based on decreased body weight, body weight gain, and food consumption, and increased water consumption at the LOAEL of 300 mg/kg/day. At 1000 mg/kg/day, i ncreased incidences of mortality and clinical signs were also observed.

The developmental NOAEL was 300 mg/kg/day, based upon an increased incidence of fetuses with poorly ossified sternebrae (6 fetuses from 4 litters v. 2 fetuses from 2 litters in the c ontrol), opening of foramen transversarium of the 7 th 

### cervical vertebrae (22 fetuses from 11 litters v. 0 fetuses in the control), and total number of skeletal variations (37 fetuses from 17 litters v. 14 fetuses from 10 litters in the control) at gestatio n day 21 and renal pelvis dilation (7 young from 6 litters v. 0 young in the control) at postnatal day 56 at the developmental LOAEL of 1000 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a prenata l developmental toxicity study in rats (870.3700a; OECD 414).

870.3700b Prenatal Developmental Toxicity Study

- Rabbit

A prenatal developmental toxicity study (MRID 42178311, 43215401, 43215402, 41321720) was conducted in pregnant JW

- NIBS rabbits, in wh ich pyriproxyfen (97.2% a.i.) was administered by gavage at doses of 100, 300, or 1000 mg/kg/day in distilled water on gestation days 6

- 18.

The maternal NOAEL was 100 mg/kg/day. The maternal LOAEL was 300 mg/kg/day, based on occurrence of premature deliv ery/abortions, soft stools, emaciation, lusterless fur, decreased activity, and bradypnea/deep breathing. At 1000 mg/kg/day, these signs increased in incidence and frequency.

The developmental NOAEL was 300 mg/kg/day, based on decreased viable litters av ailable for examinations at the LOAEL of 1000 mg/kg/day.Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 46 of 58 

### This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a prenatal developmental toxicity study in rabbits (870.3700b; OECD 414).

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

- Rat

In a two

- generation reproduction study (MRID 42178313), pyriproxyfen (95.3% purity) was administered to 26 Sprague

- Dawley rats/sex/dose at dietary levels of 0, 200, 1000, or 5000 ppm (18, 87, or 453 mg/kg /day for males and 20, 96, or 498 mg/kg/day for females) for one litter per generation.

The parental LOAEL was 5000 ( 453 mg/kg/day in males, 498 mg/kg/day in females), based on decreased body weight, body weight gain, and food consumption (both sexes) and increased liver weight in the F1 males and females, and histopathological lesions of liver and kidneys of F1 males. The parental NOAEL was 1000 ppm ( 87 mg/kg/day in males, 96 mg/kg/day in females).

The reproductive NOAEL > 5000 ppm ( 453 mg/kg/day in males, 498 mg/kg/day in females). The reproductive LOAEL was not established

.
The offspring LOAEL was 5000 ppm ( 453 mg/kg/d ay in males, 498 mg/kg/day in females) based on decreased body weight on lactation days 14 and 21 in F1 and F2 pups. The offspring NOAEL was 1000 ppm ( 87 mg/kg/day in males, 96 mg/kg/day in females).

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a reproductive toxicity study in rats (870.3800; OECD 416).

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat

In a chronic toxicity/carcinogenicity study (MRID 42178314, 43210501) groups of male and female Sprague

- Dawley rats were fed diets containing technical pyriproxyfen at doses of 0, 120, 600, or 3000 ppm (equivalent to 0, 5.42, 27.31, or 138 mg/kg/day in males and 0, 7.04, 35.1, or 182.7 mg/kg/day in females) for 104 weeks.

The LOAEL f

or females was 3000 ppm (182.7 mg/kg/day) based on a 16.9% decrease in body weight gain in females compared to controls while a LOAEL was not established for males. The NOAEL for females was 600 ppm (35.1 mg/kg/day) and the NOAEL for males was >3000 ppm ( 138 mg/kg/day).

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a chronic toxicity/carcinogenicity study in rats (870.4100a/870.4200a; OECD 452/451).Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

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### 870.4100b Chronic Toxicity

- Dog

In a chronic toxicity s tudy (MRID 42178309), S

- 31183 (94.4% a.i., Lot# 87074) was administered in gelatin capsules to 4 beagle/sex at doses of 0, 30, 100, 300, and 1000 mg/kg/day for approximately one year.

