Document ID: EPA-HQ-OPP-2009-0289-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-02-12T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF PREVENTION, PESTICIDES

									AND TOXIC SUBSTANCES

Dec 1, 2009

MEMORANDUM

SUBJECT:	Acetamiprid: Human Health Risk Assessment for Proposed Food
Uses on Clover Grown for Seed, Small Vine Climbing Fruits, except
Kiwifruit, Subgroup 13-07F, Greenhouse Grown Tomatoes and Tea. 

PC Code:  099050	DP Barcode:  D369474

Decision No.:  408298	Registration Nos.:  8033-23,  8033-36, 8033-94

Petition No.:  9E7544	Regulatory Action:  Amended Section 3

Risk Assessment Type:  Single Chemical Aggregate	Case No.:  N/A

TXR No.:  N/A	CAS No.:  135410-20-7

MRID Nos.:  N/A	40 CFR:  §180.578

FROM:	Dennis McNeilly, Chemist

		Suku Oonnithan, Biologist

		Edward J. Scollon, Ph.D., Toxicologist

Registration Action Branch 2

Health Effects Division (7509P)

THROUGH:	Mike Doherty, Ph.D, Senior Chemist

	Alan Levy, Ph.D., Senior Toxicologist

	Shih-Chi Wang, Biologist

		and

	Christina Swartz, Branch Chief

	Richard Loranger, Ph.D., Senior Scientist

Registration Action Branch 2

Health Effects Division (7509P)

TO:			Laura Nollen, Risk Manager Reviewer

			Barbara Madden, Team Leader (RM Team 5)

			RIMUERB/Registration Division (RD) (7505P)



Table of Contents

  TOC \f \h    HYPERLINK \l "_Toc247427928"  1.0  Executive Summary	 
PAGEREF _Toc247427928 \h  4  

  HYPERLINK \l "_Toc247427929"  1.1  Summary of Recommendations	 
PAGEREF _Toc247427929 \h  7  

  HYPERLINK \l "_Toc247427930"  1.2  Summary of Proposed Uses	  PAGEREF
_Toc247427930 \h  8  

  HYPERLINK \l "_Toc247427931"  2.0  Ingredient Profile	  PAGEREF
_Toc247427931 \h  11  

  HYPERLINK \l "_Toc247427932"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc247427932 \h  12  

  HYPERLINK \l "_Toc247427933"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc247427933 \h  12  

  HYPERLINK \l "_Toc247427934"  3.1.1	Database Summary	  PAGEREF
_Toc247427934 \h  12  

  HYPERLINK \l "_Toc247427935"  3.1.1.1	Studies available and considered
(animal, human, general literature)	  PAGEREF _Toc247427935 \h  12  

  HYPERLINK \l "_Toc247427936"  3.1.1.2	Mode of action	  PAGEREF
_Toc247427936 \h  12  

  HYPERLINK \l "_Toc247427937"  3.1.1.3	Sufficiency of studies/data	 
PAGEREF _Toc247427937 \h  13  

  HYPERLINK \l "_Toc247427938"  3.1.2	Toxicological Effects	  PAGEREF
_Toc247427938 \h  13  

  HYPERLINK \l "_Toc247427939"  3.1.3	Dose-response	  PAGEREF
_Toc247427939 \h  15  

  HYPERLINK \l "_Toc247427940"  3.1.4	FQPA	  PAGEREF _Toc247427940 \h 
15  

  HYPERLINK \l "_Toc247427941"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc247427941 \h  16  

  HYPERLINK \l "_Toc247427942"  3.3	FQPA Considerations	  PAGEREF
_Toc247427942 \h  16  

  HYPERLINK \l "_Toc247427943"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc247427943 \h  16  

  HYPERLINK \l "_Toc247427944"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc247427944 \h  16  

  HYPERLINK \l "_Toc247427945"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc247427945 \h  17  

  HYPERLINK \l "_Toc247427946"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc247427946 \h  17  

  HYPERLINK \l "_Toc247427947"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc247427947 \h  17  

  HYPERLINK \l "_Toc247427948"  3.3.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc247427948 \h  17  

  HYPERLINK \l "_Toc247427949"  3.3.6.1	Determination of Susceptibility	
 PAGEREF _Toc247427949 \h  17  

  HYPERLINK \l "_Toc247427950"  3.3.6.2	Degree of Concern Analysis and
Residual Uncertainties for Pre- and/or Postnatal Susceptibility	 
PAGEREF _Toc247427950 \h  17  

  HYPERLINK \l "_Toc247427951"  3.3.7	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc247427951 \h  18  

  HYPERLINK \l "_Toc247427952"  3.4	Safety Factor for Infants and
Children	  PAGEREF _Toc247427952 \h  18  

  HYPERLINK \l "_Toc247427953"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc247427953 \h  19  

  HYPERLINK \l "_Toc247427954"  3.5.1	Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc247427954 \h  19  

  HYPERLINK \l "_Toc247427955"  3.5.2	Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc247427955 \h  19  

  HYPERLINK \l "_Toc247427956"  3.5.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc247427956 \h  19  

  HYPERLINK \l "_Toc247427957"  3.5.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc247427957 \h  20  

  HYPERLINK \l "_Toc247427958"  3.5.5	Dermal Absorption	  PAGEREF
_Toc247427958 \h  20  

  HYPERLINK \l "_Toc247427959"  3.5.6	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc247427959 \h  21  

  HYPERLINK \l "_Toc247427960"  3.5.7	Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc247427960 \h  22  

  HYPERLINK \l "_Toc247427961"  3.5.8	Level of Concern for Margin of
Exposure	  PAGEREF _Toc247427961 \h  23  

  HYPERLINK \l "_Toc247427962"  3.5.9	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc247427962 \h  24  

  HYPERLINK \l "_Toc247427963"  3.5.10	Classification of Carcinogenic
Potential	  PAGEREF _Toc247427963 \h  24  

  HYPERLINK \l "_Toc247427964"  3.5.11	Summary of Toxicological Doses
and Endpoints for Use in Human Risk Assessments	  PAGEREF _Toc247427964
\h  25  

  HYPERLINK \l "_Toc247427965"  3.6	Endocrine disruption	  PAGEREF
_Toc247427965 \h  27  

  HYPERLINK \l "_Toc247427966"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc247427966 \h  27  

  HYPERLINK \l "_Toc247427967"  4.1	Other Pesticide Epidemiology
Published Literature	  PAGEREF _Toc247427967 \h  27  

  HYPERLINK \l "_Toc247427968"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc247427968 \h  27  

  HYPERLINK \l "_Toc247427969"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc247427969 \h  27  

  HYPERLINK \l "_Toc247427970"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc247427970 \h  27  

  HYPERLINK \l "_Toc247427971"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc247427971 \h  27  

  HYPERLINK \l "_Toc247427972"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc247427972 \h  28  

  HYPERLINK \l "_Toc247427973"  5.1.4	Analytical Methodology	  PAGEREF
_Toc247427973 \h  28  

  HYPERLINK \l "_Toc247427974"  5.1.5	Environmental Degradation	 
PAGEREF _Toc247427974 \h  29  

  HYPERLINK \l "_Toc247427975"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc247427975 \h  29  

  HYPERLINK \l "_Toc247427976"  5.1.7	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc247427976 \h  30  

  HYPERLINK \l "_Toc247427977"  5.1.8	Drinking Water Residue Profile	 
PAGEREF _Toc247427977 \h  30  

  HYPERLINK \l "_Toc247427978"  5.1.9 	Food Residue Profile	  PAGEREF
_Toc247427978 \h  31  

  HYPERLINK \l "_Toc247427979"  5.1.10	International Residue Limits	 
PAGEREF _Toc247427979 \h  37  

  HYPERLINK \l "_Toc247427980"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc247427980 \h  40  

  HYPERLINK \l "_Toc247427981"  6.1	Residential Handler Exposure	 
PAGEREF _Toc247427981 \h  41  

  HYPERLINK \l "_Toc247427982"  6.2.	Residential Postapplication
Exposure	  PAGEREF _Toc247427982 \h  41  

  HYPERLINK \l "_Toc247427983"  6.3	Other (Spray Drift, etc.)	  PAGEREF
_Toc247427983 \h  43  

  HYPERLINK \l "_Toc247427984"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc247427984 \h  43  

  HYPERLINK \l "_Toc247427985"  7.1	Acute Term Aggregate Risk	  PAGEREF
_Toc247427985 \h  43  

  HYPERLINK \l "_Toc247427986"  7.2	Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc247427986 \h  43  

  HYPERLINK \l "_Toc247427987"  7.3	Chronic-Term Aggregate Risk	 
PAGEREF _Toc247427987 \h  44  

  HYPERLINK \l "_Toc247427988"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc247427988 \h  45  

  HYPERLINK \l "_Toc247427989"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc247427989 \h  46  

  HYPERLINK \l "_Toc247427990"  9.1	Short-/Intermediate-/Long-Term
Handler Risk	  PAGEREF _Toc247427990 \h  46  

  HYPERLINK \l "_Toc247427991"  9.2	Handler and Pesticide Control
Operator Risk Characterization	  PAGEREF _Toc247427991 \h  46  

  HYPERLINK \l "_Toc247427992"  9.3	Postapplication Exposure and Risk	 
PAGEREF _Toc247427992 \h  46  

  HYPERLINK \l "_Toc247427993"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc247427993 \h  47  

  HYPERLINK \l "_Toc247427994"  References:	  PAGEREF _Toc247427994 \h 
48  

  HYPERLINK \l "_Toc247427995"  Appendix A:	Occupational Exposure and
Risk Tables	  PAGEREF _Toc247427995 \h  50  

  HYPERLINK \l "_Toc247427996"  Appendix B:	Toxicology Assessment	 
PAGEREF _Toc247427996 \h  57  

  HYPERLINK \l "_Toc247427997"  Appendix C:	Tolerance Summary	  PAGEREF
_Toc247427997 \h  62  

  HYPERLINK \l "_Toc247427998"  Appendix D:	International Residue Limit
Status	  PAGEREF _Toc247427998 \h  63  

 1.0	Executive Summary  TC \l1 "1.0  Executive Summary 

Acetamiprid {N 1-[(6-chloro-3-pyridyl)methyl]-N 2-cyano-N
1-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, bait, and water soluble packet formulations are registered
for residential uses.  The Interregional Research Project Number 4
(IR-4) has submitted amended Section 3 registration requests for new
uses of acetamiprid on clover grown for seed, small vine climbing
fruits, except kiwifruit, subgroup 13-07F (amending the established
grape use), greenhouse-grown tomatoes, and tea.   Tea was not included
in the original petition, but was added in a June 10, 2009 letter from
IR-4 stating that the tolerance was submitted to support both tea grown
in South Carolina and tea imported into the U.S.

