### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 1 of 33 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION 

### MEMORANDUM

Date : March 20, 2013

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

Corn and Increased Tolerance on Citrus

.

PC Code: 099050 DP Barcode: D 410182

Decision Nos.: 474870, 467044 Registration No s

. : 8033

- 23, 8033

- 36

Petition No s .: 3E8147, 2F8060 Regulatory Action: Section 3 and Amended

Tolerance Assessment Type: Single Chemical Aggregate Registration Case No.: 7617

T

XR No.: None CAS No.: 135410

- 20

- 7

MRID Nos.: 40 CFR 180.578



### FROM: Elizabeth Holman, Physical Scientist
William Drew, Chemist

Risk Assessment B ranch II Health Effects Division (7509P)

THROUGH: Christina Swartz, Chief

Risk Assessment Branch II Health Effects Division (7509P)

TO: Andrew Ertman , Chemical Review Manager Risk Integration Minor Use, and Emergency Response Branch Registration Division (7505 P)

And

Jennifer Urbanski/Venus Eagle (Team 01)

Insecticide/Rodenticide Branch Registration Division (7505P)

This revised risk assessment has been issued in order to address inconsistencies regarding exposure durations in the residential handler assessment. The earlier risk assessment (D409185, E. Holman, 03/07/2013) did not specifically address the inclusion of the intermediate

- term exposure scenario, with this revision making it clear that such an assessment has been completed.

No risks of concern were identified in this assessment , and the risk estimates have not changed

f rom those presented in the previous assessment

.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 2 of 33 Table of Contents

1.0 Executive Summary

................................ ................................ ................................ .................. 3

2.0 HED Recommendations

................................ ................................ ................................ ........... 3

2.1 Data D eficiencies/Conditions of Registration

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2.2.2 International Harmonization

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

2.2.3 Recommended Tolerances

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

2.2.4 Revisions to Petitioned

- For Tolerances

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

2.3 Label Recommendations

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

3.0 Intr oduction

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

3.1 Chemical Identity

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

3.2 Physical/Chemical Characteristics

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

3.3 Pesticide Use Pattern

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

3.4 Anticipated Exposure Pathways

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

3.5 Consideration of Environmental Justice

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

4.0 Hazard Characterization and Dose

- Response Assessment

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

4.1 Summary of Toxicological Effects

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

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

................................ . 10

4.2.1 Completeness of the Toxicology Database

................................ ................................ 10

4.2.2 Evidence of Neurotoxicity

................................ ................................ .......................... 11

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

.......... 11

4.2.4 Residual Uncertainty in the Exposure Database

................................ ........................ 11

4.3 Toxicity Endpoint and Point of Departure Selections

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

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ................ 14

5.1 Metabolite/Degradate Residue Profile

................................ ................................ ............... 14

5.2 Food Residue Profile

................................ ................................ ................................ ........... 15

5.3 Water Residue Profile

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

5.4 Di etary Risk Assessment

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

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

7.0 Aggregate Exposure/Risk Characterization

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

7.1 Acute Aggregate Risk

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

7.2 Short

- and Intermediate

- Term Aggregate Risk

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

7.3 Chronic Aggregate Risk

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

7.4 Cancer Aggregate Risk

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

8.0 Cu mulative Exposure/Risk Characterization

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

9.0 Occupational Exposure/Risk Characterization

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

9.1 Short

- and Intermediate

- Term Handler Risk

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

9.2 Short

- and Intermediate

- Term Postapplication Risk

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

9.2.1 Dermal Postapplication Risk

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

9.2.2 Inhalation Postapplication Risk

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

10.0 References

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

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

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 3 of 33 1.0 Executive Summary

The Agency has received a petition from the Interregional Research Project No. 4 (IR

- 4) to register the insecticide acetamiprid { (1 E )

- N

- [(6

- chloro

- 3

- pyridinyl)methyl]

- N '

- cyano

- N

methylethanimidamide } for post

- emergent foliar use on sweet corn. In addition, under a separate petition, Nisso America Incorporated (Nisso), representing Nippon Soda Company Limited, has requested that the exis ting tolerance on citrus (group 10

- 10) be increased in order to harmonize with European and Codex Maximum Residue Limits (MRLs) , and to allow for the higher residues expected based on the European use pattern . There has been no change in the US

use patter n for citrus. The end

- use products unde r consideration for the new use on sweet corn are the 70% wettable powder (WP) formulation, Assail® 70 WP Insecticide (EPA Reg. No.

8033

- 23), and the 30% water soluble granule (SG) formulation, Assail® 30 SG Insectic ide (EPA Reg. No. 8033

- 36).

The proposed maximum single application rate for both product formulations on sweet corn is 0.1 lb ai/A. These formulations may be applied using aerial and ground equipment. For sweet corn, the maximum number of applications is 4 per season with a 7

- day RTI and a 1

- day pre

harvest interval (PHI)

.

HED has evaluated the hazard information, proposed labels and residue data for these uses , and assessed risk associated with occupational, residential, dietary, and aggregate exposur es. Risk

estimates based on screening level, health protective inputs are well below HED’s level of concern for all scenarios and population subgroups, including those of infants and children.

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

There are no human healt h risk concerns that would preclude granting the requested uses and establishing new tolerances for residues of acetamiprid.

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 ; 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 recommends granting the requested registrations for use of acetamiprid on sweet corn and establishing tolerance s as described in Section 2.2.3

. Revisions to petitioned

- for tolerances (Section 2.2) and l abel modifications (Section 2.3) should be made by the petitioner prior to registration.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 4 of 33 2.1 Data Deficiencies/Conditions of Registration

The toxicological database lacks a 21/28 day inhalation study in rats, which is a required study

based on the registered use pattern

. HED previously determined that the required i nhalation study was needed , based on weight of evidence considerations, including the available toxicity data and the potential for exposure to acetamiprid via the inhalation route. However, the registrant recently requested that this conclusion be re

- evaluated, with the registrant indicating their willingness to implement risk mitigation on registered labels in order to address low occupational margins of exposure (MOEs) associated with aerial application mixing/loading scenarios of the wettable powder (WP) formulation. Therefore, HED re

- considered the need f or the study, and now finds that a subchronic inhalation toxicity study is not required for acetamiprid. This determination considered all of the available hazard and exposure information for acetamiprid, including: (1) the registrant’s agreement to provi de additional risk mitigation

for the use of the WP for mixing/loading; ( 2) the WP formulation is no longer used as a seed

treatment ; and ( 3) the use of an oral point of departure (P OD ) that results in MOEs greater than 1300 for all occupational and reside ntial exposures. However, if the exposure profile for acetamiprid changes, the HASPOC will reevaluate the need for a subchronic inhalation toxicity study.

