Document ID: EPA-HQ-OPP-2007-0105-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-11-28T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF PREVENTION, PESTICIDES

DATE: 10/25/07							AND TOXIC SUBSTANCES

MEMORANDUM

SUBJECT:	Acetamiprid: Human Health Risk Assessment for Proposed Food
Uses on Stone Fruits, Cucurbit Vegetables, Tree Nuts, Berries,
Strawberries, Bulb Vegetables, Legumes (Peas and Beans) and for
Residential/Commercial Insecticide/Termiticide Uses.

Regulatory Action:  Section 3 Registration 

Risk Assessment Type: Single Chemical Aggregate

PC Code: 099050

Petition Nos: 4F6833, 6F7051, 6E7163

DP Barcode: D303171

FROM:	Kimberly D. Harper, Toxicology

William Drew, Chemistry

Margarita Collantes and Zaida Figueroa, Occupational and Residential
Exposure

Tom Moriarty, Risk Assessment

Registration Action Branch 2

Health Effects Division (7509P)

THROUGH:	Christina Swartz, Branch Chief

	Richard Loranger, Branch Senior Scientist

Registration Action Branch 2

Health Effects Division (7509P)

TO:	Akiva Abramovitch/John Hebert, PM Team 07

Insecticide/Rodenticide Branch

Registration Division (7505P)

Summary:  	HED has completed a risk assessment for the three petitions
(4F6833, 6F7051, and, 6E7163) submitted by Nisso America, and the IR-4
for proposed uses of acetamiprid on stone fruits, tree nuts, cucurbits,
legumes (pea and beans), and berry and bulb vegetables.  The dietary
assessment incorporates exposure from currently registered uses along
with those being proposed.  The aggregate assessment incorporates
estimated dietary (food + water) exposure with residential exposure
estimates from currently registered uses.  Occupational and residential
risk assessments have also been performed for the proposed uses. Table
of Contents

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc181086746"  1.0	Executive
Summary	  PAGEREF _Toc181086746 \h  4  

  HYPERLINK \l "_Toc181086747"  1.1	Summary of Recommendations (see also
Section 10.0)	  PAGEREF _Toc181086747 \h  6  

  HYPERLINK \l "_Toc181086748"  1.2	Summary of Proposed Uses	  PAGEREF
_Toc181086748 \h  6  

  HYPERLINK \l "_Toc181086749"  2.0	Ingredient Profile	  PAGEREF
_Toc181086749 \h  8  

  HYPERLINK \l "_Toc181086750"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc181086750 \h  9  

  HYPERLINK \l "_Toc181086751"  3.1	Hazard Characterization	  PAGEREF
_Toc181086751 \h  9  

  HYPERLINK \l "_Toc181086752"  3.2	FQPA Hazard Considerations	  PAGEREF
_Toc181086752 \h  12  

  HYPERLINK \l "_Toc181086753"  3.2.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc181086753 \h  12  

  HYPERLINK \l "_Toc181086754"  3.2.2	Determination of Susceptibility	 
PAGEREF _Toc181086754 \h  12  

  HYPERLINK \l "_Toc181086755"  3.2.3	Degree of Concern Analysis and
Residual Uncertainties	  PAGEREF _Toc181086755 \h  13  

  HYPERLINK \l "_Toc181086756"  3.3	 FQPA Safety Factor(s) For Infants
and Children	  PAGEREF _Toc181086756 \h  13  

  HYPERLINK \l "_Toc181086757"  3.4.1	Acute Dietary Endpoint	  PAGEREF
_Toc181086757 \h  14  

  HYPERLINK \l "_Toc181086758"  3.4.2	Chronic Dietary Endpoint	  PAGEREF
_Toc181086758 \h  15  

  HYPERLINK \l "_Toc181086759"  3.4.3	Dermal Absorption	  PAGEREF
_Toc181086759 \h  17  

  HYPERLINK \l "_Toc181086760"  3.4.4	Short- and Intermediate-Term
Dermal Endpoints	  PAGEREF _Toc181086760 \h  18  

  HYPERLINK \l "_Toc181086761"  3.4.5	Short- and Intermediate-Term
Inhalation Endpoints	  PAGEREF _Toc181086761 \h  18  

  HYPERLINK \l "_Toc181086762"  3.4.6	Level of Concern for Margin of
Exposure (MOE)	  PAGEREF _Toc181086762 \h  19  

  HYPERLINK \l "_Toc181086763"  3.4.7	Recommendation for Aggregate
Exposure Risk Assessment	  PAGEREF _Toc181086763 \h  19  

  HYPERLINK \l "_Toc181086764"  3.4.8	Classification of Carcinogenic
Potential	  PAGEREF _Toc181086764 \h  20  

  HYPERLINK \l "_Toc181086765"  3.5	Endocrine Disruption	  PAGEREF
_Toc181086765 \h  23  

  HYPERLINK \l "_Toc181086766"  4.0	Public Health Data	  PAGEREF
_Toc181086766 \h  23  

  HYPERLINK \l "_Toc181086767"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc181086767 \h  23  

  HYPERLINK \l "_Toc181086768"  5.1	Metabolism in Crops and Livestock	 
PAGEREF _Toc181086768 \h  23  

  HYPERLINK \l "_Toc181086769"  5.1.1	Analytical Methodology	  PAGEREF
_Toc181086769 \h  24  

  HYPERLINK \l "_Toc181086770"  5.1.2	Metabolism and Degradates of
Concern	  PAGEREF _Toc181086770 \h  25  

  HYPERLINK \l "_Toc181086771"  5.1.3	Drinking Water Residue Profile	 
PAGEREF _Toc181086771 \h  26  

  HYPERLINK \l "_Toc181086772"  5.1.4	Food Residue Profile	  PAGEREF
_Toc181086772 \h  27  

  HYPERLINK \l "_Toc181086773"  5.1.4.1	  Crop Field Trials	  PAGEREF
_Toc181086773 \h  27  

  HYPERLINK \l "_Toc181086774"  5.1.4.2	International Residue Limits	 
PAGEREF _Toc181086774 \h  29  

  HYPERLINK \l "_Toc181086775"  5.1.4.3	Livestock Commodities	  PAGEREF
_Toc181086775 \h  29  

  HYPERLINK \l "_Toc181086776"  5.2	Dietary Exposure/Risk Pathway	 
PAGEREF _Toc181086776 \h  31  

  HYPERLINK \l "_Toc181086777"  5.2.1	Dietary Exposure and Risk	 
PAGEREF _Toc181086777 \h  31  

  HYPERLINK \l "_Toc181086778"  6.0	 Residential (Non-Occupational)
Exposure/Risk Pathway	  PAGEREF _Toc181086778 \h  33  

  HYPERLINK \l "_Toc181086779"  6.1	 Spray Drift	  PAGEREF _Toc181086779
\h  34  

  HYPERLINK \l "_Toc181086780"  7.0	Aggregate Risk Assessment and Risk
Characterizations	  PAGEREF _Toc181086780 \h  34  

  HYPERLINK \l "_Toc181086781"  7.2	 Short-Term and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc181086781 \h  35  

  HYPERLINK \l "_Toc181086782"  7.3	Chronic Aggregate Risk	  PAGEREF
_Toc181086782 \h  36  

  HYPERLINK \l "_Toc181086783"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc181086783 \h  36  

  HYPERLINK \l "_Toc181086784"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc181086784 \h  37  

  HYPERLINK \l "_Toc181086785"  9.1	 Agricultural Handlers and Pesticide
Control Operators	  PAGEREF _Toc181086785 \h  37  

  HYPERLINK \l "_Toc181086786"  9.2	 Handler and Pesticide Control
Operator Risk Characterization	  PAGEREF _Toc181086786 \h  38  

  HYPERLINK \l "_Toc181086787"  9.3	Post-application Exposure and Risk	 
PAGEREF _Toc181086787 \h  39  

  HYPERLINK \l "_Toc181086788"  10.0	Data Needs, Deficiencies, and Label
Recommendations	  PAGEREF _Toc181086788 \h  40  

  HYPERLINK \l "_Toc181086789"  Appendix A.  References	  PAGEREF
_Toc181086789 \h  41  

  HYPERLINK \l "_Toc181086790"  Appendix B.  Occupational Exposure and
Risk Table	  PAGEREF _Toc181086790 \h  42  

  HYPERLINK \l "_Toc181086791"  Appendix C.  Acetamiprid Toxicology
Assessment	  PAGEREF _Toc181086791 \h  45  

  HYPERLINK \l "_Toc181086792"  Appendix D.  Tolerance Summary Table for
Petitions	  PAGEREF _Toc181086792 \h  49  

 1.0	Executive Summary

Acetamiprid
{N1-[(6-chloro-3-pyridyl)methyl]-N2-cyano-N1-methylacetamidine} is a
chloronicotinyl insecticide registered to control sucking type insects
(e.g., aphids, whitefly, etc.) on a wide variety of crops including
cotton, leafy vegetables, fruiting vegetables, and citrus fruits. 
Tolerances are established for acetamiprid residues in assorted crops
and livestock commodities under 40 CFR 180.578.  The majority of the
agricultural uses are for broadcast foliar spray (via ground or aerial
equipment), but there are also registered seed treatment uses on mustard
and canola.  Ready-to-use, and bait formulations are registered for
residential uses.  The petitioner, Nisso America Incorporated, is
seeking Section 3 registrations for use of acetamiprid on several
agricultural crops under the two product labels ASSAIL® 70WP, and
Assail® 30SG.  HED has also included an assessment of the
termiticide/insecticide (product F4688 50WP) for use by commercial
operators at residential sites.

The acute toxicity data indicate that acetamiprid is moderately toxic
via the oral route and is minimally toxic via the dermal and inhalation
routes.  Acetamiprid is not an eye or skin irritant, and it is not a
dermal senstitizer.  The toxicity data base for acetamiprid is complete.
 Based on subchronic, chronic, developmental and reproductive studies in
rats, rabbits, and dogs, acetamiprid does not appear to have specific
target organ toxicity.  Since the last review of acetamiprid hazard data
in 2003, an acceptable developmental neurotoxicity (DNT) study has been
submitted and reviewed.  

Developmental studies showed no evidence of either quantitative or
qualitative susceptibility of the rat or rabbit fetuses from in utero
exposure.  However, both the DNT study and the multi-generation
reproduction studies showed an increase in qualitative susceptibility of
pups; effects in pups consisted of decreased pup viability, and maternal
toxicity consisted of decreased body weight and body weight gain.  HED
has reduced the FQPA Safety Factor to 1X, because: (i) the endpoints
selected for risk assessment are based upon the effects of concern in
offspring; (ii) there is a clear NOAEL for the offspring effects; (iii)
the toxicology database is complete; and, (iv) HED has no residual
uncertainties with regards to pre- and postnatal toxicity.   HED has
determined that acetamiprid is not likely to be carcinogenic to humans. 

With the exception of chronic dietary, HED has chosen the NOAEL (10
mg/kg/day) from the DNT study (LOAEL = 45 mg/kg/day) as the endpoint and
dose for dietary, non-occupational and occupational risk assessments for
all durations and routes of exposure.  For the chronic dietary
assessment, HED has chosen the NOAEL (7.1 mg/kg/day) from the chronic
toxicity/oncogenicity study (LOAEL = 17.5 mg/kg/day).

HED has refined the dermal penetration value to 10% (from 30% in the
previous assessment) based upon a closer examination of
structural/chemical characteristics of related compounds.  The default
100% absorption factor was used for all inhalation exposure scenarios.

The nature of the residue is adequately understood for both plants and
animals, and acceptable method validation has been submitted for all
proposed uses.  Acceptable residue data have been submitted to support
the proposed uses as well as the tolerances recommended at the
conclusion of this section.  The proposed use on strawberry was part of
a joint review with PMRA Canada.

The dietary assessment is partially refined, using field trial data,
percent crop-treated values, and various empirical processing factors. 
Estimated drinking water concentrations (EDWCs), which are based upon
the highest application values of all registered and proposed uses, have
been incorporated directly into the dietary exposure model.  Both acute
and chronic dietary risk estimates for all population subgroups did not
indicate a risk of concern.  Children 1-2 years old are the highest
exposed population subgroup for both acute and chronic exposure
scenarios.  Acute exposure constituted 35% of the acute population
adjusted dose (aPAD), and the chronic exposure constituted 35% of the
chronic population adjusted dose (cPAD).

Petition 4F6833 initially included a proposed insecticide/termiticide
for use (label F4688 50WSP) in residential sites.  Based upon a draft
HED assessment, this product was approved in May, 2007.  However, since
that time new toxicity endpoints have been chosen and, therefore, HED
has included these uses in the current assessment.  The proposed uses of
F4688 Insecticide/Termiticide are to subterranean structural components
during construction; subterranean, and hard-to-reach structural
components post construction and outdoor perimeter use.  Based upon the
uses of F4688, HED believes no residential/non-occupational exposures
will occur; however, the anticipated occupational exposures were
assessed.

e MOEs ≥ 900).

Occupational handler (mixer/loaders, applicators, and flaggers)
assessments were conducted for the proposed agricultural uses of
acetamiprid.  HED’s assessment indicated that exposures to
occupational handlers were not a risk concern when the personal
protective equipment (PPE) specified on the proposed labels was assumed
to be worn by the handler.  HED identified no post-application risk
concerns for the proposed uses on the day of application, and set the
restricted entry interval (REI) at 12 hours based upon the acute
toxicity categories of acetamiprid.

For the termiticide/insecticide use, HED determined that exposures to
licenced certified operators (LCOs) were not of concern when the PPE
specified on the label was assumed to be worn by the handler.

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent
possible, were considered for this human health risk assessment, in
accordance with US Executive Order 12898, Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf .

