### Acetamiprid Hum a n Health Ri s k Assessment 04 232 98

, 0 426 11 5, 04 2 6 11 7, 04 27 19 4



### U

NITED STAT E S E NVIRONM EN TAL PROTE C TIO N AGEN C Y

WA S HI N GTO N, D C 20460

OFF I CE OF C HEMI C AL S AF E TY A N D

POLLUTIO N PR E V EN T I O N



### MEM ORA N D UM

DAT E : 2 September 2015

SU BJ EC T: Acetamiprid

. Human H ealth R i s k Asses s m e nt Addressing Proposed Label

A mendm e nt s fo r Use of Two E nd- Use Pr o du c t s (E P s) on V a ri ous C rops ; Proposed ew E P fo r Contro llin g Fleas, T i cks a nd Mosquitoes o n D ogs; and a
Petition Propo s in g Label Amendments for Two E P s, and R ev i sed P e rman e nt

Tolerances

, for Us e of the i n sec ticide on Clover w i th a Decrea se d Pr e- H arve s t

I nterval (Reg i onal R egistration).

P C Code: 099050 OP B a rc o d e s : 0423298

. 0426115. 0426117

. 0427194

R eg i st r a ti o n N um be r s: 8033-20. 8033-23

. 8033-36

F ile S y mb o l : 8033- R G R D ec i s i on Nu mb e r s : 494790. 500044. 500022. 495418

P e t i ti o n : 4 E 8307 R eg u l at o r y Ac ti o n : Section 3

Ri s k Asses s m e nt T y p e: S in gle C h emica l. Aggregate

T X R N um be r : NA Case N umb e r : 76 1 7

CAS N umb e r : 1 354 1 0-20-7

40 C FR : § 18 0.578 MRID N um be r s : 4944380 I. 49443802



### F RO M :

TH R U:

TO:

and W illiam T. Dr ew

. Chemist Karlyn Middleton, Toxic o lo g i st**~** 

### Ri s k Assessment Branch II ( R A B2 · /1 

# j 

# j

J osh u a God s hall

, B i o l og i s t 

# Q....**~l/\** 

### Ri s k Assessment Branch I ( R A B 

# t'f

He a lth Effects Di v i sion ( H ED). 7509 P

Elizabeth H o lm a n
, Phy s ic J,. I

## foej~**nti s~** **~ ~**  C hristina Swa r t z, Chief**~ ~**  

### RAB2

H E D. 7509P

Barbara Madden and Sidney Jackson

, RM Team 05

Minor Use and E mer ge nc y R espo n se Branch (MUE RB ) Registrati o n Di v ision ( RD)

, 7505P

P

age I of 49Ac e tamiprid Human Health Ri s k A s sessment 042 3 298

, 0426115

, 0426117

, 0427194



### and Venus Eag l e a nd Jacquel y n Marchese, RM Team 0 I

I nvertebrate-V crtebra l e Branch 

### 3 ( TV 

### B3)
RD, 7505P

J e1rnifer Urbansk i and Eli z abeth Fertich

, RM Team 04

Invertebrate- Vertebrate Branch 1 

### (IV BI) RD, 7505P

P age 2 of 49Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 3 of 49 

### Table of Contents

1.0 Executive Summary

................................ ................................ ................................ .......................... 4

2.0 HED Recommendations

................................ ................................ ................................ .................... 5

2.1 Data Deficiencies/Conditions of Registration

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2.2.2 International Harmonization

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

2.2.3 Recommended Tolerances

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

2.2.4 Revisions to Petitioned

- For Tolerances

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

2.3 Label Recommendations

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

3.0 Introduction

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

3.1 Chemical Identity

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

3.2 Physical/Chemical Characteristics

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

3.3 Pesticide Use Pattern

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

3.4 Anticipated Exposure Pathways

................................ ................................ ................................ .. 12

3.5 Consideration of Environmental Justice

................................ ................................ ..................... 13

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ............................. 13

4.1 Summary of Toxicology Database and Toxicological Effects

................................ .................... 13

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

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

4.2.1 Completeness of the Toxicology Database

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

4.2.2 Evidence of Neurotoxicity

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

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

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

4.2.4 Residual Uncertainty in the Exposure D atabase

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

4.3 Toxicity Endpoint and Point of Departure Selections

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

5.0 Dietary Exposure and Risk Assessment

................................ ................................ .......................... 21

5.1 Metabolite/Degradate Residue Profile

................................ ................................ ........................ 21

5.2 Food Residue Profile

................................ ................................ ................................ ................... 21

5.3 Water Residue Profile

................................ ................................ ................................ ................. 2 3

5.4 Dietary Risk Assessment

................................ ................................ ................................ ............ 23

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Spray Drift

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

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .................... 29

7.1 Acute Aggregate Risk

................................ ................................ ................................ ................. 29

7.2 Short

- and Intermediate

- Term Aggregate Risk

................................ ................................ ........... 29

7.3 Chronic Aggregate Risk

................................ ................................ ................................ .............. 3 0

7.4 Cancer Aggregate Risk

................................ ................................ ................................ ............... 31

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ .................. 31

9.0 Occupational Exposure/Risk Characterization

................................ ................................ ............... 3 1

9.1 Short

- , Intermediate

- and Long

- Term Handler Risk

................................ ................................ ... 32

9.2 Short

- and Intermediate

- Term Post

- A pplication Risk

................................ ................................ 36

9.2.1 Dermal Post

- A pplication Risk

................................ ................................ ............................ 36

9.2.2 Inhalation Post

- A pplication Risk

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

10.0 References

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

................................ ................................ ..... 4 2 Appendix B. Physicochemical Properties

................................ ................................ ................................ .. 49Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 4 of 49 

### 1.0 Executive Summary

Acetamiprid (CAS name (1 E )

- N

- [(6

- chloro

- 3

- pyridinyl)methyl]

- N′

- cyano

- N

methylethanimidamide) is a selective insecticide intended for use against various sucking and chewing insect pests that feed upon fruit and vegetable crops. It is a member of the chloronicotinyl (neon icotinoid) class of insecticides, which function by binding to nicotinic acetylcholine receptors in the post

- synaptic neurons of the insect’s central nervous system. This binding results in the opening of ion pores, causing a subsequent overload of sodium ions in the neurons which leads to nervous system hyper

- excitation, and the eventual death of the insect.

Acetamiprid is registered for use on a variety of crops, and permanent tolerances have been established ranging from 0.010 ppm to 50 ppm in plant commodities (40 CFR §180.578[a][1]), and from 0.010 ppm to 0.70 ppm in livestock commodities (40 CFR §180.578[a][2]). There are also permanent tolerances (with regional registrations) established in clover forage at 0.10 ppm, and clover hay at 0.01 ppm (4 0 CFR §180.578[c]). The residue definition for risk assessment and tolerance enforcement is the parent compound in plant commodities, and combined residues of the parent compound and Metabolite IM

- 2

- 1 in livestock commodities (plus Metabolite IM

- 2

- 1

- amide in ruminant muscle for risk assessment purposes only). Acceptable analytical methods are available to enforce tolerances for residues of acetamiprid in plant and livestock

commodities. This risk assessment addresses 3 separate registration requests, con sisting of a proposed increase in tolerances for residues in clover commodities, label amendments for existing agricultural uses, and a new spot

- on product for use on dogs, as described below.

Interregional Research Project #4 (IR

- 4) has submitted a peti tion (4E8307) requesting an amended use pattern, and revised tolerances in clover forage and hay, for use of acetamiprid on clover grown for seed in ID, OR and WA only. The proposed pre

- harvest interval (PHI) is 30 days for clover, compared to the current ly registered PHI of 56 days. The end

- use products (EPs) proposed for regional registration are Assail 70WP Insecticide (EPA Registration #8033

- 23), a wettable powder (WP) formulation containing 70% of the active ingredient (ai) by weight,

and Assail 30SG Insecticide (EPA Registration #8033

- 36), a soluble granule (SG) formulation containing 30% of the ai by weight.

IR

- 4 submitted field trial data for acetamiprid on clover grown for seed in response to an Agency request for two additional clover field trials as confirmatory data (D364833; D. McNeilly; 14 October 2009). In conjunction with the petition, IR

- 4 has proposed the revision of established tolerances for residues of acetamiprid in or on clover forage (from 0.10 to 0.3 ppm) and clover hay (from 0.01 to 1.5 ppm), with regional registration (in ID, OR and WA only) . The proposed tolerance in clover forage is supported adequately by the current submitted field trial residue data, in conjunction with previously submitted field trial data (D364833; D. McNeilly; 14 October 2009) . The current submitted field trial residue data support the recommended

tolerance s of 2.0 ppm in clover hay

, and 0.30 ppm in clover forage

.

A lso

, Nippon Soda Company Limited (care of Nisso America Incorporated) has proposed multiple label amendments (D426115 and D426117) for revised use patterns of the sameAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 5 of 49 

### acetamiprid EPs (Assail 70WP and Assail 30SG) on various crops. These amendments do not require the revision of any existing acetamiprid tolerances.

Additionally, Nipp on Soda has proposed a new EP, RF2213 AE CDSO Insecticide ( EPA File Symbol 8033

- RGR ) for controlling fleas, ticks and mosquitoes on dogs. The RF2213 AE CDSO Insecticide contains 9.5% acetamiprid, 20.0% etofenprox, 8.0% piperonyl butoxide, and 5.0%

s

- metho prene. This assessment addresses exposure and risk associated with the use of acetamiprid only; it does not address etofenprox, piperonyl butoxide, or s

- methoprene exposure associated with the use of this product.

HED has evaluated the hazard informati on, proposed labels

, and residue data for these revised or

new uses , and assessed risk associated with occupational, residential, dietary and aggregate

exposures. Risk estimates based on screening level, upper

- bound inputs are below HED’s level

of concern (LOC) for all scenarios and population subgroups, including those of infants and

children.

This risk assessment has taken into consideration potential environmental justice issues. Based on the existing and proposed uses fo r acetamiprid, and on current Office of Pesticide Programs ( OPP ) assessment policies, there are no environmental justice concerns associated with acetamiprid.

There are no human health risk concerns that would preclude granting the requested uses

, and

est ablishing increased tolerances for residues of acetamiprid in clover

.

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

, which comprise the Occupational Pesticide Handlers Exposure Database (OPHED

, available at the EPA internet site s http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html )

, have been determined to require a review of their ethical conduct, have received that review, and have been determined to

have be en ethically conducted.

2.0 HED Recommendations

HED has examined the residue chemistry database for acetamiprid. Pending submission of a revised Section F (to propose tolerances in clover forage and hay in accordance with HED’s

rec ommendations), there are no residue chemistry issues that would preclude increasing the

establishe d tolerances to the recommended levels . The recommended tolerances are listed in

Table 2.2. 3 , below.

HED has no objection regarding the proposed label amendments for revised use patterns of the acetamiprid EPs, Assail 70WP and Assail 30SG, on various crops. HED also has no objection to the proposed use on dogs to control fleas, ticks and mosquitoes

.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 6 of 49 

### Notes to RD: 1) An error has been identified with a commodity definition in the existing 40CFR entry for acetamiprid, which currently lists “Vegetable, tuberous and corm, group 1” under 40CFR §180.578[a][1]. This listing should be revised to read “Vegetable, tuberous and corm, subgroup 1C” when the tolerances for clover forage and hay are revised. 2) The analytical reference standard for acetamiprid metabolite IM

- 1

- 4 (having expired on 1 April 2015) is currently unavailable in EPA’s National Pesticide Standards Reposito ry (NPSR), per Email communication from

Theresa Cole of the Biological and Economic Analysis Division’s Analytical Chemistry Branch (BEAD/ACB) on 1 June 2015. RD should notify the registrant (Nisso America Incorporated) regarding this lack of a

reference standard for metabolite IM

- 1

- 4, and request that the registrant provide a new reference standard, or updated certificate of analysis (COA), as soon as possible. 3) In order to assess post

- application exposure for workers contacting treated
cotton, HED re lied on a chemical

- specific study for tribufos; use of the surrogate study may result in data compensation issues for the registrants.

2.1 Data Deficiencies/Conditions of Registration

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Approved tolerance enforcement methods for acetamiprid residues in crops are available, including gas chromatography with electron capture detection (GC/ECD) for vegetables and

non

- citrus fruits, high performance liquid chromatography with ultravio let detection (HPLC/UV) for citrus fruits only, and HPLC with tandem mass spectrometric detection (LC/MS/MS) for vegetables and non

- citrus fruits. Two of t hese methods are ad equate for enforcing the proposed tolerances associated with this petition.

2. 2.2 International Harmonization

Codex has not established maximum residue limits (MRLs) for acetamiprid in clover forage or hay. Canada’s Pest Management Regulatory Agency (PMRA) does not establish MRLs in livestock feed items. Ergo, there are no issues with international harmonization that need to be

addressed.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 7 of 49 

### 2.2.3 Recommended Tolerances

The currently established tolerance expressions for acetamiprid (40CFR §180.578) are adequate, and include both coverage and compliance statements for enforcement purposes.

Note to RD: An error has been identified with a commodity definition in the exi sting 40CFR entry for acetamiprid, which currently lists “Vegetable, tuberous and corm, group 1” under 40CFR §180.578[a][1]. This listing should be revised to read “Vegetable, tuberous and corm, subgroup 1C” when the tolerances for clover forage and hay a re revised.

TABLE 2.2. 3 Tolerance Summary for Acetamiprid ( 40CFR §180.578[c] ). Commodity Existing

Tolerance (ppm) Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) 1 Correct Commodity Definition ; Comments

Clover

, forage 0.10 2 0.3 0. 3 0 Based on current and previous clover

field trial data submitted by IR

- 4.

Clover

, hay 0.0 1 2 1.5 2.0 Based on current clover field trial data submitted by IR

- 4.
1. Tolerance level as recommended by HED.

2. A tolerance is currently established at the listed tolerance level in the corresponding commodity.



### 2.2.4 Revisions to Petitioned

- For Tolerances

The submitted clover field trial data support a tolerance of 2.0 ppm, instead of the proposed tolerance of 1.5 ppm, in clover hay. The petitioner used residues in clover hay from all field trials to calculate the tolerance level (PHIs of 27

- 63 days). The draft labels stipulate a PHI of 30 days (decreased from 56 days on the current labels). Therefore, only residues from those trials where hay was collected at PHIs of 27

- 32 days were used to calculate the tolerance; residues from those trials where hay wa s collected at PHIs of 50

- 63 days were not used. HED utilized residue data for hay collected at PHIs of 27

- 32 as the input dataset for the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedure, yielding a

different r esult (2.0 ppm).