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 sensitizer.  The toxicological database for acetamiprid is not
complete.  As part of the new 40 CFR Part 158 guidelines, an
immunotoxicity study in rats and/or mice is required.  However, a
database uncertainty factor is not needed because acetamiprid does not
show any evidence of treatment-related effects on the immune system. The
overall weight of evidence suggests that this chemical does not directly
target the immune system and the Agency does not believe that conducting
a functional immunotoxicity study will result in a lower point of
departure (POD) than that currently used for overall risk assessment. 
Based on subchronic, chronic, developmental and reproductive studies in
rats, rabbits, and dogs, acetamiprid does not appear to have specific
target organ toxicity.  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; and,
(iii) 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 all routes of exposure.  For the chronic dietary
assessment, HED has chosen the NOAEL (7.1 mg/kg/day) from the chronic
toxicity/ carcinogenicity study (LOAEL = 17.5 mg/kg/day).

HED has used the refined dermal penetration value of 10%.  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 an acceptable method validation has been submitted. 
Acceptable residue data have been submitted to support the proposed uses
as well as the tolerances recommended in Appendix C.  The submitted
clover field trial data are not completely adequate to satisfy data
requirements.  The three clover field trials were all conducted in Zone
11 (OR) at the same location and within a very short time period of each
other.  As a condition of registration, HED recommends that two
additional clover field trials be required, as confirmatory data.  In
addition, the submitted reside data included field trial data for only
the 70WP formulation.  However, additional residue chemistry field trial
data are not required to support registration of the 30SG formulation. 
Since the residue chemistry data submitted for clover hay reflect PHIs
of between 56-63 days, the PHI for clover should be increased to 56 days
for any crop which will be harvested for hay.

The submitted grape residue data included field trial data for only the
70WP formulation (original field trials also used only a 70WP
formulation).  Although HED’s residue chemistry review (D364833,
10/14/09) recommended that as a condition of registration, three
side-by-side field trials be conducted and submitted to determine if
residues are comparable for the two different formulations, additional
information provided by the registrant has convinced HED such data are
not necessary.  In addition, the submitted grape field trials were not
conducted using an adjuvant.  The label for Assail® 30SG (EPA Reg. No.
8033-36) should be revised to remove the use of a spreader, methylated
seed oil or crop oil from the product label.  Furthermore, in line with
present OPP policy for a late season foliar use, a statement should be
added to both the 30SG and 70WP labels prohibiting addition of adjuvants
for application to grapes.  If use of an adjuvant is desired then one
should be used in side-by-side testing.

Although the greenhouse trials were conducted at a 2x rate and the
number of trials is marginal, no additional residue data will be
required to support the proposed greenhouse use pattern for tomatoes. 
The tomato greenhouse data indicate that acetamiprid residues resulting
from applications of Assail 70WP formulation of acetamiprid according to
the proposed use pattern would not exceed the established tolerance for
residues of acetamiprid in fruiting vegetables, Crop Group 8 (0.20 ppm).
 Although no data were provided for the proposed use of Tristar® 30SG
on greenhouse tomatoes, HED now concludes the WP data support use of
this additional formulation.

The submitted magnitude of the residue data for tea reflect application
of a 20% SP formulation of acetamiprid to green tea grown in Japan at
0.13 lb ai/A (0.15 kg ai/ha) and 0.27 lb ai/A (0.30 kg ai/ha) and to
black tea grown in India at 0.022 lb ai/A (0.025 kg ai/ha) and 0.045 lb
ai/A (0.050 kg ai/ha).  Acceptable methods were used for determination
residues of acetamiprid and metabolites determined as acetamiprid.  No
U.S. residue field trial data were submitted and proposed domestic use
directions were not provided.  At least one U.S. residue field trial
study is required to establish a domestic registration for use of
acetamiprid on tea.

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.  Acute and
chronic dietary risk estimates for all population subgroups do 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 constitutes 41% of the acute population
adjusted dose (aPAD), and the chronic exposure constitutes 12% of the
chronic population adjusted dose (cPAD).

Aggregate risk assessments for acute, short-term, and chronic durations
were conducted.  Residential exposures incorporated into the aggregate
assessments are based on currently registered residential uses (indoor
crack and crevice, and outdoor perimeter treatment).  All aggregate
assessments indicate no risks of concern (aggregate MOEs ≥ 290).

Occupational handler (mixer/loaders, applicators, and flaggers)
assessments were conducted for the proposed agricultural uses of
acetamiprid.  HED’s assessment indicates that exposures to
occupational handlers are not a risk concern, provided they wear
baseline personal protective equipment (PPE) consisting of long-sleeved
shirt, long pants, and shoes with socks plus gloves (MOEs > 280).    HED
identified no post-application risk concerns (MOEs > 330) 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.

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)   TC \l1 "1.1 
Summary of Recommendations 

Directions for Use:

No proposed use was submitted for the use on tea in South Carolina.  HED
cannot evaluate the domestic use without a proposed use, application
methods, and a proposed formulation.  Good Agricultural Practice (GAP)
information was provided for Japan and India.  The use directions are
adequate to establish a tolerance without U.S. registrations (an
“import” tolerance).

Because the grape field trial data submitted with this petition did not
reflect the use of a surfactant in the application sprays, the label
directions regarding use of a spreader, methylated seed oil or crop oil
should be removed from the product label of Assail® 30SG (EPA Reg. No.
8033-36).  Furthermore, in line with present OPP policy for a late
season foliar use, a statement should be added to both the 30SG and 70WP
labels prohibiting addition of adjuvants for application to grapes.  If
use of an adjuvant is desired then one should be used in side-by-side
testing.

The PHI for clover harvested for hay should be increased to 56 days on
the 30SG and 70WP labels.

Tolerances:

a)  HED recommends tolerances for acetamiprid be established as
specified in Appendix C.

b)  Additionally, the tolerance expression in section (a)(1) should be
revised to read as follows:

		Tolerances are established for residues of the insecticide acetamiprid
[N 1-[(6-chloro-3-pyridyl)methyl]-N 2-cyano-N 1-methylacetamidine],
including its metabolites and degradates, in or on the commodities in
the table below as a result of the application of acetamiprid. 
Compliance with the tolerance levels specified below is to be determined
by measuring only acetamiprid [N 1-[(6-chloro-3-pyridyl)methyl]-N
2-cyano-N 1-methylacetamidine] in or on the following commodities.

c)  The tolerance expression in section (a)(2) should be revised to read
as follows:

Tolerances are established for residues of the insecticide acetamiprid
[N 1-[(6-chloro-3-pyridyl)methyl]-N 2-cyano-N 1-methylacetamidine],
including its metabolites and degradates, in or on the commodities in
the table below as a result of the application of acetamiprid. 
Compliance with the tolerance levels specified below is to be determined
by measuring acetamiprid [N 1-[(6-chloro-3-pyridyl)methyl]-N 2-cyano-N
1-methylacetamidine] and N 1-[(6-chloro-3-pyridyl)methyl]-N
2-cyano-acetamidine in or on the following commodities.

d)  The final tolerances for subgroup 13-07F should reflect the correct
commodity definition as specified in Appendix C.  A revised Section F is
not needed for this minor change.  The established individual tolerance
for grape at 0.20 ppm should be concomitantly removed with establishment
of the subgroup 13-07F tolerance.

Conditional Data:

Two clover field trials reflecting the same use pattern utilized in the
submitted studies.

  SEQ CHAPTER \h \r 1 Submittal of Analytical Reference Standards:

Analytical standards for the IM-2-1 and IM-2-1-amide metabolites are not
available at the Repository and should be supplied.  The reference
standards should be sent to the Analytical Chemistry Lab, which is
located at Fort Meade, to the attention of Theresa Cole at the following
address:

	USEPA

	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

	701 Mapes Road

	Fort George G. Meade, MD  20755-5350

(Note that the mail will be returned if the extended zip code is not
used.)

1.2	Summary of Proposed Uses  TC \l1 "1.2  Summary of Proposed Uses 

A list of acetamiprid end-use products (EPs) relevant to this
registration action is presented below in Table 1.2.1.  All listed EPs
are registered to Nippon Soda Co., Ltd. (c/o Nisso America, Inc.).

Table 1.2.1.    List of Acetamiprid End-Use Products Associated with
PP#9E7544.

Trade Name	Reg. No.	ai (% of formulation)	Formulation Type	Label Date

Assail® 30SG Insecticide	8033-36	30% by wt	Soluble granule	3/4/2009
(draft)

Assail® 70WP Insecticide	8033-23	70% by wt	Wettable powder	3/4/2009
(draft)

Tristar® 30SG Insecticide	8033-94	30% by wt	Soluble granule	3/4/2009
(draft)

A summary of the proposed or amended use patterns is presented in Table
1.2.2.  For clover, new use is proposed for Assail® 30SG and Assail®
70WP.  For grapes, a change to the registered use pattern is proposed. 
The current labels permit up to two foliar applications on grapes at
0.05 lb ai/A/application for a maximum seasonal rate of 0.1 lb ai/A with
a 7-day preharvest interval (PHI).  The requested new use on grapes (and
small vine climbing fruits, except kiwifruit, subgroup 13-07F) will
permit up to two applications of Assail® 30SG or Assail® 70WP at 0.1
lb ai/A/application for a seasonal rate of 0.2 lb ai/A with a 3-day PHI.
 For tomatoes, new use is proposed for greenhouse-grown tomatoes.  The
current Assail® 30SG and Assail® 70WP labels permit up to four foliar
applications on field-grown tomatoes at 0.075 lb ai/A/application for a
maximum seasonal rate of 0.3 lb ai/A with a 7-day PHI.  The requested
new use on tomatoes adds a greenhouse use pattern using Tristar® 30SG,
with a maximum of two applications (reduced from four for resistance
management) at 0.075 lb ai/A/application (based on 10,000 plants per
acre) for a maximum seasonal rate of 0.15 lb ai/A, applied via
chemigation with a 1-day PHI.  

No use directions were proposed for the domestic use of acetamiprid on
tea grown in South Carolina.  The following GAP information was provided
for the 20% SP formulation in Japan:  one application at 0.10-0.40 kg
ai/ha applied in 2000-4000 L/ha, with a 14-day PHI. GAP information was
also provided for India:  one application at 0.022 lb ai/A (0.025 kg
ai/ha) or 0.045 lb ai/A (0.050 kg ai/ha), shoots along with bud are
typically harvested at a 7-day PHI.

There were no rotational crop restrictions listed on any of the
acetamiprid draft labels.

Table 1.2.2.   Summary of Directions for Use of Acetamiprid.

Applic. Timing, Type, and Equip.	Trade Name

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season 1	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Clover 2

Post emergence

Broadcast foliar

  spray

Ground/aerial	Assail®

30SG;

[8033-36]

Assail® 70WP

[8033-23]	0.047-0.075	1 	0.075	28	Proposed use is limited to clover
grown in ID, OR, and WA only.  Begin applications when treatment
thresholds have been reached.  Apply in minimum spray volumes of 5 GPA
by air or 20 GPA by ground.