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by USDA under the CSFII, and are used
in pesticide risk assessments for all registered food uses of a
pesticide.  These data are analyzed and categorized by subgroups based
on age, season of the year, ethnic group, and region of the country. 
Whenever appropriate, non-dietary exposures based on home use of
pesticide products, associated risks for adult applicators, and for
toddlers, youths, and adults entering or playing on treated areas
post-application are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethical conduct, and have received that review. The studies in PHED were
considered appropriate (or ethically conducted) for use in risk
assessments

1.1	Summary of Recommendations (see also Section 10.0)

Current labels for use on berries, bulb vegetables, edible podded legume
vegetables, succulent shelled beans, and peas, or strawberries and other
low-growing berries should be amended to remove directions regarding the
use of surfactants.

The tolerance expression proposed in Section F of PP#6E7163 by IR-4 with
respect to strawberry, bearberry, bilberry, blueberry (lowbush),
cloudberry, cranberry, lingonberry, muntries, and partridgeberry should
be revised to exclude the word “combined.”  

HED recommends the establishment of acetamiprid tolerances listed in
Appendix D, Table 1.

HED recommends the establishment of Section 3 registrations for the
proposed uses of the subject petitions.

Dermal absorption data from other neonicitinoids (thiamethoxam, and
clothianidin) was used to refine the dermal absorption factor for
acetamiprid.  HED recommends that RD consider whether any data
compensation issues are associated with this refinement.

1.2	Summary of Proposed Uses

Table 1 below summarizes the uses associated with the subject
petitions.1: PHI = pre-harvest interval

Table 1.  Summary of Subject Petitions and Proposed Uses for Acetamiprid

PP # 

	Petition Description	Product

Description	Use Sites	Single Max App. Rate (lb a.i./A)	Application
Characteristics

4F6833

	New Uses on:

cucurbit vegetables 

(crop group 9)

stone fruit (crop group 12)

tree nuts (crop group 14)	ASSAIL®  70WP 

70% ai

EPA Reg. No: 8033-23

ASSAIL® 30 SG 

30% a.i.

EPA Reg No. 8033-36	Stone fruit	0.050 - 0.15	4 apps/season; 10 day
treatment interval;  7 day PHI1; Max seasonal rate = 0.6 lb ai/A

aerial and ground spray

	Cucurbits	0.050 – 0.10	5 apps/season; 5 day treatment interval; 0 day
PHI; Max seasonal rate =    0.5 lb ai/A

aerial and ground spray

	Tree nuts	0.050 – 0.18	4 apps/season; 7 day treatment interval; 14
day PHI; Max seasonal rate = 0.72 lb ai/A

aerial and airblast spray

	New Uses for Residential Pest Control

(These new uses were not officially part of PP# 4F6833 but were assessed
at the time PP# 4F6833 was originally submitted for review.)

	F4688 50 WSP Insecticide/Termiticide

22.73 % ai

EPA Reg. No.:8033-96

For Commercial Use in Residential/

Commercial Settings

(also includes Bifenthrin as an active ingredient.)

	outdoor pest

	0.0043 lbs ai/gal	Apply to a band of soil and vegetation 3 feet wide
and 2-3 feet height around and adjacent to the structure.  Do not apply
to lawn or turf. 

Apply no more than 1 bag (0.3 oz) per 1,000 ft2

handgun sprayer;  low pressure spray or paint brush; sprinkling can;
hose-end sprayer

	ant control	0.0043 lbs ai/gal	sprinkling can; handgun sprayer; low
pressure spray or paint brush; hose-end sprayer or injection

Do not apply outside 3 feet perimeter around structures, do not apply to
lawn or turf

For ant mound treatment.

Apply no more than 1 bag (0.3 oz) per 1,000 ft2

	termiticide	0.0043 lbs ai/gal	 Control of subterranean termite
infestations. For pre-construction termite control applications shall be
made by low pressure sprayer. For post-construction termite control
applications  made by injection.

	6F7051	New Uses on:

berries (crop group 13)

bulb vegetables 

(crop group 3)

edible podded legumes (crop group 6A)  

succulent shelled peas and beans (crop group 6B)	ASSAIL® 70WP  

70% ai

EPA Reg. No: 8033-23

ASSAIL® 30 SG 

30% a.i.

EPA Reg No. 8033-36	berries	0.044 – 0.10	5 apps/season; 7-day
treatment interval; Max seasonal rate = 0.5 lb ai/acre

aerial and ground spray

	bulb vegetables	0.094 – 0.15	4 apps/season; 7-day treatment interval;
Max seasonal rate = 0.6 lb ai/acre

aerial and ground spray

	legumes, peas and beans	0.044 – 0.1	3apps/season; 7-day treatment
interval; Max seasonal rate = 0.3 lb ai/acre

aerial and ground spray

	6E7163	Strawberry and other low growing berries	ASSAIL® 70WP  

70% ai

EPA Reg. No: 8033-23

ASSAIL® 30 SG 

30% a.i.

EPA Reg No. 8033-36	Strawberries and other low growing berries	0.044 –
0.10	5 apps/season; 7-day treatment interval; Max seasonal rate = 0.5 lb
ai/acre

aerial and ground spray



2.0	Ingredient Profile

Acetamiprid
{N1-[(6-chloro-3-pyridyl)methyl]-N2-cyano-N1-methylacetamidine} is an
insecticide that falls into the chloronicotinyl class of compounds.  It
has a molecular weight of 222.68 Daltons and is not volatile (vapor
pressure = 7.5(10-9 Torr at 25(C; Henry’s Law Constant = 5.17 x10-11
atm M3/mole at 25(C).  Acetamiprid is quite soluble in water (4.25 g/L)
as well as organic solvents (>200 g/L in ethanol, acetone, and
dichloromethane).  The log KOW of acetamiprid is 0.8.  Based on these
data, acetamiprid vapors should not present a significant inhalation
risk and this compound is not expected to concentrate in fatty tissues. 
Technical-grade acetamiprid does not contain impurities of known or
potential toxicological concern.  The nomenclature and physiochemical
properties of acetamiprid are presented below in Tables 2 and 3.

Table 2.  Test Compound Nomenclature

Compound	

Chemical Structure

Common Name	

Acetamiprid

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	

(1E)-N-[(6-chloro-3-pyridinyl)methyl]-N'-cyano-N-methylethanimidamide

CAS #	

135410-20-7

End-Use Product	

Assail® 70WP, Assail® 30SG, F4688 50WSP

Chemical Name of Acetamiprid Metabolite IM-2-1

	

N 1-[(6-chloro-3-pyridyl)methyl]-N 2-cyano-acetamidine

Chemical Name of Acetamiprid Metabolite

 IM-2-1-amide

(also referred to as IM-2-2)

	

N 2-aminocarbonyl-N 1-[(6-chloro-3-pyridyl)methyl]acetamidine



Table 3.  Physicochemical Properties of Acetamiprid

Parameter	

Value

Melting Point/Range  ((C)	

98.9

pH (20(C)	

6.08 (Aqueous Solution)

Density (20(C)	

1.33 g/cm3

Water Solubility (25(C)	

4.25 g/L

Solvent Solubility (25(C) in:         

Acetone

Ethanol

Dichloromethane

n-Hexane	

>20 g/100 g

>20 g/100 g

>20 g/100 g

6.54 ppm

Vapor Pressure (mm Hg)	

7.5 x 10-9

Dissociation Constant (pKa)	

0.7

Octanol/Water Partition Coefficient, Log KOW (20(C)	

0.8

UV/Visible Absorption Spectrum	

(Not Available)

3.0	Hazard Characterization/Assessment

Since HED’s last hazard assessment of acetamiprid in 2003, a DNT study
has been received and reviewed.  The toxicity data base is complete for
the purpose of human health risk assessment.

3.1	Hazard Characterization

The scientific quality of the toxicology database is high and the
toxicity profile can be characterized for all effects, including
potential developmental, reproductive, carcinogenic, and neurotoxic
effects.  The acute toxicity data indicate that acetamiprid is
moderately toxic via the oral route (Toxicity Category II) and is
minimally toxic via the dermal and inhalation routes (Toxicity Category
III).  Acetamiprid is not an eye or skin irritant, nor is it a dermal
sensitizer.

Acetamiprid does not appear to have specific target organ toxicity.  In
all species tested, generalized nonspecific toxicity was observed as
decreases in body weight, body weight gain, food consumption and food
efficiency when determined.  Generalized effects were also observed in
the liver in the form of hepatocellular hypertrophy in both mice and
rats and hepatocellular vacuolation in the rat.  Hepatocellular
hypertrophy was observed in the rat subchronic feeding study at doses of
50 mg/kg/day and above, and in the rat chronic feeding study at doses of
17.5 mg/kg/day and above at both the 12-month sacrifice as well as at
study termination.  In mouse studies, hepatocellular hypertrophy was
observed at 430 mg/kg/day at 90 days and at 186 mg/kg/day at 12 and 18
months.  These effects are considered to be adaptive.  Hepatocellular
vacuolation was observed at 17.5 mg/kg/day in the rat chronic study.  In
light of the lack of major liver effects in the rat studies, it is
likely that the vacuolization is more related to liver activity in
response to the presence of the chemical rather than frank toxicity. 
Other effects observed in the oral studies include amyloidosis of
multiple organs in the mouse oncogenicity study, tremors in high dose
females in the mouse subchronic study, and microconcretions in the
kidney papilla and mammary hyperplasia in the rat chronic
feeding/oncogenicity study.

No effects were observed in the 21-day dermal study in the rabbit and no
inhalation studies were conducted.

A dermal absorption study with acetamiprid was conducted using male rats
with exposure durations of 0.5, 1, 2, 4, 10 and 24 hours.  Measured
absorption was small and increased with duration of exposure. The
quantity absorbed also generally increased with dose.  In the previous
acetamiprid risk assessment, the highest dermal absorption value (6.34%
at 24 hours) was added to the residue remaining on the skin at 24 hours
(25%) to estimate a 30% dermal absorption value.  However, HED has
refined the dermal absorption value (to 10%) based upon comparison to
clothianidin, which is structurally related.  HED believes that a
refined dermal penetration value for acetamiprid of 10% is reasonable
and protective.  See Section 3.4.3 for more details.

 

There is no quantitative or qualitative evidence of increased
susceptibility of rat or rabbit fetuses to in utero exposure in the
developmental studies.  In the rat, an increase in the incidence of
shortening of the 13th rib was observed in fetuses at the same LOAEL as
the dams.  Maternal effects included reduced mean body weight, body
weight gain and food consumption and increased liver weights.  No
developmental toxicity was observed in the rabbit fetuses at dose levels
that induced maternal effects including body weight loss and decreased
food consumption. 

In the multi-generation reproduction study, qualitative evidence of
increased susceptibility of rat pups was observed.  The parental and
offspring systemic NOAELs were 17.9/21.7 (M/F) mg/kg/day and the
offspring/parental systemic LOAELs were 51.0/60.1 mg/kg/day based on a
decrease in mean body weight, body weight gain, and food consumption in
the parents and significant reductions in pup weights in both
generations.  Also observed was reduction in litter size, and viability
and weaning indices among F2 offspring as well as significant delays in
the age to attain vaginal opening and preputial separation in the
offspring.  These offspring effects were considered to be more severe
than the parental effects.

In the DNT study there was evidence of increased qualitative
susceptibility.  The purpose of the DNT study is to evaluate the
potential functional and morphological effects to the nervous system
which may arise in the offspring from exposure of the mother during
pregnancy and lactation.  It provides data on sensorimotor function and
on habituation which is considered to be a simple form of learning.  In
the acetamiprid DNT, the offspring NOAEL was 10 mg/kg/day based on
decreased body weights and body weight gains in males and females,
decreased pre-weaning survival (PND 0-1), and decreased maximum auditory
startle response in males on PND 20 and PND 60, at the LOAEL of 45
mg/kg/day.  Although there were reductions in the maximum auditory
startle response in the 10 mg/kg/day in males on PND 20 and PND 60, the
mean response was within the range of historical control means and
standard deviations among other DNT studies conducted (by the same
laboratory) within a 5-year span of the Acetamiprid DNT study.  HED
noted that statistical significance could only be achieved by combining
data for both sexes at both time points (PND 20, and PND 60).  Agency
scientists agreed that it was appropriate to combine the data for the
sexes, but there was no definitive consensus regarding combining the
data from the different time points.  The discussion regarding the
combining the data from the two time points centred around the equipment
used to measure the auditory startle reflex, and how it is calibrated
differently to account for increases in body weight as the animals grow.
 Based upon the analysis of the DNT, technical arguments submitted by
the registrant, and consideration of all other data in the acetamiprid
toxicity profile, HED believes that the decrease in maximum startle
response in males is only treatment related only at the high-dose level
of 45 mg/kg/day.

In the acute neurotoxicity study, decreased locomotor activity was seen
in both sexes post dosing at 30 mg/kg/day.  HED has low confidence in
the locomotor activity data presented in the DNT study due to problems
with the controls.  The decreased auditory startle response in males in
conjunction with the decreases in pup body weight and body weight gains
and decreased pup viability lead the Agency to a weight-of-evidence
LOAEL determination of 45 mg/kg/day.    For a more detailed discussion
of the DNT study refer to the DNT DER (MRID 46255619) and cover memo
entitled Acetamiprid: Data Evaluation Record for Acetamiprid
Developmental Neurotoxicity Study and EPA Response to Rebuttals
Submitted by Nisso America, (TXR 0054508).  The decrease in auditory
startle response observed in pups occurred in the presence of maternal
toxicity.  However, the maternal toxicity observed in this study was
restricted to decreased body weight and body weight gains during
gestation only.  The decreased pup viability at 45 mg/kg/day is
considered to be more severe than the maternal effects.  Other maternal
effects observed in the DNT included a dose-related increased incidence
of clinical signs including hair loss, dried red material and scabbing
on the forelimbs as well as animals wiping their mouths/burying their
heads in the bedding post- dosing.  These clinical signs began during
gestation but were of unknown toxicological significance and were not
used to determine the study NOAEL/LOAEL.