In clover forage, the recommended tolerance level includes an additional significant figure (0.30 ppm rather than 0.3 ppm). This is in order to avoid the situation where rounding of a residue result to the level of precision of the tol erance expression would be considered non

- violative (such as 0.34 ppm being rounded to 0.3 ppm).

The petitioner should submit a revised Section F, specifying the recommended tolerances in

Table 2.2.3 (above)

.

2.3 Label Recommendations

None.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 8 of 49 

### 3.0 Introduction

Acetamiprid is a selective insecticide intended for use against various sucking/chewing insect pests that feed upon fruit and vegetable crops. It is a member of the chloronicotinyl (neonicotinoid) class of insecticides, which function by binding to nicotinic acetylcholine receptors in the post

- synaptic neurons of the insect’s central nervous system. This binding results in the opening of ion pores, causing a subsequent overload of sodium ions in the neurons which leads to nervous system hyper

- excitation, and eventual death of the insect. The chemical structure and nomenclature of acetamiprid are listed in Table 3.1 (below).

3.1 Chemical Identity

TABLE 3.1 Acetamiprid Nomenclature

. Chemical Structure

Common Name Acetamiprid

Molecular Formula C 10 H 11 ClN 4 Molecular Weight 222.68 Company Experimental Name EXP

- 61842A, AEF124370, NI

- 25

IUPAC Name ( E )

- N 1

- [(6

- chloro

- 3

- pyridyl)methyl]

- N 2

- cyano

- N 1

- methylacetamidine

CAS Name (1 E )

- N

- [(6

- chloro

- 3

- pyridinyl)methyl]

- N'

- cyano

- N

- methylethanimidamide CAS Registry Number 135410

- 20

- 7

End

- use Products (EPs) Assail 70WP (70% WP; EPA Registration #8033

- 23) Assail 30SG (30% SG; EPA Registration #8033

- 36)

RF2213 AE CDSO Insecticide (9.5% Spot

- o n; EPA File Symbol 8033

- RGR)



### 3.2 Physical/Chemical Characteristics

The physicochemical properties of technical

- grade acetamiprid are summarized in Appendix B

. The values in the table suggest that there are no exposure scenarios that are likely to require special consideration. The vapor pressure for acetamiprid is quite low and

, a s such, inhalation

exposure via volatilization is expected to be negligible. The octanol/water partition coefficient indicates that partitioning into fatty tissues is unlikely

, and that there is low potential for

bioaccumulation.

3.3 Pesticide Use Pattern

IR

- 4 has proposed an amended use pattern, and revised tolerances in clover forage and hay, for foliar broadcast use of the insecticide acetamiprid on clover grown for seed in ID, OR and WA only. The proposed PHI is 30 days for clover, compared to the curr ently registered PHI of 56 days. The EPs proposed for regional registration are Assail 70WP Insecticide (EPA RegistrationAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 9 of 49 

### #8033

- 23), a WP formulation containing 70% of the ai by weight, and Assail 30SG Insecticide (EPA Registration #8033

- 36), an SG formul ation containing 30% of the ai by weight. Examples of the proposed labels were provided, and the proposed revision of the use directions therein are summarized in Table 3.3.1, below.

TABLE 3.3.1 Summary of Proposed Label Directions for Use of Acetamipr id on Clover. Application Timing; Type; Equipment 1 Use Rate

(lb ai/A) Max. Uses

per Season Maximum

Seasonal Use Rate (lb ai/A) PHI 2

(Days) Use Directions and Limitations

Assail 70WP

Post

- emergence; foliar broadcast; ground, aerial 0.05

-

0.075 1 3 0.075 30 Minimum spray volume of 5 GPA 4 by air, or 20 GPA by ground. Begin applications when treatment thresholds have been reached. Thorough coverage is important to obtain optimum control.

Assail 30SG

Post

- emergence; foliar broadcast; ground, aerial 0.047

-

0.075 1 3 0.075 30 Minimum spray volume of 5 GPA by air, or 20 GPA by ground. Begin applications when treatment thresholds have been reached. Thorough coverage is important to obtain optimum control.
1. Not to be applied via chemigation.

2. PHI = Pre

- Harvest Interval. 3. Implied; more than 1 application at the minimum single use rate would exceed the maximum seasonal use rate.

4. GPA = Gallons Per Acre.



### Conclusion: The use directions for application to clover are sufficient to allow f or evaluation of the submitted residue data relative to the proposed use pattern.

Nisso America has also proposed multiple label amendments for revised use patterns of the same acetamiprid EPs (Assail 70WP and Assail 30SG) on various crops. The request ed revisions increase single (but not seasonal) use rates, add pests, and make additional minor changes to the EP labels. These label revisions do not change the amount of ai applied per acre per year , and no revisions to tolerances were proposed by the registrant. Required personal protective equipment (PPE) for Assail 30 SG and Assail 70 WP Insecticides include long sleeved shirts, long pants, shoes plus socks, chemical resistant gloves, and chemical resistant headgear for overhead

exposure. In additi on, for aerial applications only

, assail 70WP Insecticide require s mixers/loaders to wear a dust/ mist filtering respirator. Both labels incorporate a 12 hour

r estricted e ntry i nterval (REI). Examples of the proposed labels were provided, and the proposed use pattern revisions therein are summarized in Table 3.3.2, below.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 10 of 49 TABLE 3.3.2 Summary of Proposed Amendments to Label Directions for Use of Acetamiprid. Crop Pest Current

Use Rate (lb ai/A) Proposed

Use Rate (lb ai/A) Amendments to Use Directions and

Limitations

Assail 70WP (EPA Registration #8033

- 23)

Cotton Whitefly 0.075

- 0.10 0.075

-

0.15 To “Do not make more than 4 applications per season,” add “or more than 2 applications per season if 2 applications of the highest labeled rate is applied for both applications.” Leafy Vegetables (within Crop Group 4) Aphid 0.035

- 0.075 0.035

-

0.10 To “Do not make more than 5 applications per season,” add “or more than 3 applications per season if 3 applications of the highest labeled rate is applied for all 3 applications.” Whitefly 0.05

-

0.075 0.05

- 0.10

Head and Stem Cole Crops (within Crop Subgroup 5A) NA 1 NA NA Change “Head and Stem Cole Crops (within Crop Subgroup 5A)” to “Head and Stem Brassica (within Crop Subgroup 5A).”

Leafy Cole Crops (within Crop Subgroup 5B) NA NA NA Change “Leafy Cole Crops (within Crop Subgroup 5B)” to “Leafy Brassica (within Crop Subgroup 5B).”

Fruiting Vegetables (within Crop Group 8

- 10) Leafhopper 2 NA 0.05

- 0.075 Add “Begin applications when treatment thresholds have been reached. Thorough coverage is important to obtain optimum control.” to the use directions for the new target pest, leafhopper. Citrus (within Crop Group 10

- 10) Asian Citrus Psyllid NA NA Add “(suppression)” note to this target pest.

Apple Maggot, Plum Curculio, San Jose

Scale Remove “(suppression)” note from these target

pests.

Grapes (within Crop Sub

Group 13

- 07F) All target pests NA NA Remove “For ASSAIL WSP Insecticide Only (1

to 2 packets)” from dosage per acre. Change “WSP” to “70WP” in mealybugs use directions. Remove “Do not use adjuvants.” from

restrictions.

Cucurbits (within Crop Group 9) Whitefly 0.05

- 0.10 0.05

- 0.15 To “Do not make more than 5 applications per season,” add “or more than 3 applications per season if 3 applications of the highest labeled rate is applied for all 3 applications.” To “Do not apply less than 0 days before harvest (PHI = 0 days),” add “with application rate of 2.3 oz/A or less.” Add “Do not apply less than 5 days before harvest (PHI = 5 day s) with application rate of 3.5

oz/A.” to restrictions.
Legume Vegetables (within Crop

Sub

- Groups 6A and 6B) Colorado Potato

Beetle 2 NA 0.044

- 0.10 Add “Colorado Potato Beetle: Use higher rates when populations are high, dense foliage exists, or when large larvae or adults are present. Thorough coverage is important to obtain optimum control.” to use directions.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 11 of 49 TABLE 3.3.2 Summary of Proposed Amendments to Label Directions for Use of Acetamiprid. Crop Pest Current

Use Rate (lb ai/A) Proposed

Use Rate (lb ai/A) Amendments to Use Directions and

Limitations

Berries (within Crop Sub

Groups 13

- 07A

and 13

- 07B) EAST of Rocky

Mountains Only. Spotted Winged Drosophila (larvae) 2 NA 0.085

- 0.10 Add “Spotted Winged Drosophila (larvae): Begin applications when adults are present and fruit is ripening or already ripe. It is recommended to

tankmix with an adulticide.” to use directions.
Assail 30SG (EPA Registration #8033

- 36)

Cotton Whitefly 0.075

- 0.10 0.075

-

0.15 To “Do not make more than 4 applications per season,” add “or more than 2 applications per season if 2 applications of the highest labeled rate is applied for both applications.” Leafy Vegetables (within Crop Group 4) Aphid 0.038

- 0.075 0.038

-

0.10 To “Do not make more than 5 applications per season,” add “or more than 3 applications per season if 3 applications of the highest labeled rate is applied for all 3 applications.” Whitefly 0.056

-

0.075 0.056

-

0.10

Head and Stem Cole Crops (within Crop Subgroup 5A) NA NA NA Change “Head and Stem Cole Crops (within Crop Subgroup 5A)” to “Head and Stem Brassica (within Crop Subgroup 5A).”

Leafy Cole Crops (within Crop Subgroup 5B) NA NA NA Change “Leafy Cole Crops (within Crop Subgroup 5B)” to “Leafy Brassica (within Crop Subgroup 5B).”

Fruiting Vegetables (within Crop Group 8

- 10) Leafhopper 2 NA 0.047

- 0.075 Add “Begin applications when treatment thresholds have been reached. Thorough coverage is important to obtain optimum control.” to the use directions for the new target pest, leafhopper. Citrus (within Crop Group 10

- 10) Asian Citrus Psyllid NA NA Add “(suppression)” note to this target pest.

Grapes (within Crop Sub

Group 13

- 07F) All target pests NA NA Remove “Do not use adjuvants.” from

restrictions.

Cucurbits (within Crop Group 9) Whitefly 0.047

- 0.10 0.047

-

0.15 To “Do not make more than 5 applications per season,” add “or more than 3 applications per season if 3 applications of the highest labeled rate is applied for all 3 applications.” To “Do not apply less than 0 days before harvest (PHI = 0 days),” add “with application rate of 5.3 oz/A or less.” Add “Do not apply less than 5 days before harvest (PHI = 5 day s) with application rate of 8.0
oz/A.” to restrictions.
Legume Vegetables (within Crop

Sub

- Groups 6A

and 6B Colorado Potato

Beetle 2 NA 0.047

- 0.10 Add “Colorado Potato Beetle: Use higher rates when populations are high, dense foliage exists, or when large larvae or adults are present. Thorough coverage is important to obtain optimum control.” to use directions.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 12 of 49 TABLE 3.3.2 Summary of Proposed Amendments to Label Directions for Use of Acetamiprid. Crop Pest Current

Use Rate (lb ai/A) Proposed

Use Rate (lb ai/A) Amendments to Use Directions and

Limitations

Berries (within Crop Sub

Groups 13

- 07A

and 13

- 07B) EAST of Rocky

Mountains Only. Spotted Winged Drosophila (larvae) 2 NA 0.085

- 0.10 Add “Spotted Winged Drosophila (larvae): Begin applications when adults are present and fruit is ripening or already ripe. It is recommended to
tankmix with an adulticide.” to use directions.
1. NA = Not Applicable. 2. New pest added to the list of target pests.



### Conclusions: B ased on risk estimates for the proposed higher single application rates

, HED has no objection regarding the proposed amendments to the labels’ use directions.

Additionally, Nippon Soda has proposed a new spot

- on EP, RF2213 AE CDSO Insecticide ( EPA File Symbol 8033

- RGR) for controlling fleas, ticks and mosquitoes on dogs. Th e RF2213 AE CDSO Insecticide contains 9.5% acetamiprid

. An e xample of the proposed label w as provided, and the proposed use pattern revisions therein are summarized in Table 3.3. 3 , below.

TABLE 3

. 3

. 3 Summary of Proposed Label Directions for Spot

- On Use of Acetamiprid on Dogs

. Use Site Max imum Use Rate Per Dog Use Restrictions

Toy/ s mall dogs ( 4 to

9 lbs) 0.8 ml applicator tube (0.027 fl oz)

80 mg ai/treatment 1 ( 0 .00018 lb ai

/treatment ) 2 Do not use on dogs less than 6 months old. Do not use more than one cartridge per dog. Do not treat more than once per month (30 days)

. Do not apply to dogs weighing less than 4 lbs. Apply directly to the dog’s skin, not to the hair. Medium dogs ( 10 to

22 lbs ) 2.0 ml applicator tube (0.068 fl oz)

203.5 mg ai/treatment 1 ( 0.00045 lb ai

/treatment ) 2

Large dogs ( 23 to 55

lbs ) 5.0 ml applicator tube (0.169 fl oz)

505.8 mg ai/treatment 1 ( 0.0011 lb ai

/treatment ) 2

Extra

- l arge dogs ( ≥
56 lbs) 8.0 ml applicator tube (0.271 fl oz)

811 mg ai/treatment 1 ( 0.0018 lb ai

/treatment ) 2

1. Use rate in m g ai/treatment = [ (fl oz product ) × ( 0.84455 lbs ai/gal) ÷ ( 128 fl oz /gal ) × (453592.37 mg/lb) ].

2. Based on the proposed label for the request ed spot

- on use of RF2213 AE CDSO Insecticide EPA File Symbol

8033

- RGR

. [ (fl oz product × 0.844 55 lb ai/gal) ÷ 128 fl oz /gal ]

.



### Conclusions: HED has no objection to registration of the proposed new spot

- on EP

.

3.4 Anticipated Exposure Pathways

Acetamiprid is register ed for us e on growing crops

, as well as in and around the home. As a result of the uses on crops, as well as a recently proposed and assessed use in food/feed handling establishments, humans may be exposed to acetamiprid in food and drinking water. In ad dition, exposure may occur in residential or non

- occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as duringAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 13 of 49 

### application. There is also a potential for post

- applicatio n exposure for workers re

- entering

treated fields.

Risk assessments have been previously prepared for the existing uses of acetamiprid. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new

uses of acetamiprid, and also considers the existing uses, particularly for dietary exposure.