Grapes and Other Climbing Vine Small Fruits (Except Fuzzy Kiwifruit)
(Within Crop Subgroup 13-07F):  Amur River Grape; Gooseberry; Hardy
Kiwifruit; Maypop; Schisandra Berry; and Cultivars, Varieties, and/or
Hybrids

Post emergence

Broadcast foliar

  spray

Ground/aerial	Assail®

30SG;

[8033-36]

Assail® 70WP

[8033-23]	0.047-0.1	2	0.2	3	Begin applications when treatment thresholds
have been reached.  Do not apply more than once every 14 days.  Apply in
minimum spray volumes of 5 GPA by air or 20 GPA by ground.  Assail®
30SG states that the addition of a spreader, methylated seed oil or crop
oil will enhance pest control.3 

Greenhouse-Grown Tomatoes

Post emergence

Drip or micro

  Irrigation	Tristar®

30SG

[8033-94]	0.075 lb ai/A of crop (based on 10,000 plants/A)	2	0.15	1	For
use in greenhouse-grown tomato production.  May be applied by injection
into drip irrigation or micro-irrigation (spaghetti tube or emitter)
systems, soil drenching, or by hand-held or motorized calibrated
irrigation equipment directed to the plant roots. Application should be
made only to mature tomato plants grown in non-soil media such as rock
wool, vermiculite, perlite, or other soil-less media.  Some cultivars
may exhibit sensitivity and therefore treatment of a few plants is
recommended prior to treating an entire greenhouse.  Begin applications
when treatment thresholds have been reached.  

1   The number of treatments allowed per season when the EP is applied
at the maximum single application rate.

2   Section G of the petition specifies that the EP is proposed for use
on red clover grown for seed.  The draft label

    does not specify that use is for clover grown for seed.

3  HED recommends that this be removed from the label until side-by-side
residue data are submitted. Furthermore,

    in line with present OPP policy for a late season foliar use, a
statement should be added to both the 30SG and

    70WP labels prohibiting addition of adjuvants for application to
grapes.  If use of an adjuvant is desired then one

    should be used in side-by-side testing.

Conclusions.  The submitted labels are adequate to allow evaluation of
the residue data relative to the proposed use, except for the use on tea
in South Carolina for which directions were not proposed.  The available
field trial data reflect the proposed use patterns for all of the
submitted field trials except those submitted for grapes and clover hay.
 Because the grape field trial data submitted with this petition did not
reflect the use of a surfactant in the application sprays, the label
directions regarding use of a spreader, methylated seed oil or crop oil
should be removed from the product label of Assail® 30SG (EPA Reg. No.
8033-36).  Furthermore, in line with present OPP policy for a late
season foliar use, a statement should be added to both the 30SG and 70WP
labels prohibiting addition of adjuvants for application to grapes.  If
use of an adjuvant is desired then one should be used in side-by-side
testing.  The PHI for clover harvested for hay should be increased to 56
days on the 30SG and 70 WP labels.

2.0	Ingredient Profile  TC \l1 "2.0  Ingredient Profile 

Acetamiprid is an insecticide in 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.a and 2.b.

Table 2.a.  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 2.b.  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  TC \l1 "3.0	Hazard
Characterization/Assessment 

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization 

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

3.1.1.1	 Studies available and considered (animal, human, general
literature)  TC \l4 "3.1.1.1	Studies available and considered (animal,
human, general literature) 

The toxicity data base contains: 1) subchronic oral toxicity studies in
rats, mice, and dogs; 2) a chronic oral toxicity study in dogs and
carcinogenicity studies in rats and mice; 3) developmental and
reproduction studies in rats and a developmental study in rabbits; 4)
acute, subchronic, and developmental neurotoxicity studies in rats; and,
5) subchronic dermal toxicity and dermal penetration studies in rats. 
There is also a complete mutagenicity battery, as well as metabolism
studies in the rat.

3.1.1.2	 Mode of action  TC \l4 "3.1.1.2	Mode of action 

Acetamiprid 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. Acetamiprid acts as an agonist of the nicotinic
acetylcholine receptor, affecting the synapses in the insect central
nervous system.  

3.1.1.3	 Sufficiency of studies/data  TC \l4 "3.1.1.3	Sufficiency of
studies/data 

The toxicological database for acetamiprid is not complete.  As part of
the new 40 CFR Part 158 guidelines, an immunotoxicity study in rats
and/or mice is required.  However, acetamiprid does not show any
evidence of treatment-related effects on the immune system. The overall
weight of evidence suggests that this chemical does not directly target
the immune system and the Agency does not believe that conducting a
functional immunotoxicity study will result in a lower point of
departure (POD) than that currently used for overall risk assessment. 
Therefore, a database uncertainty factor (UFDB) is not needed to account
for lack of this study.  The scientific quality of the available studies
is relatively high and the toxicity profile of acetamiprid can be
characterized for most effects, including potential carcinogenicity,
mutagenicity, developmental toxicity and neurotoxicity.

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects 

The acute toxicity data indicate that acetamiprid is moderately toxic
via the oral route of exposure (Toxicity Category II) and is minimally
toxic via the dermal and inhalation routes of exposure (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.  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 and 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 3.5.3 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 2-generation reproduction study, qualitative evidence of
increased susceptibility of rat pups was observed.  The parental and
offspring systemic LOAELs were 51.0/60.1 (M/F) 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 were 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 LOAEL was 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.  This was observed in
the presence of decreased maternal body weight and body weight gains
during gestation.  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 of data from the two time points centered 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 at the high-dose level of 45
mg/kg/day.  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).  

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.

3.1.3	Dose-response  TC \l3 "3.1.3	Dose-response 

Since HED’s last hazard assessment of acetamiprid in 2007, endpoints
have been selected to account for occupational long-term oral, dermal,
and inhalation exposures.  For acute dietary exposure, the DNT and acute
neurotoxicity studies were co-critical for determining the acute
reference dose (aRfD) of 0.1 mg/kg/day for all populations.  These
studies share a NOAEL of 10 mg/kg/day.  In the DNT, the maternal LOAEL
(45 mg/kg/day) is based on decreased body weight and body weight gain
during gestation and the offspring LOAEL (45 mg/kg/day) is 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 LOAEL in the acute
neurotoxicity study, 30 mg/kg, is based on reduction in locomotor
activity in males. For the chronic dietary exposure, the
chronic/oncogenicity study was used to calculate the chronic reference
dose (cRfD) of 0.071 mg/kg/day for all populations.  The NOAEL, 7.1
mg/kg/day, is based on reduced body weight and body weight gains for
females and hepatocellular vacuolation for males.  The LOAEL is 17.5
mg/kg/day.  

For the incidental-oral (short- and intermediate-term), as well as
short- and intermediate-term dermal and inhalation exposures, the DNT
was used.  For long-term inhalation and dermal exposures, the
chronic/carcinogenicity study in rats was used for endpoint selection.

3.1.4	FQPA  TC \l3 "3.1.4	FQPA 

See Section 3.3.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "3.2
Absorption, Distribution, Metabolism, Excretion (ADME) 

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

Acetamiprid is rapidly absorbed and eliminated.  Metabolite studies
indicate 96-99% absorption following an oral administration.  Peak blood
concentrations in the rat occur within 1-2 hours, with nearly complete
clearance from the blood by 48 hours.  Acetamiprid distributes widely in
the body but tissue burdens rarely exceed 1% of the administered dose. 
Acetamiprid is extensively metabolized with metabolites accounting for
79-86%of the administered radioactivity.  6-Chloronicotinic acid is the
most abundant metabolite, accounting for 24-28% of the dose in
single-dose studies and 8-10% in repeated-dose studies.  Urinary
excretion was the major route of elimination, accounting for 79-97% of
the administered dose within 24 hours in single oral dose groups.  Fecal
excretion accounted for 21-35% of the administered radioactivity, with
males being slightly higher.  Excretion rates for the IV and repeated
dose studies were similar.

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

A dermal absorption factor of 10% is proposed for risk assessment.  The
factor is based on an acetamiprid dermal absorption study in rats, a
dermal absorption study in monkeys, and a comparison of structurally
similar neonicotinoid pesticides.  

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

3.3.1	Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the
Toxicity Database 

Acceptable guideline studies for developmental and reproductive toxicity
are available for FQPA assessment, including an acceptable DNT study. 
However, an immunotoxicity study is required as a part of new data
requirements in the 40 CFR Part 158 for conventional pesticide
registration.  Therefore, the lack of an immunotoxicity study is
considered to be a data gap.  (Note:  An immunotoxicity study was
previously requested in D352925, W. Drew, 11/25/2008.)

3.3.2	Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity

Acetamiprid produced signs of neurotoxicity in the high dose groups in
the acute and developmental neurotoxicity studies in rats.  In the acute
neurotoxicity study, male and female rats displayed decreased motor
activity, tremors, walking and posture abnormalities, dilated pupils,
coldness to the touch, and decreased grip strength and foot splay. 
There was a decrease in the auditory startle response in male rats in
the DNT.  Tremors in the high dose female mice in the subchronic feeding
study were the only other potentially neurotoxic effects observed in the
other studies.

3.3.3	Developmental Toxicity Studies  TC \l3 "3.3.3	Developmental
Toxicity Studies 

In the gavage developmental studies, fetal effects were observed at the
doses associated with maternal effects.  In the rat developmental study,
fetal shortening of the 13th rib and reduced maternal body weight and
body weight gain were observed at the same LOAEL.  No developmental
effects were observed in the rabbit at doses that reduced maternal body
weight and food consumption.  In the DNT, parental and offspring
systemic LOAELs were the same, 51.0/60.1 (M/F) mg/kg/day.  Offspring and
parental LOAELs were based on decreased auditory startle response in
male pups and decreased body weight and body weight gain during
gestation, respectively.

3.3.4	Reproductive Toxicity Study  TC \l3 "3.3.4	Reproductive Toxicity
Study 

In the 2-generation reproduction study, the LOAEL for the parental and
offspring systemic effects, 17.9/21.7 (M/F) mg/kg/day, were based on a
decrease in mean body weight, body weight gain, and food consumption in
the parents, and reductions in pup weights, litter size, viability, and
weanling indices, as well as age to attain vaginal opening and preputial
separation in the offspring.

3.3.5	Additional Information from Literature Sources  TC \l3 "3.3.5
Additional Information from Literature Sources 

A literature search did not reveal information that would impact the
risk assessment.

3.3.6	Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal
Toxicity 

3.3.6.1	Determination of Susceptibility  TC \l4 "3.3.6.1	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 2-generation reproduction study, qualitative
evidence of increased susceptibility of rat pups was observed.  While
parental and offspring NOAELs and LOAELs are set at the same doses (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.  

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility  TC \l4 "3.3.6.2	Degree of Concern
Analysis and Residual Uncertainties for Pre- and/or Postnatal
Susceptibility  

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 effects and
regulatory doses were selected to be protective of these 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.

3.3.7	Recommendation for a Developmental Neurotoxicity Study  TC \l3
"3.3.7	Recommendation for a Developmental Neurotoxicity Study 

A developmental neurotoxicity study has been requested, received, and
reviewed by the Agency (see Section 3.3.2).

FQPA Safety Factor for Infants and Children  TC \l2 "3.4	Safety Factor
for Infants and Children 

HED recommends the FQPA SF be reduced to 1X for the following reasons: 
(1) HED is regulating based upon the effects of concern, i.e.,
developmental effects in pups following pre-and/or post-natal exposure;
(2) 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, (3) 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.

