Acetamiprid Human Health Risk Assessment DP No. D394322

Page 1 of 43 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF
CHEMICAL SAFETY AND

POLLUTION PREVENTION MEMORANDUM

Date: April 19, 2012

SUBJECT: Acetamiprid: Human Health Risk A ssessment for New Uses on Asparagus; Brassica, Leafy Greens, Subgroup 5B, and Turnip Greens; and Sweet Corn; and Updated Crop Group Definitions for Fruiting Ve getables, Citrus, and Pome Fruit.

PC Code: 099050 DP Barcode: D394322 Decision Nos.: 454284 Registration Nos.: 8033-23, 8033-36 Petition Nos.: 1E7919 Regulatory Action: Section 3 Assessment Type: Single Chemical Aggr egate Registration Case No.: 7617

TXR No.: None CAS No.: 135410-20-7 MRID Nos.: 48590101, 48590102, 48590103, 48590104 40 CFR 180.578

FROM: Elizabeth Holman, Chemist Suku Oonnithan, Biologist Zaida Figueroa, Industrial Hygienist

Risk Assessment Branch II Health Effects Division (7509P)

THROUGH: Christina Swartz, Chief

Risk Assessment Branch II Health Effects Division (7509P)

TO: Laura Nollen, Chemical Review Manager Risk Integr ation Minor Use, and Emergency Response Branch Registration Division (7508P)Acetamiprid Human Health Risk Assessment DP No. D394322

Page 2 of 43 Table of Contents

1.0 Executive Summary ............................................................................................................. 4

2.0 HED Recommendations....................................................................................................... 5

2.1 Data Deficiencies/Conditi ons of Registration .................................................................. 5

2.2 Tolerance Considerations ................................................................................................. 5

2.2.1 Enforcement Analytical Method ............................................................................... 5

2.2.2 International Harmonization ..................................................................................... 5

2.2.3 Recommended Tolerances ........................................................................................ 6

2.2.4 Revisions to Petitione d-For Tolerances .................................................................... 6

2.3 Label Recommendations .................................................................................................. 7

3.0 Introduction .................................................................................................................. ........ 7

3.1 Chemical Identity ............................................................................................................. 8

3.2 Physical/Chemical Characteristics ................................................................................... 8

3.3 Pesticide Use Pattern ........................................................................................................ 9

3.4 Anticipated Exposure Pathways ..................................................................................... 10

3.5 Consideration of Environmental Justice ........................................................................ 10

4.0 Hazard Characterization and Dose-Response Assessment ................................................ 10

4.1 Toxicology Studies Available for Analysis ................................................................... 10

4.2 Absorption, Distribution, Metabolis m, & Elimination (ADME) ................................... 11

4.2.1 Dermal Absorption.................................................................................................. 11

4.3 Toxicological Effects ..................................................................................................... 11

4.4 Safety Factor for Infants and Ch ildren (FQPA Safety Factor) ....................................... 13

4.4.1 Completeness of the Toxicology Database ............................................................. 13

4.4.2 Evidence of Neurotoxicity ...................................................................................... 13

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 13

4.4.4 Residual Uncertainty in the Exposure Database ..................................................... 14

4.5 Toxicity Endpoint and Point of Departure Selections .................................................... 14

4.5.1 Dose-Response Assessment .................................................................................... 14

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ........ 18

4.5.3 Cancer Classification and Risk Assessment Recommendation .............................. 18

4.5.4 Summary of Points of Departure and T oxicity Endpoints Used in Human Risk

Assessment .................................................................................................................... ........ 18

5.0 Dietary Exposure and Risk Assessment ............................................................................ 20

5.1 Metabolite/Degradate Residue Profile ........................................................................... 20

5.2 Food Residue Profile ...................................................................................................... 21

5.3 Water Residue Profile .................................................................................................... 23

5.4 Dietary Risk Assessment ................................................................................................ 24

6.0 Residential (Non-Occupational) E xposure/Risk Characterization .................................... 25

6.2 Spray Drift ................................................................................................................... ... 26

7.0 Aggregate Exposure/Risk Characterization ....................................................................... 27

7.1 Acute Aggregate Risk .................................................................................................... 27

7.2 Short- and Intermediate-T erm Aggregate Risk .............................................................. 27

7.3 Chronic Aggregate Risk ................................................................................................. 28

7.4 Cancer Aggregate Risk ................................................................................................... 28

8.0 Cumulative Exposure/Risk Characterization ..................................................................... 28

9.0 Occupational Exposure/Risk Characterization .................................................................. 28Acetamiprid Human Health Risk Assessment DP No. D394322

Page 3 of 43 9.1 Short- and Intermediate -Term Handler Risk .................................................................. 29

9.2 Short- and Intermediate-Ter m Postapplication Risk ...................................................... 31

9.2.1 Dermal Postapplication Risk................................................................................... 31

9.2.2 Inhalation Postapplication Risk .............................................................................. 31

10.0 References .................................................................................................................... ...... 32 Appendix A. Toxicology Prof ile and Executive Summaries ....................................................... 34Acetamiprid Human Health Risk Assessment DP No. D394322

Page 4 of 43 1.0 Executive Summary

The Agency has received a petition from the In terregional 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-em ergent foliar use on asparagus; Brassica leafy greens, subgroup 5B, and turnip greens; and sweet corn. In addition, IR-4 is proposing to update crop group definitions for established tolerances for ve getable, fruiting, group 8-10; fruit, citrus, group 10-10; and fruit, pome, group 11-10. The end-use products under consideration for the new uses are the 70% wettable powder (W P) formulation, Assail® 70 WP Insecticide (EPA Reg. No. 8033-23), and the 30% water soluble granule (SG) formulation, Assail® 30 SG Insecticide (EPA Reg. No. 8033-36).

The proposed maximum single application rate for both product formulations on the proposed

commodities is 0.1 lb ai/A. These formulati ons may be applied using aerial and ground equipment. The maximum number of applicatio ns is 2 per season for asparagus with a 10-day re-treatment interval (RTI). For sweet corn, Brassica leafy greens (subgroup 5B), and turnip greens, the maximum number of app lications is 4 per season with a 7-day RTI. The pre-harvest intervals (PHIs) are 1 day for asparagus and sweet corn, and 3 days for turnip greens and

Brassica leafy greens (subgroup 5B). There are no changes in the existing acetamiprid use pattern for cole crops

, fruiting vegetables, ci trus and pome fruit. The updated crop group definitions didn’t require a new occupational exposure and risk assessment since the use patterns were previously assessed, and no risks of concern were identifi ed. To reflect the updated crop group definitions, the dietary exposure assessment has been updated to in clude all appropriate

commodities.

HED has evaluated the hazard information, proposed labels and residue data for these uses, and

assessed risk associated with o ccupational, residential, dietary, and aggregate exposures. Risk estimates based on screening level, health prot ective 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 consideratio n potential environmental justice issues. Based on the existing and proposed uses for acetamipr id, and on current Office of Pesticide Programs (OPP) assessment policies, there are no envir onmental justice concerns associated with acetamiprid.

There are no human health risk concerns that would preclude granting the requested uses and establishing new tolerances for residues of acetam iprid. However, at this time, HED concludes

that the available data are insufficient for estab lishing the proposed tolerances associated with the requested registratio n on sweet corn.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pest icide or other chemical. Thes e 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/scien ce/post-app-exposure-data.html), have been determined toAcetamiprid Human Health Risk Assessment DP No. D394322

Page 5 of 43 require a review of their ethical conduct, have received that revi ew, and have been determined to have been ethically conducted.

2.0 HED Recommendations

HED recommends granting the requested regist rations for use of acetamiprid on asparagus, turnip greens, and Brassica leafy greens, subgroup 5B and establishing tolera nces as described in Section 2.2.3. Revisions to petitioned-for to lerances (Section 2.2) and label modifications (Section 2.3) should be made by the petitioner prior to registration. At this time, HED concludes

that the available data are insufficient for estab lishing tolerances associat ed with the requested registration on sweet corn. As ou tlined in Section 2.1, five additional field trials are required to fill this data gap.

2.1 Data Deficiencies/Conditions of Registration

The toxicological database lacks a 21/28 day inhalation study in ra ts, which is a required study. HED has determined that the required inhala tion study cannot be waive d, based on weight of evidence considerations, including the available t oxicity data and the potential for exposure to acetamiprid via the inhalation route.

To support the proposed uses on sweet corn, five a dditional crop field trials must be conducted in the U.S. with the 30% SG formulation and an adjuva nt in Zones 1 (1 trial), 5 (3 trials), and 12 (1 trial) to provide a full set of fi eld trial data for this formulatio n. Each trial should include an additional side-by-side treated pl ot reflecting application of th e 70% WP formulation with an adjuvant. Although the available data suggest that residues are simila r following application according to the four-application/1-day PHI use pattern and the two-application/7-day PHI use pattern, HED recommends that eac h use pattern be represented in at least two of the required trials. The registrant has been made aware of these issues and intends to complete the required trials during the 2012 growing season. Until these data have been received and the sweet corn dataset re-evaluated, the proposed use and associated toleran ces for sweet corn cannot be

established.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An approved LC-MS/MS tolerance enforcement me thod, with an LOQ of 0.01 ppm, is available for vegetables and non-citrus crops. An a pproved HPLC/UV tolerance enforcement method, with an LOQ of 0.05 ppm, is available for citr us fruits. These methods are adequate for enforcing the proposed tolerances as sociated with this petition.

