Page 3 of 40



### 5.3 Wat er Residue Profile

................................ ................................ ................................ 17

5.3.1 Estimated Drinking Water Concentrations

................................ .......................... 17

5.4 Dietary and Drinking Water Exposure and Risk

................................ .................... 17

5.4.1 Acute Dietary and Drinking Water Analysis

................................ ....................... 17

5.4.2 Chronic Dietary and Drinking Water Analysis

................................ ................... 17

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

................................ .......... 18

6.1 Residential Bystander Postapplication Inhalation Exposure

................................ .... 19

6.2 Spray Drift

................................ ................................ ................................ ...................... 19

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

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

7.1 Short

- , Intermediate

- , and Long

- Term Aggregate Risk

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

8.0 CUMULATIVE RISK

................................ ................................ ................................ ...... 24

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

.............................. 24

9.1 Exposure Scenarios

................................ ................................ ................................ ....... 24

9.2 Handler Exposure

................................ ................................ ................................ .......... 25

9.3 Post Application Exposure

................................ ................................ ............................ 25

9. 3.1 Restricted Entry Interval

................................ ................................ ....................... 25

10. REFERENCES

................................ ................................ ................................ .................. 26

APPENDICES

................................ ................................ ................................ ............................. 27

A TOXICOLOGY DATA SU MMARY

................................ ................................ ............. 27

A.1 Guideline Data Requirements

................................ ................................ .................. 27

A.2 Toxicity Profiles

................................ ................................ ................................ ......... 28

A.3 Toxico logical Endpoints

................................ ................................ ............................. 33

A.4 EXECUTIVE SUMMARIES (recently submitted studies)

................................ ... 37 APPENDIX C. Physical/Chemical Properties

................................ ................................ .......... 40

APPENDIX D. Studies Reviewed for Ethical Conduct

................................ .......................... 40Page 4 of 40



### 1.0 EXECUTIVE SUMMARY

The Interregional Research Project No. 4 (IR

- 4) submitted a petition for the establishment of permanent tolerances for residues of the insecticide pyriproxyfen [2

- [1

- methyl

- 2

- (4

- phenoxyphenoxy)ethoxy]pyridine]

. Permanent tolerance are currently established for a variety

of commodities under 40 CFR 180. 510(a)(1)

. Tolerances of 0.10 ppm are also established for all food commodities as a result of uses in food handling establishments under 40 CFR

180. 510(a)(2). Time

- limited tolerances are also established under 40 CFR 180. 510(b) for bean, succulent; cele ry and strawberry.

The most recent human health risk assessment for pyriproxyfen was conducted by ARIA (DP # : 360751

, B

. Hanson

, 9 / 3 /200 9 ).

Use Profile

Pyriproxyfen is an analogue of an insect juvenile hormone and interferes with the hormonal control of insect growth and development, thereby inhibiting egg hatch, larval embryogenesis, metamorphosis, and adult emergence. There are currently several end

- us e products of pyriproxyfen with food/feed uses that are registered to Valent USA Corporation:Distance, 11.23% w/w, EPA Reg. No. 59639

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

59639

- 160; Pyriproxyfen 0.86 EC UPP, EPA Reg. No. 59639

- 163; Knack ® 

### IGR [0.86 lb/gal EC; EPA Reg. No. 59639

- 95], Esteem ® 

### 35 WP, 35% WP, EPA Reg. No. 59639

- 115; and

Esteem ® 

### Ant Bait, 0.5% w/w, EPA Reg. No. 59639

- 114: containing pyriproxyfen for use on a variety of crops. Permanent tolerances for pyriproxyfen hav e been established for a variety of commodities under 40 CFR §180.510.

Proposed New Uses

Under PP#1E7950, The Interregional Research Project Number 4 (IR

- 4) has submitted a petition for the establishment of permanent tolerances for residues of the insecticide pyriproxyfen [2

- [1

- methyl

- 2

- (4

- phenoxyphenoxy)ethoxy]pyridine] in conjunction with requests for amended Section 3 registrations of six pesticide formulations: Distance, 11.23% w/w, EPA Reg. No.

59639

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

- 160; Pyriproxyfen 0.86 EC UPP, EPA Reg. No. 59639

- 163; Knack ® 

### IGR [0.86 lb/gal EC; EPA Reg. No. 59639

- 95], Esteem ® 

### 35 WP, 35% WP, EPA Reg. No. 59639

- 115; and Esteem ® 

### Ant Bait, 0.5% w/w, EPA Reg. No. 59639

- 114: containing pyriproxyf en for use on the herb subgroup 19A. Maximum application rate is 0.087 lb a.i./A and the maximum seasonal application rate is 0.176 lb a.i./A. A maximum of two applications is proposed along with a 1

- day pre

- harvest interval (PHI).

Hazard Identification

Pyriproxyfen is of low acute toxicity by oral, dermal, inhalation and ocular routes of exposure, since all studies are in Toxicity Category III or IV. Pyriproxyfen is not a skin irritant (Toxicity Category IV) and was negative in the dermal sensitization study in guinea pigs. Based on repeated dose studies in mice, rats and dogs the liver and kidney are the principal target organs, with slight anemia occurring in rodent species. The review of the acute and subchronic neurotoxicity studies indicates p yri proxyfen is not a neurotoxic chemical. There was noPage 5 of 40



### evidence of prenatal or postnatal sensitivity or increased susceptibility in developmental studies in rats and rabbits, and in reproduction studies in rats. In the 2

- generation reproduction toxicity

stu dy, offspring toxicity (decreased body weight on pups during lactation days 14 to 21) occurred in the presence of decreased body weight in parental animals at the same dose level

. An immunotoxicity study showed no adverse effects on the immune system. N o significant systemic toxicity was observed in either the 21

- day dermal toxicity study in rats

. In a 28

- day inhalation study, the LOAEL of 1 mg/L based on salivation in females and sporadic decreased body weight gains in males was not considered biolog ically relevant

. With respect to carcinogenicity p yriproxyfen 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 i n a battery of mutagenicity studies conducted with both the parent and/ or metabolites. Pyriproxyfen was absorbed, metabolized, and rapidly excreted, primarily in the feces, in the rat metabolism study. There were no effects of gender, dose, or label posi tion on absorption or elimination in the rat metabolism study.

Dose Response Assessment

The database for pyriproxyfen is now complete. The acute and subchronic neurotoxicity studies were negative and the immunotoxicity study was negative. There is no evidence of quantitative

or qualitative susceptibility of the young following in utero prenatal exposure in rat and rabbit developmental studies and pre/postnatal exposure in the rat 2

- generation reproduction study. Therefore, the FQPA factor is reduced to 1X.

Risk assessments were conducted for the specific exposure scenarios listed below. An acute reference dose (aRfD) was not established for females 13

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

- dose exp osure could not be identified in the toxicology database, including the acute neurotoxicity study and the developmental toxicity studies. Therefore, an acute risk assessment is not required. The cRfD of 0.35 mg/kg/day was

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

in two co

- critical rat toxicity studies (subchronic and chronic). Since the FQPA Safety Factor ( SF ) has been reduced to 1X, the chronic population

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

Th e short

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

the rat developmental maternal LOAEL of 300 mg/kg/day

, based on decreased body weight, body weight gain, and food consumption, and increased water consumption . The intermediate

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

- critical rat toxicity studies (subchronic and chronic).

Short

- and intermediate

- term dermal endpoints were not s elected since there was no systemic toxicity up to the limit dose of 1,000 mg/kg/day in the 21

- day dermal toxicity study in rats. The long

- term dermal endpoint was based on the systemic toxicity no

- observed adverse

- effect level (NOAEL) of 35.1 mg/kg/day f rom the two co

- critical (subchronic and chronic) rat feeding

studies. Short

- and intermediate

- term inhalation endpoints were not selected based on the lack of biologically adverse effects at 1.0 mg/L in the 28

- day inhalation toxicity study in rats. The l ong

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

from the two co

- critical (subchronic and chronic) rat feeding studies. An inhalation

- absorption

factor of 100% was used for route

- to

- route extrapolation.Page 6 of 40



### HED c lassified pyriproxyfen as a "Group E" chemical, no evidence for carcinogenicity to

humans
, based on the absence of evidence of carcinogenicity in male and female rats as well as in male and female mice. Therefore, a cancer risk assessment is not required.

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water) and occupational exposure pathways based on the proposed new use of pyriproxyfen

. No new residential uses are associated with the proposed use; however

, the residential exposure assessment was updated

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

. An u nr efined chronic dietary and drinking water risk assessment for pyriproxyfen showed that dietary and drinking water exposure estimates are below HED’s level of concern for the general population and all population subgroups. Since no short

- or intermediate

- term inhalation or dermal endpoints were identified

, an o ccupational exposure ass essment did not need to be

conducted

. Aggregate risks are not of concern.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These stu dies , listed in Appendix D

, have been determined to require a review of their ethical conduct. Some of these studies are also subject to review by the Human Studies Review Board. All of the studies used have received the appropriate review.