3.5 Consideration of Environmental Justice

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

human health risk assess ment, in accordance with US Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations" ( at the

internet site http://ww w.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to

well

- established procedures. In line with OPP policy, HED estimates risks to population subgro ups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled from the US Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA)

, and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized b y subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when

conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products

, and associated risks for adult appli cators and for toddlers, youths and adults entering or playing on treated areas post

- application are evaluated. Further

consideration s are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm

workers

, as well as lifestyle and traditional dietary patterns among specific su bgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Comprehensive risk assessments for acetamiprid were conducted in 201 3 ( D410182 ; E. Holman ; 20 March 2013 ). For this assessment, no changes have been made regarding endpoint selection for dietary exposure (acute and chronic) n or short

- and intermediate term incidental oral, dermal, or inhalation exposure. However, endpoints and p oint s of d eparture ( PODs ) have b een selected for long

- term scenarios (incidental oral and dermal) since long term exposure is anticipated based on the proposed pet use

.

4.1 Summary of Toxicology Database and Toxicological Effects

The database for acetamiprid is considered complete. An inhalation study is not available for acetamiprid. However, the Hazard Science Policy Council (HASPOC) previously determinedAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 14 of 49 

### that the study is not needed (TXR 0056556; K. Rury; 20 February 2013). C onsequently, the 10X database uncertainty factor retained in the 2012 assessment for inhalation scenarios has been removed, with the LOC being lowered to 100 for these scenarios. The toxicity database for acetamiprid contains :

1 ) S ubchronic oral toxici ty studies in rats, mice and dogs;

2 ) a chronic oral toxicity study in dogs

, and carcinogenicity stu di es in rats and mice;

3 ) developmental and reproduction studies in rats

, and a developmental study in rabbits;

4 ) acute, subchronic and developmental ne urotoxicity studies in rats;

5 ) immunotoxicit y studies in rats and mice; and

6 ) subchronic dermal toxicity and dermal penetration studies in rats.

There is also a complete mutagenicity battery, as well as metabolism studies in the rat

. No

literature information is available that would have an impact upon risk assessment. Metabolites were only examined in some mutagenicity studies.

In all species tested, generalized nonspecific toxicity was observed as decreases in body weight, body w eight gain, food consumption

, and food efficiency. Generalized effects were also observed in the liver in the form of hepatocellular hypertrophy in both mice and rats

, and hepatocellular vacuolation in the rat. These effects are considered to be adaptive . Other effects observed in the oral studies include amyloidosis of multiple organs in the mouse oncogenicity study, tremors in high dose females in the mouse subchronic study, and microconcretions in the kidney papilla

, and mammary hyperplasia in the rat chronic/oncogenicity study.

No effects were observed in the 21

- day dermal study in the rabbit

, and no inhalation studies were

conducted. A dermal absorption study with acetamiprid was conducted using male rats with exposure durations up to 24 hours. In some earlier acetamiprid risk assessment s , a 30% dermal absorption value was estimated from this study . However, HED has refined the dermal absorption value (to 10%)

, based upon comparison to clothianidin, which is structurally related

.

Acetamiprid is rapidly absorbed and eliminated. Metaboli sm studies indicate 96

- 99% absorption following an oral administration. Peak blood concentrations in the rat occur within 1

- 2 hours, with nearly complete clearance from the blood by 48 hours. Acetamiprid distr ibutes widely in the body but tissue burdens rarely exceed 1% of the administered dose. Acetamiprid is extensively metabolized

, with metabolites accounting for 79

- 86% of the administered radioactivity. 6

- Chloronicotinic acid is the most abundant metaboli te, accounting for 24

- 28% of the dose in single

- dose studies

, and 8

- 10% in repeated

- dose studies. Urinary excretion was the major route of elimination, accounting for 79

- 97% of the administered dose within 24 hours in single oral dose groups. Fecal excre tion accounted for 21

- 35% of the administered radioactivity, with males being slightly higher. Excretion rates for the IV and repeated dose studies were

similar. Biliary excretion did not vary between genders

, and by 48 hours accounted for about 19% of the administered radioactivity.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 15 of 49 

### There wa s no evidence of increased quantitative or qualitative susceptibility of rat or rabbit

fetuses to in utero exposur e in the developmental studies.

In the 2

- generation reproduction study, qualitative evidence of increased susceptibility of rat pups was observed. The parental and offspring systemic effects were based on a decrease in mean body weight, body weight gain, and food consumption in the parents

, and significant reductions in pup weights in both generations. Also observed w ere reduction in litter size and viability and weaning indices among F 2 

### offspring

, as well as significant delays in the age to attain vaginal opening and preputial separation. The se offspring observations were considered to be more severe than the parental effects.

In the developmental neurotoxicity (DNT) study

, there was also evidence of increased qualitative susceptibility. In this study, the offspring lowest observed adverse effect level ( L OAEL ) was based on decreased body weights and body weight gains in males and females, decreased pre

weaning survival on post

- natal days (PNDs) 0

- 1, and decreased maximum auditory startle response in males on PND s 20 and 60

. This was observ ed in the presence of decreased maternal body weight and body weight gains during gestation. Although offspring and maternal effects were observed at the same doses, the offspring effects were considered to be more severe.

In a rat acute neurotoxicity study, a decrease in locomotor activity was observed in both sexes on the day of dosing. A slight decrease in the duration of movements persisted in some males during later observations . Functional observational battery evaluations revealed several

treat ment

- related observations on the day of dosing. At the high dose only, males exhibited tremors, difficulty in handling, walking on toes, dilated pupils

, coldness to the touch

, as well as decreased forelimb grip strength and hind limb foot splay. High

- dos e females displayed tremors, chewing, coldness to the touch, dilated pupils

, decreased hind limb foot splay , and abnormal gaits and/or posture, including walking on toes and hunched posture. This was not noted in a subchronic rat neurotoxicity study

. No neuropathology was observed in any of the neurotoxicity studies. Tremors in high dose female mice in the subchronic feeding study were the only other potentially neurotoxic effect observed in any other studies.

Four

- week immunotoxicity studies wer e performed for both sexes in rats and mice. No effects on the immune system were observed in either species up to the highest dose tested . Significant reductions in body weight and body weight gain were noted at that dose.

Acetamiprid did not show cl ear evidence of genotoxic potential. It was positive as a clastogen in

an in vitro mammalian chromosome aberration assay in Chinese hamster ovary (CHO) cells. However, the in vivo chromosomal aberration study does not support the results of the in vitro study. A cetamiprid metabolites IC

- 0, IM

- 1

- 2, IM

- 1

- 4, IM

- 2

- 1 and IM

- 0 tested negative for mutagenicity.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 16 of 49 

### Acute lethality studies conducted with acetamiprid indicate d that it is moderately toxic via the

acute oral route (Category II); however, it has low toxicity via the acute dermal or inhalation routes (Categories III). It is non

- irritating to the eyes and skin

, and is not a dermal sensitizer.

4.2 Safety F actor for Infants and Children (FQPA Safety Factor)

HED previously recommended the 10X Food Qua lity Protection Act ( FQPA ) S afety F actor ( SF )

be reduced to 1X for the following reasons: T he tox icology data base is complete for the purpose of the FQPA assessment ; HED is regulating the use of acetamiprid based upon the effects of concern, such as deve lopmental effects in pups following p re

- and/or post

- natal

exposure; the rat is the most sensitive species tested, and the no observed adverse effect level ( NOAEL ) and LOAEL selected from the DNT study in rats are protective of effects observed in other species throughout the toxicology database; there are no residual uncertainties for pre

and/or post

- natal toxicity ; the exposure databases (dietary food, drinking w ater, and residential) are complete ; and the risk assessment for each potential exposure scenario includes all metabolites and/or degradates of concern

, and does not underestimate the potential risk to infants

or children.

4.2.1 Completeness o f the Toxi cology Database

As summarized in Appendix Table A1, the toxicology database is considered adequate for the purpose of assessing pre

- and post

- natal susceptibility, including an immunotoxicity study. Acceptable developmental toxicity studies in the rat an d rabbit

, and a rat reproductive toxicity study have been submitted. Based on a weight of evidence ( WOE ) approach considering all the available hazard and exposure information

, and proposed addition of a respirator for mixing

and/or loading of the WP form ulation for aerial application, or other appropriate mitigation, HED’s HASPOC concluded that a subchronic inhalation toxicity study is not required for acetamiprid at this time ( TXR# 0056556 )

.

4.2.2 Evidence of N eurotoxicity

Acetamiprid produced signs of neurotoxicity in the high dose groups in the acute and developmental neurotoxicity studies in rats. In the acute neurotoxicity study, male and female rats displayed decreased motor activity, tremors, walking and posture abnor malities, dilated pupils, coldness to the touch, and decreased grip strength and foot splay. However, no neurotoxic findings were reported in the subchronic neurotoxicity study. There was a decrease in the auditory startle response in male rats in the DNT. Tremors in the high dose female mice in the subchronic feeding study were the only other potent ially neurotoxic effect observed in the

other studies.

4.2 .3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

HED determined th at evidence of neither quantitative nor qualitative increased susceptibility of

fetuses to in utero exposure to acetamiprid was observed in either d evelopmental toxicity studyAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 17 of 49 

### in rat or rabbit. However, in the 2

- generation reproduction study, evidence of qualitative increased susceptibility of rat pups was observed. While parental and offspring NOAELs and LOAELs are set at the same doses, the effects in the offspring (including decreased viability) are considered to be more severe than those observed in t he parents (decreased body weight and body weight gain)

. In the DNT study, maternal and offspring effects were observed at the same dose. However, the offspring effects included decreased pup viability

, which is considered to be

more severe than the mate rnal body weight effects. Therefore, HED concluded that there was evidence of increased qualitative susceptibility to fetuses exposed in utero and/or during lactation in the DNT study. No evidence of q uantitative increased susceptibility was observed in any study.

4.2 .4 Residual Uncertainty in the Exposure Datab ase

Since there is evidence of increased qualitative susceptibility of the young following in utero exposure to acetamiprid in the rat reproduction study, and increased qualitative susceptibility to pups in the DNT study, HED performed a degree of concern analysis to:

1) D etermine the LOC for the effects observed when considered in the context of

all available toxicity data; and 2) identify any residual uncertainties after establishing toxicity endpoints and traditional uncertainty factors to be used in the acetamiprid risk

assessment.

If residual uncertainties are identified, HED examines whether the residual uncertainties can be addressed by a n FQPA SF , and if so, what factors should be retained.

Considering the overall toxicity profile and the endpoints and doses selected for the acetamiprid risk assessment, HED characterized the degree of con cern for the effects observed in the acetamiprid DNT study as low , noting that there is a clear NOAEL for the offspring effect s
, and regulatory doses were selected to be protectiv e of these effects. No other residual uncertainties

were identified with res pect to susceptibility

. HED believes that the endpoints and doses selected for acetamiprid are protective of adverse effects in both offspring and adults.

HED has used conservative assumptions in the exposure assessment, including the use of 100%

crop treated ( % CT ) assumptions, tolerance

- level residue values, and upper

- bound estimates of potential exposure through drinking water. In addition, the residential exposure assessment was conducted such that residential exposure and risk will not be underest imated. The aggregate exposure and risk estimates presented in this assessment are expected to over

- estimate the actual exposure and risk anticipated, based on the current and proposed use patterns ; no risk estimates

of concern were identified

.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 18 of 49 

### 4.3 Tox icity Endpoint and Point of D eparture Selections

The toxicological endpoints and PODs selected for dietary and occupational exposure and risk assessment are presented in Tables 4.3.1 and 4.3.2 (below) . The complete toxicological profile

for acetamiprid is summarized in Appendix A.2. For this assessment, endpoints and PODs have been selected for long

- term incidental oral and dermal exposure

, since long term exposure is anticipated based on the proposed pet use. There have been no other changes to the

en dpoints/PODs selected for risk assessment or the cancer classification.

For acute dietary and short

- and intermediate

- term incidental oral, dermal and inhalation exposure, the DNT NOAEL of 10 mg/kg/day was selected, with a LOAEL of 45 mg/kg/day. In this DNT study, parental effects were limited to decreased body weight and body weight gains, while the offspring effects noted were decreased body weights and body weight gains, decreased

pre

- weaning survival (PNDs 0

- 1), and decreased maximum auditory startle response in males on

PNDs 20 and 60

.

For chronic dietary and long

- term incidental oral and dermal exposure, the combined chronic/carcinogenicity rat NOAEL of 7.1 mg/kg/day was selected

, with a LOAEL of 17.5 mg/kg/day. In the study, decreased bo dy weight and body weight gains were seen in females

, and hepatocellular vacuolation was observed in males.

Since an oral study was selected for assessing risks associated with dermal and inhalation exposure, a dermal absorption factor of 10% was applie d to dermal risk assessments

, and toxicity via the inhalation route is considered to be equivalent to toxicity via the oral route.

For all of the relevant routes and durations of exposure, clear NOAELs and LOAELs were identified. In addition, the toxic ity database is considered to be largely complete, and no database uncertainty factors (UFs) were needed to account for missing data. With the reduction of the FQPA SF to 1X, the standard uncertainty factors of 100X (based on 10X for intraspecies

variabil ity

, and 10X for interspecies extrapolation) were applied. For dermal and inhalation risk assessment, the LOC is a margin of exposure (MOE) of < 100. For dietary assessments, the combined UF of 100X was incorporated into the relevant reference doses (RfDs ) and population adjusted doses (PADs).Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 19 of 49 TABLE 4.3.1 Summary of Toxicological Doses and Endpoints of Acetamiprid for Use in Dietary and

Non

- Occupational Human Health Risk Assessment

. Exposure

Scenario POD Used in

Risk

Assessment Uncertainty

Factors/FQPA Safety Factors PAD; LOC

for Risk

Assessment Study and Toxicological Effect

Acute Dietary ( a ll populations) NOAEL = 10

mg/kg/day UF A = 1 0X

UF H = 1 0X FQPA SF = 1X aPAD = 0.10

mg/kg/day Co

- critical studies

Developmental Neurotoxicity in rat

LOAEL = 45 mg/kg/day

, based on decreased early pup survival on PND

0

- 1, and decreased startle response on

PND 20/60 in males. Acute Neurotoxicity Study in rat LOAEL = 30 mg/kg/day

, based on decreased locomotor activity Chronic Dietary ( all populations ) NOAEL = 7.1

mg/kg/day UF A = 1 0X

UF H = 1 0X FQPA SF = 1X cPAD = 0.071

mg/kg/day Chronic Toxicity/Oncogenicity Study

in rat LOAEL = 17.5 mg/kg/day

, based on decreased body weight and body weight gains in females

, and hepatocellular vacuolation in males.