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 on days 7 and 14. 
Functional observational battery evaluations revealed several
treatment-related observations on the day of dosing.  High-dose males
exhibited tremors, difficulty in handling, walking on toes, dilated
pupils and coldness to the touch.  High-dose males also had decreased
forelimb grip strength and hind limb foot splay.  High-dose females
displayed tremors, chewing, coldness to the touch, and dilated pupils. 
High-dose females had decreased hind limb foot splay and were seen to
have abnormal gaits and/or posture, including walking on toes and
hunched posture. However, in a subchronic rat neurotoxicity study, the
only effects observed were related to decreases in body weight/body
weight gain, food consumption and food efficiency.  No neuropathology
was observed in any of the three neurotoxicity studies.  Tremors in high
dose female mice in the subchronic feeding study were the only other
potentially neurotoxic effects observed in any other studies.  

Acetamiprid tested negative in a Salmonella typhimurium (Ames) assay, a
forward mutation assay in Chinese hamster ovary cells, an in vivo
chromosome aberration assay in Sprague-Dawley (CD) rats, a mouse
micronucleus assay, and in repeat assays for unscheduled DNA synthesis
(UDS) in rat liver primary cell cultures.  Acetamiprid tested positive
as a clastogen in an in vitro mammalian chromosome aberration assay in
Chinese hamster ovary (CHO) cells.  However, the in vivo chromosomal
aberration study does not support the results of the in vitro study. 
All acetamiprid metabolites tested were negative for mutagenicity.

As stated previously, acetamiprid does not appear to have specific
target organ toxicity. Generalized non-specific toxicity was observed in
subchronic and chronic studies as decreases in body weight, body weight
gain, food consumption and food efficiency when estimated, and
hepatocellular hypertrophy as well as hepatocellular vacuolation, which
are likely to be related to pharmacological activity rather than frank
toxicity.  Two studies in which the toxicological effects are more
significant are the multigeneration reproduction study and the
developmental neurotoxicity study.  In the two-generation reproduction
study, delays in preputial separation, vaginal opening and pinna
unfolding and reduced litter size, viability and weaning indices were
observed at dose levels where only reduced body weight and food
consumption were observed in the parents, indicating increased
qualitative susceptibility in the pups exposed in utero.  Similar
offspring effects were observed in the DNT where offspring exposed in
utero and/or post-natally  showed signs of decreased body weight and
body weight gains in males and females, decreased pup viability and
decreased maximum auditory startle response in males on PND 20 and PND
60.  These effects were seen in the presence of decreased body weight
and body weight gains in the maternal animals.  The decrease in pup
viability is considered more severe than the maternal effects;
therefore, there is evidence of increased qualitative susceptibility in
the DNT study.

3.2	FQPA Hazard Considerations

3.2.1	Adequacy of the Toxicity Database

The acetamiprid data base is adequate to characterize potential pre-
and/or postnatal risk for infants and children.  Acceptable guideline
studies for developmental and reproductive toxicity are available for
FQPA assessment.  The registrant has also submitted an acceptable DNT
study (MRID 46255619) to the Agency in 2004.

 

3.2.2	Determination of Susceptibility

HED determined that neither quantitative nor qualitative evidence of
increased susceptibility of fetuses to in utero exposure to acetamiprid
was observed in either the developmental toxicity study in rat, or in
rabbit.  However, in the multigeneration reproduction study, qualitative
evidence of increased susceptibility of rat pups was observed.  While
parental and offspring NOAELs and LOAELs are set at the same doses (17.9
and 51.0 mg/kg/day, respectively), the effects in the offspring are
considered to be more severe than the parental effects.  Likewise, in
the DNT study maternal and offspring effects were observed at the same
dose (45 mg/kg/day).  However, the offspring effects included decreased
pup viability which is considered to be more severe than the maternal
body weight effects.  Therefore, HED concluded that there was evidence
of increased qualitative susceptibility to fetuses exposed in utero
and/or during lactation in the DNT study.  Quantitative evidence of
increased susceptibility was not observed in any study.  

3.2.3	Degree of Concern Analysis and Residual Uncertainties

Since there is evidence of increased qualitative susceptibility of the
young following in utero exposure to acetamiprid in the rat reproduction
study, and increased qualitative susceptibility to pups in the DNT
study, HED performed a degree of concern analysis to: 1) determine the
level of concern for the effects observed when considered in the context
of all available toxicity data; and, 2) identify any residual
uncertainties after establishing toxicity endpoints and traditional
uncertainty factors to be used in the acetamiprid risk assessment.  If
residual uncertainties are identified, HED examines whether the residual
uncertainties can be addressed by a FQPA safety factor, and if so, what
factors should be retained.

Considering the overall toxicity profile and the endpoints and doses
selected for the acetamiprid risk assessment, HED characterized the
degree of concern for the effects observed in the acetamiprid DNT study
as low, noting that there is a clear NOAEL for the offspring effect, the
toxicology database is complete, and regulatory doses were selected to
be protective of potential offspring effects.  No other residual
uncertainties were identified.  Based on the available data, HED
determined that changes in motor activity, auditory startle reflex,
learning and memory assessments, and even changes in the brain
morphometrics can occur as the result of a single exposure at a critical
junction during pregnancy or from multiple exposures throughout
pregnancy and lactation.  Therefore, the NOAEL for offspring effects
observed in the DNT was selected as the dose for acute dietary exposures
(co-critical with the acute neurotoxicity study), as well as, short-term
and long-term non-dietary risk assessment.  The chronic dietary study in
rats yielded a lower long-term NOAEL (7.1 mg/kg/day) and will be used
for assessing chronic dietary risk.  HED believes that the endpoints and
doses selected for acetamiprid are protective of adverse effects in both
offspring and adults.  

3.3		FQPA Safety Factor(s) For Infants and Children

HED has determined that no additional FQPA safety factor is needed for
acetamiprid (i.e. the Safety Factor  has been reduced to 1X) for the
following reasons: (1) the toxicology database is complete; (2) HED is
regulating based upon the effects of concern, i.e., developmental
effects in pups following pre-and/or post-natal exposure; (3) the rat
appears to be the most sensitive species tested, and the NOAEL and LOAEL
selected from the DNT study in rats are protective of effects observed
in other species throughout the toxicology database; and, (4) there are
no residual uncertainties for pre- and/or post-natal toxicity.  The
recommended FQPA safety factor also reflects HED’s conclusion that the
exposure databases (dietary food, drinking water, and residential) are
complete and that the risk assessment for each potential exposure
scenario includes all metabolites and/or degradates of concern and does
not underestimate the potential risk to infants or children. 

3.4	Hazard Identification and Toxicity Endpoint Selection

3.4.1	Acute Dietary Endpoint

Study Selected:  Developmental Neurotoxicity Study in Rats

MRID No.: 46255619 

Executive Summary:  In a developmental neurotoxicity study (MRID
46255619), Acetamiprid (>99% a.i., lot # NNI-03) was administered to 25
mated female  Crl:CD((SD)IGS BR rats/dose by gavage at doses of 0, 2.5,
10 and 45 mg/kg/day from gestation day (GD) 6 through lactation day (LD)
21 in a volume of 5 mL/kg body weight. A Functional Operational Battery
(FOB) was performed on 10 dams/dose on GDs 6 and 12, and on LDs 4 and 7.
 On postnatal day (PND) 4, litters were culled to yield four males and
four females (as closely as possible).  Offspring were allocated for FOB
and assessment of motor activity, auditory startle reflex habituation,
learning and memory, and neuropathology at study termination (day 72 of
age).  On postnatal day 11, the whole brain was collected from 10
pups/sex/dose group for micropathologic examination and morphometric
analysis. Pup physical development was assessed by body weight.  The age
of sexual maturation (vaginal opening in females and preputial
separation in males) was assessed.

In the dams, no systemic toxicity was seen at the doses tested.  The
maternal toxicity observed was restricted to decreased body weight and
body weight gains during gestation at the LOAEL of 45 mg/kg/day (NOAEL
10 mg/kg/day). 

Treatment-related effects in the offspring at the high dose (45
mg/kg/day) include decreased body weights, and body weight gains in
males and females post-weaning, decreased pup viability and decreased
maximum auditory startle response in males on PND 20 and PND 60.
Treatment had no adverse effects on clinical signs, developmental
landmarks, FOB, brain weight or brain morphology.  There is low
confidence in the motor activity data because of problems with the
control data (i.e. the normal developmental pattern was not seen in
control animals). Therefore, no conclusions could be made on motor
activity evaluation.  The maximum auditory startle response amplitude
was decreased 27% (PND 20) and  40% (PND 60) at 10 mg/kg/day, and it was
decreased 42% (PND 20) and 53% (PND 60) at 45 mg/kg/day; only the
decreased  maximum auditory startle response in the 45 mg/kg/day males
(PND 20 and PND 60) was considered treatment related.  No conclusions
can be made on the effects of acetamiprid on learning and memory because
of the high variability in the data.   

The offspring LOAEL is 45 mg/kg/day based on decreased body weights and
body weight gains in males and females, decreased pre-weaning survival
(PND 0-1), and decreased maximum auditory startle response in males on
PND 20 and PND 60.  The offspring NOAEL is 10 mg/kg/day.

ACN Executive Summary:  In an acute neurotoxicity study (MRID 44651842),
groups of fasted male and female Crl:CD-BR rats (10/sex/dose), were
given a single oral dose of acetamiprid (99.9%) by gavage, in 0.5%
sodium carboxymethylcellulose at doses of 0, 10, 30, or 100 mg/kg bw and
observed for 14 days.  There were no mortalities during the study.  Body
weight gain, food consumption, and food efficiency were unaffected in
females.  Treatment with acetamiprid had no effect on brain size or
weight and there was no evidence of neuropathology.  Clinical signs of
toxicity were limited to the high-dose animals, and included tremors,
hunched posture, unsteady gait and coldness to touch.  In addition, one
high-dose female had slight brown nasal staining from study day 2 until
termination.

High-dose males and females had significantly reduced body temperature
on the day of dosing.  Significantly decreased motor activity was
observed in the mid- and high-dose males and in high-dose females on the
day of dosing.  A slight decrease in the duration of movements persisted
in mid- and high-dose males on days 7 and 14.  Functional observational
battery evaluations revealed several treatment-related observations on
the day of dosing.  High-dose males exhibited tremors, difficulty in
handling, walking on toes, dilated pupils and coldness to touch. 
High-dose males also had decreased forelimb grip strength and hind limb
foot splay.  High-dose females displayed tremors, chewing, coldness to
touch, and dilated pupils.  High-dose females had decreased hind limb
foot splay.  High-dose females were seen to have abnormal gaits and/or
posture, including walking on toes and hunched posture.

The LOAEL for neurotoxicity was 30 mg/kg bw, based on the observed
reduction in locomotor activity in males.  The NOAEL for neurotoxicity
was 10 mg/kg bw.

Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on
decreased body weights and body weight gains in males and females,
decreased pre-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, as well as, decreased locomotor activity in males in the ACN
study at 30 mg/kg bw.

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 dietary risk (both endpoints can be considered the result of a
single dose), and 3) they are protective of potential offspring effects.
 Based on the available data, HED determined that changes in motor
activity, auditory startle reflex, learning and memory assessments, and
changes in the brain morphometrics can occur as the result of a single
exposure at a critical junction during pregnancy or from 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).

3.4.2	Chronic Dietary Endpoint

Studies Selected:  Chronic/Oncogenicity Study in the Rat

MRID Nos.: 44988429, 45245304

Executive Summary:  In a chronic toxicity/oncogenicity study (MRID
44988429 & 45245304), acetamiprid, [NI-25 (>99% a.i.; Lot No. NNI-01)]
was administered to groups of 60 male and 60 female Crl-CD®BR rats in
the diet at concentrations of 0, 160, 400, and 1000 ppm (0, 7.1, 17.5,
and 46.4 mg/kg/day for males and 0, 8.8, 22.6, and 60 mg/kg/day for
females).  Ten rats per sex per dose were sacrificed at 12 months for
interim evaluations; the remaining animals were maintained on their
respective diets for up to 24 months.

There were no treatment-related effects on mortality; eyes; hematology,
clinical chemistry or urinalysis parameters; or gross findings in either
sex administered any dose of the test material.  Clinical signs that
were observed at significantly increased incidences in treated animals
included rales in high dose males (7/48 vs 0/46 for controls) during
weeks 66-78 and at all doses in males during weeks 79-91 (0/44, 8/49,
19/45, and 17/48 at 0, 160, 400, and 1000 ppm, respectively).  Also in
high-dose male rats, the incidences of labored breathing (15/48 vs 5/46
for controls, p<0.05) was increased during weeks 66-78, red material
around the nose during weeks 1-13 (7/60 vs 0/60 for controls) and weeks
92-104 (5/46 vs 0/37), and hunched posture (5/46 vs 0/37) during weeks
92-104.  The lack of pathologic correlates indicates that the clinical
signs are not biologically significant.

Treatment-related effects on body weight, body weight gain, and food
consumption were observed in both sexes.  High-dose male rats, weight
10-13% (p<0.01) less than controls throughout the study, gained 44%less
weight during week 1, 14% less during the first year and 18% less over
the entire study.  High-dose group males also consumed 19% (p<0.01) less
food (g/animal/day) during week 1 and 4-9% (p<0.01 or <0.05) less at
different time points during the remaining weeks of the study.  Food
efficiency measured during the first 14 weeks was reduced for males in
all dose groups during the first week of the study and showed an
inconsistent pattern for the remaining 13 weeks.  Mid-dose female rats
weighed 4-17% (p<0.01) less than controls throughout the study and
high-dose females weighed 6-27% (p<0.01) less.  Mid- and high-dose group
females, respectively, gained 27 and 42% less weight than controls
during week 1, 15% and 32% less during the first year, and 16% and 23%
less over the entire study.  Food consumption was 6-10% and 9-19% less
for mid- and high-dose group females, respectively, for most of the
study.  Food efficiency was reduced for mid- and high-dose group females
during week 1 and showed inconsistent patterns for the remaining 13
weeks.