In males receiving 300 mg/kg/day there was also significant increases i n cholesterol levels throughout the study and increases in triglyceride levels at week 50. Mild anemia was also present in males at this dose level and was characterized by significant decrease in hemoglobin and red cell count when compared to controls

.
At 1000 mg/kg, death was reported in two of the four males and was attributed to hepatic failure. In the remaining males, there was as significant increase in prothrombin time, and in both sexes there were increases in hepatic enzyme levels and gross and m icroscopic hepatic lesions. Decreases in body weight gain were also reported for both sexes and there was an increase in relative and absolute liver weights at the high dose level.

The LOAEL was 300 mg/kg/day based on statistically and biologically signif icant decreases in body weight gain and increases in relative liver weights in both sexes. The NOAEL was 100 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a chronic toxicity study in nonrodents (8 70.4100b; OECD 452).

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study

- rat

See executive summary for 870.4100a.

870.4200b Carcinogenicity (feeding)

- Mouse

In a carcinogen i city study in mice (MRID 42178310), technical pyriproxyfen (95.3%) was administered by diet to randomized groups of 50/sex/dose male and female CD

- 1 mice at levels of 0,120, 600, and 3000 ppm (16.8, 84.0, and 420 mg/kg/day in males and 21.0, 109.5, and 547 mg/kg/day in females) for 78 weeks. There was no increased tumor incidence in either sex that could be attributed to the test material.

The LOAEL for systemic effects in both sexes was 3000 ppm (420 and 547 mg/kg/day in males and females, respectively) based on renal lesions in both sexes. The NOAEL for systemic effects in both sexes was 600 ppm (84.0 and 109.5 mg/kg/day in males and females, respectively).

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a

ca rcinogenicity study in mice (870.4200b; OECD 451).Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

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### A.4.6 Mutagenicity

Gene Mutation
Guideline 870.5100, Gene Mutation MRID 44503506, 44503507, 44503508, 42178315 Acceptable Neither pyriproxyfen nor its metabolites induced mutations in S. typhimurium and E. coli at concentrations up to 5000 ug/plate in either presence or absence of metabolic activation

Cytogenetics
Guideline 870.5300, Mammalian gene mutation

assay MRID 42178316 Acceptable Negative for mutagenic response up to cytotoxic levels or insoluble concentrations both in the absence and presence of metabolic activation

Chromosome aberrations
Guideline 870.5375, Chromosome aberrations MRID 41321722 Acceptable Pyriproxyfen is not clastogenic in either presence or absence of metabolic activation

Unscheduled DNA Synthesis
Guideline 870.5550, Unscheduled DNA synthesis MRID 42178317 Acceptable Negative for a positive genotoxic responses

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study

- Hen

Not required

870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID # 48711904 ) , groups of non

- fasted

, 6 weeks old Crl:CD(SD) rats , 12/sex/dose were given a single oral dose of Pyriproxyfen T.G. (99.5%, Lot # 080506G) in corn oil at doses of 0, 300, 10 00 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 si tu for neuropathological examination. Of the perfused animals,Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

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### 6/sex/group from both controls and 2000 mg/kg were subjected to histopathological evaluation of brain and peripheral nervous system tissues.

A test substance

- related unkempt appearance was noted for one male and six females in the 2000 mg/kg group at the detailed physical examination. There were no treatment related effects on mortality, body weight, brain weight or gross and histologic pathology, neu ropathology 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 ac tivity 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 c ounts for males of both groups were unaffected by test substance.

No microscopic effects supportive of clinical signs or changes in motor activity were observed, indicating that these effects could be due to either general malaise or transient changes in neural activity.

Based on the effects seen in this study, the LOAEL was 2000 mg/kg bw/day based on deceases in motor activity on Day 0 in males and unkempt appearance in females. The NOAEL is 1000 mg/kg bw/day.

This neurotoxicity study is classified as Acceptable/Guideline and satisfies the guideline requirement for an acute neurotoxicity study in rats (870.6200; OECD 424).