The lack of an immunotoxicity study is considered a data gap.  However,
because there was no indication in any of the submitted toxicity studies
that there was an effect on the immune system, a 10x safety factor for a
data gap is not required at this time.  (Note:  An immunotoxicity study
was requested in:  D352925, W. Drew; Nov 25, 2008.)



3.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection 

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49  TC \l3 "3.5.1
Acute Reference Dose (aRfD) - Females age 13-49 

A separate aRFD is not being used for females age 13-49.  Females in
this age group will be assessed using the aRFD for the general
population (see 3.5.2). 

3.5.2	Acute Reference Dose (aRfD) - General Population  TC \l3 "3.5.2
Acute Reference Dose (aRfD) - General Population 

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

             Acute Neurotoxicity Study in Rats (MRID 44651842)

Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on
offspring decreased body weights and body weight gains, 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.  The DNT and acute neurotoxicity studies are considered
co-critical due to similar LOAELs and signs of toxicity.

 

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).

3.5.3	Chronic Reference Dose (cRfD)  TC \l3 "3.5.3	Chronic Reference
Dose (cRfD) 

Studies Selected:  Chronic/Carcinogenicity Study in the Rat

MRID Nos.: 44988429, 45245304

Dose and Endpoint for Risk Assessment: NOAEL = 7.1 mg/kg/day based on
decreased body weights and body weight gains in females and
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 effects
and potential qualitative sensitivity of offspring.  The standard
uncertainty factors were applied to all dietary exposure scenarios (10x
for intraspecies variability and 10x for interspecies extrapolation).

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)   TC \l3
"3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

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

Study Selected:  Developmental Neurotoxicity Study in Rats (MRID
46255619)

Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on
offspring decreased body weights and body weight gains, 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.

Comments about Study/Endpoint/Uncertainty Factors:  The NOAEL and LOAEL
from the DNT study were selected for the short- and intermediate-term
dermal risk assessment because they are protective of developmental
effects present in rat pups observed in the presence of less severe
maternal effects at similar doses.  The standard uncertainty factors
(100x) were applied (10x for intraspecies variability and 10x for
interspecies extrapolation).

3.5.5	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 

In the previous risk assessment (D303171; Tom Moriarty; 25 October
2007), 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 neonicotinoid 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 neonicotinoid, 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
neonicotinoid 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 3.5.5. below).

Table 3.5.5.  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.

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)  TC \l3
"3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term) 

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

Study Selected:  Developmental Neurotoxicity Study in Rats

MRID No.: 46255619

Dose and Endpoint for Risk Assessment:  NOAEL = 10 mg/kg/day based on
decreased body weights and body weight gains in males and 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 the short- and intermediate-term
dermal risk assessment because they are protective of developmental
effects present in rat pups observed in the presence of less severe
maternal effects at similar doses.

Although a dermal (route specific) toxicity study in rabbits was
submitted, no effects were seen at the highest dose tested of 1000
mg/kg/day.  Use of the route-specific study for dermal risk assessment
would not be protective of the offspring effects observed in both the
DNT and the 2-generation 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.  Since the dermal endpoint is based on an
oral study, a 10% dermal absorption factor is used to determine dermal
exposure and risk. The standard uncertainty factors were applied to all
exposure scenarios (10x for intraspecies variability and 10x for
interspecies extrapolation).

Long-Term Dermal Exposure (> 6 months)

Study Selected:  Chronic/Carcinogenicity Study in Rats

MRID No.: 44988429, 45245304

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

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

Although a dermal (route specific) toxicity study in rabbits was
submitted, no effects were seen at the highest dose tested of 1000
mg/kg/day.  Use of the route-specific study for dermal risk assessment
would not be protective of the offspring effects observed in both the
DNT and the 2-generation 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.  Since the dermal endpoint is based on an oral study, a 10%
dermal absorption factor (DAF) is used to determine dermal exposure and
risk. The standard uncertainty factors were applied to all exposure
scenarios (10x for intraspecies variability and 10x for interspecies
extrapolation).

3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)  TC \l3
"3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term) 

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

Study Selected:  Developmental Neurotoxicity Study in Rats

MRID No.: 46255619

Dose and Endpoint for Risk Assessment:  NOAEL = 10 mg/kg/day based on
decreased body weights and body weight gains in males and 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.

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 (IAF, 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 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).

Long-Term Inhalation Exposures (> 6 months)

Study Selected:  Chronic/Carcinogenicity Study in Rats

MRID No.: 44988429, 45245304

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

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 IAF (100%), are used to estimate inhalation
exposure and the associated risk.  In this case, the NOAEL and LOAEL
from the chronic/carcinogenic study were selected because the duration
is appropriate for long-term exposures and it is protective of potential
effects in offspring observed in the DNT and 2-generation study in rats.
 The standard uncertainty factors were applied to all exposure scenarios
(10x for intraspecies variability and 10x for interspecies
extrapolation).

3.5.8	Level of Concern for Margin of Exposure  TC \l3 "3.5.8	Level of
Concern for Margin of Exposure 

Table 3.5.8.  Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	100

Inhalation	100	100	100

Residential Exposure

Dermal	100	100	100

Inhalation	100	100	100

Incidental Oral	100	100	100

3.5.9	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.9	Recommendation for Aggregate Exposure Risk Assessments 

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 for short- and intermediate-term
exposure scenarios.  Therefore, the short- and intermediate dermal,
oral, and inhalation exposure can be combined and aggregated with the
dietary (food + water) exposures.

3.5.10	Classification of Carcinogenic Potential  TC \l3 "3.5.10
Classification of Carcinogenic Potential 

HED has determined that acetamiprid is “not likely to be carcinogenic
to humans.”  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.3.5.11	Summary of Toxicological Doses
and Endpoints for Use in Human Risk Assessments  TC \l3 "3.5.11	Summary
of Toxicological Doses and Endpoints for Use in Human Risk Assessments 

Table 3.5.11a.   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 (All populations)

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

UFH = 10x

FQPA SF = 1x

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

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

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 vacuolation in males.

Short- and Intermediate-Term Incidental Oral 

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

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

UFH = 10x

FQPA SF = 1x

	LOC for MOE = 100

	Developmental Neurotoxicity in rat

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

Short- and Intermediate-term Dermal

(1-30 days, 1–6 mo.)

	NOAEL = 10 mg/kg/day

DAF = 10%	UFA = 10x

UFH = 10x

FQPA SF = 1x

	LOC for MOE = 100

	Developmental Neurotoxicity in rat

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

Short- and Intermediate-term Inhalation

(1-30 days, 1–6 mo.)

	NOAEL = 10 mg/kg/day

IAF = 100%	UFA = 10x

UFH = 10x

FQPA SF = 1x

	LOC for MOE = 100

	Developmental Neurotoxicity in rat

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

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

DAF = dermal absorption factor.  Point of Departure (POD) = A data point
or an estimated point that is derived from observed dose-response data
and  used to mark the beginning of extrapolation to determine risk
associated with lower environmentally relevant human exposures.  NOAEL =
no observed adverse effect level.  LOAEL = lowest observed adverse
effect level.  UF = uncertainty factor.  UFA = extrapolation from animal
to human (interspecies).  UFH = potential variation in sensitivity among
members of the human population (intraspecies).  FQPA SF = FQPA Safety
Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD =
reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A
= not applicable.



Table 3.5.11b.  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 NOAEL= 

10 mg/kg/day

dermal absorption rate = 10%	UFA = 10x

UFH = 10x

	LOC for MOE = 100

	Developmental Neurotoxicity in rat

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

Long-term Dermal

(> 6 mo.)

	NOAEL = 7.1 mg/kg/day	UFA = 10x

UFH = 10x

FQPA SF = 1x

dermal absorption rate = 10%	LOC for MOE = 100

	Chronic Toxicity/Oncogenicity Study in rats

LOAEL = 17.5 mg/kg/day based on decreased body weight and body weight
gains in females and hepatocellular vacuolation in males.

Short- and Intermediate-term 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 

	Developmental Neurotoxicity in rat

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

Long-term Inhalation

(1-30 days, 1 – 6 mo.)

	NOAEL = 7.1 mg/kg/day

inhalation absorption rate = 100%	UFA = 10x

UFH = 10x

FQPA SF = 1x	LOC for MOE = 100

	Chronic Toxicity/Oncogenicity Study in rats

LOAEL = 17.5 mg/kg/day based on decreased body weight and body weight
gains in females and hepatocellular vacuolation in males.

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

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

3.6	Endocrine disruption  TC \l2 "3.6	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 the recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there were
scientific bases for including, as part of the program, 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.  When the appropriate
screening and/or testing protocols being considered under the Agency’s
Endocrine Disrupter Screening Program (EDSP) have been developed and
vetted, acetamiprid may be subjected to additional screening and/or
testing to better characterize effects related to endocrine disruption.

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Public
Health and Pesticide Epidemiology Data 

No public health data were considered at this time.

4.1	Other Pesticide Epidemiology Published Literature  TC \l2 "4.1	Other
Pesticide Epidemiology Published Literature 

A literature search did not reveal information that would impact the
risk assessment.

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1
Pesticide Metabolism and Environmental Degradation 

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops 

Residue Chemistry Memo D  SEQ CHAPTER \h \r 1 264154, 12/31/2001, M.
Doherty (PP#0F6082)

MARC Decision Memo, D278652, 11/13/2001, M. Doherty

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.

5.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2	Metabolism in
Rotational Crops 

Residue Chemistry Memo   SEQ CHAPTER \h \r 1 D328216, 10/23/2007, W.
Drew (PP#6F7051 and PP#6E7163)

Residue Chemistry Memo D  SEQ CHAPTER \h \r 1 264154, 12/31/2001, M.
Doherty (PP#0F6082)

  SEQ CHAPTER \h \r 1 No new confined rotational crop data were
submitted with this petition; the nature of the residue in rotational
crops is understood.  A confined rotational crop study was reviewed in
conjunction with PP#0F6082.  In the study, acetamiprid was not detected
in any rotational crop matrix (mustard greens, radish, and grain crops)
at any of the plantback intervals (PBIs), which were 30-, 58-, 120- and
365 days after treatment (DAT) following application to bare soil at
0.66 lb ai/A.  The major metabolite identified in rotational crops was
IM-1-4, at 2.94-56.65% TRR (<0.001-0.040 ppm).  Two other metabolites
were identified in most rotational crops:  IM-0-Glc, at 1.11-15.23% TRR
(<0.001-0.010 ppm), and IC-0, at 2.75-24.19% TRR (<0.001-0.014 ppm). 
Storage stability data, required as a condition of registration in the
original petition PP#0F6082, have been submitted and determined to
rectify deficiencies under PP#6F7051.

HED has determined that the residue of concern in rotational crops for
enforcement purposes is the parent only, and that tolerances would not
be needed on rotational crops.  The available rotational crop data are
adequate to support the uses proposed in this petition.

5.1.3	Metabolism in Livestock  TC \l3 "5.1.3	Metabolism in Livestock 

Residue Chemistry Memo D  SEQ CHAPTER \h \r 1 264154, 12/31/2001, M.
Doherty (PP#0F6082)

MARC Decision Memo, D278652, 11/13/2001, M. Doherty

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, 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.