2.2.2 International Harmonization

There are currently no establ ished Codex, Canadian, or Mexican maximum residue limits (MRLs) for acetamiprid on asparagus and no established Codex MRLs on any Brassica vegetables; therefore, there are no issues of ha rmonization. Canadian MRLs are established forAcetamiprid Human Health Risk Assessment DP No. D394322

Page 6 of 43 residues of acetamiprid at 1.2 ppm in/on Chinese cabbage (Bok choy), cabbages, broccoli raab, collards, kale, mustard greens, mustard spinach, and rape greens. With the establishment of separate tolerances in l eafy greens, subgroup 5B, and Brassica head and stem, subgroup 5A, the Canadian MRLs for Bok choy Chinese cabbages, br occoli raab, collards, kale, mustard greens, mustard spinach, and rape greens will no longer be harmonized with U.S. tolerances. This petition requests a revised use pattern for subgroup 5B commodities , specifically a shorter PHI; therefore, a higher U.S. tolerance of 15 pp m is required. (Subgroup 5B includes bok choy Chinese cabbage, broccoli raab, collards, kale , mustard greens, mustard spinach, and rape greens.)

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/Propo

sed Tolerance (ppm) Recommended Tolerance (ppm) Comments ( Correct Commodity Definition )

Asparagus 0.8 0.80

Brassica , leafy greens, subgroup 5B 15 15

Turnip greens 15 15 Turnip, greens
Vegetable, brassica, leafy, group 5 1.20 None With the establishment of the separate 5B tolerance, the group 5 tolerance should be

removed.

Brassica , head and stem, subgroup 5A -- 1.2 Using the existing group 5 tolerance and available data, this separate 5A tolerance

can be established without additional data.

Corn, sweet, kernel plus

cob with husks removed 0.01 To be determined Insufficient data are available to support the proposed use/tolerances for sweet corn at

this time. Corn, sweet, forage 10

Corn, sweet, stover 30
Vegetable, fruiting, group 8 0.20 None

Fruit, citrus, group 10 0.50 None

Fruit, pome, group 11 1.0 None

Vegetable, fruiting, group

8-10 0.20 0.20

Fruit, citrus, group 10-10 0.50 0.50

Fruit, pome, group 11-10 1.0 1.0

2.2.4 Revisions to Petitioned-For Tolerances

Requested and recommended tolerances are in agreement for resi dues in/on asparagus; Brassica

, leafy greens, subgroup 5B; or turnip greens. No revisions are necessary relative to the petitioned-for tolerances updating the crop group definitions for vegetable, fruiting, group 8-10; fruit, citrus, group 10-10; a nd fruit, pome, group 11-10.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 7 of 43 In keeping with HED conventions for tolera nce rounding and significan t figures, the proposed tolerance for asparagus was changed from 0.8 ppm to 0.80 ppm.

With the establishment of a tolerance in Brassica leafy greens, subgroup 5B, the established tolerance in vegetable, Brassica , leafy, group 5, should be remove d, and a new tolerance should

be established in Brassica , head and stem, subgroup 5A, at 1.2 ppm.

Insufficient data are available to support the proposed to lerances in corn, sw eet, kernel plus cob with husks removed; corn, sweet, forage; and co rn, sweet, stover. Until the outstanding field trial data are received, no tolerances will be established.

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

Table 2.2.3.

2.3 Label Recommendations

HED has concluded that insufficient data have been submitted to support the use of either the

70% WP or the 30% SG formulation on sweet corn. Until the requested crop field trial data have been submitted, use on sweet corn should be removed from both labels.

In support of the proposed use on turnip greens, the labels should be revised to prohibit the harvest of turnip root for food/feed purposes because use on turnip r oot is not supported by

residue data or an established tolerance.

In support of the proposed use on Brassica leafy greens, subgroup 5B, the labels should be revised to include Chinese Bok Choy with the subgroup 5B commodities. Chinese Bok Choy is currently misplaced on the labels with subgroup 5A commodities.

Because other adjuvant types were not tested, the labels should specify use of an NIS as adjuvant for the asparagus, Brassica leafy greens and turnip greens uses.

It was noted that the draft labe l for the 30% SG formulation in cludes the following error in the “Site” column: “Pome Fruit (within Crop Gr oup 11)” instead of “Pom e Fruit (within Crop Group 11-10)”. This error should be corrected on the label.

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 subs equent overload of sodium ions in the neurons which leads to nervous system hyper-excitat ion, and eventual death of the insect.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 8 of 43 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 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-grad e acetamiprid are summarized in Table 3.2. The values in the table suggest that there are not any exposure scenarios th at are likely to require special consideration. The vapor pressure for ace tamiprid is quite low and as such, inhalation exposure via volatilization is expected to be negligible. The octanol/water partitioning coefficient indicates that partitioni ng into fatty tissues is unlikely and that there is low potential

for bioaccumulation.

Table 3.2. 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) N N CH 3 Cl

CH 3

N CNAcetamiprid Human Health Risk Assessment DP No. D394322

Page 9 of 43 Table 3.2. Physicochemical Properties of Technical-Grade Acetamiprid.

Parameter Value Reference 1

UV/Visible Absorption Spec trum Not available

1 From D328216; W. Drew; 10/23/07

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

Asparagus

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

70 WP [8033-23] 0.05-0.1 2 0.2 1 Minimum RTI = 10 days

Assail®

30 SG [8033-36] 0.047-0.1

Head and Stem Cole Crops (Crop Subgroup 5A)
No change from established use pattern for Cole Crops (within Group 5) 3

Leafy Cole Crops (Crop Subgroup 5B) and Turnip Greens

Post-emergence, Broadcast, Aerial ( ≥ 5 gal/A) or ground, ( ≥ 30 gal/A) Assail®

70 WP [8033-23] 0.035-0.1 4 0.375 3 Minimum RTI = 7 days

Assail®

30SG [8033-36] 0.038-0.1

Sweet corn

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

70 WP [8033-23]

Assail®

30 SG [8033-36] 0.04-0.1 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)

Fruiting Vegetables (within Crop Group 8-10):

No change from established use pattern for Fruiting Vegetables (within Crop Group 8) 3

Citrus (within Crop Group 10-10)

No change from established use pattern for Citrus (within Crop Group 10) 3

Pome Fruit (within Crop Group 11-10)

No change from established use pattern for Pome Fruit (within Crop group 11) 3

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 accepted 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: “Applicators and other handlers mu st wear long-sleeved shirt and long pants, waterproof gloves, shoes plus socks and h eadgear for overhead chemical exposure”.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 10 of 43 3.4 Anticipated Exposure Pathways

Acetamiprid is registered for use on growing cr ops as well as in and around the home. As a result of the uses on crops, as well as a recen tly proposed and assessed use in food/feed handling establishments, humans may be exposed to acetam iprid in food and drinking water. In addition, exposure may occur in residential or non-occupa tional 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-app lication 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 ex isting uses, particularly for dietary exposure.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions

to Address Environmental Just ice in Minority Populations an d Low-Income Populations," ( http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP considers a large variety of c onsumer subgroups according to well-established procedures. In line with O PP policy, HED estimates risks to population subgroups from pesticide exposures that are ba sed on patterns of that subgrou p’s food and water consumption,

and activities in and around th e home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These da ta are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additi onally, OPP is able to assess dietary exposure to smaller, specia lized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures and risks based on home use of pe sticide products for a dult applicators and postapplication activities for toddl ers, youths, and adults entering or playing on tr eated areas are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and mode ls that consider exposure to bystanders and farm workers as well as lifesty le and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicity database contains: 1) subchronic oral toxi city studies in rats, mice, and dogs; 2) a chronic oral toxicity study in dogs and carcinogenicity studies in rats and mice; 3) developmental and reproduction studies in rats and a developmen tal study in rabbits; 4) acute, subchronic, and developmental neurotoxicity studies in rats; 5) immunotoxicity studies in rats and mice; and, 6) subchronic dermal toxicity and de rmal penetration studi es in rats. There is also a completeAcetamiprid Human Health Risk Assessment DP No. D394322

Page 11 of 43 mutagenicity battery, as well as metabolism studies in the rat. The lack of a 21/28 day inhalation study in rats is considered to be a data ga p; the HED HASPOC has determined that the study cannot be waived (TXR 0052354, K.Rury, 03/15/2012). No literature information is available that would have an impact upon risk assessment. Metabolites were only examined in some mutagenicity studies.

4.2 Absorption, Distribution, Metab olism, & Elimination (ADME)

Several studies have examined the in vivo metabolism and distribution of acetamiprid in the rat including single dose, 15-day repeated dose, bi liary excretion, and metabolite characterization

studies.