870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity study (MRID # 48711905), Pyriproxyfen T.G. ( 99.5% a.i, Lot # 080506G) was administered to 12 Crl:CD(SD) rats/sex/group at dose levels of 0,1500, 5000, or 15,000 ppm (equivalent to 0, 108, 359, 1111 mg/kg bw/day for males and 0, 102, 407, 1212 mg/kg bw/day for females) for 13 weeks.

Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in12 animals/sex/group at pretest (study week

- 1), study weeks 1, 3, 7, and 12, respectively . At study termination, 6 animals/sex/group were euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 6/sex/group from both control and 15,000 ppm group were subjected to histopathological evaluation of brain and peripheral nervous system tissues.

Homogeneity

, stability, and concentration of the test substance in the diet were within the acceptable range of the performing laboratory. There were no test substance

- related clinical findings noted at any concentration and all animals survived to the scheduled necropsy on Study Day 91. In the 15,000 ppm group, significantly (p<0.01) lower mean body weight gains were noted during Study Days 0

- 14 and 0

- 7 for the males and females, respectively. Mean body weig ht 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 inPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 50 of 58 

### 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 treat ment 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 administrati on. 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 N OAEL of 5000 ppm (359 mg/kg/day for males and 407 mg/kg/day for females).

The study is classified as Acceptable/Guideline and satisfies the guideline requirement for a subchronic neurotoxicity study in rats (870.6200b).

870.6300 Developmental Neurotox icity Study

Not required

A.4.8 Metabolism

870.7485 Metabolism

- Rat

In a metabolism study (MRID 42178318 and 42201402) r ats were dosed with 14 

### C labeled sumilarv at oral doses of 2 or 1000 mg/kg, and at repeated oral doses (14 daily doses) of unlabeled sumilarv at 2 mg/kg followed by administration of a single oral dose of labeled sumilarv at 2 mg/kg. The major routes of excretion of radioactivity were via the urine and feces. The excretion of radioactivity into urine and feces was rapid and over a 7

- da y period, most (92

- 97%) of the test compound administered was excreted in the urine (5

- 12%) and feces (81

- 92%) from the animals. Most (63

- 83%) of the dose was eliminated in the urine and feces within 24 hours after dosing. Expired air was not detected. Rad ioactivity in tissue residues was very low in all tissues expect the fat. Recoveries of the administered doses in the tissues including carcass were not more than 0.3% indicating that the potential for bioaccumulation of sumilarv is minimal even after high dose or repeated low dose exposures. In the urine, a total of 11 metabolites were detected and two of them (4’

- OH

- 31183 sulfate and 4’

- OH

- POP sulfate) were identified. In the feces, an unmetabolized sumi larv (7

- 37% of the dose) and a total of up to 17 met abolites were detected and 10 of them (6 unconjugated and 4 sulfate conjugates) were identified. The four major fecal metabolites were 4’

- OH

- 31183, 4’

- OH

- 31183 sulfate, 5, 4’

- OH

- 31183 sulfate, andPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 51 of 58 

### 4’

- OH

- POPA. The metabolites in the liver, kidney, blood, bi le, and fat of rats were also examined. Based on the metabolites identified by TLC cochromotography with synthetic standards the major biotransformation reactions of sumilarv include: 1) Oxidation at 4’

- postion, of the terminal phenyl group; 2) Oxidation a t 5

- psition of pyridine; 3) Cleavage of the ether linkage and conjugation of the resultant phenols with sulfuric acid. No significant sex

- or dose

related differences exist in the absorption, distribution, or metabolism of sumilarv for all dosing regimens

.



### 870.7485 Metabolism

- Rat

In a metabolism study (MRID 44036914), male and female Sprague

- Dawley rats (7 week old) were given a single oral gavage dose of pyriproxyfen [4

- phenosyphenyl ( RS )

- 2

- (2

- pyridylosy) propyl ether], which was labeled at the 2 and 6 positions of the pyridyl ring with 14 

### C ([pyridyl

2,6

- 14 

### C]pyriproxyfen), at a rate of 2 mg/kg (low

- does) or 1000 mg/kg (high

- dose).