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology 

Residue Chemistry Memo   SEQ CHAPTER \h \r 1 D342549, 11/05/2008, W.
Drew

Residue Chemistry Memo   SEQ CHAPTER \h \r 1 D328216, 10/23/2007, W.
Drew (PP#6F7051 and PP#6E7163)

Residue Chemistry Memo D303623, 11/05/2004, W. Drew (PP#4F6833)

Residue Chemistry Memo D  SEQ CHAPTER \h \r 1 264154, 12/31/2001, M.
Doherty (PP#0F6082)

Adequate gas chromatography with electron capture detection (GC/ECD) and
high performance liquid chromatography with ultraviolet detection
(HPLC/UV) residue analytical methods are available for the enforcement
of established tolerances on plant commodities.  The method limits of
quantitation (LOQ) are 0.01 ppm for vegetables and non-citrus fruits
(GC/ECD), and 0.050 ppm for citrus fruits (HPLC/UV).  A secondary liquid
chromatography with tandem mass spectrometric detection (LC/MS/MS)
method, designated by the petitioner as an alternative to the
established GC/ECD tolerance enforcement method, has been determined
suitable for tolerance enforcement, and confirmatory analysis of
vegetables and non-citrus fruits.  The GC/ECD method or LC/MS/MS Method
#KP-216R1 (or its modification) was used for the analysis of samples
from the clover, grape, and tomato field trials.  Acceptable recoveries
were obtained in method validation efforts conducted prior to the
analysis of field trial samples.

Samples of dried green tea leaves and brewed tea from the Japan study
were analyzed for residues of acetamiprid and its metabolites
convertible to 6-chloronicotinic acid (Metabolite IC-0) using a common
moiety gas chromatography method with electron capture detection
(GC/ECD).  Using this method, acetamiprid and metabolites are converted
to Metabolite IC-0 and methylated prior to determination by GC/ECD;
residues are expressed as acetamiprid.  The reported method limit of
detection (LOD) is 0.05 ppm as acetamiprid.  Samples of green shoots,
dried black tea leaves, brewed tea, and spent leaves from the India
study were analyzed for residues of acetamiprid using a high performance
liquid chromatography method with ultraviolet detection (HPLC/UV)
similar to the HPLC/UV method discussed above.

Regarding the common moiety method used in the Japan study, it was noted
that, although Metabolite IC-0 is not a residue of concern for tolerance
enforcement or risk assessment, based on the available plant metabolism
studies, it may constitute a significant portion of the total residues
(e.g., up to 24% total radioactive residues (TRR) in cotton seed and 31%
TRR in carrot flesh; refer to D278652, 11/13/01, H. Bietlot and M.
Doherty).  Therefore, the residues reported for the Japan study may
reflect an overestimation of expected residues of acetamiprid per se in
green tea.

Adequate multiresidue methods testing data have been submitted.  These
data indicate that the multiresidue methods are not appropriate for
determining residues of acetamiprid.

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation 

Acetamiprid is a mobile, rapidly biodegradable compound in most soils.
The primary degradation pathway is aerobic soil metabolism. Acetamiprid
is stable to hydrolysis at environmental temperatures, and photo
degrades relatively slowly in water. Acetamiprid is metabolized
moderately rapidly in aerobic aquatic systems, but is only slowly
metabolized in anaerobic aquatic systems. Acetamiprid is expected to be
moderately to highly mobile in most soils and aquatic sediments;
however, based on guideline study data, it is not expected to be
persistent in the environment. In environmental fate studies, residues
of acetamiprid, IB-1-1, IC-O, IM-1-2, IM-1-3, IM-1-4, and IM-1-5 were
identified.

5.1.6	Comparative Metabolic Profile TC \l3 "5.1.6	Comparative Metabolic
Profile 

Radiolabeled metabolism studies are available for carrot, cabbage,
cotton, apple, eggplant, lactating goat, laying hen, and rat. In plants,
there appears to be little translocation of acetamiprid following foliar
application. In cabbage, there was uptake and translocation of
acetamiprid to the above-ground portions of the plant following a soil
application. Due to the rapid dissipation of acetamiprid in the field,
root uptake is not considered to be a likely source of residues in
plants.  Parent acetamiprid is the predominant residue (>90% TRR) in
three of the five metabolism studies.  Confined rotational crop studies
showed no residues of acetamiprid at the 30-day plant-back interval.

Acetamiprid and metabolite IM-2-1 are the major residues in all ruminant
tissues except muscle, where IM-2-1-amide accounts for nearly 50% of the
TRR.  IM-2-1-amide was not found in any other ruminant tissue. 
Metabolite IM-2-1 is the major residue in poultry tissues and eggs
(50-80% TRR).  IM-2-5 is also a major residue in eggs (~20% TRR). 
Parent acetamiprid was not detected in poultry tissues or eggs.  The
metabolism of acetamiprid in lactating goat was similar to the profile
observed in laying hen and rat.  The initial transformation appears to
be demethylation of the parent compound. The most abundant metabolite
identified (both sexes) resulted from the removal of the cyanoacetamide
group from demethylated parent. This removal (and direct removal of the
group from the parent) resulted in cyanoacetamide metabolites.

5.1.7	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.7
Pesticide Metabolites and Degradates of Concern 

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 5.1.2 summarizes the residues of concern
(parent and metabolites) that will be considered for regulation.

Table 5.1.7  Summary of Metabolites and Degradates to be included in the
Risk

                                             Assessment and Tolerance
Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	Acetamiprid	Acetamiprid

	Rotational Crop	Not applicable	None at this time

Livestock

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

	Poultry	Acetamiprid and IM-2-1	Acetamiprid and IM-2-1

Drinking Water

	Acetamiprid	Not Applicable

5.1.8	Drinking Water Residue Profile TC \l3 "5.1.8	Drinking Water
Residue Profile 

D364248, D. Lieu 6/10/09.  Tier I Drinking Water Assessment for
Acetamiprid Proposed Uses on Red Clover (Grown for Seed Only), Grape,
and Tomato (Greenhouse).

In a memo dated 6/10/09 [D364248, D. Lieu], EFED notified RD that new
drinking water estimates would not be provided for the proposed use on
red clover (grown for seed only), grape, and tomato (greenhouse) because
the drinking water estimates derived from the uses on citrus and tree
nuts reflect the maximum use patterns for acetamiprid.  (Note: No
proposed use information has been submitted for U.S.-grown tea.)

In conjunction with the uses on citrus and tree nuts, the Environmental
Fate and Effects Division (EFED) prepared an estimate of potential
residues in drinking water [G. Orrick, Tier I Drinking Water Exposure
Assessment for Acetamiprid on Cucurbit, Stone Fruit and Tree Nut Crop
Groups, 6/21/05, D303582].  Estimated drinking water concentrations for
acetamiprid in surface water were generated using the FIRST (FQPA Index
Reservoir Screening Tool, v. 1.0) model.  The results of the model
reflect potential residues in a small drinking water reservoir
surrounded by a runoff-prone watershed, assuming maximum pesticide
application rates and no buffer between the reservoir and treated
fields.  Acetamiprid residues in ground water sources of drinking water
were estimated using the screening regression model SCI-GROW (Screening
Concentration In Ground Water, v. 2.3).  The SCI-GROW residue estimate
is based on environmental fate properties of the pesticide, maximum
application rates, and existing data from small-scale prospective
ground-water monitoring studies in vulnerable sites.

For surface water, the maximum application rate for the existing use of
acetamiprid on citrus was used to provide model estimates of drinking
water concentrations; for ground water, the proposed use on tree nut
crops was used.  However, since modeled surface water residues were
considerably higher than ground water residues (Table 5.1.8), only the
surface water residues were used quantitatively in the dietary (food +
water) assessment.

Table 5.1.8.  Tier I Analysis

1-in-10-year EDWCs in surface water and ground water for acetamiprid.

Drinking Water Source	Maximum Use Pattern	Exposure	EDWC

Surface water	Citrus fruit	Peak	20.1       ppb

Annual average	  4.9       ppb

Ground water	Tree nut	Peak & annual average	  0.0016 ppb

For the acute assessment, an estimated drinking water concentration of
20.1 ppb was entered into the DEEM™-FCID model for “water, direct,
all sources” and “water, indirect, all sources.”  For the chronic
assessment, the value of 4.9 ppb was used.  The ground water estimate of
1.6 ppt was much lower than surface water residues; therefore, dietary
exposure and risk calculated using surface water residues are considered
protective of potential exposure through ground water.

5.1.9	Food Residue Profile  TC \l3 "5.1.9 	Food Residue Profile 

D364833, Acetamiprid.  Request for Label Amendments for New Uses on
Clover; Small Vine Climbing Fruits, except Kiwifruit, Subgroup 13-07F
(amending grape use); Greenhouse-grown Tomatoes; and a Regional
Registration for Tea.  Summary of Analytical Chemistry and Residue Data.
D. McNeilly, 10/14/2009.

IR-4 has submitted magnitude of the residue data for acetamiprid on red
clover, grapes, and tomato to support the new uses on clover and
greenhouse tomatoes, and amended use on grapes (also expanded to small
vine climbing fruits, except fuzzy kiwifruit, subgroup 13-07F).  A
summary of the residue data is presented in Table 5.1.9a.  Residue data
for tea, dried leaves; black brewed tea, green brewed tea, and spent
leaves (for mass balance purposes only) are summarized in Table 5.1.9b.

Table 5.1.9a.   Summary of Residue Data from Tea Crop Field Trials with
Acetamiprid.

Crop Matrix	Total Applic. Rate

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

	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

Clover  (Proposed use = One broadcast foliar spray treatment at a
maximum of 0.075 lb ai/A; 28-day PHI)

Clover forage	0.074-0.079	28-34	6	<0.01	0.05	0.05	0.05	0.04	0.02

Clover hay

56-63	6	<0.01	<0.01	<0.01	0.01	0.01	--

Grapes and Other Climbing Vine Small Fruits (Except Fuzzy Kiwifruit)
(Within Crop Subgroup 13-07F)

(Current registered use on Grapes = 0.1 lb ai/A total application rate;
7-day PHI)

(Proposed amended use = 0.2 lb ai/A total application rate; 3-day PHI)

Grape	0.195-0.206	2-3	36	0.01	0.25	0.25	0.08	0.11	0.07

Tomatoes  (Current registered field use = 0.3 lb ai/A total application
rate; 7-day PHI)

                (Proposed greenhouse use = 0.15 lb ai/A total
application rate; 1-day PHI)

Tomato	0.300-0.324	1	6	<0.01	0.052	0.050	0.027	0.029	0.018

HAFT = Highest average field trial result.

TABLE  5.1.9b.  Summary of Residue Data from Crop Field Trials with
Acetamiprid.