In an earlier risk assessment, HED concluded that additional field trial residue data w ere requir ed for the use on sweet corn (DP394322, E. Holman, 04/19/2012). However, recent change s in

HED’s poli cy related to adjuvant use have sufficiently resolved these deficiencies. Therefore, no additional field trial data are required to support the proposed use on sweet corn and the recommended tolerances have been determined using the previously submitted data.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An approved LC

- MS/MS tolerance enforcement method, with an LOQ of 0.01 ppm, is available for vegetables and non

- citrus crops. An approved HPLC/UV tolerance enforcement method, with an LOQ of 0.05 ppm, is available for citrus fruits. These methods are ad equate for enforcing the proposed tolerances associated with this petition.

2 .2.2 International Harmonization

There are currently no established Codex, Canadian, or Mexican MRLs for acetamiprid on sweet corn; therefore, there are no issues of harmonization. There are Codex and Canadian MRLs on livestock commodities, with the revi sed livestock tolerances for the U.S. being higher than both the Codex and Canadian values. Given the revised use pattern including sweet corn, these higher U.S. livestock commodity tolerances are warranted. However, this is not considered to be a signif icant trade irritant, as livestock commodities are rarely shipped internationally. With the citrus (crop group 10

- 10) tolerance increase to 1.0 ppm, the U.S. will be harmonized with both Codex and the European Union MRLs. However , the Canadian tolerance for citrus is currently

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 5 of 33 at 0.5 ppm; HED has made Canada (PMRA) aware of these impending rev isions and they intend

to harmonize their tolerances when possible at a future date.

2.2.3 Recommended Tolerances

The current tolerance definition for acetamiprid (40 CFR 180.578) is appropriate regarding scope and compliance

.

Table 2.2.3 . Tolerance Summary for Acetamiprid.

Commodity Established/Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments ( Correct Commodity Definition )

Corn, sweet, kernel plus cob with

husks removed 0.01 0.01

Corn, sweet, forage 1 5 1 5

Corn, sweet, stover 30 30

Milk 0.30 0.30

Cattle, fat 0.20 0.20

Cattle, meat 0.30 0.30

Cattle, meat byproducts 0.70 0.70

Goat, fat 0.20 0.20

Goat, meat 0.30 0.30

Goat, meat byproducts 0.70 0.70

Horse, fat 0.20 0.20

Horse, meat 0.30 0.30

Horse, meat byproducts 0.70 0.70

Sheep, fat 0.20 0.20

Sheep, meat 0.30 0.30

Sheep, meat byproducts 0.70 0.70

Fruit, citrus, group 10

- 10 1.0 1.0 Existing tolerance is at 0.5

ppm Citrus, dried pulp 2.4 1.2 Existing tolerance is at 1.2

ppm and should be maintained



### In addition, an error has been identified with a commodity definition listing in the existing 40

CFR §180.578 , which currently lists “vegetable, tuberous and corm, group 1.” In a future action associated with acetamiprid, this listing should be revised to read “Vegetable, tuberous and corm, subgroup 1C.”

2.2.4 Revisions to Petitioned

- For Tolerances

Requested and recommended tolerances are in agreement for residues in/on sweet corn and

livestock commodities summarized in Table 2.2.3

. Therefore, no revisions are necessary for

these commodities

.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 6 of 33 For citrus fruit (group 10

- 10), the proposed and recommended tole rance are also in agreement. However, for citrus, dried pulp, HED has determined that a revised citrus pulp tolerance is not needed and that the existing tolerance of 1.2 ppm is adequate (D404596, W. Drew, 01/04/2013).

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

Table 2.2.3.

2.3 Label Recommendations

It is noted that sweet corn is one of the crops that has been identified as requiring risk mitigation for the mixing/loading scenarios for aerial applicat ion on the WP formulation label (D407373, E.
Holman, 02/07/2012 ) . HED recommends that risk mitigation measures be undertaken to address this issue, such as the addition of a PF5 respirator, with appropriate label revisions as needed.

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 nicot inic 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.

3.1 Chemical Identity

T able 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 Product (EP) Assail® 70 WP Insecticide (EPA Reg. No. 8033

- 23) Assail® 30 SG Insecticide; EPA Reg. No. 8033

- 36)



### 3.2 Physical/Chemical Characteristics

The physicochemical properties of technical

- grade acetamiprid are summarized in Appendix

Table B1

. The values in the table suggest that there are no exposure scenarios that are likely to N N C H 3 Cl

C H 3

N C N

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 7 of 33 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 o ctanol/water partitioning coefficient indicates that partitioning into fatty tissues is unlikely and that there is low potential

for bioaccumulation.

3.3 Pesticide Use Pattern

Table 3.3 . Summary of Proposed Directions for Use of Acetamiprid. 1

Applic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No. Applic. per

Season Max. Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and

Limitations 2

Sweet corn

Post

- emergence, Broadcast, Aerial (≥5 gal/A) or ground, (≥20 gal/A) Assail®

70 WP [8033

- 23]

Assail®

30 SG [8033

- 36] 0.0 4

- 0.1 4 0.21 7 Minimum RTI = 14 days

0.04

- 0 .1 4 1 Minimum RTI = 7 days (if applied in a rotation or

tank mixture with another insecticide)

Citrus (within Crop Group 10

- 10)

No change from established use pattern for Citrus (within Crop Group 10

- 10 ) 3 for the registered U.S. formulations,

with a maximum annual use rate of 0.55 lb ai/A. In the European Union, there is a higher maximum ann ual use rate of 0.62 lb ai/A.

1 From draft labels dated 8/25/11 for Assail® 70 WP and 8/24/11 for Assail® 30 SG

2 RTI = Re

- treatment interval

3 Refer to accept ed labels dated 6/29/11 for both Assail® 70 WP and Assail® 30 SG.



### Personal Protective Equipment (PPE) : Both proposed labels have the following PPE

statements: “ A pplicators and other handlers must wear long

- sleeved shirt and long pants

, waterproof gloves, shoes plus socks and headgear for overhead chemical exposure”. As noted previously, in the absence of a subchronic inhalation s tudy, sweet corn is one of the crops that has been identified as requiring risk mitigation for the mixing/loading scenarios for aerial application on the WP formulation label (D407373, E. Holman, 02/07/2012). HED recommends that risk mitigation measures b e undertaken to address this issue, such as the addition of a PF5 respirator, with appropriate label revisions as needed.