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Registration

Submission of a revised Section F is required

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The registrant submitted adequate concurrent recovery data for a GC/NPD method (RM

- 33P

- 1

- 3a or 9.66 V 1) used to determine residues of pyriproxyfen in/on the subject crops. The method has undergone an adequate radiovalidation, independent laboratory validation trial, petition method validation trial, and has been forwa rded to the FDA for inclusion in PAM Vol. II. T he level of detection ( LOD ) and level of quantitation ( LOQ ) are 0.01 and 0.02 ppm, respectively.

The GC/NPD method RM

- 33P

- 1

- 3a is adequate for enforcement of the recommended tolerance

levels for residues of pyriproxyfen in/on the subject crops. As tolerances for residues of pyriproxyfen in livestock commodities are not required at this time, enforcement methodology for determining residues in livestock is not required at this time.Page 7 of 40



### 2.2.2 International Harmonization

There is a Codex MRL for Citrus fruit of 0.50 ppm. The US will harmonize for citrus fruit at 0.50 ppm. Also, there is a Canadian tolerance of 0.8 ppm for bell peppers

, and 0.25 ppm for

tomatoes. US will harmonize for vegetable, fruiting, g roup 8

- 10 at 0.80 ppm.

2.2 .3 Recommended Tolerances

A revised Section F proposing fresh and dry Herb subgroup 19A tolerances of 30 and 100 ppm, respectively, is required (i.e. 3.3X processing factor). In addition, a tolerance for Fruit, citrus, group 10

- 10 should be revised to 0.5 ppm to harmonize with Codex and the tolerance for vegetable, fruiting, group 8

- 10 should be revised to 0.8 ppm to harmonize with the Canadian MRL for bell peppers

.

HED has examined the residue chemistry database for pyriproxyf en. With regards to pyriproxyfen for PP#1E7950, pending submission and a revised Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting

amended registrations for amended Section 3 registrations of six pesticide formulations: Distance, 11.23% w/w, EPA Reg. No. 59639

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

- 160; Pyriproxyfen 0.86 EC UPP, EPA Reg. No. 59639

- 163; Knack ® 

### IGR [0.86 lb/gal EC; EPA Reg. No. 59639

- 95], Esteem ® 

### 35 WP, 35% WP, EPA Reg. No. 59639

- 115; and Esteem ® 

### Ant Bait, 0.5% w/w, EPA Reg. No. 59639

- 114: containing pyriproxyfen for use on a variety of crops, and to expand currently registered foliar uses for bulb vegetables,

frui ting vegetables, citrus fruits, pome fruits, caneberry, bushberry and berry, low growing except strawberry, to include the additional commodities specified under the following new crop groups/subgroups, respectively: Vegetable, bulb, subgroup 3

- 07, Vege table, fruiting, group 8

- 10, Fruit, citrus, group 10

- 10, Fruit, pome 11

- 10, Caneberry subgroup 13

- 07A, Bushberry subgroup 13

- 07B, Herb subgroup 19A group 13

- 07A, Berry, low growing, except, strawberry, subgroup 13

- 07H, and Herb subgroup 19A fresh and H erb Subgroup 13A dried or es tablishment of tolerances for residues of pyriproxyfen only in/on the following commodities:

Vegetable, bulb, subgroup 3

- 07

.................................................... 0.70 ppm Vegetable, fruiting, group 8

- 10

..................................................... 0.80 ppm
Fruit, citrus, group 10

- 10

......................................................... . ... 0.50 ppm Fruit, pome, group 11

- 10

............................................................ .0.20 ppm Caneberry subgroup 13

- 07A

.................................... . ..................... 1.0 ppm Bushberry subgroup 13

- 07B

...................................................... . .... 1.0 ppm Berry, low growing, except, strawberry, subgroup 13

- 07 H

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

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

............................................................ 100 ppm



### The amended registrations are limited to expansions to add the commodities specified under the new crop groups/subgroups and do not include substantive changes to currently registered use patterns (i.e., maximum use rates, retreatment intervals, pre

- harvest intervals, use of adjuva nts, etc.).Page 8 of 40



### With regards to p y riproxyfen for PP#1E7950, pending submission of a revised Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting Section 3 registrations of six pesticide formulations: Distance, 11.23% w/w, EPA Reg. No. 59639

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

- 160; Pyriproxyfen 0.86 EC UPP, EPA Reg. No. 59639

- 163; Knack ® 

### IGR [0.86 lb/gal EC; EPA Reg.

No. 59639

- 95], Esteem ® 

### 35 WP, 35% WP, EP A Reg. No. 59639

- 115; and Esteem ® 

### Ant Bait, 0.5% w/w, EPA Reg. No. 59639

- 114: to permit a new use on Herb subgroup 19A or establishing tolerances for residues of pyriproxyfen only in/on the following commodities:

Herb subgroup 19A, fresh........................30 ppm Herb subgroup 19A, dried........................100 ppm



### 2.2.4 Revisions to Petitioned

- For Tolerances

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

MRLs with the OECD MRL calculator.

2.3 Label Recommendations

- Label for Distance (EPA Reg

. No. 59639

- 96) must be amended to specify a maximum single application label rate for the sprench application method to herbs of 6 fluid ounces/10,000

ft 2 

### or 3 fluid ounces /5000 ft 2



### .

- Label for Esteem 35 WP (EPA Reg. No. 59639

- 115) Must require gloves unless the acute tox category is category IV for acute dermal and dermal/skin irritation.

- Label for Pyriproxyfen EC Ag (EPA Reg. No. 59639

- 160) The 4th bullet under the User Safety Reco mmendations should not be in that box and should be above that box since it's not a recommendation, but a requirement.

3 .0 INGREDIENT PROFILE

3.1 Chemical Identity

Table 2. Test Compound Nomenclature

. Pyriproxyfen

Common name Pyriproxyfen

Company experimental name S

- 71639, S

- 31183

IUPAC name 4

- phenoxyphenyl (RS)

- 2

- (2

- pyridyloxy)propyl ether

CAS name 2

- [1

- methyl

- 2

- (4

- phenoxyphenoxy)ethoxy]pyridine

CAS # 95737

- 68

- 1

End

- use products/(EP) Knack ® Insect Growth Regulator, Pyriproxyfen 0.86 EC Ag Ins ect Growth Regulator,Esteem ® 35 WP Insect Growth Regulator, Esteem ® Ant



### 3.2 Physical/Chemical Characteristics

A table of the physi ochemical properties of pyriproxyfen is provided in Appendix B

.Page 9 of 40



### 3.3 Pesticide Use Pattern

3.3.1 Registered Products

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

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

.

3.3.2 Proposed New Uses

Under PP#1E7950, The Interregional Research Project Number 4 (IR

- 4) has submitted a petition for the establishment of permanent tolerances for residues of the insecticide pyriproxyfen [2

- [1

- methyl

- 2

- (4

- phenoxyphenoxy)ethoxy]pyridine] in conjunction with requests for amended

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

59639

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

- 160; Pyriproxyfen 0.86 EC UPP, EPA Reg. No. 59639

- 163; Knack ® 

### IGR [0.86 lb/gal EC; EPA Reg. No . 59639

- 95], Esteem ® 

### 35 WP, 35% WP, EPA Reg. No. 59639

- 115; and Esteem ® 

### Ant Bait, 0.5% w/w, EPA Reg. No. 59639

- 114: containing pyriproxyfen for use on the herb subgroup 19A. Maximum application rate is 0. 087 lb a.i./ A and the maximum seasonal application rate is 0.176

lb a.i./A

. A maximum of two applications is proposed along with a 1

- day pre

- harvest interval (PHI).

3.4 Anticipated Exposure Pathways

Dietary (food and water) exposures are expected based on existing uses of pyriproxyfen and the requested new use . A n updated residential exposure assessment for short

- term incidental oral and long

- term dermal is required.

3.5 Considerations of Environmental Justice

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

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates

risk s to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Whenever appropriate, non

- dietary expos ures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development, as OPP ha s committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.Page 10 of 40



### 4 .0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

A full suite of toxicity studies are now available for pyriproxyfen. The toxicology database is acceptable for characterizing pyriprox y fen hazard and includes the following studies:

Subchronic : 90

- day Dietary in Rats , Mice, and Dogs; 2 1

- day Dermal in Rats; 28

- day Inhalation

in Rats.

Chronic : 1

- year Dietary in Dogs; Carcinogenicity Dietary Mice; 2

- year Dietary Combined Chronic/Carcinogenic ity in Rats. Reproductive/Developmental : Developmental in Rats and Rabbits; Reproduction and Fertility

Effects in Rats. Neurotoxicity Battery : Acute and Subchronic in Rats Mutagenicity and Genotoxicity in Bacterial & Mammalian Model Systems Immunotoxicity : 28

- day Dietary in Rats and Mice

Metabolism and Pharmacokinetic Studies in Rats

4.2 Absorption, Distribution, Metabolism and Excretion

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

excretion estimates. Most radioactivity was excreted in the feces [81

- 92%] and urine [5

- 12%] over a 7 day collection period. Expired air containing radiolabeled CO 2 

### was not detected in the rat metabolism study. Tissue radioactivity levels were very low [less than 0.3%] except for f at. Examination of urine, feces, liver, kidney, bile and blood metabolites yielded numerous [ > 20]

identified metabolites.