Acetamiprid is rapidly absorbed and eliminate d. Metabolism studies i ndicate 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 rarely exceed 1% of the administered dose. Acetamiprid is extensively metabolized with metabolites accounting for 79-86% of the administered radioactivity. 6-Chloronicotini c acid is the most abundant me tabolite, accounting for 24-28% of the dose in single-dose studies and 8-10% in repe ated-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 radioactivity, with males being slightly higher. Excretion ra tes for the IV and repeated dose studies were similar. Biliary excretion did not vary be tween genders and, by 48 hours, accounted for about

19% of the administ ered radioactivity.

As a result of the rapid absorption, metabolism, and clearance of acetamiprid in the rat, the pharmacokinetic parameters derived from the 15- day repeated dose study were similar to the single dose study. Therefore, the potential for acetamiprid to bioaccumulate is minimal.

4.2.1 Dermal Absorption

A dermal absorption factor of 10% is being used for risk assessment. The factor is based on an acetamiprid dermal absorption study in rats, a dermal absorption study in monkeys, and a comparison of structurally simila r neonicotinoids. The derivation of this factor is fully discussed in the 2009 risk assessment for acetamiprid (D369474, D. McNeilly et al ., 1 December 2009).

4.3 Toxicological Effects

In all species tested, generalized nonspecific toxicity was observe d as decreases in body weight, body weight gain, food consumption and food effi ciency. Generalized effects were also observed in the liver in the form of hepato cellular hypertrophy in both mice and rats and hepatocellular vacuolation in the rat. These effect s 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 mous e subchronic study, and microconcretions in the kidney papilla and mammary hyperplasia in the rat chronic/oncogenicity study.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 12 of 43 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 wa s conducted using male rats with exposure durations up to 24 hours. In so me earlier acetamiprid risk assessments, a 30% dermal absorption value was estimated from this study. However, as noted above, HED has refined the dermal absorption value (to 10%) based upon comparison to clothianidin, which is structurally related.

There was no quantitative or qualitative evidence of increased suscepti bility of rat or rabbit

fetuses to in utero exposure 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 c onsumption in the parents and significant reductions in pup weights in both ge nerations. Also observed were 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 sepa ration. These offspring observations were considered to be more severe than the parental effects.

In the developmental neurotoxicity study there was also evidence of increased qualitative susceptibility. In this study, the offspring LOAEL was based on decreased body weights and body weight gains in males and females, decreas ed pre-weaning survival [post-natal days (PNDs) 0-1], and decreased maximum auditory st artle response in males on PNDs 20 and 60. This was observed in the presence of decrea sed maternal body weight and body weight gains during gestation.

In an acute rat 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. Func tional observational battery ev aluations revealed several

treatment-related ob servations on the day of dosing. At the high dose only, males exhibited tremors, difficulty in handling, walking on toes, dilated pupils, co ldness to the touch as well as decreased forelimb grip strength and hind limb fo ot splay. High-dose females displayed tremors, chewing, coldness to the touc h, dilated pupils, decreased hind limb foot splay, and abnormal gaits and/or posture, including walking on to es 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 th e subchronic feeding study were the only other potentially neurotoxic effects obs erved in any other studies.

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

Acetamiprid did not show clear evidence of genotoxi c 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 doe s not support the results of the in vitroAcetamiprid Human Health Risk Assessment DP No. D394322

Page 13 of 43 study. Acetamiprid metabolites IC-0, IM-1-2, IM -1-4, IM-2-1, and IM-0 tested negative for mutagenicity.

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

HED recommends the FQPA SF of 10X be re duced to 1X for dermal and oral exposure pathways based on the following reasons: (1) the toxicology data base is complete (with the exception of an inhalation study); (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 sens itive species tested, and the NOAEL and LOAEL selected from the DNT study in rats are protective of effects obs erved 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, dr inking water, and residential) ar e complete; and (6) the risk assessment for each potential exposure scenario includes all metabolites and/or degradates of

concern and does not underestimate th e potential risk to infants or ch ildren. In the absence of the required inhalation toxicity study, HED is recomme nding the 10X FQPA factor be retained as a database uncertainty factor only for a ssessing inhalation exposure and risk.

4.4.1 Completeness of the Toxicology Database

Acceptable guideline studies for developmenta l, reproductive toxicity and neurotoxicity (including DNT) are available for FQPA assessmen t. Immunotoxicity studies in rats and mice

have also been submitted and reviewed. A s ubchronic inhalation study remains outstanding and is considered a data deficiency.

4.4.2 Evidence of Neurotoxicity

Acetamiprid produced signs of neurotoxicity in the high dose groups in the acute and developmental neurotoxicity studies in rats. In the acute neurot oxicity study, male and female rats displayed decreased motor activity, tremors, walking and posture abnormalities, dilated pupils, coldness to the touch, a nd decreased grip strength an d foot splay. However, no neurotoxic findings were reported in the subchr onic 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 potentially neurotoxic effects observed in the

other studies.

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

HED determined that neither quantitative nor qual itative 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, qual itative evidence of increased susceptibility of rat pups was obser ved. While parental a nd 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 parent s (decreased body weight and body weight gain). In the DNT study, maternal and offspring effect s were observed at the same dose. However, the offspring effects included de creased pup viability which is considered to beAcetamiprid Human Health Risk Assessment DP No. D394322

Page 14 of 43 more severe than the maternal body weight effect s. Therefore, HED concluded that there was evidence of increased qualitative susceptibility to fetuses exposed in utero and/or during lactation in the DNT study. Quan titative evidence of in creased susceptibility was not observed in any study.

4.4.4 Residual Uncertainty in the Exposure Database

Since there is evidence of increased qual itative susceptibility of the young following in utero exposure to acetamiprid in the rat reproduction st udy, 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 afte r establishing toxicity endpoints and traditional uncertainty factors to be used in the acetamiprid risk assessment. If re sidual uncertainties are identified, HED examines whether the residual un certainties can be addressed by a FQPA safety factor, and if so, what fa ctors should be retained.

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 NOA EL for the offspring effects and regulatory doses were selected to be protective of these effects. No ot her residual uncertainties were identified with respect to susceptibilit y. HED believes that the endpoints and doses selected for acetamiprid are protective of adve rse effects in both offspring and adults.

In the absence of the 28-day inha lation study, there is uncertainty a bout potential portal of entry effects occurring via the inhalati on route of exposure, and HED is recommending retaining the 10X FQPA factor as a database uncertainty factor for the inhalation route of exposure only, pending submission of the required study.

HED has used conservative assumptions in th e exposure assessment, in cluding the use of 100% crop treated assumptions, tolerance-level residue values, and upper-bound estimates of potential exposure through drinking water. In additi on, the residential exposure assessment was conducted such that residential exposure and ri sk will not be underestimated. The aggregate exposure and risk estimates presented in this assessment 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.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

4.5.1.1 Acute Reference Dose (a RfD) - All Populations

Co-Critical Studies Selected : Developmental Neurotoxic ity Study in Rats (MRID 46255619)

Acute Neur otoxicity Study in Rats (MRID 44651842)Acetamiprid Human Health Risk Assessment DP No. D394322

Page 15 of 43 Dose and Endpoint for Risk Assessment : NOAEL = 10 mg/kg/day (both studies) based on decreased pre-weaning survival (PND 0-1), decr eased maximum auditory startle response in males on PND 20 and PND 60 of the DNT study at 45 mg/kg/day, as well as decreased locomotor activity in males in the ACN study at 30 mg/kg bw. The DNT and acute neurotoxicity

studies are considered co-critical due to similar LOAELs and signs of toxicity.

mg/kg 0.1 RfD Acute   (UF) 100 mg/kg 10

Comments about Study/Endpoint/Uncertainty Factors : These endpoints and dose were selected because: 1) the oral route of exposure is relevant to dietary risk assessment, 2) the duration of exposure is relevant to acute diet ary risk (both endpoints can be considered the result of a single dose), and 3) they are protective of potential offs pring effects. Based on the available data, HED determined that changes in motor activity, au ditory startle reflex, learning and memory assessments, and changes in the brain morphometric s can occur as the result of a single exposure at a critical junction during pregnancy or fr om multiple exposures throughout pregnancy and lactation. The standard uncertainty factors (100x ) were applied to all dietary exposure scenarios (10x for intraspecies variability and 10x for interspecies extrapolation).

4.5.1.2 Chronic Reference Dose (cRfD)

Studies Selected : Chronic/Carcinogenicity Study in the Rat

MRID Nos .: 44988429, 45245304

Dose and Endpoint for Risk Assessment : NOAEL = 7.1 mg/kg/day based on decreased body weights and body weight gains in females and he patocellular vac uolation in males observed at the LOAEL of 17.5 mg/kg/day.

mg/kg/day 0.071 RfD Chronic   (UF) 100 mg/kg/day 7.1

Comments about Study/Endpoint/Uncertainty Factors : This endpoint and dose was selected because: 1) the oral route of exposure is relevant to dietary risk assessment, 2) the duration of exposure is relevant to chronic risk scenarios, and 3) it is the lowest endpoint in the toxicology database and is therefore protectiv e of both chronic effects and poten tial qualitative sensitivity of offspring. The standard uncertainty factors were applied to all dietary exposure scenarios (10x for intraspecies variability and 10x for interspecies extrapolation).