The radiocarbon was rapidly eliminated from the body with in 7 days after administration in both groups. From 88.9% to 92.9% of the dosed 14 

### C was excreted into urine, feces, and expired air in the first two days, and 92.3

- 98.5% of the dosed 14 

### C was excreted within 7 days after administration. 14 

### C

- Excretion into expired air was less than 0.5% for all groups. Fecal excretion was predominant, being 84.7

- 93.2% of the dose. 14 

### C

- Residues in tissues on the 7 th 

### day after administration were less than 0.3% of the dosed 14 

### C, being the highest in fat (low

- dose: 0.014

- 0.015 ug equivalents of pyriproxyfen/g wet tissue (ppm), high dose: 6.0

- 6.3 ppm). 14 

### C

- Residues levels in blood, blood cell, kidney, and liver were 0.002

– 0.009 ppm for the low dose group, and 1.2

– 4.5 ppm for the high dose group. 14 

### C

- Residue levels in other tissues were low being less than 0.003 ppm and 3 ppm for the low and high dose groups, respectively. There were no significant sex

- or dose

- related differences in 14 

### C

- excretion and 14 

### C

- distribution

.
Thirteen or more metabolites were found by HPLC and TLC analyses of feces and urine collected in the first two days. Ten of them were identified, accounting for 70

- 83% of the dosed 14c. The metabolic pathways of pyriproxyfen in rats were proposed on the basis of identified metabolites. The major fecal metaboli te was 4

- (4’

- hydroxyphenosyphenyl)

- 2

- (2

- pyridyloxy)propyl ether, which had one hydroxyl group at the 4’

- position of the terminal phenyl ring and accounted for 23

- 48% of the dosed 14C. Each of the other metabolic pathways, such as hydroxylation at the 2’

- po sition of the terminal phenyl ring or at the 5’

- postion of the pyridyl ring, dephenylation, cleavage of ether linkages, and conjugations of the resulting phenols with sulfuric acid or glucuronic acid, accounted for less than 10% of the dosed 14 

### C. Pyriproxy fen was detected mainly in feces and its amount was 21

- 35% of the dosed 14 

### C. The major urinary metabolite was 2

- (2

- pyridyloxy) propionic acid, accounting for 1

- 5% of the dose.

Comparison of metabolites in feces and urine, between male rats given a single oral low dose of pyriproxyfen labeled uniformly with 14 

### C at the phenoxyphenyl ring [phenoxyphenyl

14 

### C]pyriproxyfen and those given the same dose of [pyridyl

- 2,6

- 14 

### C]pyriproxyfen, showed that metabolites resulting from cleavage of ether linkages accounted f or 5.2% of the dosed 14 

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

Page 52 of 58 

### 870.7600 Dermal Absorption

- Rat

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

- day dermal rat toxicity study resulted in no toxicity up to the limit dose and therefore short

- and intermediate

term dermal exposure a ssessments 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/da y in the 21

- day dermal study. These studies were both in the rat and approximately the same duration in exposure. Thus, a dermal

- penetration factor of 30% was used for the route

- to

- route extrapolation in this long

- term dermal risk assessment, since an oral study was selected for the endpoint.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID # 48711907 ), Pyriproxyfen (99.5% ai, Batch # 080506G) was administered to four groups of female CD

- I mice (n=10) in the diet at dose levels of 0, 1000, 2000, or 5000 ppm (0, 228, 449, 1139 mg/kg bw/day) for at least 28 days . An additional positive group of 8 female mice were administered cyclophosphamide by gavage once daily at a dose of 20 mg/kg/day for 5 consecutive days (study days 22

- 26). All animals were evaluated for mortality, clinical signs, body w eight changes food and water consumptions. On study day 25, a ll animals were immunized with an i.v. injection of 0.2 mL of sheep red blood cells (2 x 10 9 

### 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. Lo wer 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 s 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 (4 49 mg/kg/day).

There were no statistically significant changes in the numbers of cells/spleen, PFC/10 6 

### 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/10 6


### viable cells and PFC/spleen (all p < 0.001) were all significantly reduced when compared toPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 53 of 58 

### the control.

The LOAEL for immuno toxicity is not observed. The NOAEL for immunotoxicity is 5000 ppm (1139 mg/kg/day).

This immunotoxicity study is classified Acceptable/Guideline

, and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in mice.