Short

- and

Intermediate

- t erm Incidental Oral (1

- 30 days

, 1

- 6

months ) NOAEL = 10

mg/kg/day UF A = 1 0X

UF H = 1 0X FQPA SF = 1X Residential

LOC for MOE

< 100 Developmental Neurotoxicity in rat

LOAEL = 45 mg/kg/day

, based on decreased body weight and body weight gains in offspring, decreased early pup survival on PND 0

- 1, and decreased startle response on PND

20/60 in males. Long

- term
Incidental Oral (> 6 months ) NOAEL = 7.1

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE

= 100 Chronic Toxicity/Oncogenicity Study

in rat LOAEL = 17.5 mg/kg/day

, based on decreased body weight and body weight gains in females

, and hepatocellular vacuolation in males.

Short

- and

Intermediate

- term
Dermal (1

- 30 days

, 1

- 6

months ) NOAEL = 10

mg/kg/day

DAF = 10% UF A = 1 0X

UF H = 1 0X FQPA SF = 1X Residential

LOC for MOE

< 100 Developmental Neurotoxicity in rat

LOAEL = 45 mg/kg/day

, based on decreased body weight and body weight gains in offspring, decreased early pup survival on PND 0

- 1, and decreased startle response on PND

20/60 in males.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 20 of 49 TABLE 4.3.1 Summary of Toxicological Doses and Endpoints of Acetamiprid for Use in Dietary and

Non

- Occupational Human Health Risk Assessment

. Exposure

Scenario POD Used in

Risk

Assessment Uncertainty

Factors/FQPA Safety Factors PAD; LOC

for Risk

Assessment Study and Toxicological Effect

Long

- term Dermal (> 6 months ) NOAEL = 7.1

mg/kg/day

DAF = 10% UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE

< 100 Chronic Toxicity/Oncogenicity Study

in rat LOAEL = 17.5 mg/kg/day

, based on decreased body weight and body weight gains in females

, and hepatocellular vacuolation in males.

Short

- and

Intermediate

- term
Inhalat ion (1

- 30 days, 1

- 6

mo nths ) NOAEL = 10

mg/kg/day

Inhalation toxicity

assumed to be equivalent to oral toxicity UF A = 1 0X

UF H = 1 0X FQPA SF = 1X Residential

LOC for MOE

< 100 Developmental Neurotoxicity in rat

LOAEL = 45 mg/kg/day

, based on decreased body weight and body weight gains in offspring, decreased early pup survival on PND 0

- 1, and decreased startle response on PND

20/60 in males.

Can cer (oral, dermal, inhalation) = not likely to be carcinogenic to humans (2005 revised Agency cancer guidelines).
DAF = dermal absorption factor. Point of Departure (POD) = A data point or an estimated point that is derived from

observed dose

- response data and used to mark the beginni ng of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to hu man (interspecies).

UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. UF DB = Database uncertainty factor retained for missing data. PAD = population adjusted dose (a =

acute, c = chronic) = reference dose/all uncertainty factors. MOE = margin of exposure. LOC = level of concern.

TABLE 4.3.2 Summary of Toxicological Doses and Endpoints of Acetamiprid for Use in Occupational

Human Health Risk Assessment

. Exposure Scenario POD Used in

Risk Assessment Uncertainty

Factors LOC for Risk

Assessment Study and Toxicological Effect

Short

- and

Intermediate

- term
Dermal (1

- 30 days

, 1

- 6 mo nths ) NOAEL = 10 mg/kg/day

DAF = 10% UF A = 1 0X

UF H = 1 0X Occupational

LOC for MOE

< 100 Developmental Neurotoxicity in rat

LOAEL = 45 mg/kg/day

, based on decreased body weight and body weight gains in offspring, decreased early pup survival on

PND 0

- 1, and decreased startle response on PND 20/60 in males. Long

- term Dermal (> 6 months ) NOA EL = 7.1 mg/kg/day UF A = 10 X

UF H = 10X Occupational

LOC for MOE

< 100 Chronic Tox icity/Oncogenicity

Study in rat LOAEL = 17.5 mg/kg/day

, based on decreased body weight and body weight gains in females

, and hepatocellular vacuolation in

males.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 21 of 49 Short

- and

Intermediate

- term
Inhalation (1

- 30 days, 1

- 6 mo nths )

Note: N ot applicable to the proposed pet

use because in halation exposure is negligible

. NOAEL = 10 mg/kg/day

Inhalation toxicity assumed to be equivalent to oral toxicity UF A = 1 0X

UF H = 1 0X Occupational

LOC for MOE

< 100 Developmental Neurotoxicity in rat

LOAEL = 45 mg/kg/day

, based on decreased body weight and body weight gains in offspring, decreased early pup survival on

PND 0

- 1, and decreased startle response on PND 20/60 in males.

Cancer (oral, dermal, inhalation) = not likely to be carcinogenic to humans (2005 revised Agency cancer guidelines )

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

- response data and

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from anima l to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). DAF = dermal absorption factor. MOE = margin of exposure. LOC = level of concern.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

The nature of the residue for acetamiprid has been adequately delineated

, based on acceptable plant and livestock metabolism studies, as well as confined rotational crop studies

. T he parent compound is the only re sidue of concern in drinking water, based on environmental fate data

. T he residue definitions for tolerance enforcement and risk assessment are summarized in Table

5.1 (below)

. For further details on these metabolism studies, please refer to the briefing (D278352; M. Doherty et al ; 16 October 2001) and decision ( D278652 ; M. Doherty et al; 13

November 2001 ) memoranda

.

TABLE 5 .1 Summary of Acetamiprid 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 Acetamiprid Acetamiprid

Rotational Crop NA* None at this time

Livestock Ruminant Acetamiprid + IM

- 2

- 1 + IM

- 2

- 1

- amide (muscle only) Acetamiprid + IM

- 2

- 1

Poultry Acetamiprid and IM

- 2

- 1 Acetamiprid + IM

- 2

- 1 Drinking Water Acetamiprid NA * NA = Not Applicable.



### 5.2 Food Residue Profile
Residue Chemistry Summary Document D423321; W.T. Drew; 2 September 2015



### IR

- 4 submitted a petition ( 4E8307 ) requesting an amended use pattern (shorter PHI) , and revised tolerances in clover forage and hay, for use of acetamiprid on clover grown for seed in ID, OR and WA only. The proposed PHI is 30 days for clover, compared to the currently registered PHI

of 5 6 days. The petition was submitted along with field trial data for acetamiprid on cloverAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 22 of 49 

### grown for seed in response to an Agency request for two additional clover field trials as confirmatory data (D364833; D. McNeilly; 14 October 2009). In conjunction w ith the petition,

IR

- 4 has proposed the revision of established tolerances for residues of acetamiprid in or on clover forage (from 0.10 to 0.3 ppm) and clover hay (from 0.01 to 1.5 ppm), with regional registration (in ID, OR and WA only) . The proposed to lerance in clover forage is supported adequately by the current submitted field trial residue data, in conjunction with previously submitted field trial data (D364833; D. McNeilly; 14 October 2009) . The current submitted field trial residue data support t he recommended tolerance s in clover forage and in clover hay of 0.30

and 2.0 ppm , respectively

.

Two pairs of field trials were conducted in the US in North American Free Trade Agreement (NAFTA) Growing Zone 11 during the 2010 (MRID #49443801) and 2012 ( MRID #49443802) growing seasons. Applications were made in accordance with the proposed labeling

, and the residue data are supported by appropriate analytical method and storage stability data. Table

5.2.1 (below) summarizes the submitted field trial dat a for clover forage and hay

.

The OECD tolerance calculation procedure was used for setting tolerances in clover forage and in clover hay, using residue data from the submitted clover field trial studies. The submitted clover field trial data support a tolerance of 2.0 ppm, instead of the proposed tolerance of 1.5 ppm, in clover hay. The petitioner used residues in clover hay from all field trials to calculate the tolerance (PHIs of 27

- 63 days). The draft labels stipulate a PHI of 30 days (decreased from 56 days on the current labels). Therefore, only residues from those trials where hay was

collected at PHIs of 27

- 32 days (current submitted data) were used to calculate the tolerance;

residues from those trials where hay was collected at PHIs of 50

- 63 days (previously submitted data) were not used. HED utilized the residue data for hay collected at PHIs of 27

- 32 as the input dataset for the OECD tolerance calculation procedure, yielding a different result (2.0 ppm).

The proposed tolerance increase in clover forage (from 0.10 to 0.30 ppm) is supported adequately by the current submitted field trial residue data, in conjunction with previously submitted field trial data (D364833; D. McNeilly; 14 October 2 009). The current submitted field trial residue data support the recommended tolerance increase in clover hay (from 0.01 to 2.0 ppm).

TABLE 5. 2 .1 Summary of Residue Data from Clover Field Trials with Acetamiprid. Crop Matrix Total Use

Rate (lb ai/A) PHI

(Days) n 1 Residues (ppm)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3
Clover forage 0.075

- 0.080 27

- 32 3 0.0496 0.169 0.0812 0.163 0.102 0.115 0.0425 Clover hay 0.075

- 0.080 27

- 32 3 0.200 0.763 0.450 0.753 0.462 0.555 0.172

0.077

- 0.080 50

- 53 2 0.0592 0.116 0.0648 0.111 0.0879 0.0879 NA 4

1. n = number of field trials. 2. Values based on individual samples. 3. Values based on per

- trial averages. LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial;

SD = Standard Deviation. 4. NA = Not Applicable (standard deviation is not calculated for sample sets where n < 3).Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 23 of 49 

### 5.3 Water Residue Profi le
Drinking Water Assessment D423299 ; K. White ; 25 March 2015



### In a drinking water assessment memo ( D423299 ; K. White; 25 March 2015 )

, the Environmental Fate and Effects Division ( EFED ) provided estimated residues of acetamiprid in surface and groundwater sources of drinking water from the use of acetamiprid on cranberries, and as a

scatter bait. The scatter bait use results in the highest estimated drinking water concentrations (EDWCs) for chronic scenarios, while the use on cranbe rry results in the highest EDWCs for

acute scenarios

. The EDWCs used in th e dietary exposure and r isk assessment are summarized ( bold

- face type ) in Table 5.3 , below . The surface water EDWCs were generated using the Food Quality Protection Act Index Reser voir Screening Tool (FIRST) Model, and the groundwater

EDWCs are from the Pesticide Root Zone Model for GroundWater (PRZM

- GW) Model. The models and their descriptions are available at the EPA internet site http://www.epa.gov/oppefed1/models/water/

.

TABLE 5.3 EDWCs for Acetamiprid.* Source of Drinking Water [Model] EDWCs (ppm)

, scatter bait

, 0.082 lbs ai/A, 24X, 3

- day RTI, ground. EDWCs (ppm), c ranberries

, 0.13 lbs ai/A, 2 X , 7

- day RTI , aerial

. Surface water [FIRST] Acute = 0.0815 Acute = 0.0883
Groundwater [PRZM

- GW] Post

- breakthrough average = 0.045 (Daily peak = 0.0497) --
* The highest EDWCs for the proposed and previously evaluated use scenarios are in bold

- face type

.



### For the acute assessment, an EDWC of 0.08 83 pp m was entered into the DEEM

- FCID M odel for “water, direct, all sources” and “water, indirect, all sources.” For the chronic assessment, the

value of 0.045 pp m was used for the same inputs

.

No monitoring data are currently available to further characterize potential drinking water

exposure. In the dietary exposure and risk assessment conducted to support the proposed use
pattern and label changes, HED incorporated the highest EDWCs directly into the acute and

chronic dietary model s . The use of the highest EDWCs in the dietary assessment is therefore protective of potential exposure through surface and ground water sources of drinking water.

5.4 Dietary Risk Assessment
Dietary Exposure and Risk Assessme nt D427703; W.T. Drew; 2 September 2015



### Acute and chronic aggregate dietary ( food and drinking water ) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID)

, Version 3.16

. This software uses 2003

- 2008 food consumption data from the US Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA)

. Per HED policy,

residue estimates associated with t he food

- handling establishment use are not included in the acute dietary assessment.

Both the acute and chronic analyses are based on tolerance

- level residues and assume 100% CT

. Acute and chronic dietary risk estimates are below HED’s LOC for all popu lation subgroups ( seeAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 24 of 49 

### Table 5.4 , below ). For acute exposures, the dietary risk for the US population is estimated to be

25 % of the PAD. Acute risk for children 1

- 2 years old, the highest

- exposed population subgroup, is estimated to be 6 7 % of the PAD. Ch ronic risk estimates are 14 % of the P AD for the US population , and 61 % of the PAD for children 1

- 2 years old. Acetamiprid is classified as “not likely to be carcinogenic to humans,” and therefore cancer risk is not of concern for this

chemical.

There a re no dietary exposure or risk concerns that would preclude granting the requested use of acetamiprid on clover with a shorter PHI, and establishing increased tolerances in clover forage and hay associated with th e revis ed use pattern

. Further more , based on the conservative assumptions used in the dietary exposure assessment, actual dietary exposure is expected to be much lower than the estimates provided in the table.

TABLE 5. 4 Summary of Dietary Exposure and Risk Estimates for Acetamiprid.
Population Subgroup * Acute (95th Percentile) Chronic
Exposure (mg/kg/day) % aPAD Exposure (mg/kg/day) % cPAD

US Population (total) 0.0247 12 25 0.009989 1 4

All infants (<1 year) 0.050 938 5 1 0.018612 2 6

Children 1

- 2 y ea rs 0.067 393 67 0.043166 61

Children 3

- 5 y ea rs 0.045 688 46 0.028154 40

Children 6

- 12 y ea rs 0.02 6021 2 6 0.013964 20

Youth 13

- 19 y ea rs 0.015309 1 5 0.007674 11

Adults 20

- 49 y ea rs 0.015 68 2 16 0.007101 10

Adults 50

- 99 y ea rs 0.015 579 1 6 0.007532 11

Females 13

- 49 y ea rs 0.015 939 1 6 0.007299 10

* Populations with the highest exposure estimates are bolded

.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization
Occupational and Residential Exposure Assessment D427194 ; J. Godshall; 19 August 2015



### This residential exposure/risk assessment was conducted in support of the proposed new use of acetamiprid in a spot

- on product for dogs. Acetamiprid is a neonicitinoid insecticide chemical currently registered for use in controlling a wide variety of indo or and outdoor insect pests in residential settings

. Currently registered r esidential sites include various insecticide traps, spot

on pet treatment, crack and crevice treatments , soil treatments, and sprays.