3.4 Anticipated Exposure Pathways

Acetamiprid is registered for us e on growing crops as well as in and around the home. As a

res ult 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 addition, 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 during application. There is a potential for post

- application exposure for workers re

- entering treated

fields.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 8 of 33 Risk assessments have be en 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 assessment, in accordance with U.S. Executive Order 12898, "Federal Actions

to Address Enviro nmental Justice in Minority Populations and Low

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

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

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption,

and a ctivities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in Ameri ca, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP i s 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 f or adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialize d software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Comprehensive risk assessments for acetam iprid were conducted in 2012 (D394322; E. Holman). There are no changes to the endpoints or points of departure (PODs) for dietary assessment for acute, chronic or cancer risk used in the previous evaluations. However, the HED HASPOC recently re

- evaluate d the need for a subchronic inhalation study and determined that it is not needed at this time (TXR 0056556 , K.Rury, 02/20/2013). Consequently, the 10X database uncertainty factor retained in the 2012 assessment for inhalation scenarios has been removed, with the level of concern being lowered to 100 for these scenarios.

4.1 Summary of Toxicological Effects

The toxicity database contains : 1) subchronic oral toxicity 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, subchroni c, and developmental neurotoxicity studies in rats; 5) immunotoxicity 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

. The lack of a 21/28 day inhalation study in rats is not considered to be a data gap ; the HED HASPOC has determined that the study

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 9 of 33 is not needed at this time ( TXR 0056556 , K.Rury, 0 2/20/2013 )

. 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 weight gain, food consumption and food efficiency. Generali zed 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 amyloid osis 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 absorp tion 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 distributes widely in the body but tissue burdens ra rely 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 metabolite, 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 excretion accounted for 21

- 35% of the administered rad ioactivity, 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.

There wa s no qua ntitative or qualitative evidence of increased 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. T he 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. These 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 femal es, decreased pre

weaning survival [post

- natal days (PNDs) 0

- 1 ] , and decreased maximum auditory startle

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 10 of 33 response in males on PND s 20 and 60

. This was observed in the presence of decreased maternal body weight and body weight gains during gestation. Altho ugh 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 de crease in the duration of movements persisted in some males during later observations . Functional observational battery evaluations revealed several

treatment

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

, coldness to the touch as well as decreased forelimb grip strength and hind limb foot splay. High

- dose 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 effects observed in any other studies.

Four week immunotoxicity studies wer e performed in 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 clear 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

stu dy. A cetamiprid metabolites IC

- 0, IM

- 1

- 2, IM

- 1

- 4, IM

- 2

- 1, and IM

- 0 tested negative for mutagenicity.

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

acute oral route (Category II); however, it has low toxi city 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 recommends the FQPA SF of 10X be reduced to 1X for the following reasons: (1) the toxicology data base is complete; (2) HED is regulating the use of acetamiprid based upon the effects of concern, i.e., developmental effects in pups following pre

- and/or post

- natal exposure; ( 3) the rat is the most se nsitive 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; ( 4 ) there are no residual uncertainties for pre

- and/or

post

- natal toxicity ; ( 5) the exposure databases (dietary food, drinking water, and residential) are complete ; and ( 6) the risk assessment for each potential exposure scenario includes all metabolites and/or degradates of concern and does not undere stimate the potential risk to infants

or children.

4.2.1 Completeness o f the Toxicology Database

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 11 of 33 As summarized in Appendix Table A1, the toxicology database is considered adequate for the purpose of assessing pre

- and postnatal susceptibility, includin g an immunotoxicity study. Acceptable developmental toxicity studies in the rat and rabbit and a rat reproductive toxicity study have been submitted. Based on a WOE approach considering all the available hazard and exposure information and proposed addit ion of a respirator for mixing/loading WP acetamiprid 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 DN T. Tremors in the high dose female mice in the subchronic feeding study were the only other potentially neurotoxic effects observed in the

other studies.

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

HED determined that neither quantitative nor qualitative evidence of increased susceptibility of

fetuses to in utero exposure to acetamiprid was observed in either the developmental toxicity study in rat or rabbit. However, in the 2

- generation reproduction study, qualitative evidence of 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 the 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. Quantitative evidence of increased susceptibility was not 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) determine the level of concern for the effects observed when considered in the context of all available toxicity data; and, 2) identify any residual uncertainties af ter 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 FQPA safety factor, and if so, what factors should be retained.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 12 of 33 Considering the overall toxicity profile and the endpoints and doses selected for the acetamiprid risk assessment, HED characterized the degree of concern 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 respect 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 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 underestimated. The aggregate exposure and risk estimates presented in this assess ment are expected to over

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

of concern were identified

.

4.3 Toxicity Endpoint and Point of D eparture Selections

The toxicological endpoints and points of departure selected for dietary and occupational exposure and risk assessment are presented below in Tables 4.3.1 and 4.3.2. The complete toxicological profile for acetamiprid is summarized in Appendix A.2. There have been no changes to the diet ary dose

- response assessment or endpoints, the cancer classification/risk quantification or the occupational dermal assessment.

A revised occupational exposure and risk assessment has not been conducted for this assessment since the use pattern for swee t corn was previously assessed under an earlier petition. Currently, occupational exposure of only short

- or intermediate

- term durations is anticipated. A 28

- or 90

- day inhalation study is not required. Since long

- term occupational exposure is not antic ipated, the oral studies of short or subchronic duration (rat, dog and mouse 90

- day dietary; rat reproductive toxicity; rat and rabbit developmental toxicity) were considered for inhalation risk

assessment

. For inhalation exposure scenarios, as the subchr onic inhalation study is no longer required as it was in the 2012 assessment (D394322), the level of concern has been lowered to 100 and the 10X database uncertainty factor has no longer been retained.

For short

- and intermediate

- term inhalation expos ure, the developmental neurotoxicity (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 (post

- natal days (PNDs) 0

- 1), and decreased maximum auditory startle response in males on PNDs 20 and 60

. Since an oral study was selected for assessing the inhalation route, toxicity via this route was considered to be equivalent to toxicity via the oral route, for the purpose of risk assessment.