4.5.1.3 Incidental Oral Exposure

Short- and Intermediate-Term Incidental Exposure (1-30 days and 1-6 months)

Study Selected : Developmental Neurotoxic ity Study in Rats (MRID 46255619)Acetamiprid Human Health Risk Assessment DP No. D394322

Page 16 of 43 Dose and Endpoint for Risk Assessment : NOAEL = 10 mg/kg/day base d on offspring decreased body weights and body weight gains, decreased pr e-weaning survival (PND 0-1), and decreased maximum auditory startle response in males on PND 20 and PND 60 of the DNT study at 45 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors : The NOAEL and LOAEL from the DNT study were selected for the short- and intermedia te-term incidental oral risk assessment because they are protective of developmental effects pres ent in rat pups observed in the presence of less

severe maternal effects at similar doses. The standard uncertainty fact ors (100x) were applied (10x for intraspecies variability and 10x for interspecies extrapolation).

4.5.1.4 Dermal Exposure

Short- and Intermediate-Term Dermal E xposures (1-30 days and 1-6 months)

Study Selected : Developmental Neurotoxicity Study in Rats

MRID No. : 46255619

Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on decreased body weights and body weight gains in males and female s, decreased pre-weaning survival (PND 0-1), and decreased maximum auditory startle respon se in males on PND 20 and PND 60 of the DNT study at 45 mg/kg/day, as well as decreased loco motor activity in males in the ACN study at 30 mg/kg bw.

Comments about Study/Endpoint/Uncertainty Factors : The NOAEL and LOAEL from the DNT study were selected for the short- and intermedia te-term dermal risk assessment because they are protective of developmental effects present in ra t pups observed in the presence of less severe

maternal effects at similar doses.

Although a dermal (route specific) toxicity study in rabbits was submitted, no effects were seen at the highest dose tested of 1000 mg/kg/day. Use of the route- specific study for dermal risk assessment would not be protective of the offspri ng effects observed in both the DNT and the 2- generation reproduction studies beca use the effects seen could occur as a result of a single exposure at a critical junction during pre gnancy or from multiple exposures throughout pregnancy lactation. Therefor e, the NOAEL for offspring effects observed in the DNT was

selected as the dose for both short-term and inte rmediate-term dermal exposure scenarios. Since the dermal endpoint is based on an oral study, a 10% dermal absorption factor is used to determine dermal exposure and risk. The standa rd uncertainty factors were applied to all exposure scenarios (10x for intr aspecies variability and 10x for interspecies extrapolation).

Long-Term Dermal Exposure (> 6 months)

Study Selected : Chronic/Carcinogenicity Study in Rats

MRID No. : 44988429, 45245304Acetamiprid Human Health Risk Assessment DP No. D394322

Page 17 of 43 Dose and Endpoint for Risk Assessment: NOAEL = 7.1 mg/kg/day based on decreases in mean body weight and body weight gain in females a nd hepatocellular vacuolation in males.

Comments about Study/Endpoint/Uncertainty Factors : The NOAEL and LOAEL from the chronic/carcinogenicity study were selected for the long-term dermal risk assessment because they are protective of developmental effects s een in the 2-generation and DNT studies and the study is of an appropriate duration.

Although a dermal (route specific) toxicity study in rabbits was submitted, no effects were seen at the highest dose tested of 1000 mg/kg/day. Use of the route- specific study for dermal risk assessment would not be protective of the offspri ng effects observed in both the DNT and the 2- generation reproduction studies beca use the effects seen could occur as a result of a single exposure at a critical junction during pre gnancy or from multiple exposures throughout pregnancy lactation. Since the dermal endpoint is based on an oral study, a 10% dermal absorption factor (DAF) is used to determine de rmal exposure and risk. The standard uncertainty factors were applied to all e xposure scenarios (10x for intras pecies variability and 10x for interspecies extrapolation).

4.5.1.5 Inhalation Exposure

Short- and Intermediate-Term Inhalation Exposures (1-30 days and 1-6 months)

Study Selected : Developmental Neurotoxicity Study in Rats

MRID No. : 46255619

Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on decreased body weights and body weight gains in males and female s, decreased pre-weaning survival (PND 0-1), and decreased maximum auditory startle respon se in males on PND 20 and PND 60 of the DNT study at 45 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors : No route-specific information is available for the inhalation toxicity of acetamipri d. In the absence of a route-specific study, the NOAEL and LOAEL from an oral study are used to estimate inhalation exposure and the associated risk (i.e., inhalation toxic ity is assumed to be equivalent to oral toxicity). In this case, the NOAEL and LOAEL from the DNT study were se lected because the duration is appropriate for short- and intermediate-term exposures and it is protective of potential effects in offspring.

Because effects seen in the DNT can occur as the result of a si ngle exposure at a critical junction during pregnancy or from multiple exposures throughout pregnancy a nd lactation, the NOAEL for offspring effects observed in the DNT was sel ected as the dose for short- and intermediateterm inhalation exposure scenarios. The standard uncertainty factors were applied to all exposure scenarios (10x for intraspecies variability and 10x for interspecies extrapolation). In the absence of the required inhalation toxicity study, HED is recommending the 10X FQPA factor be retained as a database uncertainty factor onl y for assessing inhalation exposure and risk.

Long-Term Inhalation Exposures (> 6 months)Acetamiprid Human Health Risk Assessment DP No. D394322

Page 18 of 43 Study Selected : Chronic/Carcinogenicity Study in Rats

MRID No. : 44988429, 45245304

Dose and Endpoint for Risk Assessment: NOAEL = 7.1 mg/kg/day based on decreases in mean body weight and body weight gain in females a nd hepatocellular vacuolation in males.

Comments about Study/Endpoint/Uncertainty Factors : No route-specific information is available for the inhalation toxicity of acetamipri d. In the absence of a route-specific study, the NOAEL and LOAEL from an oral study are used to estimate inhalation exposure and the associated risk (i.e., inhalation toxic ity is assumed to be equivalent to oral toxicity). In this case, the NOAEL and LOAEL from the chronic/carcinogeni c study were selected because the duration is appropriate for long-term exposures and it is protective of potential effects in offspring observed in the DNT and 2-generation study in ra ts. The standard uncertainty factors were applied to all exposure scenarios (10x for intr aspecies variability and 10x for interspecies extrapolation). In the absen ce of the required inhalation toxi city study, HED is recommending the 10X FQPA factor be retained as a database uncertainty fact or only for assessing inhalation exposure and risk. However, HED notes that no long-term exposure via th e inhalation route is expected based on existing and proposed uses.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

The FQPA requires that HED aggregate pestic ide exposures from the three major exposure routes (oral, dermal, and inhalatio n) when there is potential reside ntial exposure to a pesticide. HED has chosen a single endpoi nt and dose from the DNT study for short- and intermediateterm exposure scenarios. Ther efore, the short- and interm ediate-term dermal, oral, and inhalation exposure can be combined and aggreg ated with the dietary (food + water) exposures.

4.5.3 Cancer Classification and Ri sk Assessment Recommendation

The CARC report, Dec. 11, 2001 (TXR No. 0050331) stat ed that acetamiprid is, “not likely to be carcinogenic to humans.” The classification is based on the following: (1) the absence of an

increase in the incidence of tumors in a mouse carcinogenicity st udy; and (2) in a rat chronic/carcinogenicity study, the absence of a dose-response and the lack of a statistically significant increase in the mammary adenocarcino ma incidence by pair-wise comparison of the mid- and high- dose groups with the controls (although the incidence exce eded the historical control data from the same laboratory, it was within the range of values fr om the supplier). There was no clear evidence of a mutagenic effect. Acetamiprid tested positive as a clastogen in an in

vitro study but not in an in vivo study.