4.2.1 Dermal Absorption

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

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

- and intermediate

term dermal exposure assessments are not warranted. An oral endpoint was selected to be protective of the long

- term dermal assessment. For the long

- term dermal assessment, d ermal penetration was estimated to be 30% by the extrapolation method of comparing the maternal toxicity LOAEL of 300 mg/kg/day in the rat developmental toxicity oral study and the dermal NOAEL of 1,000 mg/kg/day in the 21

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

- penetration factor of 30% was

used for the route

- to

- route extrapolation in this long

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

4.3 Toxicological Effects

Based on repeated dose studies in mice, rats and dogs the liver and kidney are the principal target organs, with slight anemia occurring in rodent species. Additionally, decreased body weight, body weight gain and/or food consum ption were common findings in several studies. There was no systemic toxicity in a 21

- day dermal toxicity study in rats up to the limit dose. In a 28

- day inhalation study, the LOAEL of 1 mg/L based on salivation in females and sporadic decreased body weig ht gains in males was not considered biologically relevant

.Page 11 of 40



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

p yriproxyfen is not a neurotoxic chemical. There was no neurotoxicity observed in the acute and subchronic neurotoxicity studies up to the limit dose and no indication of toxicity to the central or peripheral nervous system in other subchronic or chronic toxicity studies. The salivation

observed i n the inhalation study was not observed in either the acute or subchronic neurotoxicity study. T here were no treatment

- related alterations in brain weight or histopathology (non

perfused tissues) following exposure to pyriproxyfen.

There was no evidence of prenatal or postnatal sensitivity or increased susceptibility in developmental studies in rats and rabbits, and in reproduction studies in rats. No evidence of developmental anomalies of the fetal nervous system w as observed in prenatal developmental toxicity studies in either rats or rabbits at maternally toxic doses up to 1,000 mg/kg/day and 300 mg/kg/day, respectively. There was no evidence of an effect on functional development in a postnatal segment of a special developmental study in rats. In th e 2

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

- guideline studies that evaluated perinatal and prenatal development, there was no evidence of quantitative or qualitative increased susceptibility. In one study, when pregnant rats were treated from gestation day 17 to lacta tion day 20, the resulting toxicity was comparable between adults (clinical signs, decreased body weight gain and food consumption) and offspring (decreased body weight and dilation of the renal pelvis) at the same dose. In the other study, when rats were exposed to pyriproxyfen prior to and in the early stages of pregnancy, no developmental toxicity was seen at

the limit dose.

In a battery of mutagenicity studies, pyriproxyfen was negative in the bacterial and mammalian gene mutation assays, an in vitro cytogenetic assay, as well as, in the Unscheduled DNA Synthesis (UDS) assay with HeLa cells. Based on these results, it is concluded that the mutagenic potential of pyriproxyfen is negative. An in vivo cytogenetic assay (e.g. mouse micronucleus study) ha s not been submitted. Since all in vitro mutagenicity studies are negative and there was no carcinogenic response in long term studies in rats and mice, the requirement for

the in vivo cytogenetic assay is waived.

The recent submission and review of an immunotoxicity study showed no adverse effects on the immune system ( 48711906, 48711907)

.

With respect to carcinogenicity p yriproxyfen has been classified as a "Group E" chemical

- no evidence for carcinogenicity to humans

- based on the absence of carcinog enicity in mice and rats. Pyriproxyfen is of low acute toxicity by oral, dermal, inhalation and ocular routes of exposure, since all studies are in Toxicity Category III or IV. Pyriproxyfen is not a skin irritant (Toxicity Category IV) and was negative in the dermal sensitization study in guinea pigs.

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

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

The FQPA factor has been reduced to 1X. There was no evidence of qualitative or quantitative susceptibility in the database and t he database is now complete.Page 12 of 40



### 4.4.1 Completeness of the Toxicology Databas e

The toxicity database for pyriproxyfen is now complete.

4.4.2 Evidence of Neurotoxicity

Acute and subchronic neurotoxicity studies have been recently submitted and reviewed by the Agency. Decreases in motor activity w ere only observed at a high dose in the acute neurotoxicity (ACN) study and no n eurotoxicity observed in the subchronic neurotoxicity (SCN) study up to the limit dose (2,000 mg/kg/day). Specifically, i n the ACN, the neurotoxicity

NOAEL was 1000 mg/kg bw/day , while the LOAEL of 2000 mg/kg bw/day was based on deceases in motor activity on Day 0 in males and unkempt appearance in females. In the SCN, the neurotoxicity NOAEL was 1111 mg/kg/day for males and 1212 mg/kg/day for females

. The LOAEL for neurotoxicity was not observed (>2,000 mg/kg/day)

. Based on the results on these recently reviewed neurotoxicity studies, there are no remaining concerns regarding neurotoxicity for pyriproxyfen.

4.4.3 Evidence of Sensitivity/Susceptibili ty in the Developing or Young Animal

There are no indications from the pyriproxyfen database of sensitivity to infants and children. Specifically, there is no o f evidence of quantitative or qualitative susceptibility of the young demonstrated by in utero prenatal exposure in rat and rabbit developmental studies and pre/postnatal exposure in the rat 2

- generation reproduction study.

4.4.4 Residual Uncertainty in the Exposure Database

T here are no residual uncertainties in the hazard or exposure databases . The dietary, drinking water, and residential exposure assessment included herein are considered conservative ; the dietary assessment assumed 100% crop treated, DEEM 7.81 default processing factors

, toler ance

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

- level estimates of drinking water concentrations generated by the PRZM

- EXAMS and SCI

- GROW M odels ; and

the residential assessment did not take into account the daily dissipation of py riproxyfen

residues

.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose

- Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (food and water) and occupational scenarios are summarized below. A detailed description of the studies used as a basis for the selected endpoints are presented in Appendix A.

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

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

- dose exposure could not be identified in the toxicology database, including the acute neurotoxicity study and the developmentalPage 13 of 40



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

The cRfD of 0.35 mg/kg/day was determined on the basis of decreased body weight and changes in clinical chemistry parameters in two co

- critical rat toxic ity studies (subchronic and chronic). Since the FQPA Safety Factor ( SF ) has been reduced to 1X, the chronic population

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

Short

- term incidental oral endpoint (NOAEL 100 mg/kg/day) was determined on the basis of the rat developmental maternal LOAEL of 300 mg/kg/day

, based on decreased body weight, body weight gain, and food consumption, and increased water consumption . The intermediate

- term
incidental oral endpoint (NOAEL 35.1 mg/kg/day) was de termined based on syst emic toxicity (LOAEL 141.28 mg/kg/day) in two co

- critical rat toxicity studies (subchronic and chronic).

Short

- and intermediate

- term dermal endpoints were not selected since there was no systemic toxicity up to the limit dose of 1,000 mg/kg/day in the 21

- day dermal toxicity study in rats. The long

- term dermal endpoint was based on the systemic toxicity no

- observed adverse

- effect level (NOAEL) of 35.1 mg/kg/day from the two co

- critical (subchronic and chronic) rat feeding

studies.

Short

- and intermediat e

- term inhalation endpoints were not selected based on the lack of biologically adverse effects at 1.0 mg/L in the 28

- day inhalation toxicity study in rats. The long

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

from the two co

- critical (subchronic and chronic) rat feeding studies. An inhalation

- absorption

factor of 100% was used for route

- to

- route extrapolation.

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

humans
, based on the absence of evidence of carcinogenicity in male and female rats as well as in male and female mice. Therefore, a cancer risk assessment is not required.

4.5.2 Recommendations for Combining Exposure Routes

Aggregate exposure risk assessmen ts will be limited to long

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

- term
and intermediate

- term routes. A common toxicity endpoint (decreases in body weight and

alterations in clinical pathology parameters) was identified for the oral, dermal (oral equivalent) and inhalation (oral equivalent) routes, therefore, these routes can be combined for the appropriate populations for long

- term aggregate risk assessment.

4.5.3 Class ification of Carcinogenic Potential

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

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

4.5.4 Summary of Points of Departure Used in Risk AssessmentPage 14 of 40



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

.

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

Assessment.

Exposure

Scenario Dose Used in

Risk Assessment, UF FQPA SF and Level

of Concern for Risk

Assessment Study and Toxicological Effects

Acute Dietary

females 13

- 50 years old and general population NA NA An appropriate endpoint attributable to a single oral dose was not available in the data base, including the developmental and reproduction toxicity studies.

Chronic Dietary all populations NOAEL= 35.1

mg/kg/day

UF = 100 FQPA SF = 1X

cPAD = cRfD FQPA SF

= 0.35 mg/kg/day Subchronic (41321716 ) and chronic ( 4321050 3 )

– rat (co

- critical) LOAEL = 141.28 mg/kg/day based on

decreased body weight and alterations in clinical pathology parameters.