A.4.10 Non

- guideline stu di es

Reproduction and Fertility Effects

– Rat

In a non

- guideline study (MRID 44985001), pyriproxyfen (S

- 31183, 97.2% a.i., Lot# PTG

86011) in corn oil was administered to pregnant Slc:SD rats (23

- 24/dose) on gestation day (GD) 17 to lactation day (LD) 20 at doses of 0, 30, 100, 300, or 500 mg/kg/day. On day 4 postpartum, litters were standardized to a maximum of 8 pups/litter with 4/sex/litter, as nearly as possible; excess pups were sacrificed and examined for skeletal anomalies. Phy sical and sexual development of all F1 pups was monitored and on postnatal day (PND) 20, all pups were subjected to a sensory function test. At 3 weeks of age, all F1 pups (except the 2/sex/litter retained for learning tests and the 1 pup/sex/litter retain ed for reproductive ability) were necropsied, the organs were examined and weighed, and the pups were examined for visceral and skeletal anomalies. One F1 pup/sex/litter was subjected to an open field test, motor coordination test, learning ability test, a nd necropsied at 8 weeks of age. One F1 pup/sex/litter was raised to 11 weeks of age and then paired for mating within the same dose group for a reproductive performance assessment.

At 300 and 500 mg/kg, clinical signs observed in the P females included diarrhea (3/24 and 22/24 treated, respectively, vs 0/23 controls) and salivation (2/24 and 4/24 treated, respectively, vs 0/23 controls). Reductions (p<0.05 or 0.01) in body weight gains were noted in the P females on GD 19 (↓22 and 49%, respectively), 20 (↓17 and 57%, respectively), and 21 (↓17 and 64%, respectively). Body weight gains were increased in the P females at 500 mg/kg on LDs 4 through 21 (↑58

- 1375%) and at 300 mg/kg on LD 21 (↑270%). Decreases in P food consumption were observed in the 300 and 500 mg/kg females as follows: on GDs 19 (↓20 and 39%, respectively), 20 (↓13 and 44%, respectively), and 21 (↓10 and 50%, respectively) and LD 21 (↓11 and 17%, respectively).

At 500 mg/kg, two P animals died on day 5 of dosing after displaying clinical si gns which included hypoactivity, rough hairs, hypothermia, and lacrimation on dosing day 4 or 5. Clinical signs in P females included: erythema and swelling of the periproctal region (8/24 treated); hypoactivity (4/24 treated); rough hair (3/24 treated); l acrimation (3/24 treated); and hypothermia (4/24 treated). None of these findings were observed in any control animal. Decreases in body weight gain and food consumption were observed in the P females on GD 22 (↓109 and 63%, respectively). Increased absolu te and relative liver weights were observed in the P females (absolute: ↑18%; relative: ↑17%). Gross findings observed at necropsy of the 500 mg/kg females and no control animal (unless otherwise noted) included: atrophy of the thymus (4/23 treated); conge stion of the liver (2/23); enlargement of the liver (1/23 treated); atrophy ofPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 54 of 58 

### the spleen (4/23 treated); congestion of the kidney (1/23 treated); atrophy of the adrenal (5/23 treated v. 1/23 controls); hemorrhage of the mucous membrane of the stomach (1/2 3); and ulcers of the stomach (2/23 treated). Percent preimplantation losses were increased in the F1 dams, as calculated by reviewers, at 500 mg/kg (↑208%).

When compared to concurrent controls, no treatment

- related changes in P or F1 female body weights or F1 body weight gains were observed. No treatment

- related differences in water consumption of the P females were observed. There were no differences of toxicological concern observed in the reproductive performs

The LOAEL for maternal toxicity is 300 m g/kg/day based on clinical signs, deceased body weight gains, and decreased food consumption. The NOAEL is 100 mg/kg.

At 300 and 500 mg/kg, body weights were decreased throughout the postnatal interval as follows: 300 mg/kg F1 males and females from PND

– to weaning (↓9

- 17%); 500 mg/kg F1 males and females from PND0 to weaning (↓15

- 23%). Body weights were also decreased during the learning ability phase (PNDs 28

- 56) in both males and females at 300 (↓5

- 13%) and 500 mg/kg (↓7

- 15%). Upon visceral examination at PND 21, an increased fetal incidence [% fetal incidence (% litter incidence)] of dilation of the renal pelvis was observed at 300 [13.8 (30.4)] and 500 mg/kg [18.4(35.7)].