4.5.4 Summary of Points of Departure and T oxicity Endpoints Used in Human Risk

Assessment

Table 4.5.4a. Summary of Toxicological Doses and Endpoints of Acetamiprid for Use in Dietary and NonOccupational Human Health Risk AssessmentAcetamiprid Human Health Risk Assessment DP No. D394322

Page 19 of 43 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-Term

Incidental Oral (1-30 days and 1-6 mo.) 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 mo.) 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.) NOAEL = 10 mg/kg/day

Inhalation toxicity

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

UF H = 10x FQPA SF = 1x

UF DB = 10X LOC for MOE

= 1000 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 carcinog enic 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 do se-response data and used to mark the beginning of extrapolation to determine risk associated with lower envi ronmentally relevant human exposur es. NOAEL =

no observed adverse effect level. LOAEL = lowest observe d adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the hu man population (intraspecies). FQPA SF = FQPA Safety

Factor. UF DB = Database uncertainty factor reta ined for missing data, in this case the 28-day inhalation toxicity study. PAD = population adjusted dose (a = acute, c = chronic) = reference dose/ all uncertainty factors. MOE = margin of exposure. LOC = l evel of concern. N/A = not applicable.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 20 of 43 Table 4.5.4b. 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

Concern for

Risk

Assessment Study and Toxicological Effect

Short-,

Intermediate-term

Dermal (1 - 30 days, 1 - 6 mo.) 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.) NOAEL= 10 mg/kg/day

Inhalation toxicity

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

UF H = 10x

UF DB = 10x LOC for MOE

= 1000 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 carcinog enic to humans (2005 revised Agency cancer guidelines).
Point of Departure (POD) = A data point or an estimated point that is derived from observed dos e-response data and used to mark the beginning of extrapolation to determine risk associat ed with lower environmentally relevant human exposures. NOAEL

= no observed adverse effect level. L OAEL = lowest observed adverse effect le vel. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = Database uncertainty factor retained for missing data, in this case the 28-day inhalation toxicity study. DAF = dermal absorption fa ctor. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

5.0 Dietary Exposure and Risk Assessment

E. Holman, D394779, 6 March 2012 E. Holman, D395331, 14 February 2012

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 assessment 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 Enfo rcement Residue Definiti ons 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-2-1Acetamiprid Human Health Risk Assessment DP No. D394322

Page 21 of 43 Table 5.1. Risk Assessment and Tolerance Enfo rcement Residue Definiti ons for Acetamiprid.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression
Drinking Water Acetamiprid Not Applicable

5.2 Food Residue Profile

The established tolerances in vege table, fruiting, group 8; fruit, c itrus, group 10; and fruit, pome, group 11, can be updated to the current crop group definitions (with no accompanying data) to vegetable, fruiting, group 8-10; fruit, citrus, group 10-10; and fruit, pome, group 11-10.

To support the proposed uses, the petitioner has submitted studies depicting residues of acetamiprid following broadcast foliar or direct ed application treatm ent in/on sweet corn commodities, asparagus, and mustard greens. Applications were made in accordance with the proposed labeling and the residue data are s upported by appropriate analytical method and storage stability data. The proposed preharvestintervals (PHI) are ac ceptable for asparagus,

Brassica leafy greens, and turnip greens. Tabl es 5.2.1.-5.2.3 summarize the submitted field trial data for the proposed commodities.

The submitted residue data for asparagus are acceptable. The submitted study reflects the maximum proposed use pattern for the 70% WP fo rmulation for asparagus; however, owing to the designation of one pair of re sidue trials as a single trial wi th replicate samples, geographic representation is inad equate from NAFTA Zone 10 per OCSPP 860.1500. However, given the requested PHI of 1 day, the maximum anticipated residues are going to be driven by application parameters and not meteorological or cultural pract ices. Furthermore, the available residue data is tightly grouped around the mean, with a small ob served standard deviation. Therefore, it is highly unlikely that additional re sidue data from Zone 10 would have a significant impact on the recommended tolerance. Consequently HED is not requesting additional field trials for

asparagus.

The submitted residue data for mustard greens are also acceptable. The study reflects the maximum proposed use pattern for the 70% WP formulation for Brassica leafy greens, subgroup 5B and turnip greens, and the number and locatio n of the field trials are in accordance with OCSPP 860.1500 for mustard greens

For asparagus and mustard greens, it is noted that all of the submitted field trials used the 70% WP formulation. The registrant is requesti ng the use of both the 70% WP and the 30% SG formulation. Normally, consistent with OCSPP and OECD Crop Field Trial Guidance, additional bridging data would be required to suppor t the use of the 30% SG formulation. However, during a previous assessment, a simila r situation was encounter ed and the registrant provided additional information on the SG formulation. As a result, HED concluded that such data were not necessary, agreeing that due to hi gh water solubility both products are likely to produce a similar solution of acetamiprid (D3694 74, 12/1/09). Therefore bridging data to support the use of the 30% SG fo rmulation on these commodities ar e not required. The data are sufficient for establishing tolerances on thes e commodities associated with the requested registration of the 70% WP a nd 30% SG formulations.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 22 of 43 HED has concluded that insufficient data have been submitted to support the use on sweet corn. Although there is evidence to s upport residue equivalency for the 70% WP formulation and the

30% SG formulation and the combination of tr ials conducted with th ese two formulations provide for an adequate number of trials with sufficient geographi c variation, it is not possible to combine the two sets due to the significant diffe rences in the stover PHIs between the U.S. and

Canadian trials. These differences are reflected in the residue data for stover. In the U.S. trials, residues (and per trial averag es) of acetamiprid were <0.01 (<0.01) in K+CWHR, 0.39-10 (0.41- 9.1) in forage, and 0.12-21 (0.19-20) ppm in stover. In the Canadian trials, residues (and per trial averages) were <0.01 (<0.01) in K+CWHR, 0.23-1.1 (0.43-0.82) in forage, and <0.01-0.35 (0.011-0.285) ppm in stover. Furthermore, alth ough 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 th e 30% SG formulation included an adj uvant, whereas the Canadian trials using the 70% WP formulation did not include an adjuvant. Additional cr op field trial data are required to support the proposed uses.

Based on the crop field trial study de signs, the U.S. use pattern app ears to be less restrictive for stover (1- or 7-day PHI in the U.S. vs. harvest at maturity in Canada); therefore, to support the proposed uses on sweet corn, five additional crop fi eld trials must be conducted in the U.S. with the 30% SG formulation and an adjuvant in Zones 1 (1 trial), 5 (3 trials), and 12 (1 trial) to provide a full set of field trial data for this formulation. Each trial should include an additional side-by-side treated plot reflect ing application of the 70% WP fo rmulation with an adjuvant. Although the available data suggest that residues are similar following application according to the four-application/1-day PHI us e pattern and the two-applica tion/7-day PHI use pattern, HED recommends that each use patter n be represented in at least tw o of the required trials. The registrant has been made aware of these issues and intends to complete the required trials during the 2012 growing season.

At this time, HED concludes that the available data are insufficient for establishing tolerances associated with the requested registration on swee t corn. The available residue chemistry data for acetamiprid are sufficient for purposes of asse ssing risk and establishing tolerances on

asparagus, Brassica leafy greens, and turnip greens.

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 resu lts of the dairy cattle f eeding study are adjusted for the increased dietary burden, the maximum e xpected combined residues of acetamiprid and

IM-2-1 increase in milk and all tissues. Based on the data currently available, the tolerance in milk should be increased from 0.10 to 0.30 ppm, a nd 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. The tolerances

need not be revised at this tim e, but should be re-evaluated wh en the outstanding data for sweet

corn have been submitted and reviewed.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 23 of 43 Table 5.2.1. Summary of Residue Data from Asparagus Crop Field Trials with Acetamiprid.

Commodity Total Applic. Rate

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

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

ASPARAGUS (proposed use = 0.2 lb ai/A total application rate, 1-day PHI)

Asparagus 0.200-0.204 1 7 0.11 0.43 0.12 0.41 0.26 0.25 0.09

1 Except for sample min/max, values reflect pe r trial averages; n = no. of field trials.

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

Table 5.2.2. Summary of Residue Data from Mustard Greens Crop Field Trials with Acetamiprid.

Commodity Total Applic. Rate

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

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

BRASSICA, LEAFY GREENS, SUBG ROUP 5B and TURNIP GREENS (proposed use = 0.375 lb ai/A to tal application rate, 3-day PHI)

Mustard greens 0.374-0.476 2-4 8 0.20 10 0.30 9.2 1.9 2.6 2.8

1 Except for sample min/max, values reflect pe r trial averages; n = no. of field trials.

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

Table 5.2.3. Summary of Residue Data from Sweet Corn Crop Field Trials with Acetamiprid.

Commodity 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 0.213-0.219 (238.5-245.4) 41-89 4 <0.01 0.35 0.011 0.285 0.050 0.082 0.095

1 Except for sample min/max, values reflect per trial av erages; n = no. of field tria ls. 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 the 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 harvest.

5.3 Water Residue Profile

K. White, D394234/D394479, 11 October 2011Acetamiprid Human Health Risk Assessment DP No. D394322

Page 24 of 43 In a memo dated 11 October 2011 (K. White, D394234/D394479), the Environmental Fate and Effects Division (EFED) provided estimated resi dues 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 summari zed in Table 5.3. The surface water EDWCs were generated using the FQPA Index Reservoir Scre ening Tool (FIRST) Model and the ground water estimates are from the Screening Concentra tion In GROund Water (SCI-GroW) Model. The models and their descriptions are av ailable 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 condu cted to support the pr oposed uses and label changes, HED incorporated the surface water ED WCs directly into the dietary model, since surface water estimates were higher than thos e 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.

Table 5.3. Tier I Analysis - 1-in-10-year EDWCs in surface water and gro und 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 dietary (food+ drinking water) exposure and ri sk assessments were conducted using the Dietary Exposure Evaluation Mode l DEEM-FCIDTM, Version 2.03 which uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 a nd 1998. Per HED policy, residue estimates associated with the food-handling establishmen t use are not included in the acute dietary

assessment.