For all of the relevant routes and durations of exposure, clear NOAELs and LOAELs were identified. In addition, the toxicity database is consid ered 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

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 13 of 33 variability and 10X for inters pecies extrapolation) were applied. For dermal and inhalation risk assessment, the level of concern (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).

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 Dose Used in

Risk

Assessment Uncertainty Factors/FQPA Safety Factors PAD ; Level of

Concern for

Risk

Assessment Study and Toxicological Effect

Acute Dietary (All populations) NOAEL = 10 mg/kg/day UF A = 10x

UF H = 10x 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 = 10x

UF H = 10x FQPA SF = 1x cPAD = 0.071 mg/kg/day Chronic Toxicity/Oncogenicity Study

in rats 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 = 10x

UF H = 10x FQPA SF = 1x 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.

Short

- and

Intermediate

- term
Dermal (1

- 30 days ; 1

- 6

months ) NOAEL = 10 mg/kg/day

DAF = 10% UF A = 10x

UF H = 10x FQPA SF = 1x 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.

Short

- and

Intermediate

- term
Inhalation (1

- 30 days, 1

– 6

mo nths ) NOAEL = 10 mg/kg/day

Inhalation toxicity

assumed to be equivalent to oral toxicity UF A = 10x

UF H = 10x FQPA SF = 1x 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).
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 beginning of extrapolation to determine risk associated with lower environmentally

releva nt human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among

members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. 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. L OC = level of concern. N/A = not applicable.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 14 of 33 Table 4.3.2 . Summary of Toxicological Doses and Endpoints of Acetamiprid for Use in Occupational Human

Health Risk Assessment Exposure Scenario Dose Used in

Risk

Assessment Uncertainty

Factors Level of

Conce rn 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 = 10x

UF H = 10x 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.

Short

- and

Intermediate

- term
Inhalation (1

- 30 days, 1

- 6

mo nths ) NOAEL= 10 mg/kg/day

Inhalation toxicity

assumed to be equivalent to oral toxicity UF A = 10x

UF H = 10x 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 o n 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). DAF = dermal absorption factor. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### 5.0 Dietary Exposure and Risk Assessment

E. Holman

, D409726

, 07 March 2013 E. Holman, D409727

, 07 March 2013

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 . The residue

definitions for tolerance enforcement and risk assessmen t are summarized in Table 5.1. For further details on these metabolism studies, please refer to M. Doherty et al (D278352, 10/16/2001).

Table 5 .1

. Risk Assessment and Tolerance Enforcement Residue Definitions for Acetamiprid.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Acetamiprid Acetamiprid Rotational Crop Not applicable None at this time

Livestock Ruminant Acetamiprid + IM

- 2

- 1+ IM

- 2

- 1

- amide ( ruminant muscle only) Acetamiprid and IM

- 2

- 1

Poultry Acetamiprid and IM

- 2

- 1 Acetamiprid and IM

- 2

- 1 Drinking Water Acetamiprid Not Applicable

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 15 of 33 5.2 Food Residue Profile

The established tolerances in fruit, citrus, group 10

- 10 can be increased as proposed from 0.5 ppm to 1.0 ppm

. There is no change in the US use pattern associated with citrus ; however, the European Union maximum annual use rate on citrus is highe r at 0.62 lb ai/A vs. 0.55 lb ai/A in
the U.S. Therefore, these tolerance revision s are being made to harmonize with C odex and European Union MRLs and to accommodate the higher EU use rates on imported citrus

commodities

.

To support the proposed use on sweet corn , the petitioner has submitted studies depicting residues of acetamiprid following broadcast foliar or direc ted application treatment in/on sweet
corn commodities

. Applications were made in accordance with the proposed labeling and the residue data are supported by appropriate analytical method and storage stability data. The proposed preharvest intervals (PHI ) are acceptable for sweet corn. Table 5.2.1. summarize s the

submitted field trial da ta for the proposed commodities.

HED has concluded that sufficient data have been submitted to support th e use on sweet corn.

T here is evidence to support residue equ ivalency for the 70% WP formulation and the 30% SG formulation and the combination of trials conducted with these two formulations provide for an adequate number of trials with sufficient geographic variation . As noted previously, there are significant di fferences in the stover PHIs between the U.S. and Canadian trials (D394779, E. Holman, 03/06/2012) . These differences are reflected in the residue data for stover and forage

. In both the U.S. and Canadian trials, residues of acetamiprid were < 0.01in K+CWHR, whereas residues in forage and stover appeared to be higher in the U.S. trials (up to ~10X higher in forage and ~30X higher in stover)

. Furthermore, although the use patterns were similar between the

U.S. and Canadian trials for K+CWHR and forage (four applications, 1

- to 2

- day PHI), the U.S. trials performed with the 30% SG formulation included an adjuvant, whereas the Canadian trials using the 70% WP formulation did not include an adjuvant. However, the HED ChemSAC recently concluded that the inherent variability in field trials, coupled with the characteristics and

conservative nature of the OECD tolerance calculation method exceeds the variability seen with the use of adjuvants . Therefore, the adjuvant differences observed in the U.S. a nd Canadian field trials are no longer considered to be an issue. Consequently, a dditional crop field trial data are

not requi red to support the proposed use on sweet corn

.

The available residue chemistry data for acetamiprid are sufficient for purpose s of assessing risk and establishing tolerances on sweet corn

. The existing dataset is sufficient for assessing risk and establishing an increased tolerance on citrus, with no change in the existing use pattern.

The proposed use of acetamiprid on sweet corn will result in a significant increase in the maximum reasonable dietary burden to ruminants as a result of dietary contributions from sweet corn forage and cannery waste. When the results of the dairy cattle f eeding study are adjusted

for the potential increased dietary burden, the maximum expected combined residues of acetamiprid and IM

- 2

- 1 increase in milk and all tissues. Based on the data available, the

tolerance in milk should be increased from 0.10 to 0. 30 ppm, and the tolerances in the fat, meat, and meat byproducts of cattle, goat, horse, and sheep should be increased from 0.10 to 0.20 ppm in fat; from 0.10 to 0.30 ppm in meat; and from 0.20 to 0.70 ppm in meat byproducts.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 16 of 33 Table 5.2.1

. Summary of Res idue Data from Sweet Corn Crop Field Trials with Acetamiprid.