Short

- Term Incidental, Oral (1

- 30 days)

Residential Oral Maternal

NOAEL = 100 mg/kg/day LOC for MOE = 100 Rat developmental toxicity ( 44985002) Maternal LOAEL = 300 mg/kg/day based

on decreased body weight, body weight gain, and food consumption, and increased water consumption

Intermediate

- Term Incidental, Oral (1

- 6 months)

Residential Oral NOAEL =

35.1 mg/kg/day LOC for MOE = 100 Subchronic (41321716 ) and chronic ( 4321050 3 )

– rat (co

- critical) LOAEL = 141.28 mg/kg/day based on decreased body weight and alterations in clinical pathology parameters.

Short

- , and

Intermediate

- Term Dermal (1

- 30 days

and 1

- 6 months)

(Occupational/ Residential) NA NA Based on the systemic toxicity NOAEL of 1,000 mg/kg/day (limit dose) in the 21 day dermal toxicity study in rats, quantification of dermal risks is not required. In addition, no developmental concerns (toxicity) were

seen in either rats or rabbits.

Long

- Term Dermal (6 months

lifetime)

(Occupational/ Residential) Oral NOAEL=

35.1 mg/kg/day

(dermal absorption rate =

30% * ) LOC for MOE = 100 Subchronic (41321716 ) and chronic ( 4321050 3 )

– rat (co

- critical) LOAEL = 141.28 mg/kg/day based

decreased body weight and alterations in clinical pathology parameters.

Short

- , and

Intermediate

- Term Inhalation (1

- 30 days and 1

- 6 months)

(Occupational/ Residential) NA NA Based on the absence of biologically

relevant toxicity at the LOAEL of 1.0 mg/L

, the quantification of inhalation risks is not required. In addition, no developmental concerns (toxicity) were

seen in either rats or rabbits.

Long

- Term Inhalation (6 Oral study

NOAEL= 35.1 LOC for MOE = 100 Subchronic (41321716 ) and chronic ( 4321050 3 )

– rat (co

- critical)Page 15 of 40

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

Assessment.

Exposure

Scenario Dose Used in

Risk Assessment, UF FQPA SF and Level

of Concern for Risk

Assessment Study and Toxicological Effects

months

- lifetime)

(Occupational/ Residential) mg/kg/day

( inhalation absorption rate = 100%) LOAEL = 141.28 mg/kg/day based on decreased body weight and alterations in clinical pathology parameters

Cancer (oral, dermal, inhalation) Cancer

classification ("Group E") Risk Assessment not

required No evidence of carcinogenicity

1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, LOC = level of concern, MOE = marg in of exposure , *dermal absorption estimated by comparing the rat developmental LOAEL of 300 mg/kg/day to the 21

- day rat dermal study NOAEL of 1000 mg/kg/day (No NOAEL)= 300/1000=30%,



### 5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant /Livestock Metabolism Studies

Adequate metabolism studies for pyriproxyfen are available on apples, cotton

, and tomatoes. Based on these studies, the residue of concern in plants is pyriproxyfen (DP #: 250953, W. Donovan and W. Dykstra, 11/19/ 19 98).

Ruminant and poultry metabolism studies have previously been submitted and reviewed in conjunction with a petit ion for cotton. HED determined that should future crop uses increase the maximum theoretical dietary burden (MTDB) to the point that tolerances are needed in livestock

c ommodities

, the residue of concern will be pyriproxyfen and the free and sulfate forms of 4'

- OH

- PYR.

An adequate confined rotational crop study was conducted in support of the cotton petition.

Based on a 30

- day plant back interval ( PBI ) and a treatment rate of 0.18 lb ai/A, no pyriproxyfen residues above 0.01 ppm were found in any of the following crop matrices: lettuce leaf; radish tops and roots; and wheat grain, forage, straw and chaff. Accordingly, HED conclude d that a 30

- day PBI for non

- labeled crops is appro priate.

5.1.2 Comparison of Metabolic Pathways

HED determined that the residue of concern in plants is pyriproxyfen. HED determined that should future crop uses increase the MTDB to the point that tolerances are needed in livestock commodities, the re sidue of concern in livestock will be pyriproxyfen and the free and sulfatePage 16 of 40



### forms of 4'

- OH

- PYR.

5.1.3 Environmental Fate and Transport

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

oc 

### = 19260), and is not expected to be persistent in the open environment. Pyriproxyfen 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. Pyriproxyfen shows moderate bioconcentration in fish (465 to 2,390 x ), with a rapid depuration rate.

5.1. 4 Residues of Concern Summary and Rationale

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

.

Table 4. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

.

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop Pyriproxyfen Pyriproxyfen

Rotational Crop Pyriproxyfen Pyriproxyfen

Livestock Ruminant Pyriproxfen and the free and

sulfate forms of 4'

- OH

- PYR Pyriproxfen and the free and

sulfate forms of 4'

- OH

- PYR

Poultry Pyriproxfen and the free and

sulfate forms of 4'

- OH

- PYR Pyriproxfen and the free and

sulfate forms of 4'

- OH

- PYR

Drinking Water Pyriproxyfen NA



### 5.2 Food Residue Profile

5.2.1 Residues in Crops

The Interregional Research Project Number 4 (IR

- 4) has submitted greenhouse trial data for pyriproxyfen on basil

. Four greenhouse trials were conducted in the United States during the 2007 growing season in the North American Free Trade Agreement (NAFTA) Growing Zones 2 (MD and TN; 2 trials), 3 (FL; 1 trial), and 9 (CO; 1 trial).

A summary of the residue data is presented in Table C.4. Following two foliar directed applications of the 0.86 lb ai/gal EC formulation of pyriproxyfen at 0.172

- 0.182 lb ai/A, residues (and per trial averages) of pyriproxyfen in/on fresh basil leaves and stems harvested at a 1

- day

PHI were 0.325

- 13.0 (0.413

- 12.5) ppm; corresponding residues (and per trial averages) in/on dried basil leaves and stems (one trial only) were 12.0

- 1 2.4 (12.2) ppm. The processing factor for drying basil is 3.3X (12.2/3.69).Page 17 of 40

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

Commodity Total

Rate (lb ai/A) PHI

(days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std

. Dev.

Basil, fresh leaves and stems 0.172

- 0.182 1 4 0.325 13.0 0.413 12.5 4.81 5.64 5.12

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

1 Except for sample min/max, values reflect per trial averages; n = no

. of field trials . NA= Not applicable.

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



### 5.3 Water Residue Profile

5.3. 1 Estimated Drinking Water Concentrations

The following information concerning the environmental fate and drinking water assessment of pyriproxyfen was provided by EFED (DP#: 397089

, J. Hetrick

, 7 / 25 / 2012 ).

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

concen tration (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 modeli ng predicts that pyriproxyfen concentrations in surface source drinking water are not expected to exceed 1.952 μg/L for the daily peak and 0.111 μg/L for the annual average based on the proposed application rates for herbs. Tier 1 GENEEC modeling predicts that pyriproxyfen concentrations in ground source drinking water are not expected to exceed 0.000804 μg/L for the daily peak and annual average. Based on previous drinking water assessments for pyriproxyfen use on watercress, using the Tier 1 Rice Model, the maximum EDWC for pyriproxyfen in surface source drinking water are not expected to exceed 2.98 μg/L for peak and annual average concentrations. In ground water, the EDWCs for pyriproxyfen are not expected to exceed 0.006 μg/L for peak and

annual aver age concentrations. This assessment shows that past drinking water assessments for pyriproxyfen provide a higher EDWC. Although the remainder of this memorandum describes the modeling and results for EDWCs based on the proposed use on herbs, EFED recommen ds using 2.98 μg/L for the EDWC. The drinking water assessment is considered conservative since it was based on estimates of drinking water concentrations generated by the Tier 1 Rice Model

.

5

. 4 Dietary and Drinking Water Exposure and Risk

5

. 4 .1 Acute Dietary and Drinking Water Analysis

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

5

. 4 .2 Chronic Dietary and Drinking Water Analysis
A chronic dietary risk asses sment was conducted using the DEEM

- FCIDTM, Version 2.03, which incorporates consumption data from USDA’s CSFII, 1994

- 1996 and 1998. The chronic dietary exposure and risk estimates (food + drinking water) were estimated at 3

. 7 % of the cPAD for the U.S. popu lation and 1 2 % of the cPAD for the most highly

- exposed population subgroupPage 18 of 40



### (children 1

- 2 years old) and are thus below HED’s level of concern (<100% cPAD). See Table 6, below.

Table 6 . Summary of Dietary Exposure and Risk for Pyriproxyfen

.

Population Subgroup DEEM Chronic Dietary Analysis Exposure (mg/kg/day) % cPAD General U.S. Population 0.013105 3.7 All Infants (< 1 year old) 0.019055 5.4

Children 1

- 2 years old 0.042545 12

Children 3

- 5 years old 0.033830 9.7

Children 6

- 12 years old 0.019626 5.6

Youth 13

- 19 years old 0.011439 3.3

Adults 20

- 49 years old 0.010548 3.0 Adults 50+ years old 0.009321 2.7

Females 13

- 49 years old 0.010219 2.9



### 6 .0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

Pyriproxyfen is the active ingredient in many registered residential products for flea and tick control (home environment and pet treatments) as well as products for ant and roach control (indoor and outdoor applications). Formulations include carpet powd ers, foggers, aerosol sprays, liquids (shampoos, sprays, and pipettes for pet treatments), granules, bait (indoor and outdoor), and impregnated materials (pet collars).