Commodity	Total Applic. Rate, 

lb ai/A

[kg ai/ha]	PHI (days)	Residue Levels  (ppm)

	n	Min.	Max.	HAFT1	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Japan Study - Combined residues of acetamiprid and residues convertible
to Metabolite IC-0

Green tea - dried leaves	0.13-0.27

[0.15-0.30]	6-7	8	13.6	40.9	39.3	23.9	25.3	9.82

13-14	8	8.15	17.2	16.6	13.1	12.8	4.19

20-21	8	2.30	5.44	5.44	3.64	3.75	1.19

Green tea - brewed tea*	0.13-0.27

[0.15-0.30	6-7	8	7.74	27.7	27.0	17.3	17.4	7.29

13-14	8	5.17	12.7	12.6	9.21	9.07	3.38

20-21	8	1.57	3.30	3.27	1.87	2.15	0.70

India Study (wet and dry season tea) - Residues of acetamiprid per se
(only mean values reported)2

Black tea - green shoots	0.022-0.045

[0.025-0.050]	0	12	3.96	9.53	9.53	NC3	6.54	NC

7	12	0.20	0.51	0.51	NC	0.33	NC

15	12	0.03	0.11	0.11	NC	0.06	NC

21	12	<0.05	<0.05	<0.05	<0.05	<0.05	0

Black tea - dried leaves	0.022-0.045

[0.025-0.050]	0	12	11.2	26.4	26.4	NC	18.5	NC

7	12	0.54	1.47	1.47	NC	0.95	NC

15	12	<0.05	0.26	0.26	NC	0.11	NC

21	12	<0.05	<0.05	<0.05	<0.05	<0.05	0

Black tea - brewed tea*	0.022-0.045

[0.025-0.050]	0	12	5.4	12.6	12.6	NC	8.92	NC

7	12	0.24	0.61	0.61	NC	0.41	NC

15	12	<0.05	0.13	0.13	NC	0.07	NC

21	12	<0.05	<0.05	<0.05	<0.05	<0.05	0

Black tea - spent leaves	0.022-0.045

[0.025-0.050]	0	12	4.6	10.2	10.2	NC	7.5	NC

7	12	0.20	0.51	0.51	NC	0.36	NC

15	12	<0.05	0.09	0.09	NC	0.06	NC

21	12	<0.05	<0.05	<0.05	<0.05	<0.05	0

HAFT = Highest Average Field Trial.  2  The reported LOD (0.05 ppm) was
used for calculation of median, mean, and standard deviation where
appropriate.  Only the 0-day PHI and PHIs relevant for comparison to the
Japan trials were included in the summary.  3  NC = Not calculated. 
Median and standard deviation could not be calculated because only mean
values were reported for each sample set.  *  The relatively high
residues in the brewed tea, which HED expected to be much lower than the
residues in or on the dried tea leaves, may reflect a back calculation
of what the residues would have been on the dried tea leaves. 
Otherwise, HED can not account for why the residues were not diluted by
the water used for making the tea.

Clover

Three red clover field trials were conducted in the U.S. in Zone 11 (OR)
during the 2006 growing season.  Each trial site consisted of one
untreated plot and one treated plot.  Red clover was treated with a
single broadcast foliar application of Assail® 30SG, a 30% SG
formulation of acetamiprid, at a rate of 0.074-0.079 lb ai/A (ca. 1x the
maximum proposed seasonal rate on clover).  Application was made when
the crop was in the vegetative stage to blooming stage using ground
equipment in 23-25 GPA spray volumes, without an adjuvant.  Samples of
clover forage were harvested 28 to 34 days following application. 
Additionally, hay samples were cut at a normal harvest time (coinciding
with preharvest intervals of 56-63 days) and allowed to dry in the field
prior to collection.

Residues of acetamiprid were <0.01-0.05 ppm in/on red clover forage
harvested 28-34 days following a single broadcast foliar application of
the 30% SG at 0.074-0.079 lb ai/A.  Residues were below the LLMV (<0.01
ppm) in/on clover hay harvested 56-63 days following treatment.

Conclusions:  The use pattern of the clover field trials adequately
reflects the proposed label use pattern with the exception of the PHI
for hay.  The available field trial data indicate a regional tolerances
for residues of acetamiprid in clover forage at 0.10 ppm and clover hay
at 0.01 ppm, are appropriate.  However, the submitted clover field trial
data are not completely adequate to satisfy data requirements.  The
three clover field trials were all conducted in Zone 11 (OR) during the
2006 growing season, at the same location and within a very short time
period of each other.  The number of trials are adequate to support
restricted use on clover in ID, OR and WA (Zones 11 and 12) according to
OPPTS Guideline 860.1500, Attachment 11; however the guidelines state
that for crops requiring 8 or more trials nationally (12 are required
for clover), the trials for regional registrations must be conducted in
multiple years to account for variability due to climate conditions.  As
a condition of registration, HED recommends that two additional clover
field trials be required, as confirmatory data.  In addition, the
submitted reside data included field trial data for only the 30SG
formulation.  However, additional residue chemistry field trial data are
not required to support registration of the 70 WP formulation.  Use on
clover grown for seed is to be limited to clover grown in ID, OR, and
WA.  Since the residue chemistry data submitted for clover hay reflect
PHIs of between 56-63 days, the PHI for acetamiprid use on clover should
be increased to 56 days for any clover crop which will be harvested for
hay.

No residue decline data were included in the clover field trials. 
However, residue decline studies on cotton, head lettuce, oranges,
pears, and peppers were submitted in conjunction with PP#0F6082
(D264154, 12/31/2001, M. Doherty).  These data indicated that residues
of acetamiprid did not increase in the subject crops with increasing
harvest intervals.  Given the long PHI (28-days) for clover and
available residue decline data on other crops, residue decline data will
not be required to support the clover field trials.  The available field
trial data will support tolerances with regional registration for
residues of acetamiprid in clover forage at 0.10 ppm (with a 28-day PHI)
and clover hay at 0.01 ppm (with a 56-day PHI).

Grape; Fruit, Small Vine Climbing, Subgroup 13-07F, Except Fuzzy
Kiwifruit

Eighteen grape field trials were conducted in the U.S. and Canada in
Zones 1 (NY; 1 trial), 2 (NJ; 2 trials), 5 (ON; 4 trials), 5A (MI; 1
trial), 10 (CA; 8 trials), 11 (BC; 1 trial), and 11/12 (WA; 1 trial)
during the 2005 growing season.  Mature grape vines in established
orchards were treated with two directed foliar applications of Assail®
70WP, a 70% WP formulation of acetamiprid, at 0.096-0.103 lb
ai/A/application, with a 13- to 14-day retreatment interval, for a total
rate of 0.195-0.206 lb ai/A (ca. 1x the maximum proposed seasonal rate
on grapes and other climbing vine small fruits.

Residues of acetamiprid were 0.01-0.25 ppm in/on grapes harvested 2-3
days following the last of two directed foliar applications of the 70%
WP for a total rate of 0.195-0.206 lb ai/A.  No residue decline data
were included in the field study.

Conclusions:  The submitted grape residue data included field trial data
for only the 70WP formulation (the original field trials also used a
70WP formulation).  Although HED’s residue chemistry review (D364833,
10/14/09) recommended that additional residue chemistry field trial data
are needed to support registration of the 30SG formulation, additional
information provided by the registrant has convinced HED that such data
are not necessary.  HED agrees that both products are likely to produce
a solution of acetamiprid due to its high water solubility.

The submitted grape field trial data are adequate for the 70 WP
formulation pending label revision.  Because the grape field trial data
did not reflect the use of a surfactant in the application sprays, the
label directions regarding use of a spreader, methylated seed oil or
crop oil should be removed from the product label of Assail® 30SG (EPA
Reg. No. 8033-36).  Furthermore, in line with present OPP policy for a
late season foliar use, a statement should be added to both the 30SG and
70WP labels prohibiting addition of adjuvants for application to grapes.
 If use of an adjuvant is desired then one should be used in
side-by-side testing.  The number and locations of the field trials are
in accordance with OPPTS Guideline 860.1500 for grapes, and the use
pattern of the field trials reflects the use pattern proposed for grapes
(and other climbing vine small fruits,  except fuzzy kiwifruit, within
subgroup 13-07F), except for the adjuvant use.  

No residue decline data were included in the grape field trials.  The
residue decline studies from PP#0F6082 (D264154, M. Doherty,
12/31/2001), which indicated that residues of acetamiprid did not
increase in various crops with increasing harvest intervals, will be
used to fulfill the requirements for residue decline data.  The
available field trial data from the current submission, which reflect a
higher seasonal rate and a shortened PHI from that which is currently
registered for grape, will support a tolerance for residues of
acetamiprid at 0.35 ppm.  

Grape is the representative crop of the fruit, small vine climbing,
subgroup 13-07F, except fuzzy kiwifruit, and the available grape data
will support a subgroup tolerance at 0.35 ppm.  The established
individual tolerance for grape at 0.20 ppm should be deleted when the
subgroup 13-07F tolerance is established.

Tomatoes (Greenhouse Study)

Three trials were conducted on tomatoes in the U.S. and Canada in Zones
4 (TN), 5 (ON), and 6 (TX) during the 2002 and 2003 growing seasons. 
Each trial site included one untreated plot and one treated plot. 
Tomato plants grown in rock wool substrate under greenhouse conditions
were treated at the fruiting stage with four simulated drip-irrigation
(chemigation) treatments of Assail® 70WP, a 70% WP formulation of
acetamiprid, at rates equivalent to 0.074-0.081 lb ai/A/application. 
Applications were made with 7-day retreatment intervals, for a total
rate of 0.300-0.324 lb ai/A (ca. 2x the maximum proposed seasonal rate
for greenhouse-grown tomato); no adjuvant was used.  Samples of mature
tomato were harvested one day after the last application.  At the TX
trial, additional treated samples were harvested 3, 5, and 7 days after
the last application to generate residue decline data.

Residues of acetamiprid ranged from below the LLMV (<0.01 ppm) to 0.052
ppm in/on greenhouse-grown tomatoes harvested one day following the last
of four drip-irrigation (chemigation) treatments of the 70% WP for a
total rate equivalent to 0.300-0.324 lb ai/A.  The decline data show
that residues accumulated slightly, from an average of 0.027 ppm at the
1-day PHI to an average of 0.037 ppm at the 7-day PHI.

Conclusions:  Although the greenhouse trials were conducted at a 2x rate
and the number of trials is marginal, no additional residue data will be
required to support the proposed greenhouse use pattern for tomatoes. 
The tomato greenhouse data indicate that acetamiprid residues resulting
from applications of Assail 70WP formulation of acetamiprid according to
the proposed use pattern would not exceed the established tolerance for
residues of acetamiprid in fruiting vegetables, crop group 8 (0.20 ppm).
 Although no data were provided for the proposed use of Tristar® 30SG
on greenhouse tomatoes, HED now concludes the WP data support use of
this additional formulation based on the water solubility of the active
ingredient and the application being made to the roots of the plants by
soil drench or irrigation water.

Tea

The Interregional Research Project No. 4 (IR-4) has submitted a report
summarizing the results of two studies on tea conducted in Japan (by
Nippon Soda Co., Ltd.) and India (by the Institute of Himalayan
Bioresource Technology; IHBT).  No raw data were included in the
submission, all data presented herein are as reported in the original
studies.