Com

modity No. Apps. Total Applic.

Rate (lb ai/A) PHI (days) Residue Levels (ppm) 1

n Sampl

e Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

SWEET CORN (proposed use = 0.21 lb ai/A total application rate; 4 applications with a 1

- day PHI or 2 applications with a 7

- day PHI)

U.S. Trials (30% SG formulation)

K+CWHR 4 0.212

- 0.220 1 7 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

2 0.195

- 0.214 5

- 8 7 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

Forage 4 0.212

- 0.220 1 7 0.42 8.1 0.54 7.3 1.3 3.0 2.8

2 0.195

- 0.214 5

- 8 7 0.39 10 0.41 9.1 1.4 2.9 3.1

Stover 4 0.212

- 0.220 1 3 7 0.12 16 0.19 15.5 4.1 5.7 5.7

2 0.195

- 0.214 5

- 8 3 7 0.21 21 0.21 20 2.8 5.3 7.0

Canada Trials (70% WP formulation)

K+CWHR 4 0.213

- 0.281 (238.5

- 314.7) 1

- 2 5 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

Forage 4 5 0.23 1.1 0.43 0.82 0.61 0.60 0.15

Stover 4 0.213

- 0.281 (238.5

- 314.7) 38

- 89 4 <0.01 0. 35 0.011 0. 285 0.0 50 0. 0 82 0.0 95

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

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

3 Including PHIs of 28 and 35 days for stover from plots 2 and 3 of t he NY trial , respectively. Although the PHIs

from this trial differed by >25%, this data was included in the summary results because the residues were within the range of those in the other trials, and the use pattern was consistent with typical stover har vest

.



### 5.3 Water Residue Profile

K. White, D394234/D394479, 11 October 2011

In a memo dated 11 October 2011 (K. White, D394234/D394479)

, the Environmental Fate and Effects Division ( EFED ) provided estimated residues of acetamiprid in drinking water from the use of acetamiprid as a scatter bait as well as on tree nuts . The bait use results in the highest estimated drinking water concentrations (EDWCs) for all assessed use scenarios

. The EDWCs used in this dietary assessment are summarized in Table 5 .3. The surface water EDWCs were generated using the FQPA Index Reservoir Screening Tool (FIRST) Model and the ground water

estimates are from the Screening Concentration In GROund Water (SCI

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

.

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

exposure. In the dietary risk assessment conducted to support the proposed uses and label changes, HED incorporated the surface water EDWCs directly into the dietary model, since surface water estimates were higher than those provided for ground water. The use of the surface water values in the dietary assessment is therefore protective of potential exposure through ground water sources of drinking water.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 17 of 33 Table 5.3 . Tier I Analysis

- 1

- in

- 10

- year EDWCs in surface water and ground water for acetamiprid. Drinking Water Source Maximum Use Pattern Exposure EDWC (ppb)

Surface water Scatter Bait Peak (acute) 95.2 Annual average (chronic) 26.6

Ground water Scatter Bait Peak & annual average 0.035



### 5.4 Dietary Risk Assessment

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 da ta from the U.S. 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 the food

- handling establishment use are not included in

the a cute dietary assessment.

Both the acute and chronic analyses are based on tolerance

- level residues and assume 100% crop treated. Acute and chronic dietary risk estimates are below HED’s level of concern for all population subgroups (Table 5.4). For acut e exposures, the dietary risk for the U.S. population is

estimated to be 25 % of the population

- adjusted dose (PAD). Acute risk for children 1

- 2 years old, the highest

- exposed population subgroup, is estimated to be 68 % of the PAD. Chronic risk

estimates are 14 % of the P AD for the U.S. population and 60 % 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 an issue for this chem ical.

There are no dietary exposure or risk concerns that would preclude granting the requested uses of acetamiprid and establishing tolerances associated with th ese use s

.

Table 5.4. Summary of Dietary Exposure and Risk Estimates for Acetamiprid.
Population Subgroup Acute (95th Percentile) Chronic
Exposure (mg/kg/day) % PAD Exposure (mg/kg/day) % PAD

U.S. Population (total) 0.024916 25 0.009604 1 4
All infants (< 1 year) 0.051557 5 2 0.017618 2 5

Children 1

- 2 yrs 0.067723 68 0.042610 60

Children 3

- 5 yrs 0.045932 46 0.027686 39

Children 6

- 12 yrs 0.026282 2 6 0.013626 19

Youth 13

- 19 yrs 0.015610 1 6 0.007393 10

Adults 20

- 49 yrs 0.016009 1 6 0.006717 10

Adults 50

- 99 yrs 0.015813 1 6 0.007152 10

Females 13

- 49 yrs 0.016260 1 6 0.006916 10 Populations with the highest exposure estimates are bolded.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

M. Collantes

, D3 83325, 22 July 2011

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 18 of 33 Acetamiprid is registered for controlling a wide variety of indoor and outdoor insect pests in residential settings. T he registrant is not proposing any new residential uses with this

su bmission, and therefore a new residential exposure assessment was not conducted. Exposure to acetamiprid in residential settings is expected to be short

- (1 to 30 days) and intermediate

- term (1 to 6 months) in duration. For acetamiprid, HED’s level of co ncern (LOC) is a margin of exposure (MOE) of 100. In the most recent residential handler and postapplication exposure assessment, all scenarios resulted in MOEs greater than 100 and are not of concern (M. Collantes, D383325, 22 July 2011).

The applicabl e combined residential risk estimates to adult s (handler and postapplication) and children (3

- 6 years ; postapplication only ) are summarized in Table 6. Although there is the potential for co

- occurrence of adult exposure resulting from applying and enterin g treated areas (postapplication), the risks from both exposures are not combined because HED believes that this

would result in an over

- estimat ion of exposures.

The risk estimates presented in Table 6 do not reflect the most recent (Feb. 201 2 ) updates to the SOPs for residential exposure assessment, or the updated assumptions for body weights, in accordance with the October 2011 Exposure Factors Handbook. However, HED has determined that the updated SOPs and body weights will not result in si gnificantly different exposure and risk estimates, and therefore would not significantly impact this aggregate risk assessment. The impact of the SOPs and body weights will be assessed in conjunction with registration review (docket opening scheduled for FY2013).