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

in a previous memo (DP#: 281982, T. Swackhammer, 5/2/2002). O nly a post

- application

incidental oral assessment was conducted, since HED did not select any short

- term dermal or inhalation endpoints. HED has recently updated the residential st andard operating procedures (SOPs) and body weights to be used in all human health risk assessments. Therefore, the existing residential use patterns have been reassessed for residential handler and post application

exposures.

Residential Handler

There is the potential for short

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

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

Residentia l Post

- application Based on the registered use patterns, the following post

- application scenarios were assessed:

Hand

- to

- Mouth:

o Short

- and intermediate

- term hand

- to

- mouth exposures for 1 to <2 year olds from treated carpets and flooring and petting treated animals (shampoos, sprays, spot

- on treatments and collars).

o Long

- term hand

- to

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

Dermal:

o Long

- term dermal exposures from treated carpets, flooring, and pets (note efficacy of carpet powders is 365 days and efficacy of pet collars up to 395 days). Since no short

- or intermediate

term dermal endpoints were sele cted, no dermal assessment for these durations is included.Page 19 of 40



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

specifi c residue data for pyriproxyfen to determine the dissipation rate of residues or whether residues may be additive upon retreatment. Therefore, a Tier 1, screening level assessment was performed based on Day 0 residues without accounting for daily residue dissipation. HED anticipates that this assessment is protective as pyriproxyfen residues would be expected to dissipate from Day 0 residue values.

6.1 Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative post

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

identified for short

- and intermediate

- term inhalation exposures from pyriproxyfen

. V olatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and

Ro denticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109m eeting.html 

### ) and is in the process of evaluating the SAP report. The Agency may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place or if inhalation PODs are selected in the future , the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for

p yriproxyfen

.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application metho d employed for pyriproxyfen

. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to

its risk a ssessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with sig nificant risks

associated with drift.Page 20 of 40



### 7 .0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

In accordance with the FQPA, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major routes: ora l, dermal, and inhalation. There are three sources for these types of exposures: food, drinking water, and residential uses. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. T here are previously registered

residential uses of pyriproxyfen

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

7 .1 Short

- , Intermediate

- , and Long

- Term Aggregate Risk

In aggregating short

- term risk, HED considered background chronic

- dietary exposure (food + drinking water) and short

- term, residential non

- dietary oral exposures (hand

- to

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

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

- term dermal endpoint, a dermal

exposure assessment is not included in the short

- term aggregate assessment. The total short

- term dietary and residential aggregate (incidental oral) MOE is 2000

. As th is MOE is greater than 100, the chronic aggregate risk does not exceed HED’s level of concern. Table 7

. 1.5

summarizes the short

- term aggregate exposure to pyriproxyfen residues for Children 1

- 2 years of age which is the high est

- risk population subgroup (lowest MOE > 100)

.Page 21 of 40

Table 7.1.1

. Summary of Risk Estimates for Existing Residential Uses of Pyriproxyfen

Formulation

Use Maximum

Application

Rate a Route of Exposure Short

- Term

MOE Int ermediate

Term MOE Long

- Term

MOE b Combined

MOEs (Long

- term only)

Household/Pet Flea and Tick Control

Carpet powder

- flea

and tick

treatment 1 x10 - 6 lb ai /ft 2 Incidental oral (Hand

- to

- Mouth) 35 000 12 000 12000

4000

Dermal 1 to < 2

year olds N/A N/A 6100

Adults 5800 N/A

Fogger 4.99x10 - 7 lb

ai /ft 2 Incidental oral

(Hand

- to

- Mouth) 87 000 31 000 N/A N/A

Dermal N/A N/A N/A

Pet spray

mist 1.3x10 - 5 lb

ai/appl ication Incidental oral

(Hand

- to

- Mouth) 980000 340000 N/A N/A

Dermal N/A N/A N/A

Pet spot

- on for cats 1.7x10 - 4 lb

ai/appl ication Incidental oral

(Hand

- to

- Mouth) 76000 27000 N/A N/A

Dermal N/A N/A N/A

Pet spot

- on for dogs 2.1x 10 - 4 lb

ai/appl ication Incidental oral

(Hand

- to

- Mouth) 120000 44000 N/A N/A

Dermal N/A N/A N/A

Pet collars 4.63 x10 - 4 lb

ai/collar Incidental oral

(Hand

- to

- Mouth) 28000 9800 9800

320

Dermal 1 to < 2

year olds N/A N/A 330

Adults 830 N/A

Pet shampoos 1.13x10 - 4 lb

ai/appl ication Incidental oral

(Hand

- to

- Mouth) 12 0,000 41 ,000 N/A N/A

Dermal N/A N/A N/A

Ant and Roach Control

Granular Bait 0.225 lb ai/A Incidental oral (Hand

- to

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

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

b. Long

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

– pet collars and indoor carpet powder.Page 22 of 40

Table 7.1.2 : Non

- Cancer Residential Combined (Multiple Exposure Scenarios) Exposure and Risk Estimates for Pyriproxyfen

. Combined Exposure

Scenario Lifestage Exposure Scenario Route of Exposure Combined Within

Scenario MOEs Combined Across Scenarios MOE

ST IT LT ST IT LT

Flea

Scenario Adult Post

- application: Indoor Carpet

- Broadcast Dermal N/A N/A 5800

N/A N/A 730

Post

- application:

Pet

– Collar Dermal N/A N/A 830

Child Post

- application:

Indoor Carpet

- Broadcast Dermal N/A N/A

4000

16000 5400 300

Hand to

Mouth 35000 12000

Post

- application:

Pet

– Collar Dermal N/A N/A

320

Hand to

Mouth 28000 9800

Table 7.1.3 : Recommendations for the Residential Exposures for the Pyriproxyfen Aggregate Assessment. 1

Lifestage Route of Exposure Residential Post

- application MOE 2

Short

- term

Adult Male N/A N/A

Child Incidental oral 16000

Intermediate

- Term

Adult Male N/A N/A

Child Incidental oral 5400 Long

- Term

Adult Male Dermal 730

Child Dermal + Incidental oral 300

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

2 Residential Post

- application MOE = Combined flea treatment multiple scenario MOE (indoor carpet powder + pet treatment). For adults, th e only applicable exposure route is long

- term dermal. For children, the applicable exposure routes are short

- and

intermediate

- term incidental oral and combined long

- term incidental oral + dermal.



### In aggregating intermediate

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

- term, residential non

- dietary oral exposures (by toddlers following flea and tick control applications around the home and on pets for products

with labeled efficacies of more than 30 days

- carpet powder and pet shampoo ). Since HED did

not select an intermediate

- term dermal endpoint, a dermal

- exposure assessment is not included in

the intermediate

- term aggregate assessment. The total intermediate

- term dietary and residential

aggreg ate MOE is 720

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

exceed HED’s level of concern. Table 7

. 1.5 summarizes the intermediate

- term aggregate exposure to pyriproxyfen residues for Children 1

- 2 years of age which is the high es t

- risk population subgroup (lowest MOE > 100)

.Page 23 of 40

Table 7. 1.4 Short

- Term Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

LOC for Aggregate

Risk 1 Dietary

MOE 2 M OE Oral

Residential Exposure 3 M OE

Dermal

Residential Exposure 4 M OE

Inhalation

Residential Exposure 5 Aggregate

MOE (food, water, and residential) 6

Children 1

- 2 years old 100 2350 16000 NA NA 2000

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

- species)

2 MOE dietary = [(short

- or intermediate

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

3 MOE oral = [(short

- or intermediate

- term oral NOAEL)/(hand

- to

- mouth residential exposure)]. Oral study NOAEL= 35.1 mg/kg/ day . ( MOE f rom Table 7.1.3 ).

4 MOE dermal = Not applicable

5 MOE inhalation = Not applicable

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

Table 7. 1.5 Intermediate

- Term Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

LOC for Aggregate

Risk 1 Dietary

MOE 2 M OE Oral

Residential Exposure 3 M OE

Dermal

Residential Exposure 4 M OE

Inhalation

Residential Exposure 5 Aggregate

MOE (food, water, and residential) 6

Children 1

- 2 years old 100 825 5400 NA NA 720

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

- species)

2 MOE dietary = [(short

- or intermediate

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

3 MOE oral = [(short

- or intermediate

- term oral NOAEL)/( hand

- to

- mouth residential exposure)]. Oral study NOAEL= 35.1 mg/kg/ day. (MOE from Table 7.1.3).

4 MOE dermal = Not applicable

5 MOE inhalation = Not applicable

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

Table 7. 1.6 Long

- Term Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

LOC for Aggregate

Risk 1 Dietary

MOE 2 M OE Oral

+ Dermal

Residential Exposure 3 M OE

Dermal

Residential Exposure 4 M OE

Inhalation

Residential Exposure 5 Aggregate

MOE (food, water, and residential) 6

Adult Male

Adult Female

Children 1

- 2 years old 100 825 300 NA NA 220

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

- species)

2 MOE dietary = [( long

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

3 MOE oral + dermal = [( long

- term oral NOAEL)/( long

- term incidental oral + dermal exposure)]. Oral study NOAEL= 35.1 mg/kg/ day. (MOE from Table 7.1.3).