Both the acute and chronic analyses are based on tolerance-level residue s and assume 100% crop

treated. Acute and chronic diet ary risk estimates are below HE D’s level of concern for all population subgroups (Table 5.4). For acute exposure s, the dietary risk for the U.S. population is estimated to be 21% of the population-adjusted do se (PAD). Acute risk for children 1-2 years old, the highest-exposed population subgroup, is estimated to be 52% of the PAD. Chronic risk estimates are 10% of the PAD for the U.S. popula tion and 33% 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 chemical.

There are no dietary exposure or risk concerns th at would preclude granting the requested uses of acetamiprid and establishing tolerances associated with these uses.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 25 of 43 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) 0.020582 21 0.007145 10
All infants (< 1 year) 0.049933 50 0.014333 20
Children 1-2 yrs 0.051942 52 0.023734 33
Children 3-5 yrs 0.037549 38 0.017226 24
Children 6-12 yrs 0.021678 22 0.009434 13
Youth 13-19 yrs 0.013955 14 0.005705 8
Adults 20-49 yrs 0.013804 14 0.005229 7
Adults 50+ yrs 0.014640 15 0.005836 8
Females 13-49 yrs 0.014121 14 0.005424 8 Populations with the highest exposure estimates are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

M. Collantes, D383325, 22 July 2011

Acetamiprid is registered for controlling a wide variety of indoor and outdoor insect pests in residential settings. The regi strant is not proposing any new residential uses with this submission, and therefore a new residential e xposure assessment was not conducted. For acetamiprid, HED’s level of concern (LOC) is 100. In the most recent residential handler and postapplication exposure assessmen t, all scenarios resulted in margins of exposure (MOEs) greater than 100 and are not of concer n (M. Collantes, D383325, 22 July 2011).

The applicable combined residential risk estimat es to adults (handler and postapplication) and children (3-6 years; post application only) are summa rized in Table 6. All scenarios resulted in an aggregate risk index (ARI) greater than 1 and are not of concern. Although there is the potential for co-occurrence of adult exposure re sulting from applying and entering treated areas (postapplication), the risks from both exposures are not combined because HED believes that this would result in an over-estimation of exposures.

The risk estimates presented in Table 6 do not re flect the most recent (Feb. 2011) 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 re sult in significantly different exposure and risk estimates, and therefore woul d not significantly impact this aggregate risk assessment. The impact of the SOPs and body weights will be as sessed in conjunction with registration review (docket opening scheduled for FY2013). Due to the lack of the require d inhalation toxicity study, HED has determined that an additional 10X FQ PA factor must be retained as a database uncertainty factor, raising the level of concern (LOC) to 1000 for inhalation scenarios. The ARI results presented in Table 6 were not included in the July 2011 assessment and are calculated here for the purposes of assessing this increased LOC, with these risks not being of concern as

indicated above.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 26 of 43 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 ARI 3

Adult Handler

Mattress Treatment - Dermal 0.00088 11,000 26.1

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 4.2

Inhalation– Crack & Crevice 0.000018 560,000

Dermal - Mattress Treatment 0.00015 66,000

Child Postapplication

Dermal – Crack & Crevice 0.0333 300 2.2

Inhalation – Crack & Crevice 0.000046 220,000

Hand-To-Mouth – Crack and Crevice 0.011 900

Dermal - Mattress Treatment 0.000323 31,000

1 With the exception of the Aggregate Risk Index (ARI), all information from this table is taken from D383325, M.

Collantes, 22 July 2011.

2 MOE = NOAEL (10 mg/kg/day) / Daily Dose.

3 Adult Handler ARI = 1/[(1/dermal MOE/100)+(1/inhalation MOE/1000)] Adult Postapplication ARI = 1/[(1/dermal MOE/100)+(1/inhalation MOE/1000)] Child Postapplication ARI = 1/[(1/dermal MOE/100)+(1 /inhalation MOE/1000) + (1/Hand-to-Mouth MOE/100)]

6.2 Spray Drift

Spray drift is always a potential source of expos ure to residents nearby sp raying operations. This is particularly the case with aeri al application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for acetamiprid. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other partie s to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/f actsheets/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 comp leted its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appr opriately apply the data and th e AgDRIFT computer model to its risk assessments for pesticides applied by ai r, 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 drif t with specific products with significant risks

associated with drift.

Although a quantitative residential postapplic ation inhalation exposure assessment was not performed as a result of pesticide drift from nei ghboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers who assist with aerial applications of acetamiprid on field crops. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protec tive of most outdoor agri cultural and commercial postapplication inhalatio n exposure scenarios.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 27 of 43 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 residentia l exposures. When a ggregating exposures and risks from various sources, HED considers toxi cological endpoints as well as the route and duration of exposure.

7.1 Acute Aggregate Risk

Typically, HED does not consider residential ex posures when assessing acute aggregate risk unless such exposures can be characterized as a se ries of single-day exposures. For acetamiprid, residential exposures are assessed as short- and intermediate-ter m exposures. Therefore, acute aggregate risk estimates for acetamiprid are equi valent to the acute dietary risk estimates (Section 5.4) and are below HED’s level of concern.

7.2 Short- and Intermediate-Term Aggregate Risk

Toxicological endpoints and point s of departure for assessing short- (1 to 30 days) and intermediate-term (1 to 6 months) risks associat ed with exposure to acetamiprid are identical; therefore, separate assessments are not bei ng conducted for these dur ations. Short- and

intermediate-term residen tial exposures to acetamiprid may o ccur from uses of this chemical around the home (Section 6) as well as from acetamiprid residues in food and drinking water (Section 5). For assessing aggreg ate risk, the chronic dietary expos ure estimate is used since it represents a background exposure level from food and drinking water that may co-occur with residential exposures. Dermal, oral, and inha lation risks for short- and intermediate-term exposures were combined in this assessment, si nce the toxicological e ndpoints and points of departure were the same. However, the level of concern (LOC) values were different (i.e. dermal and oral LOC = 100, while inhalation LOC = 1000); therefore, the respective risk estimates are combined using the ARI approach. Th is approach reflects ri sk estimates resulting from exposure via the dermal, inhalation, and oral routes. The results of these calculations are presented in Table 7.2. All ARI’s are greater than 1 and indicate that risks are not of concern.

Table 7.2 Short-Term and Intermediate Term Aggregate Risk Calculations 1

Population Short- or Intermediate-Term Scenario

Dietary Exposure 2 Oral

Residential Exposure 3 Dermal

Residential Exposure 4 Inhalation

Residential Exposure 5 Aggregate ARI (food, water, and residential) 6 MOE ARI MOE ARI MOE ARI MOE ARI

Adult 1714 17.14 NA 428 4.28 555556 556 3.41

Child 909 9.1 900 9 297 2.97 217391 217 1.45

1 HED is concerned if the ARI is less than 1. (ARI = Aggregate Risk Index.)

2 MOE dietary = [(short- or intermediate-term oral NOAE L of 10 mg/kg-day)/(chronic dietary exposure)]. ARI dietary = [(MOE dietary)/(MOE ta rget)]. MOE target = 100. From Table 5.4, Child Chronic Dietary Exposure = Children 1-2 years (maximum exposure) = 0.023734 mg/kg-day; and Adult Chronic Dietary Exposure = Adult 50+ years (maximum exposure) = 0.005836 mg/kg-day

3 MOE oral = [(10 mg/kg-day)/(hand-to-mouth residential exposure)]. ARI oral = [(MOE oral)/(MOE target)]. Hand-to-mouth residential exposure (from Table 6) = 0.011 mg/kg-day (child only). MOE target = 100.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 28 of 43 4 MOE dermal = [(10 mg/kg-day)/(high end dermal resi dential exposure)]. ARI dermal = [(MOE dermal)/(MOE target)]. From Table 6, High end dermal residential exposure = 0.02335 (adult) and 0.0033623 (child). MOE target = 100.

5 MOE inhalation = [(10 mg/kg-day)/(high end inhalation residential exposure)]. ARI inhalation = [(MOE inhalation)/(MOE target)]. From Table 6, High end inhalation residential exposure = 0.000018 (adult) and 0.000046 (child). MOE target = 1000.

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

7.3 Chronic Aggregate Risk

There are no long-term residen tial exposures expected for acet amiprid. Therefore, chronic aggregate risk estimates are equivalent to the ch ronic dietary risk estimat es (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 carcinogeni c to human;” therefore, cancer

risk is not of concern for this chemical.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has fo llowed 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 substances and acetamiprid does not appe ar 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 substances. For information regarding EPA’s ef forts to determine which chemicals have a common mechanism of toxicity and to evaluate th e cumulative effects of such chemicals, see the policy statements released by EPA’s OPP con cerning common mechanism determinations and procedures for cumulating effects from subs tances found to have a common mechanism on

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

.