The proposed new EP, RF2213 AE CDSO Insecti cide

, is formulated as a pet spot

- on treatment containing 9.5% acetamiprid combined with other pesticides ( 20.0% etofenprox, 8.0% piperonyl butoxide, and 5.0% s

- methoprene ) to broaden the efficacy spectrum. This assessment addresses exposure and risk associated with the use of acetamiprid only; it does not address etofenprox, piperonyl butoxide, or s

- methoprene exposure associated with the use of the spot

- on product.

Th e new EP is proposed by Nippon Soda for use as a monthly topical spot

- on product for dogs to provide continuous protection against fleas, ticks and mosquitoes. RF2213 AE CDSO isAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 25 of 49 

### proposed for use by homeowners and commercial applicators. The proposed spot

- on product label allows for applicatio n to four dog weight ranges: small, 4 to 9 lbs; medium, 10 to 22 lbs; large, 23 to 55 lbs; and extra

- large, ≥56 lbs. The product is not proposed for use on cats.

Non

- occupational (residential) use of the proposed dog spot

- on product is anticipated to result in dermal exposures for adult handlers. In addition, residential post

- application dermal exposures are expected for adults and children 1 to 2 years old, and incidental oral exposures for children 1

to 2 years old. Inhalation exposure from the use of the spot

- on product is considered negligible

. T herefore, only dermal and incidental oral exposure were assessed for the proposed product.

Current HED policy requires assessment for residential post

- application exposures associated

with short

- (1 to 30 days), intermediate

- (1 to 6 months), and long

- term (greater than 6 months) durations from pet spot

- on products due to the preventative nature of pet products

, and the potential for extended usage in more temperate parts of the country.

Short

- term

R esidential handler exposure is assumed to be short

- term due to the intermittent nature of homeowner spot

- on applications (once

- monthly treatment). A summary of residential handler exposure risk e stimates is presented in Table 6

. 0. 1 (below)

.

TABLE 6.0 .1 Residential Handler Short

- Term Non

- cancer Exposure and Risk Estimates from the

Proposed Spot

- On Pet Use.

Exposure

Scenario Dermal Unit

Exposure (mg/lb ai) Maximum Use Rate 1

(lb ai/pet) Amount

Treated Daily 2 Dermal

Dose (mg/kg/day) 3 MOE 4

Spot

- o n

treatment
(9.5% ai) 120 0.00018 (small) 2 Dogs 0.000063 160,000

0.00045 (medium) 0.00016 64,000

0.0011 (large) 0.00038 26,000

0.0018 (extra

- large) 0.00063 16,000

1

. Based on the proposed label (EPA File Symbol 8033

- RGR ). [ (fl oz product) × (0.84455 lb ai/gal) ÷ ( 128 fl

oz /gal )]

. 2

. Based on HED’s 2012 Residential SOPs for Treated Pets ( http://www.epa.gov/pesticides/science/residential

exposure

- sop.html ).

3

. Dermal d ose = dermal unit e xposure (mg/lb ai) × a pplication r ate (lb ai/treatment) × a mount t reated (2 d ogs/day)

× d ermal a bsorpti on f

actor (0.1 ) ÷ body w eight (69 kg).

4

. Dermal MOE = d ermal NOAEL (10 mg/kg/day) ÷ d ermal d ose (mg/kg/day). I nhalatio n exposure is expected to be negligible.



### Conclusion : Residential handler short

- term dermal risk estimates are not of concern (MOEs are all ≥ 100) for application to all dog weight ranges proposed.

Short

- , Intermediate

- and Long

- Term 

### HED combines risk values resulting from separate routes of exposure when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposedAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 26 of 49 

### population, and if the hazard associated with the PODs is similar acro ss routes. Residential post

application inhalation exposure is expected to be negligible fr om the proposed spot

- on product;

th erefore , a quantitative assessment was not performed.

Post

- application dermal and incidental oral exposures were combined for children 1 to 2 years old. Children’s combined exposures (all durations) are presented as t otal MOEs. For adults, only post

- application dermal exposure is anticipated from contact wi th a treated dog.

Residential short

- and intermediate

- term post

- application exposures are presented in Table 6

. 0. 2 (below)

.

TABLE 6.0.2 Residential Short

- and Intermediate

- Term Post

- Application Non

- Cancer Exposure and

R isk Estimates from the Proposed Spot

- On Pet Use. Lifestage Post

- application Exposure

Scenario Application Rate (mg ai) 1 Dose

(mg/kg/day) 2 Short

- /Int

Term

MOEs 3 Total

MOE 4

Use Site Exposure Route

Adult Dog Spot

-

On Dermal 80 (small) 0.006 1,700 NA
203.5 (medium) 0.008 1,200 505.8 (large) 0.012 860
811 (extra

- large) 0.010 950

Children

1 to 2

Years Old Dermal 80 (small) 0.013 790 720

Incidental Oral 0.0013 7,900

Dermal 203.5 (medium) 0.018 570 510

Incidental Oral 0.0018 5,700

Dermal 505.8 (large) 0.026 390 360

Incidental Oral 0.0026 3,900

Dermal 811 (extra

- large) 0.023 440 400

Incidental Oral 0.0023 4,300

1

. Based on the proposed label ( EPA File Symbol 8033

- RGR ).

2 a

. Dermal d ose (mg/kg/day) = [( transfer co efficient (cm 2 /hr) × (application r ate (mg ai) × f raction a pplication rate (0.02) ÷ surface a rea of d og (cm 2 )) × exposure t ime (hours/day) × a bsorption f actor (unitless)) ÷ b ody

w eight (kg)]

. 2b. Hand

- to

- m outh d ose (mg/kg/day) = [(h and r esidue l oading (mg/cm 2 ) × f raction of hand m outhed (0.13) ×

s urface area of 1 h and (150 cm 2 ) × exposure t ime (1.5 hrs/day) × # of r eplenishment i ntervals/h our (4 int/hr) × (1

- ((1

- s aliva e xtraction factor (0.5))^(number of h and

- to

- m outh e vents /h our (13.9 events/hr)) ÷ ( #

of replenishment i ntervals/h ou r))] ÷ body w eight (kg)]

. 3

. Short

- and i ntermediate

- t erm MOE = d ermal or i ncidental o ral POD (mg/kg/day) ÷ d ose (mg/kg/day)

. 4. Short

- and intermediate

- t erm t otal MOE = 1/ [(1/ dermal MOE) + (1/incidental o ral MOE)]

.



### Resid ential long

- term post

- application exposures are presented in Table 6.0.3 (below).Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 27 of 49 TABLE 6.0.3 Residential Long

- Term Post

- Application Non

- Cancer Exposure and Risk Estimates from

the Proposed Spot

- On Pet Use

. Lifestage Post

- application Exposure

Scenario Application Rate (mg ai) 1 Dose (mg/kg/day) 2 Route Specific

MOEs 3 Total MOE 4

Use Site Exposure Route

Adult Dog Spot

On Dermal 80 (small) 0.0050 1,400 NA
203.5 (medium) 0.0070 1,000 505.8 (large) 0.010 710
811 (extra

- large) 0.0090 790

Children

1 to 2 Years

Old Dermal 80 (small) 0.013 560 510

Incidental Oral 0.0013 5,600

Dermal 203.5 (medium) 0.018 400 370

Incidental Oral 0.0018 4,000

Dermal 505.8 (large) 0.026 280 250

Incidental Oral 0.0026 2,800

Dermal 811 (extra

- large) 0.023 310 280

Incidental Oral 0.0023 3,100

1

. Based on the proposed label ( EPA File Symbol 8033

- RGR ).

2 a. Dermal d ose (mg/kg/day) = [( transfer co efficient (cm 2 /hr) × (application r ate (mg ai) × f raction a pplication rate (0.02) ÷ surface a rea of d og (cm 2 )) × exposure t ime (hours/day) × a bsorption f actor (unitless)) ÷ b ody

w eight (kg)]

. 2b. Hand

- to

- m outh d ose (mg/kg/day) = [(h and r esidue l oading (mg/cm 2 ) × f raction of hand m outhed (0.13) ×

s urface area of 1 h and (150 cm 2 ) × exposure t ime (1.5 hrs/day) × # of r eplenishment i ntervals/h our (4 int/hr) × (1

- ((1

- s aliva e xtraction factor (0.5))^(number of h and

- to

- m outh e vents /h our (13.9 events/hr)) ÷ ( # of replenishment i ntervals/h ou r))] ÷ body w eight (kg)]

. 3

. Short

- and i ntermediate

- t erm MOE = d ermal or i ncidental o ral POD (mg/kg/day) ÷ d ose (mg/kg/day)

. 4. Short

- and intermediate

- t erm t otal MOE = 1/ [(1/ dermal MOE) + (1/incidental o ral MOE)]

.



### Conclusion: Residential post

- application exposure and risk estimates are not of concern for any sized dog (adult dermal MOEs are all ≥ 100, and children 1 to 2 years old t otal MOEs are all

≥ 100) for all exposure durations.

Residential Risk Estimates for Use in Aggregate Assessments

Table 6.0.4 presents the residential risk estimates recommended for use in the aggregate assessment for acetamiprid

. T he short

- and intermediate

- term endpoints were derived from a previous assessment ( D383325 ; M. Collantes ; 22 July 2 011)

, and are listed in the table. Please

no te the following considerations:

1) The recommended residential exposure for use in the adult aggregate short

intermediate term assessment reflects dermal and inhalation exposure from applicatio ns to mattresses, cracks and crevices;

2 ) t he recommended residential exposure for use in the children 1 to 2 years old

short

- and intermediate

- term aggregate assessm ent reflects dermal,

inhalation and hand

- to

- mouth exposures from post

- application exposure to
i ndoor applications;Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 28 of 49 

### 3) t he recommended residential exposure for use in the adult aggregate long term assessment reflects post

- application dermal exposures from co ntact with
spot

- on treated pets; and

4 ) t he recommended residential exposure for use in the children 1 to 2 years old long term aggregate assessment reflects post

- application dermal and hand

to

- mouth exposures from contact with spot

- on treated pets.

TABLE 6.0.4 Recommend ed Residential Exposures for Use in Acetamiprid Aggregate Assessment s

. Lifestage Exposure Scenario Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Short

- and Intermediate

- Term 3

Adult

Male/Female Handler Mattress Treatment 0.00088 0.000039 NA 4 0.00092 11,000 260,000 NA 3,600

Handler Crack & Crevice 0.0018 0.000078 NA 0.0019 5,600 130,000 N A

Post

- app Mattress Treatment 0.00015 NA NA 0.00015 66,000 NA N A 430

Post

- app Crack & Crevice 0.023 0.000018 NA 0.023 430 560,000 N A

Child Post

- app Mattress Treatment 0.00032 NA NA 0.00032 900 NA N A 220

Post

- app Crack & Crevice 0.033 0.000046 NA 0.033 300 220,000 N A

Post

- app Hand

- to

- Mouth NA NA 0.011 0.011 NA NA 900

Long

- Term 5

Adult

Male/Female Post

- app Pet Spot

- on 0.010 NA NA 0.010 710 NA N A 710

Child Post

- app Pet Spot

- on 0.026 NA 0.0026 0.029 280 NA 2,800 250
1. Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral (where applicable). 2. MOE = the MOEs associated with the highest resi dential doses. Total = 1 ÷ (1/dermal MOE) + (1/i nhalation MOE) + (1/Incidental Oral MOE), where applicable. 3. Values taken from D383325; M. Collantes ; 22 July 2011.

4. NA = Not Applicable.

5. Values taken from Table 6.0.3 (above).



### 6. 1 Spray Drift

Due to the application technique and product formulation, spray drift is not considered to be a concern for the pet spot

- on use.

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the c ase with aerial application s allowed on acetamiprid labels but, to a lesser extent, could also be a potential source of exposure from ground application method s employed

for acetamiprid . The Agency has been working with the Spray Drift Task Force, EPA Regional

Offices

, 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 i ts evaluation of the new databaseAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 29 of 49 

### submitted by the Spray Drift Task Force, a membership of US pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides app lied 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 of specific products having significant risks

associated wit h drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. Th is exposure scenario is representative of a worse case inhalation (drift) exposure

, and may be considered protective of most outdoor agricultural and commercial post

- applicati on inhalation exposure scenarios.

7.0 Aggregate Exposure/Risk Characterizatio n

In accordance with the FQPA, HED must consider and aggregate (add) pesticide risks from three major sources ( food, drinking water, and residential exposures ) . When aggregating exposures and risks from various sources, HED considers toxicological endpoi nts

, as well as th e route and duration of exposure.

7.1 Acute Aggregate Risk

Typically, HED does not consider residential exposures when assessing acute aggregate risk unless such exposures can be characterized as a series of single

- day exposures

. For acetamiprid, residential exposures are assessed as short

- and intermediate

- term exposures. Therefore, acute aggregate risk estimates for acetamiprid are equivalent to the acute dietary risk estimates ( see Section 5 .4 ) and are below HED’s LOC

.

7.2 Short

- and Intermediate

- Term Aggregate Risk

Toxicological endpoints and points of departure for assessing short

- (1 to 30 days) and

intermediate

- term (1 to 6 months) risks associated with exposure to acetamiprid are identical

. T herefore, separate assessm ents are not being conducted for these durations. Short

- and

intermediate

- term residential exposures to acetamiprid may occur from uses of this chemical around the home (Section 6 .0 )

. The proposed spot

- on use of acetamiprid results in a lower

exposure es timate than the currently registered crack/crevice use, which serves as the basis for calculating aggregate risk. I n addition, dietary exposure is possible from acetamiprid residues in food and drinking water (Section 5 .4 ). For assessing aggregate risk, the chronic dietary exposure

estimate is used

, since it represents a background exposure level from food and drinking water that may co

- occur with residential exposures. The toxicological endpoints, PODs , and LOC are the same across oral, dermal, and inha lation rou tes of exposure for acetamiprid. T herefore, aggregate risk can be estimated by combining the various exposure estimates

, and comparing theAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 30 of 49 

### resulting aggregate exposure estimate ( see Table 7.2 , below ) t o the short

- and intermediate

- term
POD

.