4 MOE dermal = Not applicable

5 MOE inha lation = Not applicable

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



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

- term, residential non

- dieta ry oral and dermal exposures (by toddlers following flea and tick control applications around the home and on pets for products with

labeled efficacies of more than 6 months

- carpet powder and pet collar). Since HED did not select a long

- term oral endpoint for pyriproxyfen, the chronic aggregate risk was performed using the chronic dietary endpoint. A long

- term post

- application residential assessment was performed for toddlers only since they are anticipated to have the higher exposures than adults

from tr eated home environments and pets due to their behavior patterns. The total chronic dietary and residential aggregate MOE is 220 . As th is MOE is greater than 100, the chronic aggregate risk does not exceed HED’s level of concern. Table 7

. 1.6 summarizes t he chronic aggregate exposure to pyriproxyfen residues for Children 1

- 2 years of age which is the high est

risk population subgroup (lowest MOE > 100)

.

8.0 CUMULATIVE RISK

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to pyriproxyfen and any other substances, and pyriproxyfen does not appear to produce a toxic metabolite produc ed by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that paraquat has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common

m echanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found t o have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

9 .0 OCCUPATIONAL EXPOSURE / RISK CHARACTERIZATION

9 .1 Exposure Scenarios

Based upon the proposed use pattern, HED believes the most highly exposed occupational pesticide handlers will be 1) mixer/loaders using open

- pour loading of liquid formulation, 2) mixer/loaders using open

- pour loading of wettable powders, 3) mixer/loaders using open pour loading of granules, 4) applicators using open

- cab ground

- boom sprayers, 5) applicators using

open

- cab airblast sprayers, 6) aerial applicators/ spray, 7) aerial applicators/ broadcast granule, 8) applicators using ground broadcast granules, 9) applicators using the “spoon” m ethod for distributing granules.

The label directed use of personal

- protective equipment (PPE) is as follows:

For the ant bait

– applicators and other handlers must wear long pants, long

sleeved shirt, shoes plus socks and waterproof gloves.Page 25 of 40 

### For the wett able powder

– applicators and other handlers must wear long

- sleeved shirt, long pants and shoes plus socks.

For Knack ® 

### insect growth regulator

– applicators and other handlers must wear

coveralls over short

- sleeved shirt and short pants or long

- sleeved shi rt and long pants, chemical

resistant gloves such as barrier laminate or Viton = 14 mils, chemical

- resistant footwear plus socks, chemical

- resistant headgear for overhead exposure, chemical resistant apron when cleaning equipment, mixing, or loading.

For P yriproxyfen 0.86 EC Ag Insect Growth Regulator

– Applicators and other handlers must wear long

- sleeved shirt, long pants, socks, shoes and chemical

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

Based upon the proposed use patter ns, HED expects pesticide handler exposures to be short

- term (1

- 30 days). Since there are no short

- term or intermediate

- term dermal or inhalation toxicological endpoints identified and since HED does not expect long

- term exposures, exposure and risk asses sments are not necessary for the proposed uses and are therefore not presented

here.

9

. 2 Handler Exposure

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

there are no short

- term or intermediate

- term dermal or inhalation toxicological endpoints

identified and since HED does not expect long

- term exposures, exposure and risk assessments are not necessary for the proposed uses

.

9.3 Post Application Exposure

For occupational handlers, there is no dermal toxicological endpoint; therefore, it is not necessary to estimate post

- application exposure or risk to agricultural workers.

9.3. 1 Restricted Entry Interval

Pyriproxyfen is classified as Toxicity Category III for acute dermal and inhalation toxicity and Category IV for acute oral, primary eye and skin irritation and it is not a skin sensitizer. The Worker Protection Standard interim REI is 12 hours for compounds in Toxicity Categories III and IV for the acute effects noted above. Therefore, a 12 hou r REI is sufficient to protect agricultural workers re

- entering treated areas.Page 26 of 40



### 10. REFERENCES

Pyriproxyfen. Amended Use. Expansions of Existing Crop Group/Representative Commodity Uses to Numerous Crop Subgroups, Adding Use on Herb Subgroup 1 9A. Summary of Analytical Chemistry and Residue Data., G.

Otakie

, D 3 97523

, 5/31/12

Pyriproxyfen. Chronic Dietary (Food and Drinking Water) Exposure Assessment for thePetition Proposing Tolerances for Residues of Pyriproxyfen on Herb Subgroup 19A, and th e Expansions of Existing Crop Group Uses to Numerous Crop Subgroups ., T. Morton, D397522

, 8/21/2012

Pyriproxyfen : Occupational and Residential Assessment to Support the New Use on the Herb Subgroup 19A and the Expansion of the Following Crop Groups/Subgroups: Bulb Vegetable Group 3

- 07; Fruiting Vegetable Group 8

- 10; Citrus Fruit Group 10

- 10; Pome Fruit Group 11

- 10; Caneberry subgroup 13

- 07A; Bushberry Subgroup 13

- 07B; and Low Growing Berry, Except Strawberry Subgroup 13

- 07H

. , I

. Nieves

, D40 4203

, 8/22/2012

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

- [1

- methyl

- 2

- (4

- phenoxyphenoxy)ethoxy]pyridine Pyriproxyfen on Herb Subgroup 19A

– J

. Hetrick

, D397089

, 7 / 25 / 20 1 2Page 27 of 40



### APPENDICES

A TOXICOLOGY DATA SUMMARY

A .1 Guideline Data Requirements

Guideline

No. Study Type Technical MRID No. Required Submitted

870.3100

870.3150

870.3200

870.3250

870.3465 Subchronic (Oral) Toxicity

- Rodent

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

Subchronic (Oral) Toxicity

- Non

- Rodent

................................ ...................... 21/28

- Day Dermal Toxicity

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

90

- Day Dermal Toxicity

90

- Day Inhalation Toxicity

................................ ................................ ............ N

Y

N

N

N Y

Y

Y

N

Y 41321716

00072416

44037205

00113718

870.3700a

870.3700b

870.3800 Prenatal Developmental Toxicity

- Rodent

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

Prenatal Developmental Toxicity

- Non

- Rodent

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

................................ ................................ .. Y

Y

Y Y

Y

Y 00113714

43964701

00096338

43949902

43215403

00126783

00149748

00149749

870.4100a

870.4100b

870.4200a

870.4200b

870.4300 Chronic (Oral) Toxicity

- Rodent

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

Chronic (Oral) Toxicity

- Non

- Rodent (Dog)

................................ ................. Carcinogenicity

- Rat..................

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

Carcinogenicity

- Mouse

Combined Chronic Toxicity /Carcinogenicity

- Rat Y

Y

Y

Y

Y Y

Y

N

Y

Y 43210503

00132472

43210503

00087924

40202403

40218001

00138637

870.6100a

870.6100b

870.6200a

870.6200b

870.6300

870.7800 Neurotoxicity

- Acute Delayed Neurotox.

- Hen

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

Neurotoxicity

- Subchronic

- Hen

................................ ................................ .. Neurotoxicity

- Acute

- Rat

................................ ................................ ............. Neurotoxicity

- Subchronic

- Rat

................................ ................................ ..... Developmental Neurotoxicity.................. Immunotoxicity.............................

................................ ......................... N

N

Y

Y

N

Y N

N

Y

Y

N

Y 47794201

47794202

48667301Page 28 of 40



### A .2 Toxicity Profiles

Table A.1

. b Toxicity Profile of Pyriproxyfen Technical

Guideline No./Study Type MRID No. (year)/

Classification /Doses Results

870.3100

90

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

Acceptable/guideline

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

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

196.5 mg/kg/day in females LOAEL =

838.1 mg/kg/day in males, 963.9 mg/kg/day in females based on pathological changes in the kidney, increased absolute and relative (to body) liver weight, decreased red blood cell parameters (both sexes) and decreased body weight gain (M)

870.3100

90

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

Acceptable/guideline

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

M: 0, 23.49, 117.79, 309.05 or 641.81 mg/kg/day F: 0, 27.68, 141.28, 356.30 or 783.96 mg/kg/day NOAEL = 23.49 mg/kg/day in males,

27.68 mg/kg/day in females LOAEL =

117.79 mg/kg/day in males, 141.28

based on increased total cholesterol and phospholipids (M),decreased red blood cell, hematocrit, and hemoglobin counts, increased relative (to body) liver weight (M), and negative trend in red blood cell volume (F) 

### Table A .1 .a Acute Toxicity of Pyriproxyfen Technical

Guideline

No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral 42178302 LD 50 > 5,000 mg/kg IV

870.1200 Acute Dermal 42178303 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation 42178304 LC 50 > 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 sensitizerPage 29 of 40

870. 3150

90

- Day oral toxicity non

- rodents (dog) 42178307 (1988)

Acceptable/guideline

0, 100, 300 or 1000 mg/kg/day (capsule NOAEL = 100 mg/kg/day in males and

females LOAEL = 300 mg/kg/day in

males and females based on increased absolute and relative ( to body) liver weight (both sexes) and hepatocyte enlargement (F)

870.3200

21

- Day dermal toxicity(rat) 43994102 (1993)

Acceptable/guideline

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

870.3200

21

- Day dermal toxicity(rat) 44037205 (1996)

Acceptable/guideline

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

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

dermal irritation including acanthosis, dermal lymphoid cell infiltrate and dermal hemorrhage (M&F).