In the most recently completed risk assessment, HED had concluded that a subchronic inhalation study was required, and an additional 10X FQPA factor was retained as a database uncertainty factor, which raised the level of concern (LOC) to 1000 for inhalation scen arios. Therefore, the risk estimates were expressed using an aggregate risk index (ARI) in this most recent 2012 assessment (D394322, E. Holman, 04/20/2012). However, this conclusion was reevaluated based on a request from the registra nt, and HED has now concluded tha t this study is not required (T XR 0056556 , K.Rury, 02/20/2013). Therefore, the risk estimates presented below in Table 6 utilize the combined MOE approach, with these risks not being of concern as indicated

above.

Table 6. Combined Residential Exposure and Risk Estimates from the Indoor Crack and Crevice and Bed Bug

Mattress Use 1

Scenarios Daily Dose (mg/kg/day) MOE 2 Combined

MOE

Adult Handler

Mattress Treatment

- Dermal 0.00088 11,000 3,600

Mattress Treatment

- Inhalation 0.000039 260,000

Crack & Crevice

- Dermal 0.00178 5,600

Crack & Crevice

- Inhalation 0.000078 130,000
Adult Postapplication

Dermal

– Crack & Crevice 0.0232 430 430

Inhalation

– Crack & Crevice 0.000018 560,000

Dermal

- Mattress Treatment 0.00015 66,000

Child Postapplication

Dermal

– Crack & Crevice 0.0333 300 220

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 19 of 33 Table 6. Combined Residential Exposure and Risk Estimates from the Indoor Crack and Crevice and Bed Bug

Mattress Use 1

Inhalation

– Crack & Crevice 0.000046 220,000

Dermal

- Mattress Treatment 0.000323 31,000

Hand

- To

- Mouth 0.011 900

1 Table and all values taken from D383325, M. Collantes, 22 July 2011.

2 MOE = NOAEL (10 mg/kg/day) / D aily Dose

.



### 6. 2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application 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 and State Lead Agencies f or 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 Agenc y is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide regi strants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may im pose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant

risks associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not perfor med as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered prote ctive of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

7.0 Aggregate Exposure/Risk Characterization

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

7.1 Acute Aggregate Risk

Typically, HED does not consider r esidential 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

aggre gate risk estimates for acetamiprid are equivalent to the acute dietary risk estimates (Section 5 .4 ) and are below HED’s level of concern.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 20 of 33 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; therefore, separate assessments are not being conducted for these durations. Short

- and

intermediate

- term residential exposures to acetamip rid may occur from uses of this chemical around the home (Section 6) ; in addition, dietary exposure is possible from acetamiprid residues in food and drinking water (Section 5). For assessing aggregate risk, the chronic dietary exposure estimate is used s ince it represents a background exposure level from food and drinking water that may co

- occur with residential exposures. The toxicological endpoints, points of departure, and level of concern are the same across oral, dermal, and inhalation routes of

exp osure for acetamiprid; therefore, aggregate risk can be estimated by combining the various exposure estimates and comparing the resulting aggregate exposure estimates (Table 7.2) against

the short

- and intermediate

- term point of departure.

All aggregate MOEs are greater than 100 and indicate that risks are not of concern. It is noted

that the chronic dietary exposure estimates are highly conservative, assuming tolerance

- level residues and 100% crop treated for all commodities. Therefore, HED also consi ders the aggregate MOEs to be conservative estimates, with the actual exposures likely being much lower

than those characterized here.

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

Adult 10 100 0.00 7152 0.0 23368 0.030520 3 30

Child 10 100 0.0 42610 0.0 44669 0.087279 1 20

1 The LOC is based on the standard inter

- and intra

- species uncertainty factors totaling 100

. 2 From Section 5. Adult = 50+ years group (maximum exposure). Child = Children 1

- 2 years.

3 Combined residential exposure estimate from Section 6.

4 Aggregate Exposure = Avg Food and Water Exposure + R esidential Exposure

5 Aggregate MOE = NOAEL ÷ Aggregate Exposure. Values rounded to two significant figures.



### 7. 3 Chronic Aggregate Risk

There are no long

- term residential exposure s expect ed for acetamiprid. Therefore, chronic aggregate risk estimates a re equivalent to the chronic dietary risk estimates (Section 5.4) and are

below HED’s level of concern.

7. 4 Cancer Aggregate Risk

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

risk is not of concern for th is 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

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 21 of 33 to acetamiprid and any other substances and acetamiprid does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,

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

s ubstances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determ inations and procedures for cumulating effects from substances found to have a common mechanism on

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

.

9.0 Occupational Exposure/Risk Character ization

S. Oonnithan, D395464/D395468/D395470



### , 15 February 2012

The Health Effects Division (HED) has conducted a n occupational and residential exposure (ORE) assessment for the proposed new uses of acetamiprid insecticide on sweet corn.

Assessed scena rios include workers handling and/or applying end

- use products as well as

workers re

- entering treated areas/fields. Occupational exposure to acetamiprid from the requested uses are expected to be of short

- term (1

- 30 days) or intermediate

- term (1

- 6 months)

duration. As the short

- and intermediate

- term points of departure are the same, separate short

and intermediate

- term assessments were not conducted. Long

- term exposures are not expected.

9.1 Short

- and Intermediate

- Term Handler Risk

E stimates of hand ler exposure to acetamiprid associated with the requested uses were assessed using surrogate study data available in the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force (AHETF) database

. For all

crops , assessed activities include mixers/loaders and applicators for ground

- based and aerial appl ications, as well as flaggers. This assessment was originally conducted for proposed new uses on sweet corn, turnip greens, and asparagus; the new uses o n turnip greens and asparagus were approved under an earlier risk assessment (D394322, E. Holman, 04/19/2012). All of the proposed uses are on crops with the same use pattern (i.e., application rates and methods). Therefore, sweet corn was selected as a representative crop because it is the crop with the highest acreage treated. The exposures from dermal and inhalation routes were added together to

calculate a combined MOE since the endpoints were the same (i.e., the same toxic effects ) with

the same le vel of concern

. All MOEs assume a baseline level of personal protective equipment (PPE) plus chemical resistant gloves, with the exception of the mixer/loader scenario for aerial applications of the WP f ormulation.