At 500 mg/kg, changes in mean litter size and viability indices were observed as follows: increased stillborn index (↑473%, calculated by reviewer); decreased day 4 viability in the females only (↓18%); decreased day 7 viability (↓12%, calculated by reviewer); decreased day 21 viability (↓21

- 24%); decreased mean litter size over the entire PNDs 0

- 21 interval (↓12

- 29%, calculated by reviewer); decreased number of live pups (↓24

- 39%, calculated by reviewer PND 0

- 21); and increased number of deaths for days 0

- 4 (↑350%, calculated by reviewer) and days 0

- 21 (↑463%, calculated by reviewer ). Upon visceral examination at PND 21, an increased fetal incidence of hyperemia and/or inflammatory cell infiltration in the propria of urinary bladder was observed microscopically (fetal incidence: 12.2%; litter incidence: 28.6%).

No changes in viabili ty were noted in the pups selected for learning or reproductive phases; additionally, no differences in body weights were observed in the reproductive animals. No differences were noted in the physical or sexual development, behavioral aspects, locomotor

a ctivity, rotorod performance, or learning ability of the pups. There were not differences of toxicological concern in organ weights, external examination, or skeletal exam9ination at 3 weeks, 8 weeks, or following the reproductive performance test. No trea tment

- related findings were observed in the cesarean section parameters for the F1 reproductive performance.

The LOAEL for reproductive toxicity in males and females is 300 mg/kg/day based on decreased body weight and increased incidence of dilation of th e renal pelvis. The NOAEL is 100 mg/kg/day.

This study is classified as Acceptable/Non

- guideline

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

Page 55 of 58 

### Developmental Toxicity

– Rat

In a non

- guideline study (MRID 44985002), pyriproxyfen (S

- 31183, 97.2% a.i., Lot# PTG

86011) was administered by gavage in corn oil once daily to Slc:SD rats (24 rats/sex/dose) at dose levels of 0, 100, 300, 500, or 1000 mg/kg/day. In the parental animals, males were administered the test substance beginning at 6 weeks of age, were dosed for 9 weeks prior to mating, and for a n additional 3 weeks until the end of the mating period; females were administered the test substance beginning at 9 weeks of age, for 2 weeks prior to the start of the mating, and continued to be dosed throughout mating and until gestation day (GD) 7. All live fetuses were weighed, sexed, and examined for external abnormalities. Approximately one

- third of the fetuses per litter were subjected to a visceral examination, while all remaining fetuses were examined for skeletal anomalies.

At 300, 500, and 1000 mg/kg, clinical signs observed in males and females included: diarrhea in females (9/24. 22/24. And 24/24 treated, respectively, v. 0/24 controls); erythema and swelling of the periproctal region in females (1/24. 9/24, and 23/24 treated, respectively v. 0/24 controls). Reductions in body weight gains were noted in the males at 300 (↓8

- 11%, day 35

- 83), 500 (↓9

- 21%, day 21

- 83), and 1000 mg/kg (↓25

- 41%, day 7

- 83); additionally, decreases in body weight gains were observed throughout the pre

- mating interval i n females at 300 (↓19

- 27%), 500 (↓26

- 79%), and 1000 mg/kg (↓27

- 194%). Increases in food consumption observed in males were as follows: at 300 mg/kg, increases were noted on day 0, days 10

- 21, and days 35

- 62 (↑7

- 17%); at 500 mg/kg, increases were observed o n day 0 and on days 10

- 62 (↑5

- 24%); and at 1000 mg/kg, increases were noted on days 14

- 62 (↑8

- 34%). Increased water consumption was observed in males at 300 (↑13

- 41%, days 3

- 62), 500 (↑24

- 72%, days 3

- 62) and 1000 mg/kg (↑60

- 117%, days 3

- 63). During the ges tation interval, increases in water consumption were observed in the 300 (↑15