870.3265

28

- Day inhalation toxicity (rat) 42178308 (1988)

Supplementary

0, 269, 482 or 1000 mg/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 bi ologically

relevant.

870.3700a

Prenatal developmental (rat) (non

guideline) 44985002 (1988)

Acceptable/nonguideline

0, 100, 300, 500 or 1000 mg/kg/day (gavage) Parental NOAEL = 100 mg/kg/day.

LOAEL = 300 mg/kg/day based on clinical signs, decreased body weight gains, increased water consumption (both sexes) and increased food consumption, changes in organ weights, and gross pathological changes (M)

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

870.3700a

Prenatal developmental (rat) (non

guideline) 44985001 (1988)

Acceptable/nonguideline

0, 30, 100, 300, or 500 mg/kg/day (gavage) Maternal NOAEL = 100 mg/kg/day.

LOAEL = 300 mg/kg/day based on clinical signs, decreased body weight gains, and decreased food consumption.

Developmental NOAEL = 100 mg/kg/day. LOAEL = 300 mg/kg/day based on decreased body weight and

increased incidence of dilation of the renal pelvis.Page 30 of 40

870.3700b

Prenatal developmental (rabbit) 41321720, 42178311, 43215401, 43215402, 4 3215403 (1989)

Acceptable/guideline

0, 100, 300 or 1000 mg/kg/day (gavage) Maternal NOAEL = 100 mg/kg/day.

LOAEL = 300 mg/kg/day based on premature delivery/abortions, soft stools, emaciation, lusterless fur, decreased activity, and bradypnea.

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

based on decreased viable litters

available for evaluation

870.3700a

Prenatal developmental (rat) 42178312 (1988)

Acceptable/guideline

0, 100, 300 or 1000 mg/kg/day (gavage) Maternal NOA EL = 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 vari ations at gestation day 21 and unspecified visceral variations at post natal day (PND) 56.

870.3800

Reproduction and fertility effects (rat) 42178313 (1991)

Acceptable/guideline

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

M: 0, 18, 87, or 453 mg/kg/day F: 0, 20, 96, or 498 mg/kg/day Parental/Systemic NOAEL = 87 mg/kg/day in males, 96 mg/kg/day in

females. LOAEL = 453 mg/kg/day in males, 498 mg/kg/day in females based on decreased body weight, body weight gain, and food consumption (both sexes) and incr eased liver weight (both sexes) and histopathological lesions of liver and kidneys (M)

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

females. LOAEL not established

.

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

LOAEL = 453 mg/kg/day in males,

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

870.4100b

Chronic toxicity (dog) 42178309 (1991)

Acceptable/guideline

0, 30, 100, 300 or 1000 mg/kg/day (capsule) NOAEL = 100 mg/kg/day in males and

females LOAEL = 300 mg/kg/day in males, 300 mg/kg/day in females based on decreased body weight gain and increased relative liver weight (both sexes) and increased cholesterol and triglycerides and decreased re d cell counts and hemoglobin in malesPage 31 of 40

870.4300

Chronic/Carcinogenicity (rat) 42178314, 43210501, 43210502, 43210503 (1991)

Acceptable/guideline

0, 120, 600 or 3000 ppm (diet)

M: 0, 5.42, 27.31 or 138.0 mg/kg/day F: 0, 7.04, 35.1 or 182.7 mg/kg/day NOAEL = 138 mg/kg/day in males,

35.1 mg/kg/day in females LOAEL not
established in males, 182.7 mg/kg/day in females based on decreases in body weight gain. No evidence of carcinogen icity

870.4200

Carcinogenicity (mouse) 42178310 (1991)

Acceptable/guideline

0, 120, 600 or 3000 ppm (diet)

M: 0, 16.8, 84.0, or 420 mg/kg/day F: 0, 21.9, 109.5, or 547 mg/kg/day NOAEL = 84 mg/kg/day in males,

109.5 mg/kg/day in females LOAEL =

420 mg/kg/day in males, 547 mg/kg/day in females based on renal

lesions in males and females. No evidence of carcinogenicity

870.5100

Bacterial Reverse Mutation Test 44503506 (1995)

Acceptable/guideline

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

and E.coli strain WP2uvra Non

- mutagenic with 2

- OH

- PY (metabolite of pyriproxyfen).

870.5100

Bacterial Reverse Mutation Test 44503507 (1993)

Acceptable/guideline

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

and E.coli strain WP2uvra Non

- mutagen ic with 4'

- OH

- PY, 5"

- OH

- PYR, DPH

- PYR, POPA, and PYPAC (metabolites of pyriproxyfen).

870.5100

Bacterial Reverse Mutation Test 44503508 (1995)

Acceptable/guideline

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

and E.coli strain WP2uvra Non

- mutagenic with 2,5

- OH

- PY (metabolite of pyriproxyfen).

870.5100

Bacterial Rev erse Mutation Test 42178315 (1988)

Acceptable/guideline

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

TA1538 and E.coli strain WP2uvra Non

- mutagenicPage 32 of 40

870.5300

In vitro Mammalian Cell Gene

Mutation Test 42178316 (1990)

Acceptable/guideline

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

of activation. Non

- mutagenic at the HGPRT locus

870.5375

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

Acceptable/guideline

Chinese hamster ovary (CHO) cell cultures in the absence or presence of

activation. Negative. Did not induce structural

chromosome aberrations

870.5550

Unscheduled DNA Synthesis in

Mammalian Cells in Culture 42178317 (1988)

Acceptable/guideline

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

of S

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

was induced

870.6200a

Neurotoxicity screening battery

- Acute neurotoxicity (rat) 48711901, 48711903, 48711904 (2011)

Acceptable /guideline

0, 300, 1000 or 2000 mg/kg (gavage) The NOAEL is 1000 mg/kg bw/day.

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) 48711901, 48711902, 48711905 (2011)

Acceptable /guideline

0,1500, 5000, or 15,000 ppm (diet)

M: 0, 108, 359, 1111 mg/kg /day

F: 0, 102, 407, 1212 mg/kg /day Neurotoxicity. NOAEL = 15,000 ppm ( 1111 mg/kg/day for males and 1212 mg/kg/day for females). T he LOAEL for neurotoxicity was not observed

.

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

.Page 33 of 40

870.7485

Metabolism and pharmacokinetics (rat) 42178318 (1988)

Acceptable/guideline Rats were orally dosed with 14 C

- labeled pyriproxyfen at 2 or 1000 mg/kg and at repeated oral doses [14 daily doses] of unlabeled pyriproxyfen at 2 mg/kg followed by administration of a single oral dose of labeled pyriproxyfen at 2 mg/kg. Most radioactivity was excreted in the feces [8 1

- 92%] and urine [5

- 12%] over a 7 day collection period. Expired air containing CO2 was not detected. Tissue radioactivity levels were very low [less than 0.3%] except for fat. Examination of urine, feces, liver, kidney, bile and blood metabolites yielded numerous [ > 20] identified metabolites when compared to synthetic standards. The major

biotransformation reactions of pyriproxyfen include: 1. Oxidation of

the 4'

- position of the terminal phenyl group; 2. Oxidation at the 5'

- position of pyridine; 3. C leavage of the ether linkage and conjugation of the resultant phenols with sulfuric acid.

870.7800

Immunotoxicity (mouse) 48711906

, 4871190 7 (2012)

Acceptable The systemic toxicity LOAEL is 5000 ppm (1139 mg/kg/day), based on lower bodyweight gain and increase of absolute and relative body weight to liver weight . The NOAEL for systemic toxicity is 2000 ppm (449 mg/kg/day).

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



### A.3 Toxicological Endpoints

A .3.1 Acute Reference Dose (aRfD)

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

- 49

Study Selected: None

MRID Nos.: NA

Comments about Study/Endpoint: An appropriate endpoint attributable to a single oral dose was not available in the data base, including developmental toxicity in the developmental toxicity

studies.Page 34 of 40



### A .3. 2 Chronic Reference Dose ( c RfD)

-

Study Selected: Subchronic toxicity and chronic toxicity (feeding)

- rat (co

- critical)

MRID No 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic) Dose and Endpoint for Establishing a cRfD: NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 mg/kg/day based on decreased body weight and alterations in clinical pathology parameters

. 

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

Comments about Study/Endpoint/Uncertainty Factor: This endpoint from co

- critical studies is an appropriate endpoint of duration and provides the lowest NOAEL in the databa se for chronic

effects via the oral route.

A

. 3

. 3 Incidental Oral Exposure ( S hort

- Term)

Study Selected: rat developmental

MRID Nos.: 44985002



### Executive Summary: Parental NOAEL = 100 mg/kg/day. LOAEL = 300 mg/kg/day based on clinical signs, decreased body weight gains, increased water consumption (both sexes) and increased food consumption, changes in organ weights, and gross pathological changes (M)

Comments about Study/Endpoin t: 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. Th e endpoint from the rat developmental stud y provides the highest NOAEL for the short

- term exposure assessment.