U se of acetamiprid on assessed crops resulted in combined MOE s greater than 1 00 (Table 9.1)

and are not of concern. It is noted tha t the mixing/loading scenario for aerial application of the

WP for mulation yields an MOE of 280 with baseline PPE. Although this MOE is above the LOC of 100, in the absence of a subchronic inhalation study a PF5 respirator is required to obtain an MOE greater than 1000. HED recommends that appropriate risk mitigation, such as the addition of a respirator, be added to the WP label for this applicat ion scenario.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 22 of 33 Table 9.1

. Occupational Exposure and Risk Estimates for Handlers From Use of Acetamiprid.

Exposure Scenario Crop or Target 1 Mitigation

Level 2 Max. Single Appl.

R ate ( lb ai/A ) Area

T reated (Acres) Dermal

UE ( μg/lb ai ) Derm al D ose ( mg/kg/day ) 3 Inhal ation

UE ( μg/lb ai ) Inhal ation

D ose ( mg/kg/day ) 4 Total D ose ( mg/kg/day ) 5 Total MOE 6

Mixer/ L oader

1. WP (assessed for highest acreage using aerial equipment) All crops B + G

0.1 350 170 (PHED) 0.00992 43.4 (PHED) 0.02532 0.03523 280

2. DF assessed for highest acreage using aerial equipment) (DF surrogate for SG) All crops B + G 51.6 (AHETF) 0.00301 8.96 (AHETF) 0.00523 0.00824 1,200

Applicator 3. Aerial spray with fixed wing aircraft (DF surrogate for SG) All crops Encl. Cockpit 0.1 350 5.0 (PHED) 0.00029 0.068 (PHED) 0.00004 0.00033 30,000

4. Groundboom

sprayer All crops B + G, Open

Cab 80 16.1 (AHETF) 0.00021 0.34 (AHETF) 0.00005 0.00026 38,000

Flagger

5. Flagger All crops B + G 0.1 350 12 (PHED) 0.00070 0.35 (PHED) 0.0002 0.0009 11,000

Ab breviations used: B = baseline PPE, G = gloves, MOE = margin of exposure, PPE = personal protective equipment, UE = unit expo sure. 1. All crops (asparagus, sweet corn, and turnip greens) have the same use pattern. Therefore, sweet corn was selected as a representative crop because it is the

crop with the highest acreage treated. 2. Baseline PPE includes long

- sleeved shirt, long pants and shoes with socks. L abel recommended PPE is baseline plus chemical resistant gloves

. 3. Dermal Dose (mg/kg/day) = [ A ppl. R ate (lb ai/A) * Acres T reated/ D ay * Dermal U nit E xposure ( μg/ lb ai handled/day /1000) * Dermal Absorption Factor (10%) ] / Bo dy wt ( 60 kg). 4. Inhalation Dose (mg/kg/day) = [ A ppl. R ate (lb ai/A) * Acres T reated/ D ay * I nhalation U nit E xposure ( μg/ lb ai handled/day /1000) ] / B ody wt ( 60 kg ). 5. Total Dose is the total exposure from dermal and inhalation routes for the day. Total Dose (mg/kg/day) = Dermal Dose + In halation Dose.

6. Short

- term Total MOE = Short

- term NOAEL (10 mg/kg/day) / Total Dose (mg/k g/day)

. Intermediate

- term MOEs were not assessed separately, since the same endpoint/study and dose were selected to assess both short

- term and intermediate

- term durations. The short

- term MOEs are protective of risks associated

with intermediate

- term dur ations of exposure.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 23 of 33 9.2 Short

- and Intermediate

- Term Post a pplication Risk

The proposed label s for Assail® 70 Wettable Powder (WP) and Assail® 30 Soluble Granule (SG) Insecticides have a 12

- hour REI and are in compliance with the Worker Protection Standard because acetamiprid is Toxicity Category III via the dermal route and is not an eye or skin irritant, and is not a skin sensitizer.

9.2.1 Dermal Postapplication Risk

The registrant did not submit a c hemi cal specific post

- application exposure study for a quantitative evaluation of risks resulting from use of Assail ® 

### WP and SG products on the sweet

corn

. Therefore, d ermal exposures during post

- application activities were estimated using

standard default va lues for dermal transfer coefficients from the Science Advisory Council for Exposure Policy Number 3.2: Agricultural Transfer Coefficients, June 3, 2011 and based on proprietary data (from the Agricultural Reentry Task Force [ARTF]) and non

- proprietary dat a. Farm workers who enter treated fields after the REI period to perform postapplication activities such as irrigation, weeding, scouting and harvesting may be exposed to residues of acetamiprid. These activities result in post

- application dermal MOEs of 190 to 1,8 00 and are not of concern (Table 9.2). The lowest MOE of 190 was associated with detasseling sweet corn and harvesting it by hand.

Table 9.2

. R isk Estimates to Workers Resulting from Postapplication Activities Performed in Fields

Treated with Acetamiprid

.

Crop High Contact Activity Appl. Rate (lb ai/A) DFR (ug/cm 2 ) 1 Transfer

Coeff icient (cm 2 /hr) 2 Sh ort

- term

Dermal Dose 3
(mg/kg/day) Sh ort

- term

Dermal

MOE 4

Asparagus Irrigation (hand weeding)

0.1 0.224 1,900 (MRID No.

45726301 ) 0.00567 1,800

Sweet corn Detassel ing and Harvesting Hand 17,600 (MRID No.

45005905 ) 0.05256 190

Turnip

greens Irrigation (hand set) 1,900 0.00567 1,800

1. Dislodgeable Foliar Residue ( DFR) = A ppl . R ate (lb ai/A) * (1

- D aily D issipation R ate) t * Conv. Factor 1 (4.54E+8 μg/lb) * Conv. Factor 2 (2.47E

- 8 A/cm 2 ) * Residue Transfer Rate (20% default) after treatment. 2. Transfer coefficient is a surrogate value for workers having low

- high contact with field crops foliage during postapplication activit ies (ExpoSAC Policy #3, June 3, 2011).

3. D aily Dose (mg/kg/day) = [DFR * T ransfer Coefficient * Conv. Factor ( 0.001 mg/μg ) * D ermal A bsorption ( 10 %) * 8 hrs/day] / B ody W eight ( 6 0 kg)

. 4 : Short

- term Margin of Exposure (MOE) = S hort

- term Dermal N OAEL (10 mg/kg/day) / Daily Dose ( mg/kg/day)

.