Nippon Soda Co, Ltd. conducted two trials in the Mie Prefecture and the
Fukuoka Prefecture of Japan investigating the magnitude of the residue
in dried green tea leaves and brewed tea following a single foliar
application of a 20% water-soluble powder (SP) formulation of
acetamiprid made to green tea in separate plots at 0.13 lb ai/A (0.15 kg
ai/ha) and 0.27 lb ai/A (0.30 kg ai/ha).  Applications were made in
spray volumes of 321 gal/A (3000 L/ha).  The following Good Agricultural
Practice (GAP) information was provided for the 20% SP formulation in
Japan:  one foliar application at 0.10-0.40 kg ai/ha applied in
2000-4000 L/ha, with a 14-day preharvest interval (PHI).  In a separate
study, the Institute of Himalayan Bioresource Technology (IHBT)
conducted two sets of trials in Palampur (Himachal Pradesh, India)
investigating the magnitude of the residue in black tea for green
shoots, dried tea leaves, brewed tea, and spent leaves after brewing. 
Acetamiprid was applied to black tea in separate plots as a single
foliar application of a 20% SP formulation of acetamiprid at 0.022 lb
ai/A (0.025 kg ai/ha) and 0.045 lb ai/A (0.050 kg ai/ha) in spray
volumes of 43 gal/A (400 L/ha).  The application rates were reported to
be 1x and 2x the recommended application rate for acetamiprid on tea. 
Two sets of trials were conducted, one during the dry season (June) and
the second during the wet season (August).  The following GAP
information was provided for India:  shoots along with bud are typically
harvested at a 7-day PHI.

Samples of dried green tea leaves and brewed tea from the Japan study
were analyzed for residues of acetamiprid and its metabolites
convertible to 6-chloronicotinic acid (Metabolite IC-0) using a common
moiety gas chromatography method with electron capture detection
(GC/ECD).  Using this method, acetamiprid and metabolites are converted
to Metabolite IC-0 and methylated prior to determination by GC/ECD;
residues are expressed as acetamiprid.  The reported method limit of
detection (LOD) is 0.05 ppm as acetamiprid.  Samples of green shoots,
dried black tea leaves, brewed tea, and spent leaves from the India
study were analyzed for residues of acetamiprid using a high performance
liquid chromatography method with ultraviolet detection (HPLC/UV).  The
reported LOD was 0.05 ppm. Both methods are adequate for data collection
based on the submitted concurrent recovery data.

Regarding the common moiety method used in the Japan study, we note
that, although Metabolite IC-0 is not a residue of concern for tolerance
enforcement or risk assessment, based on the available plant metabolism
studies, it may constitute a significant portion of the total residues
(e.g., up to 24% total radioactive residues (TRR) in cotton seed and 31%
TRR in carrot flesh; refer to D278652, 11/13/01, H. Bietlot and M.
Doherty).  Therefore, the residues reported for the Japan study may
reflect an overestimation of expected residues of acetamiprid per se in
green tea.

Samples of dried green tea leaves and brewed tea from the Japan study
were stored frozen from collection to analysis for up to 3.5 and 1.7
months, respectively.  HED believes there are sufficient storage
stability data available for acetamiprid, demonstrating that residues
are stable in crop commodities stored frozen for up to 12 months and
crop commodities stored at ambient temperatures for up to 7 days, to
support both studies (refer to D264154, M. Doherty, 12/31/01).

The study report also contained a list of multiresidue method analysis
results for residues of acetamiprid in tea received in commercial
shipments from various countries.  Although residues were nondetectable
in the majority of green and black tea samples received from Argentina,
Bangladesh, Burundi, China, Ecuador, Ethiopia, India, Indonesia, Iran,
Kenya, Malawi, Mozambique, Rwanda, Sri Lanka, South Africa, Tanzania,
Turkey, Uganda, Vietnam, Zimbabwe, detectable residues of acetamiprid
were found in tea samples from China (0.03-0.04 ppm; n=3), Indonesia
(0.03 ppm; n=1), and Vietnam (0.03-0.12 ppm; n=7).  The source of these
data was not identified.

Conclusions:  No use was proposed for domestically grown tea.  The
acetamiprid data for tea grown in Japan and India consisted of field
trial data representing application rates of 0.022-0.27 lb ai/A (1
foliar application) with a 6- to 14-day PHI and were entered into the
tolerance spreadsheet as it matched the global GAP of 7-14 day PHIs. 
All 38 field trial sample results were equal to or greater than the LOD
(LOD = 0.05 ppm ).  HED believes that the 50.0 ppm tolerance (without
U.S. registrations, i.e., an import tolerance) is adequate to cover
residues in or on tea and instant tea and hence is not recommending for
a separate instant tea tolerance.  HED notes that the 50.0 ppm tolerance
harmonizes with Japan.  The residue data from Japan included the IC-0
metabolite, which is not in the U.S. tolerance expression and is
considered conservative.

A summary table of proposed and recommended tolerances for acetamiprid
associated with all the proposed commodities and uses can be found in
Appendix C.

5.1.10	International Residue Limits TC \l3 "5.1.10	International Residue
Limits 

There are no Codex maximum residue limits (MRLs) established for
residues of acetamiprid on crop or animal commodities; no Mexican MRLs
are established on crops associated with this petition.  Canada has
established an MRL for acetamiprid residues in grapes at 0.20 ppm.  The
recommended U.S. tolerance for Subgroup 13-07F tolerance at 0.35 ppm is
not harmonized with the Canadian MRL, presumably because of differences
in good agricultural practices.  Japan has a 50 ppm MRL for tea and HED
recommends setting the tolerance at the same level.  An International
Residue Limit Status (IRLS) sheet is appended to this document.

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 to Support Section 3 Registration of Uses on Clover, Small
Vine Climbing Fruits, except Kiwifruit, Subgroup 13-07F, Greenhouse
Grown Tomatoes and Tea.  D369019, 12/01/09.

The current acute and chronic dietary exposure assessments include
existing uses and the tolerances proposed by the Interregional Research
Project Number 4 (IR-4) for new uses of acetamiprid on clover grown for
seed, small vine climbing fruits, except kiwifruit, subgroup 13-07F
(amending established grape uses), greenhouse-grown tomatoes, and tea.

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.

Usage Data

In order to refine the dietary exposure estimates for acetamiprid, HED
requested a Screening Level Usage Analysis (SLUA), which was conducted
by the Biological and Economic Analysis Division (BEAD), 6/11/09.  The
SLUA includes estimates of maximum %CT for the acute assessment and
average %CT for determining chronic exposure (Table 5.2.1.). 
Commodities with the most significant acetamiprid usage in terms of
maximum %CT include pears (60%), apples (30%), celery (45%), and lettuce
(20%).  Commodities with the most significant usage in terms of lbs ai
applied include apples (10,000), cotton (20,000), and pears (5,000).

Table 5.2.1.   Percent Crop Treated Data Used in DEEM

Commodity	Avg	Max

Apples	20	30

Broccoli	5	15

Cabbage	5	10

Cauliflower	10	15

Celery	25	45

Cotton	5	5

Grapefruit	2.5	2.5

Grapes	5	10

Lemons	5	5

Lettuce	10	20

Oranges	2.5	5

Peaches	1	2.5

Pears	35	60

Peppers	2.5	5

Potatoes	2.5	2.5

Pumpkins	1	2.5

Spinach	5	15

Squash	2.5	2.5

Tomatoes	5	10

For the acute analysis, %CT was incorporated into RDFs.  For the chronic
analysis, average %CT was included for the commodities listed in the
table above.

As mentioned above, under Section 5.1.8, 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 (Table 5.2.2).

Acute Dietary (Food and Drinking Water) Exposure Results and
Characterization

The probabilistic acute dietary exposure assessment included anticipated
residues from field residue trials, processing factors, maximum %CT
estimates (for existing uses only) generated by the Biological and
Economic Analysis Division (BEAD), and the modeled peak concentration of
acetamiprid residues in surface water sources of drinking water.  100
%CT was assumed for crops where % crop treated information was not
available.  Although the acute assessment has been refined, the
resulting exposure estimates are still considered conservative since
field trial data were the basis for the anticipated residues, and
because a lower tier drinking water model (FIRST) was used to estimate
residues in drinking water.

Acute dietary exposure estimates at the 99.9th percentile are below
HED’s level of concern for the general US population and all other
population subgroups.  For the US population, the estimated exposure of
0.020 mg/kg/day corresponds to 20% aPAD; for children 1-2 years old, the
estimated exposure of 0.041 mg/kg/day corresponds to an acute dietary
risk of 41% aPAD.

 

Chronic Dietary (Food and Drinking Water) Exposure Results and
Characterization

For the chronic analysis, tolerance-level residues were assumed for all
food commodities with existing and proposed acetamiprid tolerances. 
Percent crop treated was used for many commodities as detailed in Table
5.2.1.  The chronic analysis also included the modeled surface water
annual average residue in drinking water.  Even though %CT information
was used in the chronic analysis, the exposure and risk estimates are
still conservative since tolerance level residues were used, because 100
%CT was assumed for crops where % crop treated information was not
available, and because a lower tier drinking water model (FIRST) was
used.

Chronic dietary exposure to acetamiprid, including existing and proposed
uses, is below HED’s level of concern for the US population and all
other population subgroups.  For the general US population, an estimated
exposure of 0.0024 mg/kg/day corresponds to 3% of the chronic population
adjusted dose (cPAD); children 1-2 years old were the highest exposed
population subgroup, with an estimate of 0.0087 mg/kg/day, or 12% cPAD. 
Risks for all population subgroups are less than 100% cPAD, and are not
of concern.

Table 5.2.2.  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	0.020190	20	0.002375	3.3

All Infants (< 1 year old)	0.026336	26	0.004780	6.7

Children 1-2 years old	0.040892	41	0.008693	12

Children 3-5 years old	0.029647	30	0.006066	8.5

Children 6-12 years old	0.016429	16	0.003396	4.8

Youth 13-19 years old	0.013137	13	0.001739	2.5

Adults 20-49 years old	0.013988	14	0.001683	2.4

Adults 50+ years old	0.012372	12	0.001808	2.5

Females 13-49 years old	0.011917	12	0.001708	2.4

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 existing and proposed uses. 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization 

The registrant has not proposed new or revised residential uses. 
Therefore, new residential handler and postapplication exposure
assessments were not conducted.   Acetamiprid is registered for
controlling a wide variety of indoor and outdoor insect pests in
residential settings.  The MOEs for residents applying bait and gel
products were 1500-3500 (D303171, T. Moriarity, 10/25/07).  In a more
recent assessment of exposures to residential handlers from products
used on indoor and outdoor residential settings, the risks were found to
be not of concern for all scenarios identified (D353040, Z. Figueroa,
12/1/08).  An analysis of the postapplication risks to adults and
children from contacting treated areas has also been performed recently
(D353012, C. Swartz, 12/12/08).  In the tables below, only the risk to
children are shown since as noted in the 12/12/08 memo they are the
worse case versus those for adults.