- 25%, GDs 3

- 8), 500 (↑29

- 63%, GD 1

- 12), and 1000 mg/kg (↑48

- 135%, GDs 1

- 12) females. In the males dosed at >300 mg/kg, it was stated that histopathological changes in the kidneys included regenerative changes of the tubules, dilation of the tubules, and accumulation of neutrophils or degenerated cells within the dilated and regenerated tubules; however, no incidence data were reported and only photographs of these findings were pro vided. Differences in absolute and relative organ weights in the >300 mg/kg males were as follows: decrease absolute (300 mg/kg: ↓11%; 500 mg/kg: ↓22%; and 1000 mg/kg: ↓42%) and relative (500 mg/kg: ↓11%; and 1000 mg/kg: ↓26%) thymus weights: increased abs olute (300 mg/kg: ↑23%; 500 mg/kg: ↑24%; and 1000 mg/kg: ↑27%) and relative (300 mg/kg: ↑31%; 500 mg/kg: ↑41%; and 1000 mg/kg: ↑62%)liver weights; increased absolute (300 mg/kg: ↑9%; and 1000 mg/kg: ↑8%) and relative (300 mg/kg: ↑16%; 500 mg/kg: ↑22%; and 1000 mg/kg: ↑38%) kidney weights; and increased absolute (300 mg/kg: ↑28%; 500 mg/kg: ↑36%; and 1000 mg/kg: ↑62%) and relative (300 mg/kg: ↑37%; 500 mg/kg: ↑56%; and 1000 mg/kg: ↑108%) adrenal weights. At necropsy, gross findings were observed in the 300, 500, and 1000 mg/kg males and not in the controls included: atrophy of the thymus (1/24. 1/23, and 12/24 treated, respectively); enlargement of the liver (18/24. 21/23, and 22/24 treated, respectively); dark

- red color of the liver (21/24, 23/23, and 24/24 treated, respectively); enlargement of the kidney (1/24, 6/23, and 16/24 treated, respectively); pitted surface of the kidney (8/24, 22/23, and 22/24 treated, respectively); and enlargement of the adrenal (12/24, 18/23, and 24/24 treated, respectively).

A t 500 and 1000 mg/kg, clinical signs observed in the males included diarrhea (20/24 and 24/24Pyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 56 of 58 

### treated, respectively, vs 0/24 controls) and erythema and swelling of the periproctal region (22/24 and 24/24 treated, respectively, vs 0/24 controls). Decreased male body weights were observed at 500 mg/kg (↓6

- 12%, day 28

- 83) and at 1000 mg/kg (↓9

- 21%, day 3

- 83). Increases in water consumption were observed during pre

- mating days 3

- 13 in the 500 and 1000 mg/kg females (↑60

- 82% and ↑100

- 137%, respectively). There w ere no differences of toxicological concern observed in the reproductive performance or Cesarean section parameters

.
At 1000 mg/kg, two females died on days 5 or 7 of administration after displaying clinical signs including severe diarrhea, hypoactivity, and wasting. At necropsy, liver congestion, atrophy of the spleen and thymus, adrenal and liver enlargement and stomach ulcers were noted in either 1 or both of these females that died prematurely. Lacrimation was observed in 3/24 males vs 0/24 controls. I n females, hypoactivity (4/24 treated vs 0/24 controls) and wasting (6/24 treated vs 0/24 controls) were observed. In males, a single extreme decrease in body weight gains was observed on day 3 (↓108%). At necropsy, protrusion of the liver parenchyma on th e diaphragmatic side was observed in 1/24 males vs 0/24 controls.

The LOAEL for parental toxicity in males and females is 300 mg/kg/day based on clinical signs, decreased body weight gains, and increased water consumption in both sexes, and increased food consumption, changes in organ weights, and gross pathological findings in males only. The NOAEL for both sexes is 100 mg/kg/day.

No developmental toxicity was observed at any dose level tested.

The developmental LOAEL was not observed. The developmental NOAEL was >1000 mg/kg/day (limit dose).

This study is classified as Acceptable/Non

- guideline

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

Page 57 of 58 

### Appendix B: Proposed Metabolic Pathway for PyriproxyfenPyriproxyfen (129032) Human Health Risk Assessment DP#: 427112

Page 58 of 58 

### Appendix C. Studies Reviewed for Ethical Conduct

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

Agricultural Re

- entry Task Force (ARTF) data base (SOP #3.1)