### 9.2.2 Inhalation Postapplication Risk

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

- application inhalation exposure assessment was not performed for acetamiprid at this time primarily because of the low acute inhalation toxicity (Toxicity Category III ) , low vapor pressure ( 7.5 × 10 - 9 

### mm Hg ), and the low proposed application rate (0.1 lb ai/A). However, there are multiple potential sources of post

-

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 24 of 33 application inhalation exposure to individuals perfo rming 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 Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 2 March 2 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Forc e and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational

post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational

post

- application inhalation exposure assessment for acetamiprid

.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, HED has assess ed inhalation exposure and risk f or occupational/commercial flaggers for aerial applications of acetamiprid on sweet corn and the risk was not of concern. Inhalation

e xposure of flaggers resulting from aerial application of pesticides is likely to result in higher exposure than the exposure resulting from post

- application activities . Therefore, it is expected

that the flagger inhalation risk estimate conducted for sweet corn would be protective of all post

app lication inhalation exposure scenarios.

10.0 References

K. White. D 394234 /D 394479

. 11 October 2011. Tier I Drinking Water Exposure Assessment for the Section 3 New Use of Acetamiprid on Various Agricultural Crops and as a Scatter

Bait to Control Insect s

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

M. Doherty. D278352. 16 October 2001. Acetamiprid

- Metabolism Assessment Review Committee Briefing Memorandum

.

M. Doherty. D264154. 31 December 2001. Section 3 Registration for Use of Acetamiprid on Cotton, Leafy Vegetables, Cole Vegetables, Fruiting Vegetables, Citrus Fruits, Pome Fruits, Grapes, and Canola and Mustard Seed. Summary of Analytical Methods and Residue Chemistry DERs.

E. Holman. D394779. 6 March 2012. Acetamiprid. Petition for the Establishment of Permanent Tolerances and Registration for Use on Asparagus; Brassica, Leafy Greens, Subgroup 5B, and Turnip Greens; and Sweet Corn; and Update o f Crop Group Definitions for Established Tolerances for Vegetable, Fruiting, Group 8

- 10; Fruit, Citrus, Group 10

- 10; and Fruit, Pome, Group 11

- 10. Summary of Analytical Chemistry and Residue Data.

E. Holman. D394322. 19 April 2012. Acetamiprid: Human Health Risk Assessment for New

Uses on Asparagus; Brassica, Leafy Greens, Subgroup 5B, and Turnip Greens; and Sweet

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 25 of 33 Corn; and Updated Crop Group Definitions for Fruiting Vegetables, Citrus, and Pome Fruit

.

E. Holman. D395331. 14 February 2012

. Acetamiprid Acute and Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment

– Uses on Asparagus, Brassica Leafy Greens (Subgroup 5B), Sweet Corn, and Updated Crop Groups for Pome, Citrus Fruit, and Fruiting Vegetables.

E. Holman. D409726

. 7 March 2013

. Acetamiprid Acute and Chronic Dietary Exposure and

Risk Assessment

– Use on Sweet Corn and Increased Citrus (Crop Group 10

- 10) Tolerance.

E. Holman. D409727

. 7 March 2013

. Acetamiprid. Petition for the Establishment of

Permanent Tolerances and Registration for Use on Sweet Corn. Summary of Analytical Chemistry and Residue Data.

E. Holman. D407373. 7 February 2013. Acetamiprid. HED’s Response to Comments on the Human Health Assessment Scoping Document in Support of Registratio n Review.

S. Oonnithan. D395464, D395468, and D395470

. 15 February 2012

. Acetamiprid: Occupational and Residential Exposure Assessment for the Proposed New Uses on Asparagus and Sweet Corn, and for an Increased Application Rate for Turnip Greens.

K. Ru ry

. TXR 0052354

. 15 March 2012

. Acetamiprid: Summary of Hazard and Science Policy Council (HASPOC) Meeting of March 12, 2012. Recommendations on the need for a 28

- day inhalation study.

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 26 of 33 A ppendix A . Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for based on food uses of acetamiprid are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

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

870.2600 Dermal Sensitization Yes

Yes

Yes

Yes

Yes

Yes Yes

Yes

Yes

Yes

Yes

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

870.3200 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 (nonrodent) 870.3800 Reproduction Yes

Yes

Yes Yes

Yes

Yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (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

Yes

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 27 of 33 A.2 Toxicity Profiles

Acute Toxicity of Technical Acetamiprid

GDLN 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 Is not a sensitizer under conditions of study. N/A



### Toxic ity Profile for Acetamiprid: Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification /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 (Dietary) 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 determined

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 28 of 33 Toxic ity Profile for Acetamiprid: Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification /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; d elay 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 (Dietary) 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 gain

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 29 of 33 Toxic ity Profile for Acetamiprid: Subchronic, Chronic, and Other Toxicity Studies

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

8 70.5395

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 DP No. D4 10182

Page 30 of 33 Toxic ity Profile for Acetamiprid: Subchronic, Chronic, and Other Toxicity Studies

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

- rats (gavage) 4465 1842 (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

- rats (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: NOAEL= 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)

Ac ceptable/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

Metabolism and pharmacokinetics

- rats 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

excret ion 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

- dose

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 DP No. D4 10182

Page 31 of 33 Toxic ity Profile for Acetamiprid: Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification /Doses Results

870.7485

Metabolism

- mice, rats,

rabbits 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/k g. The animals were assessed for a variety of neurobehavioral

parameters. In vitro experiments 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

e ffects on water and electrolyte balance in urine, and blood coagulation, hemolytic potential and plasma cholinesterase activity. Based on a number of neuromuscular, behavioral and physiological effects of acetamiprid in male mice, under the conditions of this study, a n 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 weight gain, food consumption and water consumption (males only).

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

LOAEL = not attained

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: NOAEL = 128/157 (M/F) mg/kg/day

LOAEL = not attained

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 32 of 33 Toxic ity Profile for Acetamiprid: Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification /Doses Results

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 gain

### Acetamiprid Human Health Risk Assessment DP No. D4 10182

Page 33 of 33 Appendix B1.

Physicochemical Properties of Technical

- Grade Acetamiprid.

Parameter Value Reference 1

Melting Point/Range ( ° C) 98.9 PP#6F7051
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) M

. Doherty

, D264154

, 31 December 2001 Dissociation Constant, pK

a 0.7 (at 25 ° C) PP#6F7051
Octanol/Water Partition Coefficient, Log K OW 0.8 (at 25 ° C)

UV/Visible Absorption Spectrum Not available

1 From D 3 2 8216; W. Drew; 10/23/07