9.0 Occupational Exposure/Risk Characterization

S. Oonnithan, D395464/D395468/D395470 , 15 February 2012

The Health Effects Division (HED) has conducte d an occupational and residential exposure (ORE) assessment for the proposed new uses of acetamiprid insecticide on asparagus, and sweet corn, and for the proposed increased maximum si ngle application rate on turnip greens. Assessed scenarios include workers handling an d/or applying end-use products as well as workers re-entering treated area s/fields. Occupational exposu re 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 inte rmediate-term points of departur e are the same, separate shortand intermediate-term assessments were not co nducted. Long-term exposures are not expected.

In addition to the new uses, the proposed labels have been amended to include the Agency’s updated crop group definitions for cole crops, fru iting vegetables, citrus and pome fruit. TheAcetamiprid Human Health Risk Assessment DP No. D394322

Page 29 of 43 updated crop group definitions don’t require a new occupational exposure and risk assessment since the use patterns have been previously asse ssed, and no risks of c oncern were identified.

9.1 Short- and Intermediate-Term Handler Risk

Estimates of handler exposure to acetamiprid a ssociated with the requested uses were assessed using surrogate study data available in the Pe sticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler Expos ure Task Force (AHETF) database. For all crops, assessed activities include mixers/loaders and applicator s for ground-based and aerial applications, as well as flaggers. 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 togeth er to calculate an AR I since the endpoints were the same (i.e., the same toxic effects), but with different levels 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 formulation. With the exception of this mixer/loader aerial application scenario (usi ng only baseline PPE), use of acetamiprid on assessed crops resulted in ARIs greater than 1 (Table 9.1) are not of concern. With the addition of a PF5 respirator to the mixer /loader scenario, the ARI is increas ed to 1.7 and is not of concern.

Due to the lack of an inhalation study, HED dete rmined that an addition al 10X FQPA must be retained as a database uncertainty factor, raising the level of concern (LOC) to 1000 for

inhalation scenarios. The ARI re sults presented in Table 9.1 were not included in the February 2012 occupational assessment and ar e calculated here for the purpos e of assessing this increased LOC, with these risks not being of concern as indicated above.Acetamiprid Human Health Risk Assessment DP No. D394322Page 30 of 43Table 9.1. Occupational Handler Exposure and Aggregate Risk Estimates From the Use of Acetamiprid1.ExposureScenario2HandlerMitigationLevel3SingleAppl. Rate(lb ai/A)AcresTreatedUnit exposures(μg/lb ai)4Dermal Dose(mg/kg/day)5Inhal. Dose(mg/kg/day)6DermalMOEInhal.MOEARI7DermalInhal.All cropsWP for aerial appl.M/L B + G 0.1 350170(PHED)43.4(PHED)0.009920.02532 1,008 395 0.4All cropsWP for aerial appl.M/LB + G+R (PF5)0.1 350170(PHED)8.68(PHED)0.009920.00506 1,008 1,975 1.7All cropsDF for aerial appl.M/L B + G 0.1 35051.6(AHETF)8.96(AHETF)0.0030133220.00523 3,322 1,913 1.8All crops, spray withfixed wing aircraftApplicatorEncl.Cockpit0.13505.0(PHED)0.068(PHED)0.00029 0.00004 34,286 252,101 145.3All crops,Groundboom sprayerApplicatorB + G,Open Cab0.1 8016.1(AHETF)0.34(AHETF)0.00021 0.00005 46,584 220,588 149.7All crops, aerial Flagger B+G 0.1 35012.0(PHED)0.35(PHED)0.0007 0.0002 14,286 48,980 36.5Abbreviations used: AHETF = Agricultural Handler Exposure Task Force, ARI = Aggregate risk index, B = Baseline personal protective equipment (PPE, alsosee # 3 below), DF = Dry flowable, G = Gloves, LOC= Level of concern, MOE = Margin of exposure, PHED = Pesticide Handler Exposure Database, R = PF5respirator, WP = Wettable powder.1. Table (S. Oonnithan/D395470/2/15/2012) modified to estimate Aggregate risk index.2. All crops are asparagus, sweet corn, and turnipgreens. The use pattern is same for all crops.3. Baseline PPE includes long-sleeved shirt, long pants and shoes with socks. Label recommended PPE is baseline plus chemicalresistant gloves.4. Unit exposures are surrogate values selected from AHETF and PHED data bases.5. Dermal dose (mg/kg/day) = [Appl. rate (lb ai/A) * Acres treated/day * Dermal unit exposure (μg/lb ai handled/day/1000) * Dermal absorp. factor (10%)] /Body wt (60 kg).; LOC = 100.6. Inhalation dose (mg/kg/day) = [Appl. rate (lb ai/A) * Acres treated/day * Inhal. unit exposure (μg/lb ai handled/day/1000)] * Inhal. absorp. factor (100%] /Body wt (60 kg); LOC = 1,000.7. Aggregate risk index = 1/[(1/dermal MOE/100) + (1/inhalation MOE/1000)].Acetamiprid Human Health Risk Assessment DP No. D394322

Page 31 of 43 9.2 Short- and Intermediate-Term Postapplication Risk

The proposed labels for Assail® 70 Wettable Po wder (WP) and Assail® 30 Soluble Granule (SG) Insecticides have a 12-hour REI and ar e 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 chemical specific postapplication exposure study for a quantitative evaluation of risks resulting from use of Assail ® WP and SG products on the proposed crops. Dermal exposures during posta pplication activities were estimated using

standard default values for dermal transfer co efficients from the Science Advisory Council for Exposure Policy Number 3.2: Agricultural Tran sfer Coefficients, June 3, 2011 and based on proprietary data (from the Agri cultural Reentry Task Force [A RTF]) and non-proprietary data.

Farm workers who enter treated fields after th e REI period to perform postapplication activities such as irrigation, weeding, scouting and harvesting may be exposed to residues of acetamiprid.

These activities result in short-and intermediate-term posta pplication dermal MOEs of 190 to 1,800 and are not of concern (Table 9.2).

Table 9.2. Risk 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

Coefficient (cm 2 /hr) 2 Short-term

Dermal Dose 3
(mg/kg/day) Short-term

Dermal

MOE 4

Asparagus Irrigation (hand weeding)

0.1 0.224 1,900 (MRID No. 45726301) 0.00567 1,800

Sweet corn Detasseling 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) = Appl. Rate (lb ai/A) * (1- Daily Dissipation Rate) 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 activities (ExpoSAC Policy #3, June 3, 2011). 3. Daily Dose (mg/kg/day) = [DFR * Transfer Coefficient * Conv. Factor (0.001 mg/μg) * Dermal Absorption (10 %) * 8 hrs/day] / Body Weight (60 kg). 4: Short-term Margin of Exposure (MOE) = Short-term Dermal NOAEL (10 mg/kg/day) / Daily Dose (mg/kg/day).

9.2.2 Inhalation Postapplication Risk

Based on the Agency's current practices, a qua ntitative postapplication inhalation exposure assessment was not performed for acetamiprid at th is time primarily because of the low acute inhalation toxicity (Toxicity Categor y III), low vapor pressure (7.5×10 -9 mm Hg), and the low proposed application rate (0.1 lb ai/A). Howe ver, there are multiple potential sources of postapplication inhalation exposure to individu als performing postapplication activities inAcetamiprid Human Health Risk Assessment DP No. D394322

Page 32 of 43 previously treated fields. Th ese potential sources include vol atilization of pesticides and resuspension of dusts and/or pa rticulates that contain pesticid es. The Agency sought expert advice and input on issues related to volatilization of pe sticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and

received the SAP’s fina l report on 2 March 2 2010 ( http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post-applicat ion inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, s ubsequently, the way to incorporate occupational postapplication inhalation exposure into the Agen cy's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational postapplication inhalation exposur e assessment for acetamiprid.

Although a quantitative occupati onal postapplication inhalation exposure assessment was not performed, HED has assessed inhalation exposure a nd risk for occupational/commercial flaggers for aerial applications of acetamiprid on sweet corn and the risk was not of concern. Inhalation exposure of flaggers resulting from aerial applicati on of pesticides is likely to result in higher exposure than the exposure resulting from postapp lication activities. Ther efore, it is expected that the flagger inhalation risk estimate conduc ted for sweet corn would be protective of all postapplication inhalatio n exposure scenarios.

10.0 References

K. White. D394234/D394479. 11 October 2011. Ti er I Drinking Water Exposure Assessment for the Section 3 New Use of Acetamiprid on Various Agricultural Crops and as a Scatter

Bait to Control Insects

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

M. Doherty. D278352. 16 October 2001. Acet amiprid - 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, Frui ting Vegetables, Citrus Fruits, Pome Fruits, Grapes, and Canola and Mustar d Seed. Summary of Analyt ical Methods and Residue Chemistry DERs.

E. Holman. D394779. 6 March 2012. Acetamiprid. Petition for the Establishment of Permanent Tolerances and Registration for Use on Aspa ragus; Brassica, Leafy Greens, Subgroup 5B, and Turnip Greens; and Sweet Corn; and Update of 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 Analyt ical Chemistry and Residue Data.