TABLE 7.2 Short

- and Intermediate

- Term Aggregate Risk Estimates for Acetamiprid. Population NOAEL

mg/kg/day LOC 1 Average Food and Water Exposure mg/kg/day 2 Residential Exposure mg/kg/day 3 Aggregate

Exposure mg/kg/day 4 Aggregate

MOE 5

Short

- and Intermediate

- Term

Adult 10 100 0.007532 0.0 2 597 0.03 3 5 0 2 3 0 0

Child 10 100 0.043166 0.0 44 32 0.087 486 1 1 0

1. The LOC is based on the standard inter

- and intra

- species uncertainty factors totaling 100

. 2. Dietary exposures are f rom Section 5 .4 (above)

. Adult = 50

- 99 years old group (maximum exposure). Child =

c hildren 1

- 2 years. 3. Combined residential exposure estimate from Section 6

. 0

, above ( specifically

, from Table 6.0.4 )

. 4. Aggregate e xposu re = a v erage f ood and w ater e xposure + r esidential e xposure

. 5. Aggregate MOE = NOAEL ÷ aggregate e xposure. Values are rounded to two significant figures.



### Conclusion s : Both short

- and intermediate

- term aggregate MOEs are ≥100, and indicate that

risks are not of concern. T he chronic dietary exposure estimates are highly conservative, assuming tolerance

- level residues and 100 % CT for all commodities. Therefore, HED also considers the aggregate MOEs to be conservative estimates, with the actual exposures likely being much lower than those characterized here.

7. 3 Chronic Aggregate Risk

Long

- term residential exposures to acetamiprid may occur from uses of this chemical as a pet
spot

- on treatment (Section 6.0) , which drives the aggregate risk

, as the crack/crevice use does not have long term exposure

. I n addition, dietary exposure is possible from acetamiprid residues in food and drinking water (Section 5.4). T he chronic dietary exposure and post

- application pet
spot

- on residential exposure were aggregate d and compar ed to the long

- term POD (see Table

7. 3 , below).

TABLE 7.3 Long

- Term Aggregate Risk Estimates for Acetamiprid. Population NOAEL

mg/kg/day LOC 1 Average Food and Water Exposure mg/kg/day 2 Residential Exposure mg/kg/day 3 Aggregate

Exposure mg/kg/day 4 Aggregate

MOE 5

Long

- Term

Adult 7.1 100 0.007532 0.010 0.017532 570

Child 7.1 100 0.043166 0.029 0.072166 1 0 0

1. The LOC is based on the standard inter

- and intra

- species uncertainty factors totaling 100

. 2. Dietary exposures are from Section 5.4 (above). Adult = 50

- 99 years old group (maximum exposure). Child =

c hildren 1

- 2 years. 3. Combined residential exposure estimate from Section 6.0 , above (specifically, from Table 6.0.4)

. 4. Aggregate e xposure = average food and water expo sure + residential exposure

. 5. Aggregate MOE = NOAEL ÷ a ggregate e xposure. Values are rounded to two significant figures.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 31 of 49 

### Conclusion s : Both long

- term aggregate MOEs are ≥100, and indicate that risks are not of

concern. T he chronic dietary exposure estimates are highly conservative, assuming tolerance

level residues and 100 % CT for all commodities. Therefore, HED also considers the aggregate MOEs to be conservative estimates, with the actual exposures likely being much lower than

those characterize d here.

7. 4 Cancer Aggregate Risk

Acetamiprid has been classified as “ not likely to be carcinogenic to human ” and, therefore,

cancer risk is not of concern for this chemical.

8.0 Cumulative Exposure/Risk Characterization

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 acetamiprid and any other substance

, and acetamiprid does not appear to pro duce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,

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

substances. For information regarding EPA’s efforts to determin e which chemicals have a common mechanism of toxicity

, and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determinations

, and procedures for cumulating effects from substanc es found to have a common mechanism

, on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

9.0 Occupational Exposure/Risk Characterization
Occupational and Residential Exposure Assessmen t D427194; J. Godshall; 19 August 2015



### This occupational exposure/risk assessment was conducted in support of the proposed new use of acetamiprid in a spot

- on product for dogs

, along with the proposed amend ments to the label application rates of Assail 30 SG Insecticide and Assail 70 WP Insecticide. Acetamiprid is a neonicitinoid insecticide chemical currently registered for use on a number of agricultural,

ornamental and residential sites. It is also used for see d treatment on canola, mustard and
potatoes.

Occupational handler exposures are anticipated from the application of the proposed acetamiprid
spot

- on product and augmented agricultural use labels. Occupational post

- application exposure is anticipated fr om both the pet spot

- on and agricultural uses. However, only a quantitative assessment has been conducted for the agricultural uses since occupational exposures are expected to be significantly less than residential post

- application exposures from the spo t

- on product.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 32 of 49 

### Proposed New Use

The proposed new EP, RF2213 AE CDSO Insecticide

, is formulated as a pet spot

- on treatment containing 9.5% acetamiprid combined with other pesticides (20.0% etofenprox, 8.0% piperonyl butoxide, and 5.0% s

- methoprene ) to bro aden the efficacy spectrum. This assessment addresses exposure and risk associated with the use of acetamiprid only; it does not address etofenprox, piperonyl butoxide, or s

- methoprene exposure associated with the use of the spot

- on product.

The new EP i s proposed by Nippon Soda for use as a monthly topical spot

- on product for dogs to provide continuous protection against fleas, ticks and mosquitoes. RF2213 AE CDSO is proposed for use by homeowners and commercial applicators. The proposed spot

- on produc t label allows for application to four dog weight ranges: small, 4 to 9 lbs; medium, 10 to 22 lbs; large, 23 to 55 lbs; and extra

- large, ≥ 56 lbs. The product is not proposed for use on cats.

Proposed Amended Uses

The Assail 30 SG Insecticide and Assa il 70 WP Insecticide products are formulated for broadcast agricultural use; both are for use by commercial applicators only. The amended labels propose increasing the maximum single application rates for cotton and leafy vegetables, while decreasing the number of applications per year. This does not result in an increase of the yearly application rate for either use. The amended label also includes new directions for application to fruiting vegetables crop group 8

- 10 to treat leafhoppers, but the applic ation rates are no greater than currently exist for this crop group which has been previously assessed with no risks of concern identified (D394322; E. Holman; 19 April 2012). Therefore, a new assessment has not been included for fruiting vegetables crop group 8

- 10. The amended labels also included updated directions for use on leafy brassica, grapes, cucurbits, edible podded legume vegetables, succulent shelled peas and beans, and bush and cane berries. However, the changes will not impact worker risk/e xposure, and were not assessed in this document. Required PPE for Assail 30 SG and Assail 70 WP include long sleeved shirts, long pants, shoes plus socks, chemical resistant gloves, and chemical resistant headgear for overhead exposure. In addition, for aerial applications, Assail 70WP requires mixers/loaders to wear a dust mist filtering respirator. Both labels incorporate a 12 hour REI.

9.1 Short

- , Intermediate

- and Long

- Term Handler Risk

Proposed New Use Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure could be expected from the acetamiprid spot

- on use for veterinarians, veterinary assistants, and groomers. The quantitative exposure/risk asses sment developed for occupational handlers (adults) is based on dermal exposure from the application of the spot

- on product to dogs. Inhalation exposures are expected to be negligible from application of the spot

- on product.

For acetamiprid, occupationa l handler exposures from the pet spot

- on use are expected to extend beyond a short

- or intermediate

- term duration due to temperate climates in some parts of the country, and the preventative nature of spot

- on pet products. For these reasons, it is expecte d that veterinarians, veterinary assistants, and groomers could treat dogs with the proposedAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 33 of 49 

### acetamiprid spot

- on product for all durations of exposure (short

- , intermediate

- and long

- term) for flea and tick prevention and/or treatment. Agricultural use han dlers are expected to experience short

- and intermediate

- term exposures.

Conclusion s : Occupational handlers of the proposed acetamiprid spot

- on product could treat as many as 200 dogs per day (based on the long

- term POD, which is protective of short

- and

intermediate

- term exposure) without resulting in dermal risks of concern ( all MOEs are ≥100). It is highly unlikely that this large a number of dogs could be treated daily in an occupational setting

. T herefore, no risk concerns are anticipated from o ccupational use of the proposed dog
spot

- on product. A summary of occupational handler dermal risk estimates for this use is presented in Table 9.1 .1 (below)

.

TABLE 9.1.1 Occupational Handlers Long

- Term 1 N on

- Canc er Exposure and Risk Estimates for Spot

- on Pet Use

. Exposure

Scenario Target Dermal Unit Exposure (mg/lb ai) 2 Inhalation Unit

Exposure (mg/lb ai) 2 Max.

Use Rate (lb ai/pet) 3 Max.

Amount

Handled Daily (Pets) 4 Dermal Inhalation

Single Layer, No

Gloves No Respirator Dose (mg/kg/day) 5 MOE 6 Dose (mg/kg/day) MOE

Applying

s pot

- on

p roduct Dogs 112 Negligible 0.00018 (small) 200

Dogs 0.0058 1,200 Negligible

0.00045 (medium) 0.015 490

0.0011 (large) 0.036 200

0.0018 (extra

large) 0.058 120

1. The long

- term risk estimates are protective of short

- and intermediate

- term exposure.
2. Based on the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (March 2012)

. Level of mitigation = b aseline

. 3

. Based on proposed label ( EPA File Symbol 8033

- RGR ). 4. High

- end estimate of the number of dogs that could be treated per day.

5. Dermal d ose = d ermal unit e xposure (120 mg/lb ai) × a pplication r ate (lb ai/ treatment) × a mount h andled d aily (treatments/day) × DAF (0.1) ÷ BW (69 kg)

. 6. Dermal MOE = l ong

- term d ermal NOAEL (7.1 mg/kg/day) ÷ dermal d ose (mg/kg/day).



### Proposed Amended Uses Occupational exposure could also be expected from the amended agricultural uses on cotton and leafy vegetables.

Based on the anticipated use patterns and current l abeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

 Applying s pot

- on p roduct to d ogs.

 Mixing/ loading WP for g roundboom a pplications.

 Mixing/l oading SG/WP for g roundboom a pplications.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 34 of 49 

###  Mixing/l oading WP for a erial a pplications.

 Mixing/l oading SG/WP for a erial a pplications.

 Applying spray by g roundboom e quipment.

 Applying spray by a erial e quipment.

 Flagging for spray by a erial e quipment.

HED classifies exposures from 1 to 30 days as short

- term

, and exposures 30 days to six months

as intermediate

- term. Exposure duration is determined by many things, incl uding the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for m ore than a one

- month

time frame. H owever, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks ( such as, completing multiple applications for multiple

clients within a region).

Conclusion s : There are no risk estimates of concern for occupational handlers who mix, load and/or apply acetamiprid (as the S G and WP formulations) to cotton and leafy vegetables when following the PPE directions for the amended use s ( all MOE s are ≥100). A summary of occupational handler dermal risk estimates for th e s e use s is presented in Table 9.1. 2 (below).Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 35 of 49 TABLE 9.1.2 Occupational Handler Short

- and Intermediate

- term Non

- Cancer Exposure and Risk Estimates for Agricultural

Uses.

Exposure

Scenario 1 Crop or

Target Mitigation

Level 2 Single

Use Rate
(lb ai/A) Acres

Treated Dermal Inhalation Total

Dose (mg/kg/day) 3 MOE Dose (mg/kg/day) 4 MOE MOE 5

Mixer/Loader

SG /W P for

aerial appl ication Leafy

Vegetables SL/no G 0.1 350 0.012 870 0.0046 620 620

SL/G 0.0026 3,800 1400

SL/G

PF5 R 0.00091 11,000 2800

SG/WP for

aerial application Cotton SL/no G 0.15 1200 0.059 170 0.023 120 120

SL/G 0.014 740 270

SL/G

PF5 R 0.0047 2,100 550

SG/WP

g roundboom. Leafy

Vegetables SL/no G 0.1 80 0.0026 3,800 0.0010 9,600 2700

SL/G 0.00060 17,000 6100

SL/G

PF5 R 0.00021 48,000 13000

SG/WP

g roundboom. Cotton SL/no G 0.15 200 0.0099 1,000 0.0039 2,600 720

SL/G 0.0023 4,400 1600

SL/G

PF5 R 0.00078 13,000 3300

WP for aerial application Leafy

Vegetables SL/no G 0.1 350 0.19 53 0.022 460 48

SL/G 0.0086 1,200 330

SL/G

PF5 R 0.0044 2,300 790

WP for aerial application Cotton SL/no G 0.15 1,200 0.97 10 0.11 89 9

SL/G 0.044 230 64

SL/G

PF5 R 0.023 440 150

WP

g roundboom Leafy

Vegetables SL/no G 0.1 80 0.043 230 0.0050 2,000 210

SL/G 0.0020 5,100 1400

SL/G

PF5 R 0.00010 10,000 3400

WP

g roundboom Cotton SL/no G 0.15 200 0.16 62 0.019 530 56

SL/G 0.0074 1,400 380

SL/G

PF5 R 0.0037 2,700 920

Applicator
Spray with fixed wing aircraft Leafy

Vegetables EC 0.1 350 0.00011 94,000 0.0000025 4,000,0

00 92,000

Cotton 0.15 1,200 0.00054 18,000 0.000013 780,000 18,000

Spray with

g roundboom Leafy

Vegetables SL/G 0.1 80 0.00019 53,000 0.000039 250,000 44,000

Cotton 0.15 200 0.00070 14,000 0.00015 68,000 12,000Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 36 of 49 Abbreviations used: SL = Single Layer baseline personal protective equipment (PPE, also see # 3 below), SG = Soluble Granule , EC = Engineering Controls

, G = chemical resistant Gloves, LOC= Level O f Concern, MOE = Margin O f E xposure, PF5 R = Protection Factor 5 R espira tor, WP = Wettable P owder. 1. The use pattern is the same for all crops. 2. Baseline PPE includes long

- sleeved shirt, long pants

, and shoes with socks. Label recommended PPE is base line plus chemical resistant gloves. Aerial applications using Assail 70 WP Insecticide require m ixer/ l oader to wear NIOSH approved dust filtering respirators. 3. Dermal dose (mg/kg/day) = [ a ppl ication rate (lb ai/A) × a cres treated/day × d ermal unit exposure (μg/lb ai handled/day/1000) × d ermal absorp tion factor (10%)] ÷ b ody w eigh t (69 kg). LOC < 100. 4. Inhalation dose (mg/kg/day) = [ application rate (lb ai/A) × a cres treated/day × i nhal ation unit exposure (μg/lb ai handled/day/1000)] × i nhal ation absorption factor (100%] ÷ body weight (69 kg)

. LOC < 1,000.

5. Total MOE = 1 ÷ [(1/ d ermal MOE) + (1/ i nhalation MOE)]

.