The postmortem examination showed statistically significant changes in
absolute and/or relative weights of several organs in high-dose group
male and female rats, and these changes are attributed to the decreased
terminal body weight.  Treatment-related microscopic changes were
observed in the liver, kidney, and mammary glands.  Trace to mild
hepatocyte hypertrophy in the liver of mid- and high-dose male rats and
high-dose female rats at interim sacrifice and in the main study groups
is considered an adaptive response rather than an adverse effect. 
Hepatocyte vacuolation also was observed in mid- and high-dose group
male rats; the incidence was 10/12 and 10/11, respectively, compared
with 2/12 for controls at interim sacrifice and 22/48 and 29/48,
respectively, compared with 10/48 for the controls in the main study. 
An increased incidence of microconcretions in the kidney papilla was
noted for high-dose male rats (37/49 vs 17/48 for controls, p<0.01) in
the main study.  The incidence of 24/49 (p<0.05) for mammary hyperplasia
in high-dose group females compared with 14/49 for controls appeared to
be treatment related, but the toxicologic significance of this finding
is uncertain.

The lowest-obeserved-adverse-effect-level (LOAEL) for acetamiprid is 400
ppm (17.5 mg/kg/day for males and 22.6 mg/kg/day for females) for male
and female rats based on reduced body weight and body weight gains for
females and hepatocellular vacuolation for males.  The
no-observed-adverse-effect-level (NOAEL) is 160 ppm (7.1 mg/kg/day for
males and 8.8 mg/kg/day for females)

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

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 protective of both chronic and
potential offspring effects.  The standard uncertainty factors were
applied to all dietary exposure scenarios (10x for intraspecies
variability and 10x for interspecies extrapolation).

3.4.3	Dermal Absorption

In the previous risk assessment (3/11/2002; D263648), HED used a 30%
dermal penetration value derived from an acetamiprid dermal penetration
study in rats (MRID 44651858), in which multiple doses were tested for
durations ranging from 0.5 to 24 hours.  To arrive at the 30% value, HED
added the highest dermal absorption value (6.34%) to the amount
sequestered in the skin at 24 hours (approximately 25%). To validate
this estimate and determine whether further refinement was needed, HED
reexamined the dermal penetration study with acetamiprid, and reviewed
the dermal penetration information of several other neonicitinoid
insecticides.

To refine its assumption regarding treatment of sequestered acetamiprid
on the skin, HED looked at the amount of radioactivity remaining at the
application site.  The amount of radiolabeled material remaining at the
application site at various intervals varied between 0–5% percent
between time points.  If the radioactivity remaining at the application
site is added to that which is absorbed, a maximum penetration value for
acetamiprid would be 11%.  However, since the duration of the
acetamiprid study was only 24 hours, HED examined the thiamethoxam
dermal penetration study, another neonicitinoid, which was terminated
after 336 hours (14 days).  Results from that study indicate little
additional absorption (1 – 3%) occurred between 24 hours post dosing
and 14 days post dosing.  

HED also considered the Kow and octanol/water coefficient data of other
neonicitinoid compounds, and found acetamiprid is most closely related
to clothianidin with respect to its log Kow and octanol/water
coefficient, and therefore would likely act most similarly to
clothianidin when applied to the skin.  The dermal penetration value for
clothianidin (1%) is based upon dermal penetration study with monkeys. 
See Table 4 below.

Table 4.  Absorption Parameters for Selected Neonicitinoids.

Compound	Log Kow	Octanol/Water Coefficient	Dermal Penetration Value

Acetamiprid	0.8	6.3	30% 

(dermal penetration study with rat)

Clothianidin	0.9	8	1% 

(dermal penetration study in monkeys)



Adjustment of the monkey dermal penetration value for clothianidin to
account for the 2-10 fold increased dermal sensitivity of rats compared
to humans (dermal penetration of monkey is considered equivalent to
human) would yield a comparative rat dermal penetration value for
acetamiprid of 2% – 10%.  Likewise, if the current dermal penetration
value for acetamiprid is adjusted downward to account for the increased
sensitivity of rats to humans, then a value of 10% - 15% results.  Since
the acetamiprid study shows 6% dermal penetration at 24 hours, a refined
dermal penetration value reflecting a longer dermal exposure, would
likely be greater than 6%, and may lie between 10 -15 %. 

Based upon its reconsideration of the acetamiprid dermal penetration
study, and on comparison of acetamiprid to the structurally related
clothianidin, HED determined that a refined dermal penetration value for
acetamiprid of 10% is reasonable and protective.  Based upon this, HED
would not require any additional dermal penetration data for
acetamiprid.

3.4.4	Short- and Intermediate-Term Dermal Endpoints

Study Selected:  Developmental Neurotoxicity Study in Rats

MRID No.: 46255619

Executive Summary:  see Section 4.3.1

Dose and Endpoint for Risk Assessment:  NOAEL = 10 mg/kg/day based on
decreased body weights and body weight gains in males and females,
decreased pre-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, as well as decreased locomotor 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 dermal risk assessment because they
are protective of developmental effects present in rat pups seen 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 offspring effects observed in both the
DNT, and the multigeneration reproduction studies because the effects
seen could occur as a result of a single exposure at a critical junction
during pregnancy or from multiple exposures throughout pregnancy
lactation.  Therefore,  the NOAEL for offspring effects observed in the
DNT was selected  as the dose for both short-term, and intermediate-term
dermal exposure scenarios.  The standard uncertainty factors were
applied to all exposure scenarios (10x for intraspecies variability and
10x for interspecies extrapolation).

3.4.5	Short- and Intermediate-Term Inhalation Endpoints

Study Selected:  Developmental Neurotoxicity Study in Rats

MRID No.: 46255619

Executive Summary:  see Section 4.3.1

Dose and Endpoint for Risk Assessment:  NOAEL = 10 mg/kg/day based on
decreased body weights and body weight gains in males and females,
decreased pre-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, as well as, decreased locomotor activity in males of the ACN
study at 30 mg/kg bw.

Comments about Study/Endpoint/Uncertainty Factors:  No route-specific
information is available for the inhalation toxicity of acetamiprid.  In
the absence of a route-specific study, the NOAEL and LOAEL from an oral
study, along with an inhalation absorption factor (100%), are used to
estimate inhalation exposure and the associated risk.  In this case, the
NOAEL and LOAEL from the DNT study were selected 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 single exposure at a critical
junction during pregnancy or from multiple exposures throughout
pregnancy and lactation, the NOAEL for offspring effects observed in the
DNT was selected as the dose for both short- and intermediate-term
inhalation exposure scenarios.  The standard uncertainty factors were
applied to all exposure scenarios (10x for intraspecies variability and
10x for interspecies extrapolation).

Based upon the proposed use patterns, HED dose not anticipate any
long-term dermal or inhalation exposure scenarios.  Therefore, no
long-term dose/endpoints were selected.

3.4.6	Level of Concern for Margin of Exposure (MOE)

Table 5.  Level of Concern for Margin of Exposure*

Route	Short-Term

(1-30 Days)	Intermediate-Term

(1-6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	N/A

Inhalation	100	100	N/A

Residential Exposure

Dermal	100	100	N/A

Inhalation	100	100	N/A

Incidental Oral	100	100	N/A

* The level of concern is based upon a 10X intra-species variability
factor, and a 10X inter-species extrapolation factor.  

3.4.7	Recommendation for Aggregate Exposure Risk Assessment

The FQPA requires that HED aggregate pesticide exposures from the three
major exposure routes (oral, dermal, and inhalation) when there is
potential residential exposure to a pesticide.  HED has chosen a single
endpoint and dose from the DNT study as the appropriate endpoint for all
exposure scenarios and all durations for acetamiprid, with the exception
of chronic dietary exposure.  Therefore, short-, and intermediate-term
dermal, oral and inhalation exposures can be combined and aggregated
with the dietary (food + water) exposures.

3.4.8	Classification of Carcinogenic Potential

HED has determined that acetamiprid is not likely to be carcinogenic to
humans (EPA Draft Guidelines for Carcinogen Risk Assessment; July,
1999).  The classification is based on the absence of a dose-response
and the lack of a statistically significant increase in the mammary
adenocarcinoma incidence by pair-wise comparison of the mid- and high-
dose groups with the controls; although the incidence exceeded the
historical control data from the same laboratory, it was within the
range of values from the supplier.

Table 6.   Summary of Toxicological Doses and Endpoints of Acetamiprid
for Use in Dietary and Non-Occupational Human Health Risk Assessment

Exposure Scenario	Dose Used in Risk Assessment	Uncertainty Factors/FQPA
Safety Factors	RfD, PAD Level of Concern for Risk Assessment	Study and
Toxicological Effect

Acute Dietary

general population including infants and children	NOAEL1 = 10 mg/kg/day
UFA 1= 10x

UFH 1= 10x

FQPA SF2 = 1x

	aPAD = 0.10 mg/kg/day	Developmental Neurotoxicity in rat

LOAEL5 = 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.

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	UFA = 10x

UFH = 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 vacualation in males.

Short- and Intermediate-Term  Incidental Oral 

(1-30 days and 1 - 6 mo.)

Residential setting	NOAEL = 10 mg/kg/day	UFA = 10x

UFH = 10x

FQPA SF2 = 1x

	LOC3 for MOE4 = 100

(Residential)	Developmental Neurotoxicity in rat

LOAEL5 = 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.)

Residential setting	NOAEL = 10 mg/kg/day	UFA = 10x

UFH = 10x

FQPA SF2 = 1x

dermal absorption rate = 10%	LOC for MOE = 100

(Residential)	Developmental Neurotoxicity in rat

LOAEL5 = 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.)

Residential setting	NOAEL = 10 mg/kg/day	UFA = 10x

UFH = 10x

FQPA SF2 = 1x

inhalation absorption rate = 100%	LOC for MOE = 100

(Residential)	Developmental Neurotoxicity in rat

LOAEL5 = 45 mg/kg/day based on decreased body weight and body weight
gains in offspring, decreased early pup survival on PND 0-1, and
decreased startle response on PND 20/60 in males.

Cancer (oral, dermal, inhalation) - not likely to be carcinogenic to
humans.

1: NOAEL = No Observed Adverse Effect Level.

UFA: uncertainty factor applied for extrapolation from animal to human
(interspecies)

UFH: uncertainty factor applied for extrapolation from human to human
due to potential variation in sensitivity among members of the human
population (intra-species)

2: FQPA SF= Food Quality Protection Act Safety Factor

3: LOC = Level of Concern

4: MOE = Margin of Exposure

5: LOAEL = Lowest Observed Adverse Effect Level

Table 7.  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.)

	oral study NOAEL1= 

10 mg/kg/day

dermal absorption rate = 10%	UFA 1= 10x

UFH 1= 10x

	LOC2 for MOE3 = 100

(Occupational)

	Developmental Neurotoxicity in rat

LOAEL4 = 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.)

	Oral study NOAEL=

 10 mg/kg/day

inhalation absorption rate = 100%	

UFA = 10x

UFH = 10x

	LOC for MOE = 100 

(Occupational)

	Cancer (oral, dermal, inhalation) - not likely to be carcinogenic to
humans.

1: NOAEL = No Observed Adverse Effect Level.

UFA: uncertainty factor applied for extrapolation from animal to human
(interspecies)

UFH: uncertainty factor applied for extrapolation form human to human
due to potential variation in sensitivity among members of the human
population (intra-species)

2: LOC = Level of Concern

3: MOE = Margin of Exposure

4: LOAEL = Lowest Observed Adverse Effect Level

3.5	Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was a
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. 
EPA also adopted EDSTAC’s recommendation that the Program include
evaluations of potential effects in wildlife.  For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations.  As the science develops,
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, acetamiprid may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	Public Health Data

No public health data were considered at this time.

5.0	Dietary Exposure/Risk Characterization

5.1	Metabolism in Crops and Livestock

The nature of acetamiprid residue in plants has been adequately
delineated and is based on radiolabeled studies with carrot, cabbage,
cotton, apple, and eggplant.  In plants, there appears to be little
translocation of acetamiprid following foliar application.  In cabbage,
there was significant uptake and translocation of acetamiprid to the
above ground portions of the plant following a soil application. 
However, due to the rapid dissipation of acetamiprid in the field, root
uptake is not a likely source of residues in plants.  

The qualitative nature of acetamiprid residue in livestock is also
adequately understood based upon metabolism studies in ruminants
(lactating goat) and laying hens.  HED has determined that for risk
assessment purposes, the residues of concern in livestock tissue (except
ruminant muscle) are acetamiprid per se, plus its IM-2-1 metabolite.  In
ruminant muscle, the residues of concern for risk assessment are
acetamiprid plus IM-2-1 plus IM-2-1-amide.  Residues of IM-2-1-amide in
ruminant muscle tissue can be estimated by applying a 10-fold factor to
residues of IM-2-1 in muscle.  



HED has concluded that the tolerance expression should include
acetamiprid per se for plant commodities and combined residues of
acetamiprid and IM-2-1 [N1-[(6-chloro-3-
pyridyl)methyl]-N2-cyano-acetamidine] for livestock commodities.  Based
upon available rotational crop data, HED has determined that the residue
of concern in rotational crops would be acetamiprid, per se, but
tolerances for acetamiprid are not needed in rotational crops. 
Discussion of the nature of the acetamiprid residue and analytical
methodology associated with the subject petitions can be found in the
following HED memoranda: for cucurbit vegetables, stone fruits, and tree
nuts, see HED memorandum, W.Drew, 11/5/2004, D303623; and, for berries,
bulb vegetables, succulent shelled pea and beans, and strawberry and
other low growing berries, see HED memorandum, W.Drew, 10/23/2007,
D328216.