E. Holman. D395331. 14 February 2012. Acet amiprid Acute and Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment – Uses on Asparagus, Brassica Leafy Greens (Subgroup 5B), Sweet Corn, and Update d Crop Groups for Pome, Citrus Fruit, andAcetamiprid Human Health Risk Assessment DP No. D394322

Page 33 of 43 Fruiting Vegetables.

S. Oonnithan. D395464, D395468, and D395470. 15 February 2012. Acetamiprid: Occupational and Residential Exposure A ssessment for the Proposed New Uses on Asparagus and Sweet Corn, and for an Increase d Application Rate for Turnip Greens.

K. Rury. 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. D394322

Page 34 of 43 Appendix A. Toxicology Prof ile and Executive Summaries

A.1 Toxicology Data Requirements
The requirements (40 CFR 158.3 40) 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

Yes Yes

Yes

Yes

-- No 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

YesAcetamiprid Human Health Risk Assessment DP No. D394322

Page 35 of 43 A.2 Toxicity Profiles

Acute Toxicity of Techni cal 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

870.1200 Acute Dermal - rat 44651836 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation - rat 44651837 LC 50 : > 1.15 mg/L (~) > 1.15 mg/L (~) III

870.2400 Primary Eye Irritation - rabbit 44651838 Not irritating to the eye IV 870.2500 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

Toxicity Profile for Acetamiprid: Subchr onic, 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

870.320021-Day dermal toxicityrabbit 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 DP No. D394322

Page 36 of 43 Toxicity Profile for Acetamiprid: Subchr onic, 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; 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 (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 gainAcetamiprid Human Health Risk Assessment DP No. D394322

Page 37 of 43 Toxicity Profile for Acetamiprid: Subchr onic, 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 inmammary tumors, not considered treatmentrelated

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 testChinese hamster ovary (CHO) cells 44651855 (1997) Acceptable/guideline 175, 350, 700 μ g/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 indu ce 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 clas togen in the mouse bone

marrow micronucleus test.Acetamiprid Human Health Risk Assessment DP No. D394322

Page 38 of 43 Toxicity Profile for Acetamiprid: Subchr onic, 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 μ g/mL Acetamiprid tested negatively for UDS in mammalian hepatocytes in vivo.

870.6200a Acute neurotoxicity screening battery-rats (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 - 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) 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

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 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-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. D394322

Page 39 of 43 Toxicity Profile for Acetamiprid: Subchr onic, 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/kg. 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 re spiratory 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 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, 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 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 attainedAcetamiprid Human Health Risk Assessment DP No. D394322

Page 40 of 43 Toxicity Profile for Acetamiprid: Subchr onic, 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 gainAcetamiprid Human Health Risk Assessment DP No. D394322

Page 41 of 43 A3. Executive Summaries – Immunotoxicity Studies

STUDY TYPE : 4-Week Dietary Immunotoxicity Study – Mouse;

OPPTS 870.7800

EXECUTIVE SUMMARY :

In a 4-week dietary imm unotoxicity study (MRID 48113401) A cetamiprid (99.9% a.i., Lot No.NFG-02) was administered to 10 Crl:CD-1 (ICR) mice/sex/dose in the diet at dose levels of 0 (control and positive control groups), 100, 300, or 900 ppm (equivalent to 0, 15.3, 47.0, or 128 mg/kg/day in males; 0, 20.2, 54.1, or 157 mg/kg/da y in females). On Day 25, animals received a 0.2 mL intravenous injection of sheep re d blood cells (SRBCs) in 0.9% saline (2 x 10 9
SRBCs)/mL). Cyclophosphamide in water (20 mg/ kg body weight/day) was administered to the positive control group (8 mice/sex) by oral gavage on Days 22-26.

A significant decrease in mean body weight gain over the 4-week treatment period was seen in males in the 900 ppm treatment group when co mpared with the control (reduction of 56%, p<0.01); female mean body weight also was reduced over this period (reduction of 52%, not statistically significant). The e ffect upon mean body weight gain was greatest during the first week of treatment, with a mean weight loss seen in both sexes (p<0.01 in males, p<0.05 in females). A slight decrease in body weight gain seen in females in the 300 ppm group (reduction of 12%, not statistically significan t) was also attributed to trea tment. Mean food consumption in the 900 ppm treatment group was significantly redu ced in both sexes during the first two weeks of treatment (p<0.01 in males, p<0.05 in female s). Overall weeks 1-4 m ean water consumption was significantly reduced in males in the 900 ppm treatment group ( 25% reduction compared with control, p<0.01). The decreases in mean body weight gain, food consumption, and water consumption were considered to be non-specific toxic effects of treatment with Acetamiprid. Rales, observed in the 900 ppm group in 2/10 males and 3/10 females during Week 4, also was attributed to treatment although the cause was not determined. Th ere were no mortalities during the treatment period.

The systemic NOAEL was 47.0 mg/kg/day for males and 54.4 mg/kg/day for females with the LOAEL being 128 mg/kg/day for males and 157 mg/kg/day for females based on decreases in body weight (slight), body weight gain, food consumption and water consumption (males only).

There was no effect on immune function associ ated with exposure of mice to dietary concentrations of Acetamiprid of up to 900 ppm. Although females in the 900 ppm group had a significant decrease in th e mean number of plaque forming cells (PFC)/spleen (p<0.05); this finding correlated with a signifi cant decrease in the mean numb er of cells/spleen (p<0.05) and was attributed to a decrease in spleen size a nd cell numbers, rather than a decrease in immune

function. The NOAEL is 128 mg/kg/day in males and 157 mg/kg/day in females (highest tested dose), based on antigen-specific, T- cell dependent antibody formation. The LOAEL for immunotoxicity could not be determined (i.e., greater than the highest dose tested).Acetamiprid Human Health Risk Assessment DP No. D394322

Page 42 of 43 This 4-week dietary immunotoxi city study in the mouse is ACCEPTABLE/GUIDELINE and satisfies the guideline requirement for a 4-week dietary imm unotoxicity study (OPPTS 870.7800) in mice

.

STUDY TYPE : 4-Week Dietary Imm unotoxicity Study – Rat;

OPPTS 870.7800

EXECUTIVE SUMMARY :

In a 4-week dietary imm unotoxicity study (MRID 48113402) A cetamiprid (99.9% a.i., Lot No.NFG-02) was administered to 10 Crl:CD (SD) rats/sex/dose in the diet at dose levels of 0 (control and positive control groups), 100, 300, or 900 ppm (equivalent to 0, 7.4, 21.6, or 62.9 mg/kg/day in males; 0, 8.6, 24.3, or 67.7 mg/kg/da y in females). On Day 25, animals received a 1 mL intravenous injection of sheep red blood cells (SRBCs) in 0.9% saline (2 x 10 8
SRBCs)/mL). Cyclophosphamide in water (50 mg /kg body weight) was administered to the positive control group (8 rats/sex) by intraperitoneal injection on Day 27.

A significant decrease in mean body weight gain over the 4-week treatment period was seen in both sexes in the 900 ppm treatment group when comp ared with the control (reduction of 33% in males, 52% in females; p<0.01, both sexes). The effect upon mean body weight gain was greatest during the first few days (Days 1-4) of treatment (p<0.01, both sexes). Mean body weight gain in males in the 300 ppm treatmen t group also was significantly lower than the control (p<0.05) during Days 1- 4. Mean food consumption during the treatment period was reduced in males and females in the 900 ppm tr eatment group (85% of control, both sexes). Weekly mean water consumption was decreased in males in the 900 ppm group (71 to 85% of mean control values). Food and water consumpti on data were not statis tically analyzed. The decreases in mean body weight gain, food consum ption, and water consumption were considered to be non-specific toxic effects of treatment. Th ere were no clinical signs considered to be

treatment-related. No mortalit ies occurred during the treatment period. No treatment-related affects were associated with exposure to 100 ppm.

The systemic NOAEL was 21.6 mg/kg/day for males and 24.3 mg/kg/day for females with the LOAEL being 62.9 mg/kg/day for males and 67.7 mg/kg/day for females based on decreases in body weight, body weight gain, food consumption and water consumption (males only).

There were no effects on immune function, as assessed by measur ing antigen-specific, T-cell dependent antibody formation. No significant differences were seen in the number of cells/spleen, plaque forming cells (PFC)/10 6 cells, or PFC/spleen at di etary concentrations of Acetamiprid of up to 900 ppm. The NOAEL is 62.9 mg/kg/day in males and 67.7 mg/kg/day in females (highest tested dose), based on antigen-specific, T-cell dependent antibody formation. The LOAEL for immunotoxicity coul d not be determined (i.e., greater than the highest dose tested).Acetamiprid Human Health Risk Assessment DP No. D394322

Page 43 of 43 This 4-week dietary immunot oxicity study in the rat is ACCEPTABLE/GUIDELINE and satisfies the guideline requirement for a 4-week dietary imm unotoxicity study (OPPTS 870.7800) in rats.