### 9.2 Short

- and Intermediate

- Term Post

- A pplication Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activi ties related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide applicat ion, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

Proposed New Use Occupational post

- application activities are expected to be significantly less than residential
post

- application exposures. Dogs are expected to be treated and returned to their owners such that occupational post

- application contact will be negligible. As a result, no quantitative occupational post

- application exposure and risk assessment has been performed for this use. The residential post

- application exposure and risk assessment (Section 6.0 ) is considered protective for any potential occupational post

- application exposures and risks.

Pr oposed Amended Use Occupational post

- application activities are anticipated for agricultural uses.

9.2.1 Dermal Post

- A pplication Risk

A quantitative dermal post

- application assessment was conducted for the amended acetamiprid uses on cotton and leafy v egetables due to its use as a post

- emergence foliar application

treatment. Flagger
Spray with aerial Leafy

Vegetables SL/G 0.1 350 0.00061 18,000 0.00018 56,000 12,000

Spray with aerial Cotton 0.15 350 0.00091 11,000 0.00027 37,000 8,500Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 37 of 49 

### Transfer Coefficients: It is the policy of HED to use the best available data to assess post

application exposure. Sources of generic post

- application data, used as surrogate d ata in the

absence of chemical

- specific data, are derived from the Agricult ural Reentry Task Force (ARTF) exposure monitoring studies and, as proprietary data, are subject to the data protection provisions

of Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA ) . The standard values recommended for use in predicting post

- application exposure that are used in this assessment,
known as “transfer coefficients

, ” are presented in ExpoSAC Policy 3 ( http://www.epa.gov/pesticides/science/exposac_policy3.pdf ) which, along with additional information about the ARTF data, can be found at the Agency website ( http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html ) . Table 9 .2.1 .1 (below) provides a summary of the anticipated post

- application activities and associated transfer coefficients for the prop ose d crop use sites.

For use on cotton, HED has also assessed the post

- application dermal exposure and risk estimates for workers involved in harvesting cotton bolls. Although most of cotton harvesting is done mechanically, there are still some activities , with the potential for exposure, that are associated with the harvesting of cotton. The anticipated post

- application activities

, and dermal

transfer coefficients for these activities

, are presented in Table 9 .2. 1 .1. The recommended

transfer coefficient s are derived from EPA’s Science Advisory Council for Exposure (ExpoSAC) Policy 3 ( http://www.epa.gov/pesticides/science/exposac

- policy3

- march2013.pdf ).

TABLE 9.2.1.1 Anticipated Post

- Application Activities and Transfer Coefficients.

Crop Policy Crop

Group Category Crop

Height Foliage

Density Transfer Coefficients Activities

Cotton Field / row. crop,

low / medium Low Min 70 cm 2 /hr Weeding, Hand

Full

Min 210 cm 2 /hr Scouting

Full

High Min 900 g cotton boll/hr Mechanical Harvesting (Module Builder Operator)

2,400 g cotton boll/hr Mechanical Harvesting (Picker Operator and Raker)

5,050 g cotton boll/hr Mechanical Harvesting (Tramper)Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 38 of 49 TABLE 9.2.1.1 Anticipated Post

- Application Activities and Transfer Coefficients.

Crop Policy Crop

Group Category Crop

Height Foliage

Density Transfer Coefficients Activities

Crop Group 4 Leafy Vegetables Low Min 70 cm 2 /hr Weeding, Hand &
Thinning Plants Full

Min 210 cm 2 /hr Scouting

Full

Min 230 cm 2 /hr Transplanting

Min 1,100 cm 2 /hr Harvesting, Hand

Full

Min 1,900 cm 2 /hr Hand Set Irrigation

Full



### Residues: Chemical

- specific dislodgeable foliar residue (DFR) data have not been submitted for acetamiprid. Therefore, this assessment uses HED’s default assumption that 25% of the application is available for transfer on Day 0 following the application

, and the residues dissipate at a rate of 10% each following day.

In addition, no chemical

- specific data are available for the amount of residue available on the

cotton bolls

, to wit , dislodgeable boll residue (DBR) data. However, surrogate data are available from a study with the active ingredient tribufos (MRID # 42701601). Note to RD: These data may trigger a data compensation issue between registrants. The residue data from thi s study were reviewed previously and found to be acceptable in risk assessment ( Memo; D227007 ; B. Tarplee; 12 March 1997). The average DBR levels (μg/50 gram sample) were analyzed using linear regression to estimate the dissipation over time. Since the p roposed acetamiprid labels

include a 28

- day PHI , the 28

- day predicted cotton boll residue data for that timeframe was presented as surrogate data for this assessment

, and then adjusted for the difference in application rates between the study and amended l abel. In addition, for characterization purposes, Day 0 estimates have been presented with use of the surrogate data in Table 9 .2. 1 .2 (below)

.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 39 of 49 TABLE 9.2.1.2 Occupational Post

- application Exposure and Risk Estimates for Cotton Harvesting

Activities

. Mechanical Harvesting Activity Application

Rate (lb ai/A) DBR

(μg/g) 1 Transfer

Coefficient (g/hr) 2 Dermal Dose 3

(mg/kg/day) Dermal

MOE 4
Day 0 1.a
Module Builder Operator 0.15 0.12 900 0.0013 8,000

Picker Operator and Raker 0.15 0.12 2,400 0.0033 3,000

Tramper 0.15 0.12 5,050 0.0070 1,400

Day 28 1.b
Module Builder Operator 0.15 0.00019 900 0.0000020 5,000,000

Picker Operator and Raker 0.15 0.00019 2,400 0.0000053 1,900,000

Tramper 0.15 0.00019 5,050 0.000011 900,000

1. Cotton Harvesting Dislodgeable Boll Residue (DBR) = [ Best fit DBR at [X 1.a or 1.b ] days MRID# 42701601 ([X 1.a

or 1.b ] μg/50g = Y μg/g) × application r ate ( lb ai/A) ] ÷ study a pplication r ate ( lb ai/A ) 1.a. Best fit DBR at Day 0 is 75.55 μg/50g. DBR = (75.55 μg/50g = 0.0024 μg/g) (0.15 lb ai/A)) / (1.88 lb ai/A) = 0.12μg/g 1.b. Best fit DBR at Day 28 is 0.12 μg/50g. DBR = (0.12 μg/50g = 0.0024 μg/g) (0.15 lb ai/A)) / (1.88 lb ai/A) = 0.00019μg/g

2. From Non

- Foliar Transfer Coefficient Table: http://epa.gov/pesticides/science/exposac

- policy

- 3

- march2013.pdf 3. Daily d ose (mg/kg/day) = [DBR × transfer c oefficient × c onv ersion f actor (0.001 mg/μg) × dermal absorption factor (0.10) × 8 h ou r s /day] ÷ b ody w eight (69 kg).

4: Short

- and i ntermediate

- term MOE = s hort

- term d ermal NOAEL (10 mg/kg/day) ÷ daily d ose (mg/kg/day).



### With the use of surrogate data, the mechanical cotton harvesting activities estimate of risk at the PHI (Day 28) resulted in MOEs ranging from 900,000 to 5,000,000, which do not exceed the

LOC. Even with consideration of the surrogate data at Day 0, the mechanical cotton harvesting activities would not result in risks of concern; MOEs ranging from 1,40 0 to 8,000 ( see Table

9.2.1 .2 )

. Only the highest exposure post

- application activities (based on the transfer coefficient) for each crop were assessed for non

- mechanical harvesting

, as they are considered to be protective of all other applicable scenarios. With use of default (25%) data, scouting and hand set irrigation MOEs range from 1,600 to 9,800; see Table 9 .2. 1 .3 (below)

.

TABLE 9.2.1.3 Occupational Post

- application Exposure and Risk Estimates for High Contact Activities

Performed in Fields Treated with Acetamiprid. Crop High Contact

Activity Appl ication

Rate (lb ai/A) DFR

(ug/cm 2 ) Transfer

Coefficient (cm 2 /hr) 1 Dermal Dose 2

(mg/kg/day) Dermal

MOE 3

Cotton Scouting 0.15 0. 42 210 0.001 9,800

Leafy v egetables (crop group 4) Hand

- set

Irrigation 0.1 0.2 8 1,900 0.006 1, 600

1. Transfer coefficient is a surrogate value for workers having low

- high contact with field crops foliage during post

application activities (ExpoSAC Policy 3 ; 3 June 2011).

2. Daily dose (mg/kg/day) = [DBR × transfer coefficient × conversion factor (0.001 mg/μg) × dermal absorption factor (0.10) × 8 hours/day] ÷ body weight (69 kg).

3. Short

- term MOE = short

- term dermal NOAEL (10 mg/kg/day) ÷ daily dose (mg/kg/day)

.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 40 of 49 

### Acetamipr id is classified as Toxicity Category III via the dermal route

, and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Short

- and intermediate

- term post

application risk estimates were not a concern on day 0 (12 hours follow ing application) for all
post

- application activities. Under 40 CFR § 156.208 [ c ][ 2 ] , ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Therefore,

the §156 subpart K Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to acetamiprid. HED would recommend a REI of 12 hours. This is the REI listed on the proposed labels, and is considered protective of
post

- appli cation exposure.

9.2.2 Inhalation Post

- A pplication Risk

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources

include volatilization of pesticides

, and resuspension of dusts and/or particulates that contain pesticides. The A gency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 200 9, and received the SAP’s final report on 2 March 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report

, and has deve loped a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During r egis tration r eview, the agency will utilize this analysis to determine if data ( such as flux studies, route

- specific inhalation toxicological studies

, or further analysis ) is required for acetamiprid.

In addition, the Agency is continuing to evaluate the av ailable post

- application inhalation exposure data generated by the ARTF . Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency 's risk assessments.

10.0 References

Acetamiprid. Request for Label Amendments for New Uses on Clover; Small Vine Climbing Fruits, except Kiwifruit, Subgroup 13

- 07F (amending grape use); Greenhouse

- grown Tomatoes; and a Regional Registration for Tea. Summary of Analytical Chemistry and Residue Data. ; D364833

, D 

### 366269; D. McNeilly; 14 October 2009

.

Acetamiprid: Revised Human Health Risk Assessment for the New Use on Sweet Corn and

Increased Tolerance on Citrus

. ; D410182; E. Holman; 20 March 2013

.

Acetamiprid

- Metabolism Assessment Review Committee Briefing Memorandum ; D278352; M. Doherty et al; 16 October 2001

.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 41 of 49 

### Acetamiprid. Results of the HED Metabolism Assessment Review Committee Meeting Held on October 16, 2001. ; D278652; M. Doherty et al; 13 November 2001

.

Tier I Drinking Water Exposure Assessment for Acetamiprid in Regards to a Proposed Reduction in the Preharvest Interval for Clover and Hay ; D423299; K. White; 25 March 2015

.

Acetamiprid. Proposed Label Amendments for Use of Two End

- Use Products on Various Crops; Petition Proposing Label Amendments, and Revised Permanent Tolerances, for Use of the

Insecticide on Clover with a Decreased Pre

- Harvest Interval (Regional Registration). Summary of Analytical Chemistry and Residue Data. ; D423321 , D426115, D426117 ; W.T. Drew; 2 September 2015

.

Acetamiprid. Acute and Chronic Dietary Exposure and Risk Assessment for Use of the Insecticide on Clover Grown for Seed in Idaho, Oregon and Washington Only. ; D427703; W.T.
Drew; 2 September 201 5

.

Acetamiprid. Occupational and Residential Exposure Assessment for New Uses as a Pet Spot

- on Treatment; And Increased Application Rates on Cotton, Leafy Vegetables. ; D427194; J. Godshall; 19 August 2015

.

Acetamiprid: Human Health Risk Assessment for New Uses on Asparagus; Brassica, Leafy Greens, Subgroup 5B, and Turnip Greens; and Sweet Corn; and Updated Crop Group Definitions for Fruiting Vegetables, Citrus, and Pome Fruit

. ; D394322; E. Holman; 19 April

2012

.

Acetamiprid: Occupational and Residential Exposure Assessment for Use to Control Bed Bugs ; D383325; M. Collantes; 22 July 2011

.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 42 of 49 

### A ppendix A

. Toxicology Profile and Executive Summaries

A .1 Toxicology Data Requirements

The data requirements (40CFR § 158.340) based on food use of acetamiprid are listed in Table

A. 1 (below )

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

TABLE A.1 Toxicology Data Requirements

. Study Technical Required Satisfied 870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization Yes

Yes

Yes

Yes

Yes

Yes Yes

Yes

Yes

Yes

Yes

Yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (non

- rodent)

870.3200 21

- Day Dermal

870.3250 90

- Day Dermal

870.3465 21/28

- Day Inhalation Yes

Yes

Yes

No

No Yes

Yes

Yes

--

-- 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (non

- rodent) 870.3800 Reproduction Yes

Yes

Yes Yes

Yes

Yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (non

- rodent) 870.4200a Oncogenicity (rat)

870.4200b On cogenicity (mouse) 870.4300 Chronic/Oncogenicity Yes

Yes

Yes

Yes

Yes Yes

Yes

Yes

Yes

Yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations 870.5xxx Mutagenicity

— Other Genotoxic Effects Yes

Yes

Yes

Yes Yes

Yes

Yes

Yes 870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90

- Day Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Develop. Neurotoxicity No

No

Yes

Yes

Yes --

-- Yes

Yes

Yes

870.7485 General Metabolism

870.7600 Dermal Penetration 870.7800 Immunotoxicity Yes

Yes

Yes Yes

Yes

YesAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 43 of 49 

### A.2 Toxicity Profiles

TABLE A.2 .1 Acute Toxic ity Profile for Technical Acetamiprid.