5.1.1	Analytical Methodology

The method used to analyze samples for acetamiprid residues in/on raw
agricultural commodities (RACs) was Method Number 45800, entitled
Methods for the Analysis of Acetamiprid (NI-25) In Plants and Plant
Processed Fractions (MRID # 44988529).  This method is adequate for data
collection based on acceptable concurrent method recovery data. 
Acetamiprid is not recovered through the FDA Multiresidue Protocols.

Adequate residue analytical methods are available for the enforcement of
established and proposed tolerances for plant commodities (GC/ECD and
HPLC/UV) and animal commodities (HPLC/UV).  These methods were submitted
to ACB/BEAD for petition method validation (PMV) and were successfully
validated.  The registrant has also requested that the HPLC/MS/MS method
utilized for data collection (in PP#3F6575 and PP#4F6833) replace the
current tolerance enforcement method (GC/ECD) for the proposed uses on
stone fruits, tree nuts, and cucurbit vegetables.  An independent
laboratory validation (ILV) for this method was previously required by
HED.  These data have been submitted (MRID 47185401), and are currently
under review.  Table 8 summarizes the analytical methodologies for
acetamiprid.



Table 8.  Summary of Analytical Methods for Acetamiprid.

Target Matrices	Method/

Method Description	Validated for Enforcement	LOQ (ppm)	Method Validation

Fortification levels  (ppm)	Recovery Range (%)

Vegetables and Non-Citrus Fruits	GC/ECD Method

Methanol extraction, residues partitioned into dichloromethane,
Florisil/silica gel column cleanup, and GC/ECD determination	Yes	0.010
0.010, 0.050	68-112

	Proposed

HPLC/MS/MS Method 	The submitted ILV for this method is currently under
review 

	Citrus Fruits	HPLC/UV Method

Acetonitrile extraction, coextractives partitioned into hexane, residues
partitioned into dichloromethane, Florisil/C18 column cleanup, and
HPLC/UV determination.	Yes	0.050	0.050, 0.250	77-100

Eggs, Milk, and Ruminant and Poultry Tissues	HPLC/UV Method

Acetonitrile extraction, residues partitioned into dichloromethane,
Florisil/C18 column cleanup, and HPLC/UV determination.  The method
determines both acetamiprid and IM-2-1.	Yes	0.010 ppm (muscle, fat,
milk, and eggs)	0.010, 0.100	78-103 (acetamiprid)

81-109

 (IM-2-1)

	0.050 (liver and kidney)	0.050, 0.500

	

5.1.2	Metabolism and Degradates of Concern

The residue chemistry database for acetamiprid has been previously
examined and can be found in earlier HED memorandum (H.Bietlot,
11/16/2001, D278652; and, M.Doherty, 12/31/2001, D264154). 

A comparison of the available acute toxicity data for the parent versus
the metabolites indicates that the metabolites IC-0, IM-0, IM-2-1,
IM-1-4, IM-1-2, are either similar, or less acutely toxic than the
parent.  In subchronic feeding and mutagenicity studies the tested
metabolites were shown to be either equivalent to, or less toxic than
the parent.  The acute toxicity and mutagenicity data indicate that the
metabolite of concern in livestock, IM-2-1, is less toxic than the
parent and is of similar mutagenic potential to the parent.  Subchronic
studies were not submitted to address the long-term toxicity of the
IM-2-1 metabolite.  Table 9 summarizes the residues of concern (parent
and metabolites) that will be considered for regulation.



Table 9.  Summary of  Metabolism Findings for Acetamiprid

Matrix	Residues of Concern

	Risk Assessment	Tolerance Expression

Target Crops	Acetamiprid	Acetamiprid

Livestock	Acetamiprid and IM-2-1

(and IM-2-1-amide in ruminant muscle only)	Acetamiprid and IM-2-1

Rotational Crops	Acetamiprid	None at this time

Drinking Water	Acetamiprid	Not applicable

5.1.3	Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were
provided by EFED (G.Orrick, 6/21/2005, D303582, and G.Orrick, 6/24/2007,
D331596 and D336256), and were incorporated directly into the dietary
assessment.  Acute and chronic estimates of drinking water
concentrations (EDWCs) in surface water were generated using the
screening mechanistic model, FIRST v1.0 (Aug. 1, 2001).  Ground water
concentration estimates were generated using the screening regression
model SCI-GROW v2.3 (Jul 29, 2003).  For the surface water assessment,
the application rate for citrus was used (0.25 lb ai/acre, at 2
applications), which represents the highest label rate for a single
application of any currently registered or proposed use of acetamiprid. 
For the groundwater assessment, the maximum application rate for tree
nut, was used which represents the highest label rate on a seasonal
basis (0.72 lb ai/acre/season, applied in four applications at 0.18 lb
ai/acre).  Concentrations of acetamiprid degradates were not estimated
since HED has determined that they are not of concern in drinking water.
 Because the EDWCs are based on the highest application rates, the
estimated concentrations can be considered conservative.  EDWCs are
summarized in Table 10. 

Table 10.  Estimated Drinking Water Concentrations for Acetamiprid

Drinking Water Source	Maximum Use Pattern	Exposure Duration	EDWC

Surface water	Citrus fruit	Acute	20.1 ppb

Chronic	4.9 ppb

Ground water	Tree nut	Acute and Chronic	1.6 ppt

5.1.4	Food Residue Profile

5.1.4.1	  Crop Field Trials

Crop Field Trials

HED has reviewed the field trial data submitted to support the three
subject petitions, 4F6833, 6F7051, and, 6E7163.  The MRID’s for the
submitted studies are listed in Table 11 below.  In an earlier review,
completed in connection with PP# 0F6082 (M.Doherty, 12/2004, D264154)
HED noted a data gap associated with rotational crop storage stability. 
Since that time, these data have been submitted (MRID 46729102) and
reviewed and, therefore, are no longer considered a data gap.

Table 11.

 Summary of Field Trial Data Submitted in Connection with Petitions
4F6833, 6F7051, and 6E7163.

Petition	Crop(s)	Field Trial Data

4F6833	Cucurbit Vegetables (Crop Group 9)	MRID 46265701

	Stone Fruits (Crop Group 12)	MRID 46265702

	Tree Nuts (Crop Group 14)	MRID 46265703

6F7051	Bulb vegetables (Crop Group 3)	MRID 46785503

	Berries (crop group 13)	MRID 46785502

	Edible Podded Legum Vegetables  (Crop Subgroup 6A)	MRID 46785504

	Succulent Shelled Peas and Beans (Crop Subgroup 6B)	MRID 46785504

6E7163	Strawberry	MRID 47013601

 

Cucurbit Vegetables, Stone Fruits, Tree Nuts

The data submitted to support the uses on the cucurbit vegetables crop
group, the stone fruits crop group, and the tree nuts crop group are
adequate.  Based upon submitted residue data, HED has determined that a
group tolerance in the stone fruits group can be established at 1.20
ppm, (where the petitioner requested 1.2 ppm); and, a separate tolerance
(0.20 ppm) in prune plum is recommended, (where the petitioner requested
0.30 ppm).  In addition, although the submitted almond and pecan field
trial data may be used to support use on pistachios, a separate
tolerance must be established in pistachios until the Code of Federal
Regulations No. 40 is modified to include pistachio in the crop group
definition for tree nuts.

Processing data indicate that residues of acetamiprid may concentrate in
dried prunes.  Based upon the average processing factor (2.9X) reported
in the data, and the residue data for plum (HAFT residue of 0.112), HED
recommends a separate tolerance of 0.40 ppm in dried prune plum.

Based upon the data submitted in connection with PP# 4F6833, HED
recommends establishing the tolerances for acetamiprid, per se, in/on
the commodities listed below in Table 12.

Bulb Vegetables 

Field trial data have been submitted on the representative commodities
(bulb and green onions) for Crop Group 3.  While no residue decline data
were submitted with the field trial data, previously submitted residue
decline data indicate that residues of acetamiprid do not increase with
increasing harvest intervals.  Because the residues in the green onions
exceeded those of the bulb onions by more than 5x, HED does not
recommend a single group tolerance, as requested by the petitioner. 
Rather, HED recommends that tolerances be set on the individual crops in
the two pending bulb vegetable subgroups (i) a 0.02 ppm tolerance in
bulb onion subgroup 3A; and (ii) a 4.5 ppm tolerance in the green onion
subgroup 3B.

Eddible Podded Legume Vegetables (Crop Subgroup 6A) and Succulent
Shelled Pea and Beans (Crop Subgroup 6B)

Adequate field trial data have been submitted on the representative
commodities of the two crop subgroups, 6A and 6B.  Even though reported
residues from representative commodities within the 6B crop subgroup
differed greater than the usual 5x limit, (i.e., 5.9x), HED can
recommend a single crop subgroup tolerance be set because the residues
were all relatively low.  Therefore, HED recommends a 0.60 ppm
acetamiprid tolerance in edible podded legume vegetables (Crop Subgroup
6A) and a 0.40 ppm acetamiprid tolerance in succulent shelled pea and
beans (Crop Subgroup 6B).

Berries (Crop Group 13)

At the time of the review, HED determined that inadequate field trial
data were submitted in connection with the petition for a Berries group
tolerance (Crop Group 13).  The data submitted for one of the two
representative crops (a bushberry crop for crop subgroup 13A) were
sufficient.  However, the data submitted for the other representative
crop (a caneberry crop for crop subgroup 13B) were inadequate.  These
data have already been submitted and currently are under review (MRID
47224701).  Based upon the adequate bushberry crop field trial data and
HED’s preliminary review of the caneberry data, HED recommends that a
1.6 ppm tolerance for berries (Crop Group 13) be established.

HED also recommends a separate 1.6 ppm acetamiprid tolerance be set in
lingonberry, which is pending to become a member of Crop Subgroup 13B. 

Strawberry

Field trial data submitted for strawberries are adequate.  Residue
decline data submitted with the strawberries indicate that acetamiprid
residues decline with lengthened sampling intervals.  The submitted data
on strawberries are also adequate to support acetamiprid tolerances on
the following crops: bearberries, bilberries, cloudberries, cranberries,
muntries, and partridgeberries.  Since the establishment of a crop
subgroup is pending for these crops (Crop Subgroup 13G), HED currently
recommends a 0.60 ppm tolerance be set in each commodity.

In its submission, the petitioner requested a tolerance for acetamiprid
on lowbush blueberries, and included this request in conjunction with
its strawberry petition.  HED notes that an acetamiprid tolerance for
lowbush blueberry would be covered by the recommended tolerance for
Berries (Crop Group 13).  A summary of recommended tolerances for the
commodities associated with the three subject petitions is listed below
in Table 12.

Based upon the submitted data, HED recommends establishing unconditional
registrations and tolerances for acetamiprid, per se, in connection with
the three subject petitions.  The acetamiprid tolerances should be
revised not only to reflect the HED recommended tolerance levels,
including individual and crop group tolerances while the establishment
of various crop groups is pending, but also to reflect the correct
commodity definitions.  A summary table of proposed and recommended
tolerances for acetamiprid associated with all three subject petitions
can be found in Appendix D, Table 1.

 International Residue Limits

There are no Codex, Canadian or Mexican MRL’s established on the
commodities associated with these petitions.

 Livestock Commodities

Adequate cattle feeding study data are also available to support the
proposed uses of acetamiprid.  No poultry feed items are associated with
this petition.  The existing tolerances for residues in livestock
commodities are adequate to cover all uses associated with the present
petitions.  

Table 12.   Summary of Crop and Crop Groups Recommended for Tolerances
in Connection with Subject Petitions

Petition No.	Crop Group or Commodity Recommended for Tolerance
Recommended Tolerance (ppm)	List of Commodities Included

PP#

4F6833	Tree Nuts (Crop Group 14)	0.1	almonds; beechnut; butternut;
cashew; chestnut; chinquapin; filbert; brazil nut; hickory nut;
macadamia nut; processed nutmeat (except peanut); nuts; pecan; walnut

	Pistachio	0.10	Pistachio 

	Almond, hulls	5.0	Almond, hulls

	Fruit, stone, except plum, prune fresh and dried (Crop Group 12)	1.2
apricot; cherry (sweet and tart); nectarine; peach; plum; plum,
chickasaw; plum, damson; plum, Japanese

	Plum, prune, fresh	0.2	plum, prune; plum, prune, fresh

	Plum, prune, dried	0.4	plum, prune, dried

	Vegetable, cucurbit group (Crop Group 9)	0.5	balsam apple; balsam pear;
cantaloupe; chayote fruit; cucumber; cucumber, Chinese; gherkin, West
Indian; gourd, edible; melon; melon, citron; muskmelon; pumpkin; squash;
squash, summer; squash, winter; watermelon; waxgourd, chinese

PP#

6F7051	Vegetable, legume, edible podded, (Subgroup 6A)	0.6	Bean, moth;
bean, runner; bean, snap; bean, wax; bean, yardlong; jackbean; longbean,
Chinese; pea, dwarf; pea, edible podded; pea, pigeon; pea, snow; pea,
sugar snap; soybean, immature seed; swordbean.