Incidental Oral Exposure ( I ntermediate

- Term)

Study Selected: Subchronic toxicity and chronic toxicity (feeding)

- rat (co

- critical)

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

NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 mg/kg/day based on decreased body weight and alterations in clinical pathology parameters

. 

### Uncertainty Factor(s): 100x (10x for interspecies extrapolation and 10x for intraspeci es variations). Chronic RfD = 35.1 mg/kg/day = 0. 351 mg/kg/day

100Page 35 of 40



### Comments about Study/Endpoint: Evaluation of effects across durations of exposure suggests toxicity increases with duration of exposure. Therefore the short

- term endpoint is not appropriate for the intermediate duration of exposure. Th e endpoint from co

- critical studies is

the highest NOAEL in the database for the intermediate

- term scenario via the oral route.

A

. 3

. 4 Dermal Absorption

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

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

- and intermediate

term dermal exposure assessments are not warranted. An oral endpoint was selected to be protective of the long

- term dermal as sessment. For the long

- term dermal assessment, d ermal penetration was estimated to be 30% by the extrapolation method of comparing the maternal toxicity LOAEL of 300 mg/kg/day in the rat developmental toxicity oral study and the dermal NOAEL of 1,000 mg/kg /day in the 21

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

- penetration factor of 30% was

used for the route

- to

- route extrapolation in this long

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

A

. 3

. 5 Dermal Exposure ( Short

- , Intermediate

- , and Long

- Term )

Short

- and Intermediate

- Term

Study Selected: NA

MRID Nos.: NA

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

- day dermal rat toxicity study.

Comments about Study/Endpoint: The 21

- day dermal rat toxicity study did not result in toxicity up to the limit dose. There are no developmental susceptibility or neurotoxicity concerns from the oral database, therefore a quantitative dermal assessment is not warranted.

Dermal Exposure (Long Term)

Study Selected: Subchro nic toxicity and chronic toxicity (feeding)

- rat (co

- critical)

MRID No 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic)

Dose and Endpoint for Establishing a cRfD: NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 mg/kg/day based on decreased body weight and alterations in clinical pathology parameters

. 

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

### Page 36 of 40

Comments about Study/Endpoint/Uncertainty Factor: A long

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

- term dermal assessment. An oral endpoint was selected to be protective of the long

- term dermal assessment. For the long

term dermal assessment, d ermal penetrat ion was estimated to be 30% by the extrapolation method of comparing the maternal toxicity LOAEL of 300 mg/kg/day in the rat developmental toxicity oral study and the dermal NOAEL of 1,000 mg/kg/day in the 21

- day dermal study.

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

dermal

- penetration factor of 30% was used for the route

- to

- route extrapolation in this long

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

A .3. 6 Inhalation Exposure ( Short and Intermediate

- Term )

Study Selected: 21

- Day inhalation toxicity study in rats

MRID No.: 42178308 Executive Summary: NA

Dose and Endpoint for Risk Assessment : NOAEL = 0.482 mg/L (males and females) LOAEL =

1.000 mg/L based on salivation (both sexes), sporadic decreased body weight gain (M), and increased lactate dehydrogenase (M). Decreases in actual body weights were not observed. These minor changes are not considered biologically relevant.

Comments about Study/Endpoin t: The minor changes observed at the highest concentration tested are not considered to be biologically relevant. Therefore a quantitative inhalation

assessment is not warranted for the short and intermediate

- term durations.

Inhalation Exposure (Long Term)

Study Selected: Subchronic toxicity and chronic toxicity (feeding)

- rat (co

- critical)

MRID No 41321716 (subchronic) 42178314, 43210501, 43210502, 43210503 (chronic) Executive Summary:

Dose and Endpoint for Establishing a cRfD: NOAEL = 35.1 mg/kg/day, LOAEL = 141.28 mg/kg/day based on decreased body weight and alterations in clinical pathology parameters

. 

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

Comments about Study

/Endpoint/Uncertainty Factor: A long

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

- term inhalation assessment. This

oral endpoint from co

- critical studies is the lowest NOAEL in the database for chronic effec ts via

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

assessment.

### Page 37 of 40

A.4 EXECUTIVE SUMMAR IES (recently submitted studies)

A. 4.1 Neurotoxicity

870. 6200a Acute

– Rat

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

- fasted

, 6 weeks old Crl:CD(SD) rats , 12/sex/dose were given a single oral dose of Pyriproxyfen T.G. (99.5%, Lot # 080506G) in corn oil at doses of 0, 300, 1000 or 2000 mg/kg bw and observed for 14 days.

Neurobehavioral assessment functional observational battery and motor activity testing was performed on all animals at 8 hours post dosing. At study termination, all animals were euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 6/sex/gro up 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 patholo gy, neuropathology or FOB measurements. Motor activity testing revealed test substance

- related, lower total and ambulatory counts at 1000 and 2000 mg/kg group males, compared with the control group on study Day 0 only. Compared to the control group, mean m otor activity counts were 20.9% and 21.4% lower (total) and 20.0% and 27.4% lower (ambulatory) for the 1000 and 2000 mg/kg group males, respectively, and were significant (p<0.032) for the 2000 mg/kg group. By study Days 7

- 14, mean total and ambulatory act ivity counts for males of both groups were unaffected by test

substance.

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

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

NOAEL is 1000 mg/kg bw/day.

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

870. 6200b Subchronic

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

### Page 38 of 40

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

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

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

- related clinical findings noted at any concentration and all animals survived to the scheduled necropsy on Study

D ay 91. In the 15,000 ppm group, significantly (p<0.01) lower mean body weight gains were noted during Study Days 0

- 14 and 0

- 7 for the males and females, respectively. Mean body weight gains for males and females in this group generally remained lower (occa sionally significant; p<0.01) than the control group throughout the remainder of the study and resulted in significantly (p<0.01) lower mean cumulative body weight gains (Study Days 0

- 91). As a result, mean body weights for the 15,000 ppm group males and f emales 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 observ ed throughout the remainder of the study. Test

substance

- related, lower mean food consumption (g/animal/day) was noted in the 15,000 ppm group males and females throughout the treatment period (Study Days 0

- 91); differences were generally significant (p<0. 05 or p<0.01) for males and occasionally significant (p<0.05 or p<0.01) for females. FOB and motor activity parameters were not significantly affected by test substance administration. Gross and histopathological examinations, as well as brain weights and measurements, were not affected by test substance administration.

Based on the effects seen in this study, the LOAEL for neurotoxicity was not observed, with

a NOAEL of 15,000 ppm (1111 mg/kg/day for males and 1212 mg/kg/day for females).

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

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

Immunotoxicity

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

- I mice (n=10) in the diet at dose levels of 0, 1000, 2000, or 5000 ppm (0, 228, 449, 1139 mg/kg bw/day) for at least 28 days. An additional positive group of 8 female mice were administered cycl ophosphamide 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

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mortality, clinical signs, body w eight changes food and water consumptions. On study day 25, a ll

animals were immunized wi th 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) w ere determined by an antibody plaque

- forming

- cell (PFC) assay.

There were no test substance

- related clinical signs of toxicity, morbidity, or mortality during the treatment period. Lower bodyweight gain compared to the controls, was observed in animals receiving 1000 or 5000 ppm (30% lower from controls). There were no test substance

- related effects on food consumption. There were no treatment

- related effects on macroscopic pathology of any treated group. There was a dose

- related increase of absolute and relative body weight to liver weight and, with the exception of absolute liver weights at 1000 ppm, these differences were statistically significant from controls. There were no effe ct of treatment on spleen, thymus or adrenal weight.

The systemic toxicity LOAEL is 5000 ppm (1139 mg/kg/day), based on lower bodyweight gain and increase of absolute and relative body weight to liver weight . The NOAEL for systemic toxicity is 2000 ppm (449 mg/kg/day).

There were no statistically significant changes in the numbers of cells/spleen, PFC/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 seve n 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 compar ed to the

control.

The LOAEL for immu notoxicity 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.

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APPENDIX C. Physical/Chemical Properties

Physicochemical Properties of Technical Grade Paraquat Dichloride.

Parameter Value Reference

Melting point/range decomposes at ca. 340 °C Product Chemistry Chapter of the Paraquat Dichloride Update, 10/10/91 pH 6.4 at 20 °C

Density 1.5 g/cm 3 at 25 °C

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

618

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

Solvent solubility (20 °C) <0.1 g/L in acetone, dichloromethane, toluene, ethyl acetate, and hexane; 143 g/L in methanol

Vapor pressure <<10 - 8 kPa at 25 °C

Octanol/water partition coefficient, Log(K OW ) log K OW =

- 4.5 at 20 °C

Dissociation constant, pK

a 0.95 (pure active ingredient) Product Chemistry Chapter of the Paraquat Reregistration Standard,

11/25/85



### APPENDIX D. Studies Reviewed for Ethical Conduct

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

Agricultural Re

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