G uideline Study Type MRID # Results Tox Category

870.1100 Acute Oral

- rat 44651833 LD 50 : 217 mg/kg (M)

LD 50 : 146 mg/kg (F) II

870.12 00 Acute Dermal

- rat 44651836 LD 50 > 2000 mg/kg III

870.13 00 Acute Inhalation

- rat 44651837 LC 50 : > 1.15 mg/L (~) > 1.15 mg/L (~) III

870.24 00 Primary Eye Irritation

- rabbit 44651838 Not irritating to the eye IV

870.25 00 Primary Skin Irritation

- rabbit 44651839 Not irritating to the skin IV

870 .2600 Dermal Sensitization

- Guinea pig 44651840 N ot a sensitizer under

conditions of the study. N ot applicable

TABLE A.2 .2 Subchronic, Chronic and Other Toxicity Profile for Acetamiprid

. Guideline N umber, Study Type MRID N umber ( Y ear)

,

Classification and Doses Results

870.3100

90

- Day oral toxicity

– rat (dietary) 44651843 (1997) Acceptable/guideline

0, 50, 100, 200, 800, 1600 ppm

0/0, 3.1/3.7, 6.0/7.2, 12.4/14.6, 50.8/56.0, 99.9/117 (M/F) mg/kg/day NOAEL = 12.4/14.6 (M/F) mg/kg/day

LOAEL = 50.8/56.0 mg/kg/day (M/F) based on decreased BW, BW gain and food consumption

870.3100

90

- Day feeding

–

mouse 44988425 (1997) Acceptable/guideline

0, 400, 800, 1600, 3200 ppm

0/0, 53.2/64.6, 106.1/129.4, 211.1/249.1, 430.4/466.3 (M/F) mg/kg/day NOAEL = 106.1/129.4 (M/F) mg/kg/day

LOAEL = 211.1/249.1 (M/F) mg/kg/day based on reduced BW and BW gain, decreased glucose and cholesterol levels, reduced absolute organ weights

870.3150

90

- Day oral toxicity

– dog ( d ietary) 44988424 (1998) Acceptable/guideline

0, 320, 800, 2000 ppm

0/0, 13/14, 32/32, 58/64 (M/F) mg/kg/day NOAEL = 13/14 (M/F) mg/kg/day

LOAEL = 32 mg/kg/day based on reduced BW gain

in both sexes

870.3200

21

- Day dermal toxicity

– rabbit 44651844 (1997) Acceptable/guideline

0, 100, 500, 1000 mg/kg/day Systemic NOAEL = 1000 mg/kg/day

LOAEL = not determined

Dermal NOAEL = 1000 mg/kg/day

LOAEL = not determinedAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 44 of 49 TABLE A.2 .2 Subchronic, Chronic and Other Toxicity Profile for Acetamiprid

. Guideline N umber, Study Type MRID N umber ( Y ear)

,

Classification and Doses Results

870.3700 Developmental toxicity

– rat (gavage) 44651847 (1997) Acceptable/guideline

0, 5, 16, 50 mg/kg/day Maternal: NOAEL = 16 mg/kg/day LOAEL = 50 mg/kg/day based on reduced BW & BW gain and food consumption, increased liver weights

Developmental: NOAEL = 16 mg/kg/day LOAEL = 50 mg/kg/day based on increased incidence of shortening of the 13 th rib

870.3700 Developmental toxicity

– rabbit (gavage) 44651848 (1997) Acceptable/guideline

0, 7.5, 15, 30 mg/kg/day Maternal: NOAEL = 15 mg/kg/day LOAEL = 30 mg/kg/day (BW loss and decreased food consumption).

Developmental: NOAEL = 30 mg/kg/day (HDT)

LOAEL = not determined

870.3800 Reproduction and fertility effects

– rats (dietary) 44988430 (1999) Acceptable/guideline

0, 100, 280, 800 ppm

Parental animals 0/0, 6.5/7.6, 17.9/21.7, 51.0/60.1 (M/F) mg/kg/day

F 1 animals 0/0, 7.5/8.4, 21.0/23.8, 63.3/72.6 (M/F) mg/kg/day Parental/Systemic: NOAEL = 17.9/21.7 (M/F) mg/kg/day LOAEL = 51.0/60.1 (M/F) mg/kg/day based on decreased body weight, body weight gain and food consumption

Offspring: NOAEL = 17.9/21.7 (M/F) mg/kg/day LOAEL = 51.0/60.1 (M/F ) mg/kg/day based on reductions in pup weight, litter size, viability and weaning indices; delay in age to attain preputial separation and vaginal opening

Reproductive: NOAEL = 17.9/21.7 (M/F) mg/kg/day LOAEL = 51.0/60.1 (M/F) mg/ kg/day based on reductions in litter weights and individual pup weights on day of delivery

870.4100 Chronic toxicity

– rat Same as Chronic Toxicity/Carcinogenicity

- rat see below (870.4300) See below (870.4300)

870.4100 Chronic toxicity

– dog ( d ietary) 44651846 (1998) Acceptable/guideline 0, 240, 600, 1500 ppm

0/0, 9/9, 20/21, 55/61 (M/F) mg/kg/day NOAEL = 20/21 (M/F) mg/kg/day

LOAEL = 55/61 (M/F) mg/kg/day based on initial BW loss and overall reduction in BW gainAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 45 of 49 TABLE A.2 .2 Subchronic, Chronic and Other Toxicity Profile for Acetamiprid

. Guideline N umber, Study Type MRID N umber ( Y ear)

,

Classification and Doses Results

870.4200 Carcinogenicity

–

mouse (dietary) 44988428, 45245305 (1999) Acceptable/guideline

0, 130, 400, 1200 ppm (equivalent to 0/0, 20.3/25.2, 65.6/75.9, 186.3/214.6 mg/kg/day in males/females) NOAEL = 20.3/75.9 mg/kg/day (M/F)

LOAEL = 65.6/214.6 (M/F ) mg/kg/day based on

decreased BW & BW gain and amyloidosis in numerous organs (M) and decreased BW and BW gain (F)

Not oncogenic under conditions of study

870.4300

Chronic/ Carcinogenicity

– rat 44988429, 45245304 (1999) Acceptable/guideline

0, 160, 400, 1000 ppm (equivalent to 0/0, 7.1/8.8, 17.5/22.6, 46.4/60.0 (M/F) mg/kg/day) NOAEL = 7.1/8.8 (M/F) mg/kg/day

LOAEL = 17.5/22.6 mg/kg/day (M/F) based on decreases in mean BW & BW gain (F) and hepatocellular vacuolation (M)

Evidence of treatment

- related increase in mammary

tumors, not considered treatment

- related

870.5100

Salmonella typhimurium/E. coli Reverse gene mutation

assay 44651849 (1997) Acceptable/guideline

313 to 5000 μg a i/plate incubated

65.5 hours with +/

- S9 Not mutagenic under the conditions of the study

870.5300

Mammalian cells in

culture Forward gene mutation

assay

– CHO cells 44651857 (1998) Acceptable/guideline

500

- 4000 ug/mL

– S9 or 250

- 3000ug/mL + S9 Not mutagenic under the conditions of the study.

870.5375

In vitro mammalian

chromosome aberration

test

– Chinese hamster ovary (CHO) cells 44651855 (1997) Acceptable/guideline 175, 350, 700 μg/mL

- S9 or 338, 675, 1350 ug/mL + S9 (Highest doses slight to moderately cytotoxic). Acetamiprid is a clastogen under the cond itions of the study.

870.5385

In vivo mammalian

chromosome

aberrations

– rat bone

marrow 44651854 (1998) Acceptable/guideline

250 mk/kg (maximum tolerated dose)

Bone marrow analyzed at 6, 24,

and 48 hours. Acetamiprid did not induce a significant increase in

chromosome aberrations in bone marrow cells when compared to the vehicle control group.

870.5395

In vivo mammalian cytogenetics

– micronucleus assay in

mice 44651852 (1998) Acceptable/guideline

20, 40, 80 mg/kg

Bone marrow analyzed at 24, 48

, or 72 hours Acetamiprid is not a clastogen in the mouse bone

marrow micronucleus test.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 46 of 49 TABLE A.2 .2 Subchronic, Chronic and Other Toxicity Profile for Acetamiprid

. Guideline N umber, Study Type MRID N umber ( Y ear)

,

Classification and Doses Results

870.5550

Unscheduled DNA synthesis in primary rat hepatocytes

, mammalian cell culture 44651856 (1998)

Acceptable/guideline

0.5 to 1000 μg/mL Acetamiprid tested negatively for UDS in mammalian hepatocytes in vivo.

870.6200a Acute neurotoxicity screening battery

– rat (gavage) 44651842 (1997) Acceptable/guideline

0, 10, 30, 100 mg/kg Neurotoxicity: NOAEL= 10 mg/kg/day LOAEL = 30 mg/kg based on reduction in locomotor activity

870.6200b

Subchronic neurotoxicity screening battery

– rat (dietary) 44651845 (1997) Acceptable/guideline

0, 100, 200, 800, 1600 ppm

(equivalent to 0/0, 7.4/8.5, 14.8/16.3, 59.7/67.6, 118/134 mg/kg/day) Neurotoxicity:

NOA EL= 14.8/16.3 mg/kg/day (M/F) LOAEL = 59.7/67.6 (M/F) mg/kg/day based on reductions in BW, BW gain, food consumption and food efficiency

870.6300 Developmental neurotoxicity

– rat (gavage) 46255619 (2003) Acceptable/Non

- Guideline

0, 2.5, 10, 45 mg/kg/day

Volume: 5 mL/kg Vehicle: 5% gum Arabic with

0.01% Tween 80 Maternal:

NOAEL = 10 mg/kg/day

LOAEL = 45 mg/kg/day based on decreased body weight and body weight gains during gestation only

Offspring:

NOAEL = 10 mg/kg/day

. LOAEL = 45 mg/kg/day based on decreased maximum auditory startle response in males on PND 20 and PND 60, and decreased body weight and body weight gain, and pup viability

870.7485

Meta bolism and pharmacokinetics

– rat 44988503

- 7 (1997) Acceptable/guideline

Single dose study with 1 mg/kg (iv), 1 or 50 mg/kg (gavage)

15

- day repeated doses study with 1 mg/kg (gavage); Biliary excretion study with 1 mg/kg (gavage) Extensively and rapidly metabolized. Metabolites

79

- 86% of administered dose. Profiles similar for

males and females for both oral and intravenous dosing. Thirty

- seven percent of dose recovered in urine and feces as unchanged test article. Urinary

and fecal metabolites from 15

- day repeat dose experiment only showed minor differences from single

- d ose test. Initial Phase I biotransformation: demethylation of parent. 6

- chloronicotinic acid was the most prevalent metabolite. Phase II metabolism shown by the increase in glycine conjugate.Acetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 47 of 49 TABLE A.2 .2 Subchronic, Chronic and Other Toxicity Profile for Acetamiprid

. Guideline N umber, Study Type MRID N umber ( Y ear)

,

Classification and Doses Results

870.7485

Metabolism

– m ous e
, rat, rabbit

Special study Male mice, rats or rabbits were administered single doses of acetamiprid by gavage, intraperitoneal injection (i.p.) or intravenous injection (i.v.) up to 60 mg/kg. The animals were assessed for a variety of neurobehavioral parameters. In vitro experimen ts were also done using isolated ileum sections from guinea pigs to assess contractile responses in the absence and presence of agonists (acetylcholine, histamine diphosphate, barium chloride and nicotine tartrate). Acetamiprid was also assessed via i.v. in rabbits for effects on respiratory rate, heart rate and blood pressure; via gavage in mice for effects on gastrointestinal motility; and via i.p. in rats for effects on water and electrolyte balance in urine, and blood coagulation, hemolytic potential a nd plasma cholinesterase activity. Based on a number of neuromuscular, behavioral and physiological effects of acetamiprid in male mice, under the conditions of this study, an overall NOAEL of 10 mg/kg (threshold) and LOAEL of 20 mg/kg could

be estimated for a single dose by various
exposure routes.

870.7600 Dermal penetration

– rat 44651858 (1997) Acceptable/non

- guideline

1.09, 9.53, 90.2 ug/cm 2 Absorption was highest at the mid

- dose and increased with duration (4.07% at 10 after 10 hours

and 6.34% after 24 hours). Residue remaining in

the skin at 24 hours is 25.0%. In addition to absorbed dose (6.34%), total absorption is estimated at 30%. Discuss revised dermal absorption briefly

here or refer to dermal abs. section

870.7800 Immunotoxicity

– rat (dietary) 48113402 (2010) acceptable/guideline 0, 100, 300, 900 ppm Equivalent to 0/0, 7.4/8.6, 21.6/24.3, 62.9/67.7 (M/F) mg/kg/day Systemic: NOAEL = 21.6/24.3 (M/F) mg/kg/day LOAEL = 62.9/67.7 (M/F) mg/kg/day based on decreases in body weight, body weig ht gain, food consumption and water consumption (males only).

Immunotoxicity: NOAEL = 62.9/67.7 (M/F) mg/kg/day

LOAEL = not attainedAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 48 of 49 TABLE A.2 .2 Subchronic, Chronic and Other Toxicity Profile for Acetamiprid

. Guideline N umber, Study Type MRID N umber ( Y ear)

,

Classification and Doses Results

870.7800 Immunotoxicity

– mouse (dietary) 48113401 (2010) acceptable/guideline 0, 100,300, 900 ppm Equivalent to 0/0, 15.3/20.2, 47.0/54.4, 128/157 (M/F) mg/kg/day Systemic: NOAEL = 47.0/54.4 (M/F) mg/kg/day LOAEL = 128/157 (M/F) mg/kg/day based on decreases in body weight (slight), body weight gain, food consumption and water consumption (males only)

Immunotoxicity:

NOA EL = 128/157 (M/F) mg/kg/day

LOAEL = not attained

N/A

28

- Day Range

- finding Study

– dog (dietary) 45245306 (1998) Acceptable/Non

- guideline 0, 125/3000, 250, 500, 1000 ppm mg/kg/day: M= 0, 4.1/42.5, 8.4, 16.7, 28.0; F= 0, 4.8/46.2, 8.7, 19.1, 35.8 [ppm: 125/3000 = 125 for 2 weeks, 3000 for 2 weeks] NOAEL = 16.7/19.1 (M/F) mg/kg/day

LOAEL = 28.0/35.8 (M/F) mg/kg/day based on reduced BW gainAcetamiprid Human Health Risk Assessment D42 3298, D426115, D426117, D427194



### Page 49 of 49 

### Appendix B. Physicochemical Properties

TABLE B.1 Physicochemical Properties of Technical

- Grade Acetamiprid.

Parameter Value Reference
Melting Point/Range (  C) 98.9 D328216 ; W. T. Drew ; 23 October 2007
pH 6.08 (Aqueous solution at 20  C) Density (g/cm 3 ) 1.33 (at 20  C) Water Solubility (g/L) 4.25 (at 25  C) Solvent Solubility (at 25  C) Acetone >20 g/100 g

Methanol >20 g/100 g

Ethanol >20 g/100 g

Dichloromethane >20 g/100 g

Chloroform >20 g/100 g

Acetonitrile >20 g/100 g Tetrahydrofuran >20 g/100 g

Benzene 2.44 g/100 g Xylene 4.01 g/100 g

n

- Hexane 6.54 ppm

Carbon disulfide 507 ppm Vapor Pressure (mm Hg) 7.5 x 10

- 9 (at 25  C) D 264154; M. Doherty ; 31 December

2001 Dissociation Constant, pK
a 0.7 (at 25  C) D328216; W.T. Drew; 23 October2007

Octanol/Water Partition Coefficient, Log K OW 0.8 (at 25  C)

UV/Visible Absorption Spectrum Not available