	Pea and bean, succulent, shelled (Subgroup 6B)	0.4	Bean, broad; bean,
lima succulent; cowpea; cowpea seed; pea, blackeyed; pea, English; pea,
garden; pea, green; pea, pigeon; pea, southern

	Bushberry Subgroup 13B	1.6	Blueberry; currant; elderberry; gooseberry;
huckleberry; Aronia berry; Buffalo currant; Chilean guava; European
barberry; Highbush cranberry; Honeysuckle; Jostaberry; Juneberry;
Lingonberry; Native currant; Salal; Sea buckthorn

	Bulb Onion (Subgroup 3A)	0.02	Onion, bulb; Fritillaria, bulb; Daylily,
bulb; Garlic, bulb; Garlic, great headed, bulb; Garlic, Serpent, bulb;
Lily, bulb; Onion, Chinese, bulb; Onion, Pearl; Onion, potato, bulb;
Shallot, bulb

	Green Onion (Subgroup 3B)	4.5	Onion, green; Chive, fresh leaves; Chive,
Chinese, fresh leaves; Elegans hosta; Fritillaria, leaves; Kurrat;
Lady’s leek; Leek; Leek, wild; Onion, Beltsville bunching; Onion,
fresh; Onion, macrostem; Onion, tree, tops; Onion, Welsh, tops; Shallot,
fresh leaves

PP#

6E7163	Berry, group 13	1.6	Blackberry; blueberry; caneberry; currant;
elderberry; gooseberry; huckleberry; loganberry; raspberry

	Berries, low-growing, subgroup 13G	0.6	bearberry, bilberry, cloudberry,
cranberry, muntries, partridgeberry, strawberry

.

5.2	Dietary Exposure/Risk Pathway

Dietary risk assessment incorporates both exposure and toxicity of a
given pesticide.  For acute and chronic dietary risk assessments, the
risk is expressed as a percentage of the population adjusted dose (PAD).
 The acute PAD (aPAD) is derived by dividing the selected acute dietary
dose (NOAEL) by the appropriate uncertainty and FQPA safety factors. 
The chronic PAD (cPAD) is derived by dividing the selected chronic
dietary dose (NOAEL) by the appropriate uncertainty and FQPA safety
factors.  Typically, HED has dietary risk concerns when the estimated
exposure exceeds 100% of the aPAD and/or cPAD. 

5.2.1	Dietary Exposure and Risk

Acute and chronic dietary risk assessments were conducted for
acetamiprid using the Dietary Exposure Evaluation Model (DEEM-FCID(,
Version 2.03) which uses food consumption data from the USDA’s
Continuing Surveys of Food Intakes by Individuals (CSFII, 1994-1996 and
1998).  The acute and chronic dietary analyses are considered partially
refined by the inclusion of percent crop treated values and processing
data.  The full dietary analysis for the subject peitions can be found
in the HED memorandum Acetamiprid: Acute and Chronic Dietary Exposure
Assessments, 10/12/07, D335205.

The current acute and chronic dietary exposure assessments include
existing uses and the tolerances proposed by Nisso America Incorporated
(representing Nippon Soda Company Limited), and IR-4 associated with PP#
4F6833, 6F7051, and 6E7163.  The recommended tolerances incorporated
into the dietary analysis are shown above in Table 12.  These crops are
supported by adequate field trial data.

For the acute dietary assessment, field trial residues were refined when
possible.  If field trial residues were reported below the limit of
quantification (LOQ), HED assumed ½ LOQ (i.e., 0.005 ppm).  In certain
cases where it was appropriate, HED translated field trial data from one
commodity to another (e.g., peaches to nectarines, or plum to apricots).
 Percent crop treated estimates, which exist for only several of the
subject crops (apples, broccoli, celery, lettuce, pears, grapefruit,
grapes, oranges, peppers, spinach, and tomatoes), were incorporated into
the acute dietary assessment as a refinement.  Average percent crop
treated values for apples and oranges were applied to the chronic
dietary assessment, and maximum percent crop treated values were applied
to the acute dietary assessment.   Processing data is applied to the
dietary analysis in order to further characterize the effect (reduction
or concentration) on pesticide residues on a commodity as a result of
various processing or preparation procedures (such as washing, juicing,
trimming, etc).  Processing factors based on submitted studies were
incorporated into the acute dietary analyses for the following
commodities: apple juice, orange juice, grape juice, raisins, dried
prunes, tomato paste, and tomato puree.  For all other commodities
included in the acute assessment, the DEEM™ Version 7.87 default
processing factors were used.  Those default factors were used for all
processed commodities in the chronic assessment except for dried prunes.
 Finally, tolerance level residues were also used for livestock
commodities.

As mentioned above, under Section 5.1.3, HED incorporated EDWCs directly
into the DEEM™ FCID model for “water, direct, all sources” and
“water, indirect, all sources.”  For the acute assessment, an EDWC
of 20.1 ppb was entered into the model, and for the chronic assessment,
the value of 4.9 ppb was used.

5.2.2	Exposure and Risk Characterization

The dietary analyses reflect all currently registered and proposed
acetamiprid uses and indicate that both the acute and chronic dietary
exposure do not present a risk concern for HED for the general U.S.
population or any of population subgroup.

The most highly exposed population subgroup for both acute and chronic
dietary exposure durations is children 1-2 years old.  Children 1-2
years old are exposed to approximately 35% of  both the aPAD and the
cPAD.  The general population is exposed to approximately 18% of the
aPAD and 9% of the cPAD.  Dietary exposure and risk estimates are
summarized below in Table 13.

Table 13.  Summary of Dietary (Food + Water) Exposure and Risk for
Acetamiprid

Population Subgroup	Acute Dietary

(99.9th Percentile)	Chronic Dietary

	Dietary Exposure (mg/kg/day)	% aPAD	Dietary Exposure (mg/kg/day)	% cPAD

General U.S. Population	0.018258	18	0.006186	8.7

All Infants (< 1 year old)	0.026198	26	0.014224	20

Children 1-2 years old	0.034993	35	0.024647	35

Children 3-5 years old	0.024443	24	0.016879	24

Children 6-12 years old	0.016024	16	0.008748	12

Youth 13-19 years old	0.011152	11	0.004819	6.8

Adults 20-49 years old	0.011895	12	0.004189	5.9

Adults 50+ years old	0.009593	9.6	0.004486	6.3

Females 13-49 years old	0.009539	9.5	0.004414	6.2

5.2.3	Cancer Dietary Risk

HED has classified acetamiprid as “not likely to be carcinogenic to
humans.”  Based upon this classification, HED has determined there is
no cancer risk associated with the proposed uses. 

6.0		Residential (Non-Occupational) Exposure/Risk Pathway

Residential Handler Exposure

Product F4688 50WSP, which was assessed at the time PP# 4F6833 was
originally submitted for review, is currently registered for use in
commercial and residential settings (EPA stamped approved 5/2007).  The
registration approval was based upon a draft occupational/residential
risk assessment.  The draft assessment indicated that, based on the then
proposed uses of F4688 50WSP, residential handler (and residential
post-application) exposures were negligible.  Intended uses of F4688
50WSP included subterranean structure components during construction,
subterranean, and hard-to-reach structure components associated with
post construction and outdoor perimeter uses.  In addition, the label
specified that application was permitted by licensed individuals only
(also known as Pest Control Operators – PCO’s), not homeowners.  The
draft assessment also indicated that the occupational exposures were not
of risk concern to HED. 

Even though this product is now registered, HED has included it in this
assessment in order to formalize its risk conclusions.  HED continues to
believe that no residential exposures result from its use, and
therefore, it does not present any residential risks concerns for HED.

HED previously conducted a residential assessment on acetamiprid
products, such as the “Bait Gel” products for ant and cockroach
control, used in a residential setting (2/17/2005; DP 304214).  In this
previous assessment, HED determined that the Bait products could result
in potential handler exposure.  Since completion of the previous
assessment, HED has selected a new toxicological endpoint (10 mg/kg/day
from the DNT study).  Based upon the updated toxicological endpoint, the
recalculated residential handler risks from the bait products remain
below HED’s level of concern (for both short-, and intermediate-term
durations).  A summary of updated residential handler risks from the
acetamiprid bait products is presented below in Table 14. 

As discussed in its previous assessment cited above, HED believes that
potential post-application exposures from the “bait” products are
negligible for the following reasons.  First, HED does not anticipate
homeowners are likely to revisit the crack crevice or spot where the Gel
Bait has been applied, thereby minimalizing potential dermal or
incidental oral exposure.  Secondly, inhalation exposure is expected to
be minimal due to acetamiprid’s low vapor pressure, and gel
formulation which further reduces the potential of acetamiprid to become
airborne.  Finally, gel bait products contain a bittering agent,
(Bitrex®), which is used to prevent ingestion by children and animals,
further reducing potential incidental ingestion.  Based on these
reasons, HED determined that a quantitative post-application exposure
assessment was not required.  

Table 14.

Short- and Intermediate-term Dermal Handler (Mixer/Loader/Applicator)
Exposure and Risk for Acetamiprid Bait and Gel Products

Product	Weight Fraction (ai)a        	Dermal Daily Doseb                
Absorbed Dermal Daily 

Dosec  (mg/kg/day)	MOE d                

Acetamiprid (F5025) 15%  products

(EPA Reg. Nos.: 8033-28;8033-29; 8033-30; and 8033-31)	0.0015	0.0283
0.00283	3500

Acetamiprid (F5025) 35% products

(EPA Reg. Nos.: 8033-32; and 8033-35	0.0035	0.0659	0.00659	1500

a. Weight Fraction (ai) - Fraction of active ingredient on product
(0.0015 or 0.0035) 

b. Daily Dermal Dose (DDD) = [ weight fraction (0.15% ai or 0.35%  ai) 
x  formulation density (1.0 g/cm3)  x conversion factor (1.0  x 103
mg/g) x  gel thickness (2.0 x 10-3 cm)  x skin surface area (565 cm2)] /
BW (60 kg)

c. Absorbed Daily Dermal Dose (mg/kg/day) = DDD x DA (0.10)

d. MOE= NOAEL (10 mg/kg/day) / Absorbed Daily Dermal Dose (mg/kg/day)

6.1		Spray Drift

Spray drift is a potential source of exposure for residents living in
close proximity to spraying operations.  This situation is particularly
the case with aerial application.  However, to a lesser extent, spray
drift resulting from the ground application of acetamiprid could also be
a potential source of exposure.  The Agency has been working with the
Spray Drift Task Force (a membership of US pesticide registrants), EPA
Regional Offices, State lead Agencies for pesticide regulation, and
other parties to develop the best spray drift management practices.  The
Agency is now requiring interim mitigation measures for aerial
applications that must be placed on product labels/labeling.  The Agency
has completed its evaluation of the new database submitted by the Spray
Drift Task Force, and is developing a policy on how to appropriately
apply the data and the AgDRIFT computer model to its risk assessments
for pesticides applied by air, orchard airblast, and ground hydraulic
methods.  After the policy is in place, the Agency may impose further
refinements in spray drift management practices to reduce off-target
drift and risks associated with pesticide application. 

7.0	Aggregate Risk Assessment and Risk Characterizations

Consistent with FQPA, HED considers aggregate risk to a pesticide from
the three major routes (dermal, oral, and inhalation) when potential
residential exposures exist.  In its acetamiprid aggregate assessment,
HED combined dietary (food + water) and non-dietary (residential
handler) exposure sources to obtain an estimated aggregate exposure. 
When aggregating exposures and risks from various sources, HED considers
both the route and duration of exposure.  Based upon the residential use
pattern of acetamiprid products, HED has determined that acute,
short-term, intermediate-term and chronic aggregate risk assessments are
appropriate.  

7.1	Acute Aggregate Risk

The acute aggregate risk is equal to the acute dietary exposure via food
and drinking water, and therefore is identical to the exposure and risk
characterization found in Section 5.2.2.  The acute aggregate risks for
acetamiprid are less than 100% of the aPAD for all population subgroups
and, therefore, do not pose a risk concern for HED.

7.2		Short-Term and Intermediate-Term Aggregate Risk

Short-term aggregate risk is based on the chronic (average) dietary
exposure (food + water) combined with short-term residential exposure. 
Intermediate-term aggregate risk is based on the chronic (average)
dietary exposure combined with intermediate-term residential exposure.

As noted above, HED does not believe that the uses of F4688 50WSP result
in either handler or post-application residential exposures.  However,
other currently registered acetamiprid products, such as “bait”
products have residential (handler) exposures.  HED incorporated the
(high-end) residential handler exposure estimates from the “bait”
products into the short-term and intermediate-term aggregate assessment
(see Table 14, above).

Because the short-term and intermediate-term dermal exposures and
endpoints are the same, the short-term and intermediate term residential
risks are also the same.  Consequently, short-term and intermediate-term
aggregate risks are identical. 

cern to HED (MOE ≥ 100), and are summarized below in Table 15.



Table 15.   Acetamiprid Short- and  Intermediate–term Aggregate Risk
Calculations

Population Subgroup1	Dietary Exposure2

(mg/kg/day)	Dietary MOE3	Residential Dermal Exposure4	Residential Dermal
MOE5	Aggregate MOE6

Adults 20 – 49 years old	0.004189	2400	0.00659	1500	930

Adults 50+ years old	0.004486	2200	0.00659	1500	900

1. Population subgroup chosen was adults 20 – 49 yrs old and 50+ years
since these individuals would likely handle Bait products.

2. Dietary exposure = [food exposure + drinking water exposure] taken
from Table 13.  

3. Dietary MOE = short-term, and intermediate-term incidental oral NOAEL
(10 mg/kg/day) ( average dietary exposure (mg/kg/day) from DEEM

4.  Residential dermal exposure estimated for adults who handle Bait
products, Table 14. 

5.  Residential dermal MOE = short-, and intermediate-term NOAEL (10
mg/kg/day) ÷ residential dermal exposure (mg/kg/day).

6. Aggregate MOE : since short-, and intermediate term incidental oral
endpoint and short-,and intermediate dermal endpoints are the same, the
exposures from these two routes can be added. Therefore, aggregate MOE=
NOAEL [10 mg/kg/day]) ÷ dietary exposure + residential dermal exposure.

7.3	Chronic Aggregate Risk 

The dietary exposure pathway (food and drinking water) is the only
source of chronic exposure to acetamiprid (i.e., 180 consecutive days or
more).  Therefore, the chronic aggregate exposure and risk estimates are
equivalent to the chronic dietary exposure and risk estimates discussed
in Section 5.2.2 above.  The chronic aggregate risks for acetamiprid are
less than 100% of the cPAD for all population subgroups and, do not pose
a risk concern for HED.

8.0	Cumulative Risk Characterization/Assessment

FQPA (1996) stipulates that when determining the safety of a pesticide
chemical, EPA shall base its assessment of the risk posed by the
chemical on, among other things, available information concerning the
cumulative effects to human health that may result from dietary,
residential, or other non-occupational exposure to other substances that
have a common mechanism of toxicity.  The reason for consideration of
other substances is due to the possibility that low-level exposures to
multiple chemical substances that cause a common toxic effect by a
common mechanism could lead to the same adverse health effect as would a
higher level of exposure to any of the other substances individually.  A
person exposed to a pesticide at a level that is considered safe may in
fact experience harm if that person is also exposed to other substances
that cause a common toxic effect by a mechanism common with that of the
subject pesticide, even if the individual exposure levels to the other
substances are also considered safe.

Acetamiprid is a member of the neonicotinoid class of pesticides which
also includes thiamethoxam, clothianidin, imidacloprid and several other
active ingredients.  Structural similarities or common effects do not
constitute a common mechanism of toxicity.  Evidence is needed to
establish that the chemicals operate by the same, or essentially the
same sequence of major biochemical events (EPA, 2002).  Although the
neonicotinoids bind selectively to insect nicotinic acetylcholine
receptors (nAChR), the specific binding site(s)/receptor(s) are unknown
at this time.  Additionally, the commonality of the binding activity
itself is uncertain, as preliminary evidence suggests that clothianidin
operates by direct competitive inhibition, while thiamethoxam is a
non-competitive inhibitor.  Furthermore, even if future research shows
that neonicotinoids share a common binding activity to a specific site
on insect nicotinic acetylcholine receptors, there is not necessarily a
relationship between this pesticidal action and a mechanism of toxicity
in mammals.  Structural variations between the insect and mammalian
nAChRs produce quantitative differences in the binding affinity of the
neonicotinoids towards these receptors, which, in turn, confers the
notably greater selective toxicity of this class towards insects,
including aphids and leafhoppers, compared to mammals.  Additionally,
the most sensitive toxicological effect in mammals differs across the
neonicotinoids (e.g., testicular tubular atrophy with thiamethoxam;
mineralized particles in thyroid colloid with imidaclopid).  Thus, there
is currently no evidence to indicate that neonicotinoids share common
mechanisms of toxicity, and EPA is not following a cumulative risk
approach based on a common mechanism of toxicity for the neonicotinoids.
 In addition, acetamiprid does not appear to produce a toxic metabolite
produced by other substances.  Therefore, for the purposes of this
tolerance action, EPA has not assumed that acetamiprid has a common
mechanism of toxicity with other substances.  For information regarding
EPA’s efforts to determine which chemicals have a common mechanism of
toxicity and to evaluate the cumulative effects of such chemicals, see
the policy statements concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism released by EPA’s Office of Pesticide Programs on EPA’s
website at   HYPERLINK "http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

9.0	Occupational Exposure/Risk Pathway

9.1		Agricultural Handlers and Pesticide Control Operators

No chemical-specific data for assessing handler exposures were submitted
to the Agency in support of the proposed uses associated with the three
subject petitions.  Therefore, when estimating occupational exposures,
HED used surrogate data from the Pesticide Handlers Exposure Data Base
(PHED) v1.1, Outdoor Residential Exposure Task Force (ORETF) data, and
standard assessment variables established by the Health Effects Division
Science Advisory Council for Exposure (e.g. maximum application rates,
standard acres treated per day, 70 kg body weight for workers, and
standard protection factors assumed with specified personal protective
equipment).  The estimated exposures are believed to be reasonable
high-end estimates. 

Based on the anticipated application practices for the Assail® 70WP and
Assail® 30 SG products, and the currently registered F4688 50WSP
product label, as well as information provided by the registrant, HED
anticipates that handler exposures are of short- and intermediate-term
duration.  Table 16 below summarizes the proposed personal protective
equipment for each label and associated occupational exposure scenario
conducted for each label/formulation/use.

Table 16.  Summary of Exposure Scenarios Assessed and PPE as Stated on
the Proposed Labels

Exposure Scenario Assessed	Product/

Formulation	App. Methods Assessed	Use Sites	PPE Specified on Proposed
Label

Mixer/Loader	Wettable Powder 

Assail® 70 WP

	groundboom	Cucurbits, stone fruits, legumes, peas and beans, berry,
including strawberry and bulb vegetables	- long pants, long-sleeved
shirt, shoes plus socks;

- waterproof gloves.

- chemical resistant headgear for overhead exposures

- 12 hour Restricted Entry Interval (REI)

airblast

aerial

	soluble granule Assail®30 SG

	groundboom

air blast

aerial

Applicator	Formulation is not relevant to applicator exposure

Assail® 70 WP

Assail®30 SG	groundboom,

airblast,

aerial	Cucurbits, stone fruits, legumes, peas and beans, berry,
including strawberry and bulb vegetables

	Flagger	Formulation is not relevant to applicator exposure

Assail® 70 WP

Assail®30 SG	groundboom,

airblast,

aerial	Cucurbits, stone fruits, legumes, peas and beans, berry,
including strawberry and bulb vegetables

	Mixer/Loader/

Applicator	Liquid, and

Water Soluble

Packets,

F4688 50 WSP

Insecticide Termiticide

	low pressure hand wand;	Outdoor pests, ants, termite control	- long
pants, long-sleeved shirt, shoes plus socks;

- chemical resistant gloves (for mixing).

- after the product is diluted, or when using closed system, or in-line
system, handlers must wear shirt, pants, shoes plus socks, and water
proof gloves.

- respitory protection and protective eyewear when working in a
non-ventilated space or applying by rodding or sub-slab injection.

- No Restricted Entry Interval (REI) is specified

handgun sprayer;

injector;

foam application;

sprinkling can

hose-end sprayer

9.2		Handler and Pesticide Control Operator Risk Characterization

Since both dermal and inhalation endpoints for occupational exposures
were the same, the route specific exposure values were combined to
calculate a total exposure which was compared to the NOAEL (10 mg/kg/day
from the DNT) to determine the MOEs.  Estimated exposures for all
scenarios of the three product labels do not present a risk concern to
HED when the PPE stated on the proposed label is assumed.  That is,
exposures to agricultural handlers associated with the proposed uses on
Assail® 70WP, and Assail® 30SG are not a risk concern to HED provided
handlers obey the personal protection directions specified on the
proposed labels.  Likewise, exposures to PCO’s from the labeled uses
of F4688 50WSP are not a risk concern to HED provided PCO’s obey the
personal protection directions specified on the label.  An expanded
table of handler MOEs is attached as Appendix B.

9.3	Post-application Exposure and Risk

No chemical specific post-application data were submitted in support of
the subject petitions.  Therefore, exposures during post-application
agricultural activities were estimated using dermal transfer
coefficients from the Science Advisory Council for Exposure SOP Number
3.1., and standard assumptions with respect to dislodgeable residues. 
Both short-term, and intermediate-term post-application MOEs were
greater than 100 on day zero after application and, do not present a
risk concern to HED.  However, as per the Worker Protection Standard,
(WPS), a restricted entry interval (REI) of 12 hours is required based
on the acute toxicity of acetamiprid technical material which is
classified as Category III and IV for acute dermal, dermal irritation,
and eye irritation. Therefore, the 12-hour REI which appears on the
proposed labels Assail® 70WP, and Assail® 30SG is adequate.  A summary
of post-application MOEs is provided below in Table 17.

Table 17.  Post-application Risks for Acetamiprid

Crop	App. Rate	Contact Potential	Activity	Transfer 

Coefficient Value	MOE2  At Day Zero

Stone Fruits	0.15

 lb ai/A	low	Propping, scouting, irrigation, and hand harvesting	1,500
1500

high	Thinning	3,000	750

Cucurbit Vegetables	0.10

 lb ai/A	low	Scouting, thinning, irrigation and hand weeding	1,500	2,200

high	Leaf pulling, turning, thinning, hand harvesting and pruning	2,500
1,300

Bulb Vegetables	0.15

 lb ai/A	low	Irrigation, scouting, thinning, and hand weeding	300	7,700

high	Hand harvesting	2,500	910

Tree nuts	0.18

 lb ai/A	low	Scouting, thinning, and irrigation	500	3,700

high	Thinning, hand harvesting and pruning	2,500	740

Legumes	0.1 lb ai/a	low	Scouting, irrigation, hand weeding , and
thinning 	100	33,000

high	Hand harvest	2,500	1,300

Low Berry

low	Pruning, thinning, and scouting	400	8,300

high	Hand pruning and harvesting	1,500	2,200

High Berry

low	Hedging, irrigation, hand weeding	500	6,700

high	Hand harvest, pruning, training, tying	5,000	670

The information in the table is based on proprietary and non-proprietary
data.

1:  daily dose = [DFR (ug/cm2) x Tc (cm2/hr) x 0.001 mg/ug x dermal
absorption (0.1) x 8 hrs/day] ÷ body weight (60 kg)

2:  NOAEL/Daily Dose (Short- and Intermediate-term NOAEL = 10 mg/kg/day)



10.0	Data Needs, Deficiencies, and Label Recommendations

Directions for Use:

Current labels for use on berries, bulb vegetables, edible podded legume
vegetables, succulent shelled beans, and peas, or strawberries and other
low-growing berries should be amended to remove directions regarding the
use of surfactants.  The field trials submitted to support these crops
were not conducted with surfactants, and the labels should be amended to
be consistent with the field trial data.

Petition for Tolerances for “Combined” Residues:

The tolerance expression proposed by IR-4 with respect to strawberry,
bearberry, bilberry, blueberry (lowbush), cloudberry, cranberry,
lingonbery, muntries, and, partridgeberry should be revised to exclude
the word “combined.”  HED has determined that combined residues of
acetamiprid and its IM-2-1 metabolite are only valid with respect to
residues in livestock commodities.

Unconditional Registrations:

HED recommends unconditional registrations for the following proposed
uses:

Tree nuts,

Cucurbit vegetables,

Stone fruit,

Edible podded legume vegetables (crop subgroup 6A)

Succulent shelled peas and beans (crop subgroup 6B)

Bulb vegetables (crop subgroups 3A, and 3B)

Berries (crop subgroup 13B and 13G)

Tolerances:

HED recommends tolerances for acetamiprid be established as specified in
Appendix D, Table 1.

Appendix A.  References

Acetamiprid.  Acute and Chronic Dietary Exposure Assessments to Support
Section 3 Registration of Uses on Tree Nuts; Cucurbits; Stone Fruit;
Legumes (Subgroup 6A); Pea and bean (Subgroup 6B); Berry (Subgroups 13B
and 13G); and Bulb vegetables (Subgroups 3A and 3B).  October 12, 2007;
D335205.

Acetamprid:  Occupational/Residential Exposure and Risk Assessment for
Proposed Food Use on Stone Fruits, Cucurbit Vegetables, Tree Nuts,
Berries, Bulb Vegetables, Edible Podded Legumes and Succulent Shelled
Peas and Beans and Insecticide/Termiticide Uses.  October 23, 2007;
Z.Figueroa, M.Collantes; D345240.

Acetamiprid:  Occupational and Residential Exposure Assessment for
Proposed Section 3 Registration for General Pest Control Uses. 
02/17/05; D304214.

Acetamiprid.  Tolerance Petition Requesting Section 3 Registration for
Food Use of the Insecticide on Cucurbit Vegetables (Crop Group 9), Stone
Fruits (Crop Group 12), and Tree Nuts (Crop Group 14).  Summary of
Analytical Chemistry and Residue Data.  Petition Number 4F6833. 
11/5/2004; W.T.Drew; D303623.

Acetamiprid.  Petitions Requesting the Establishment of Permanent
Tolerances (Associated with Section 3 Registration) for New Food/Feed
Uses of the Insecticide on Berries (Crop Group 13), Bulb Vegetables
(Crop Group 3), Edible Podded Legume Vegetables (Crop Subgroup 6A),
Succulent Shelled Pea and Bean (Crop Subgroup 6B), and Strawberry and
Other Low-growing Berries.  Summary of Analytical Chemistry and Residue
Data.  Petition Numbers 6F7051 (Various Crops) and 6E7163 (Strawberry). 
10/23/2007; W.T.Drew;  D328216.

Tier I Drinking Water Exposure Assessment for Acetamiprid on Cucutbit,
Stone Fruit, and Tree Nut Crop Groups.  June 21, 2005;  G.Orrick;
D303582.

Acetamiprid New Uses (Bulb Vegetables, Succulent Legumes, Strawberries,
and Other Berries):  Transmittal of Tier I Drinking Water Exposure
Assessment.  July 24, 2007; D331596, and D336256.



Appendix B.  Occupational Exposure and Risk Table

Appendix B, Table 1   Occupational Handler Exposure and Risk for
Proposed Uses of Acetamiprid

Exposure Scenario	Crop	Mtigation Level	Dermal Unit Exposure (mg/lb a.i.)
Inhalation Unit Exposure (mg/lb a.i.)	Maximum

Application Rate

 (lb a.i./A)	Area Treated (A/Day)	Dermal Dose (mg/kg/day)	Inhalation
Dose (mg/kg/day)	Total Dose (mg/kg/day)	Total MOE

MIXER/LOADER

Groundboom

Wettable Powder	Curcurbits, berries, legumes	Baseline	3.7	.043	0.1	80
0.04933	0.005733	0.055	180

	Bulb vegetables

0.15

0.074	0.0086	0.0826	120

Groundboom 

Soluble Granule	Curcurbits, berries, legumes	Single layer & Gloves	0.066
0.00077	0.1

0.00088	0.0001	0.00098	10,000

	Bulb vegetables

0.15

0.00132	0.000154	0.00147	6,800

Airblast 

Wettable Powder	Stone fruit	Baseline	3.7	0.043	0.15	40	0.037	0.0043
0.0413	240

	Tree nuts

0.18

0.0444	0.00516	0.04956	200

Airblast 

Soluble Granule	Stone Fruit	Single layer & Gloves	0.066	0.00077	0.15

0.00066	0.000077	0.000737	14,000

	Tree nuts

0.18

0.000792	0.00000924	0.00084	11,000

Aerial

 Wettable Powder	Curcurbit, berry, legume	Single layer & Gloves	0.17
0.043	0.1	350	0.009917	0.025	0.035	290

	Stone fruit, bulb vegetables

0.15

0.0148	0.0376	0.0525	190

	Tree nut

0.18

0.01785	0.04515	0.063	160

Aerial

 Soluble Granule	Curcurbit, berry, legume

0.066	0.00077	0.1	350	0.00385	0.000449	0.004299	2,300

	Stone fruit, bulb vegetables

0.15

0.005775	0.000674	0.006445	1600

	Tree nut

0.18

0.00693	0.0008	0.007739	1,300

APPLICATOR

Groundboom	Curcurbit, berry, legume	Single layer & Gloves	0.014	0.00074
0.1	80	0.000187	0.000098	0.000285	35,000

	Bulb vegetables

0.15

0.00028	0.000148	0.000430	23,000

Airblast	Stonefruit	Baseline	0.36	0.0045	0.15	40	0.0036	0.00045	0.00405
2500

	Tree Nut

0.18

0.00432	0.00054	0.00486	2100

Aerial	Curcurbit, berry, legume	Engineering Controls	0.005	0.000068	0.1
350	0.00029	3.9E-5	0.00033	30,000

	Bulb Veg. Stone Fruit

0.15

0.00044	5.9E-5	0.000497	20,000

	Tree Nut

0.18

0.000525	7.1E-5	0.00059	17,000

Flagger	Curcurbit, berry, legume	Baseline	0.011	0.00035	0.1	350	0.000642
0.0002	0.000846	12,000

	Bulb Veg., Stone Fruit

0.15

0.00096	0.0003	0.00127	7900

	Tree Nut

0.18

0.001155	0.000368	0.001523	6600

MIXER/LOADER/APPLICATOR

Liquids for Low Pressure Handwand (ORETF data surrogate for WSP)	Outdoor
pest, ant, termite control	Baseline	15	0.0027	

0.0043

 (lb ai/gal)	40 gals/day	0.0043	0.0000077	0.0043	2300

Water Soluble Packets for Handgun Sprayer (LCO ORETF)	Outdoor pest, ant,
termite control

	Single Layer, Gloves

	0.64	0.0072

100 gals./day	0.00046	0.0000516	0.00051	20,000

Liquids w/ Injector	Termiticide

0.36	0.0022

1000 gal/day	0.00258	0.000158	0.00274	3700

MIXER/LOADER/APPLICATOR (continued)

Water Soluble Packets for Foam Application (using PHED data for low
pressure handwand)	Ant control, Termiticide	Single Layer, Gloves

	8.6	1.1	

0.0043

 (lb ai/gal)	40 gals/day	0.00247	0.0032	0.0056	1800

Liquids with a Paint Brush	Outdoor pest, ant control	Baseline	180	0.280

2 gals/day	0.00258	0.00004	0.00262	3800

Liquids with Sprinkling Can (ORETF hose-end data as surrogate for WSP)

	5	0.017

10 gals/day	0.00036	0.000012	0.000371	27,000

Liquids with Hose-end Sprayer (ORETF data as surrogate for WSP)

100 gals/day	0.00358	0.000122	0.0037	2700

1:  Dermal Dose  (mg/kg/day)  =   Rate (lb ai/A) x  UE (mg /lb ai )  x 
DA (0.1)  x  Acres Treated (A/day) or (gal/day) 

 BW (60 kg)			                      							

2:  Inhalation Dose (mg/kg/day)  =   Rate (lb ai/A) x UE (mg /lb ai ) x 
Acres Treated (A/day)  or (gal/day)	

											BW (60 kg)

5:  Total Dose (mg/kg/day) = Dermal Dose (mg/kg/day) + Inhalation Dose
(mg/kg/day)

6:  Total MOE =	NOAEL (10 mg/kg/day)/Total Dose (mg/kg/day)



Appendix C.  Acetamiprid Toxicology Assessment 

Toxicity Profile for Acetamiprid

Appendix C, Table 1.

Acute Toxicity of Technical Acetamiprid    

GDLN

	Study Type	MRID	Results	Tox Category

870.1100	Acute Oral - rat	 44651833	LD50: 217 mg/kg (M)

LD50: 146 mg/kg (F)	II

870.12	Acute Dermal - rat	44651836	LD50 > 2000 mg/kg	III

870.13	Acute Inhalation - rat	44651837	LC50: > 1.15 mg/L (~)

> 1.15 mg/L (~)	III

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

870.25	Primary Skin Irritation - rabbit	44651839	Not irritating to the
skin	IV

870	Dermal Sensitization - Guinea pig	44651840	Is not a sensitizer under
conditions of study.	N/A

Subchronic, Chronic and Other Toxicity Profile for Acetamiprid

Appendix C, Table 2.

Toxicity Profile of Technical Acetamiprid 

Guideline No./Study Type	Results

870.3100

13-Week feeding - rat 	NOAEL: 12.4/14.6 mg/kg/day (M/F)

LOAEL: 50.8/56.0 mg/kg/day (M/F: decreased BW, BW gain and food
consumption).

870.3100

13-Week feeding - mouse	NOAEL: 106.1/129.4 mg/kg/day (M/F)

LOAEL: 211.1/249.1 mg/kg/day (reduced BW and BW gain, decreased glucose
and cholesterol levels, reduced absolute organ weights).

870.3150

3-Month feeding - dog	NOAEL: 13/14 mg/kg/day (M/F)

LOAEL: 32 mg/kg/day (reduced BW gain in both sexes).

870.3200

21-Day dermal toxicity - rabbit	NOAEL: 1000 mg/kg/day (HDT)

LOAEL: >1000 mg/kg/day

870.3700

Developmental toxicity - rat	Maternal NOAEL: 16 mg/kg/day

Maternal LOAEL: 50 mg/kg/day (reduced BW & BW gain and food consumption,
increased liver weights).

Developmental NOAEL: 16 mg/kg/day

Developmental LOAEL: 50 mg/kg/day (increased incidence of shortening of
the 13th rib)

870.3700

Developmental toxicity - rabbit	Maternal NOAEL: 15 mg/kg/day

Maternal LOAEL: 30 mg/kg/day (BW loss and decreased food consumption).

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

Developmental LOAEL: > 30 mg/kg/day

870.3800

2-Generation reproduction - rat	Parental systemic NOAEL: 17.9/21.7
mg/kg/day (M/F)

Parental systemic LOAEL: 51.0/60.1 mg/kg/day (M/F) (decreased body
weight, body weight gain and food consumption).

Offspring systemic NOAEL: 17.9/21.7 mg/kg/day (M/F)

Offspring systemic LOAEL: 51.0/60.1 mg/kg/day (M/F: 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 mg/kg/day (M/F)

Reproductive LOAEL: 51.0/60.1 mg/kg/day (M/F: reductions in litter
weights and individual pup weights on day of delivery). 

870.4100

1-Year oral - dog	NOAEL: 20/21 mg/kg/day (M/F)

LOAEL: 55/61 mg/kg/day (M/F: initial BW loss and overall reduction in BW
gain).

870.4200

Carcinogenicity - mouse	NOAEL: 20.3/75.9 mg/kg/day (M/F)

LOAEL: 65.6/214.6 mg/kg/day (M/F: 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	NOAEL: 7.1/8.8 mg/kg/day (M/F)

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

Evidence of treatment-related increase in mammary tumors.

870.5100

Salmonella typhimurium/E. coli

Reverse gene mutation assay	Not mutagenic under the conditions of the
study.

870.5300

Mammalian cells in culture

Forward gene mutation assay - CHO cells	Not mutagenic under the
conditions of the study.

870.5375

In vitro mammalian chromosomal aberrations - CHO cells	Acetamiprid is a
clastogen under the conditions of the study.

870.5385

In vivo mammalian chromosome aberrations - rat bone marrow	Acetamiprid
did not induce a significant increase in chromosome aberrations in bone
marrow cells when compared to the vehicle control group.

970.5395

In vivo mammalian cytogenetics - micronucleus assay in mice	Acetamiprid
is not a clastogen in the mouse bone marrow micronucleus test.

870.5550

UDS assay in primary rat hepatocytes/mammalian cell culture	Acetamiprid
tested negatively for UDS in mammalian hepatocytes in vivo.

870.6200

Acute neurotoxicity - rat	NOAEL: 10 mg/kg

LOAEL: 30 mg/kg (reduction in locomotor activity).

870.6200

Subchronic neurotoxicity - rat	NOAEL: 14.8/16.3 mg/kg/day (M/F)

LOAEL: 59.7/67.6 mg/kg/day (M/F: reductions in BW, BW gain, food
consumption and food efficiency).

870.6300

Developmental neurotoxicity study - rat	Maternal NOAEL: 10 mg/kg/day

Maternal LOAEL: 45 mg/kg/day, (decreased body weight and body weight
gains during gestation only)

Developmental NOAEL: 10 mg/kg/day

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

N/A

28-Day feeding - dog	NOAEL: 16.7/19.1 mg/kg/day (M/F)

LOAEL: 28.0/35.8 mg/kg/day (reduced BW gain).

870.7485 

Metabolism - rat	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.

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 respiratory rate, heart rate and blood pressure; via gavage
in mice for effects on gastrointestinal motility; and via i.p. in rats
for effects on water and electrolyte balance in urine, and blood
coagulation, hemolytic potential and plasma cholinesterase activity.  
Based on a number of neuromuscular, behavioral and physiological effects
of acetamiprid in male mice, under the conditions of this study, a
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 absorption	Revised dermal absorption rate of 10% (from 30%) is
based upon the dermal absorption study with acetamiprid (MRID 44651858)
and consideration of dermal penetration values from other neonicitinoid
insecticides (thiamethoxam), and consideration of Kow and octanol/water
coefficient data of other neonicitinoid compounds (clothianidin).

Appendix D.  Tolerance Summary Table for Petitions  

Appendix D, Table 1.

Tolerance Summary for Acetamiprid  PP# 4F6833, PP#6F7051, and PP#6E7163

Commodity	Proposed Tolerance (ppm)	Recommended

„@

^„@

(

)

5

U

¹

º

	

 

+

5

6

8

9

q

hp

+

,

T



œ

¼

½

ë

 q

~

„

Š

‘

š

Ë

û

j¸

j;

j¬

j/

j

ô

@

h

h‡m

h

h

h

h˜

  h˜

h˜

h˜

yt

yt

yt

yt

h˜

h˜

h˜

h˜

yt

yt

yt

yt

yt

yt

yt

yt

yt

h˜

h‰

kd

\

\

\

h˜

䀀Ȧ摧䮾H

摧䮾H

h˜

摧䮾H

ô

¼

 



 

 

!

<

=

I

K

N

O

U

^

_

z

{

‘

š

Û

ñ

ü

þ

{





 

怀

#

$

=

J

K

 

O

z

{

Ȇ

摧䮾H

摧䮾H

h˜

h˜

h˜

h˜

h˜

h˜

摧䮾H

@

@

@

@

@

h›

h˜

h˜

h˜

h˜

h˜

h˜

h˜

@

@

@

@

@

@

@

摧䮾H

hY

 hæ	

h›

h˜

”ÿâ

”ÿâ

”ÿâ

 h

hý

 h

hý

hŠK

ÿ

h L

hŠK

hŠK

hŠK

hŠK

à

	@

	@

Ff

š

š

š

š

@

ô

ô

꜆

꜆

꜆

§

§

§

§

§

§

§

§

§

§

§

§

§

§

§

§

§

§

§

s	--	4.5

	Elegans hosta	--	4.5

	Fritillaria, leaves	--	4.5

	Kurrat	--	4.5

	Lady’s leek	--	4.5

	Leek	--	4.5

	Leek, wild	--	4.5

	Onion, Beltsville bunching	--	4.5

	Onion, fresh	--	4.5

	Onion, macrostem	--	4.5

	Onion, tree, tops	--	4.5

	Onion, Welsh, tops	--	4.5

	Shallot, fresh leaves	--	4.5

	Stone Fruit group, except prune plum	1.2	1.20	Fruit, stone, group 12
(except plum, prune)

Fresh prune plum	0.30	0.20	Proposed tolerance was too high.

Plum, prune, fresh

Dried prune plum	0.30	0.40	Proposed tolerance was too low.

Plum, prune, dried

Tree nut group	0.10	0.10	Nut, tree, group 14

Pistachio	None proposed	0.10	Although tree nut field trial data may be
used to support use on pistachio, a separate tolerance is needed for
pistachio.

Pistachio

Cucurbit vegetable group	0.50	0.50	Vegetable, cucurbit, group 9

* Refer to HED Memorandum dated 6/14/2006 by Bernard Schneider for
pending changes to crop groups, and commodity definitions.  

Page   PAGE  3  of   NUMPAGES  51