Table 6a.  Acetamiprid: Short- and Intermediate-Term Postapplication
Exposures and Risks to Toddlers Following

                                                          Turf
Treatments in Residential Settings.1 

Exposure Scenario	Application Rate

(lb AI/acre)	Exposure  (mg/kg/day)	MOE 2

Short-term	Interm. term	Short-term	Interm. term

Residential turf  (dermal) 	0.187	0.0072	0.0036	1,400	2,800

Hand to mouth (oral) 

0.0028	0.0013	3,600	7,600

Object to mouth (oral)  

0.00069	NA	14,500	NA

Incidental soil ingestion (oral)

0.0000093	NA	1,100,000	NA

Total exposure  (dermal & oral)	N/A	0.0107	0.0049	900	2,000

1.  From C. Swartz, D353012, 12/12/08.

2.  Short- & intermediate-term dermal or oral NOAEL (10
mg/kg/day)/exposure (mg/kg/day).

TABLE 6b:  Acetamiprid: Short-term Postapplication Exposure and Risk to
Toddlers Following Indoor Crack 

                                                                        
  and Crevice Treatments 1

Exposure Scenario	Descriptor	Exposure (mg/kg/day)	MOE 2

Dermal exposure	Carpet and hard surfaces	0.0195	510

Incidental oral exposure

0.0065	1500

Total dermal & oral exposures 

0.026	380

1. From C. Swartz, D353012, 12/12/08.

2.  Short- & intermediate-term dermal or oral NOAEL (10
mg/kg/day)/exposure (mg/kg/day).

Aggregate exposures of acetamiprid include the short- and
intermediate-term postapplication exposures following turf treatment and
the short-term postapplication exposure following indoor crack and
crevice treatment.

6.1	Residential Handler Exposure TC \l2 "6.1	Residential Handler
Exposure 

The MOEs for residents applying bait and gel products were 1500-3500
(D303171, T. Moriarity, 10/25/07).  In a recent assessment of exposures
to residential handlers from products used on indoor and outdoor
residential settings, the risks are not of concern for all applicable
scenarios identified (D353040, Z. Figueroa, 12/1/08).

6.2.	Residential Postapplication Exposure TC \l2 "6.2.	Residential
Postapplication Exposure 

An evaluation of postapplication exposure resulting from the proposed
use and label change was completed (D353040, Z. Figueroa, 12/1/08 and
D366701, S. Oonnithan, 10/9/09); risks were not of concern for any of
the scenarios identified and assessed.  Detailed discussions of the
assumptions and methods used for assessing residential exposure from the
proposed use are provided in the 12/1/08 memorandum.

The postapplication scenarios assessed for toddlers’ exposure
following perimeter treatment include:

Dermal exposure from treated lawns due to high contact lawn activities; 

Hand-to-mouth transfer of pesticide residues on lawns; 

Object-to-mouth transfer of pesticide residues on lawns; and 

Incidental ingestion of soil from pesticide-treated residential areas.

Risks for these scenarios are provided in Table 6.2a.

Table 6.2a. Short- and Intermediate-Term Dermal & Indirect Ingestion -
Toddler Residential Risk Estimates for Postapplication Exposure on Turf

Exposure Scenario	Route of Exposure	Application Rate

(lb ai/acre)	Dermal Transfer Coefficient (µg/cm2)	Absorbed Dose
(mg/kg/day)	MOE

Residential Turf 	Dermal	0.187	5,200

(Short-term)	0.0072

(Short-term)	1,400

	2,600

(Intermediate-term)	0.0036

(Intermediate-term)	2,800

Hand to Mouth	Oral

NA	0.0028

(Short-term)	3,600

0.0013

(Intermediate-term)	7,600

Object to Mouth 	Oral

NA	0.00069	14,500

Incidental Soil Ingestion	Oral

NA	0.0000093	1,100,000

Combined Exposure1	N/A	N/A	N/A	0.01071

(Short-term)	9001

0.00491

(Intermediate-term)	2,0001

1- Combined exposure is the sum of dermal and oral exposures.

Table 6.2b summarizes the postapplication exposure and risk for toddlers
resulting from contact with carpet and hard surfaces following crack and
crevice application of F4688 50 WP Insecticide/Termiticide on indoor
surfaces.  The bolded values represent the exposure to be aggregated
with exposure from food and drinking water.

TABLE 6.2b:  Postapplication Exposure and Risk Following Indoor
Crack/Crevice Treatment.

Scenario	Descriptor	Daily Dose

(mg/kg/day)	MOE

Dermal Exposure	Carpet and

Hard Surfaces	0.0195	510

Incidental Oral Exposure	Carpet and Hard Surfaces	0.0065	1500

Combined Dermal Incidental Oral Exposure	Carpet and Hard Surfaces	0.0260
380

6.3	Other (Spray Drift, etc.) TC \l2 "6.3	Other (Spray Drift, etc.) 

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 Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization 

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)
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 Term Aggregate Risk TC \l2 "7.1	Acute Term 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- and Intermediate-Term Aggregate Risk TC \l2 "7.2	Short- 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.

Short- and intermediate-term aggregate risks for residential handlers
were assessed previously by T. Moriarity (see Table 15, D303171,
10/25/07).  The aggregate MOEs for two adult populations (20-49 years;
50+ years) were 900 to 930.  Since the dietary exposure estimates are
now more refined due to the greater use of percent crop treated, these
aggregate risks would be even lower and are not of concern.  

For short-term and intermediate-term aggregate risks, the combined
chronic dietary (food + water) exposure is combined with short- and
intermediate-term residential postapplication exposures for toddlers. 
The combined food, water and residential exposures are then compared to
the dose for risk assessment to determine the resulting margin of
exposure (MOE).  HED has updated the dietary component (food and water)
in this assessment.  In the case of acetamiprid, all short- and
intermediate-term risk assessments are based on the effects observed in
the DNT study, and therefore exposures from dermal and oral routes have
been combined.  See Table 7.2 for a summary of short- and
intermediate-term aggregate risks for toddlers.

TABLE 7.2:  Acetamiprid Short- and Intermediate-Term Aggregate Exposure

                                                     and Risk for
Toddlers.

Scenario	Combined Dermal/Oral Exposure

(mg/kg/day)1	Chronic Food Exposure Food

(mg/kg/day)2	Aggregate Exposure

(mg/kg/day)3	MOE4

Indoor Exposure Crack and Crevice Treatment

(short-term)	0.0260	0.008693	0.0347	290

Turf Exposure

(short-term)	0.0107	0.008693	0.0194	520

Turf Exposure (intermediate-term)	0.0049	0.008693	0.0136	740

Combined dermal and oral exposures were taken from D366701, S.
Oonnithan, 10/9/09.

Chronic food exposure does not change with each scenario; see Table
5.2.2.

Aggregate exposure = Combined dermal/oral exposure + chronic food
exposure.

MOE = NOAEL/Aggregate Exposure = 10 (mg/kg/day)/aggregate exposure
(mg/kg/day).

Short- and intermediate-term aggregate risks (MOEs) are not of concern. 
 HED notes that the lowest aggregate MOE of 290 is based on the indoor
use.  The MOEs calculated for exposure from turf are higher, but are
considered to be more conservative, because the intended use pattern
does not include broadcast treatment of lawns, but has been assessed as
such in order to be protective.  Adult aggregate risks due to
postapplication exposure have not been assessed since the toddler risks
are the worst case.

7.3	Chronic-Term Aggregate Risk TC \l2 "7.3	Chronic-Term 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  TC \l1 "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 imidacloprid).  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  TC \l1 "9.0	Occupational
Exposure/Risk Pathway 

9.1	Short-/Intermediate-/Long-Term Handler Risk  TC \l2 "9.1
Short-/Intermediate-/Long-Term Handler Risk 

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:  1) surrogate data from the Pesticide Handlers Exposure Data
Base (PHED v1.1; 2) Outdoor Residential Exposure Task Force (ORETF)
data; 3) 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, 4) standard protection factors assumed with specified personal
protective equipment).  The estimated exposures are believed to be
reasonable high-end estimates. 

The proposed use patterns of acetamiprid indicate that the Assail® 70WP
and Assail® 30SG are applied 1-2 times per season at 1-14 day intervals
on clover and grapes resulting in short-term exposure to mixers,
loaders, and applicators.  Repeated use of these products by commercial
handlers on several farms growing clover and/or grapes would also result
in intermediate-term exposure to handlers as well.  In the case of
greenhouse grown tomatoes using TriStar® 30SG, the handlers are
subjected to short-, intermediate, and long-term exposures due to the
year-round growing operations.

9.2		Handler and Pesticide Control Operator (PCO) Risk Characterization 
TC \l2 "9.2	Handler and Pesticide Control Operator Risk Characterization
 

Since both dermal (short- and intermediate-term) and inhalation (short-
and intermediate-term) 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 study) 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.  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.  In addition, exposures to PCO’s from the proposed labeled
uses are not a risk concern to HED provided PCO’s comply with the
personal protection directions specified on the label.  MOEs for
handlers are attached in Appendix A.

9.3	Postapplication Exposure and Risk  TC \l2 "9.3	Postapplication
Exposure and Risk  

The registrant has not submitted a chemical-specific postapplication
exposure study to quantify  postapplication exposure for proposed crops
of clover, grape, and tomatoes.  In the absence of chemical-specific
data, dermal exposures were estimated using default dislodgeable foliar
residue (DFR) and surrogate transfer coefficient (TC) values.

"0".  The estimated postapplication risk for all crop-related activities
is MOE ≥ 330 (the LOC=100); therefore, not of concern.  Long-term risk
to workers performing scouting, irrigation, and harvesting of tomatoes
grown in greenhouses also is not of concern.  The use of acetamiprid in
the greenhouse as a soil drench and micro-irrigation is also not of
concern with regard to postapplication exposure to workers.

Restricted Entry Interval (REI)

All three labels, Assail® 70WP, Assail® 30SG, and TriStar® 30SG have
CAUTION as the SIGNAL WORD.  An REI of 12 hours is set based on the
acute toxicity of acetamiprid technical, which is classified as Category
III and IV for acute dermal toxicity, dermal irritation, and eye
irritation.  Acetamiprid is not a dermal sensitizer.   Acute toxicity
Category III and IV chemicals are assigned a 12-hour REI.   The current
assessment of postapplication exposures and risks for the proposed uses
on clover, grapes, and greenhouse grown tomatoes indicates that the
12-hour REI set for acetamiprid is adequate to protect the workers who
may enter treated fields to do any crop-related agricultural activities.

10.0	Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and
Label Recommendations 

Directions for Use:

No proposed use was submitted for the use on tea in South Carolina.  HED
cannot evaluate the domestic use without a proposed use, application
methods, and a proposed formulation.  GAP information was provided for
Japan and India.  The use directions are adequate to establish a
tolerance without U.S. registrations (an “import” tolerance).

Because the grape field trial data submitted with this petition did not
reflect the use of a surfactant in the application sprays, the label
directions regarding use of a spreader, methylated seed oil or crop oil
should be removed from the product label of Assail® 30SG (EPA Reg. No.
8033-36).  Furthermore, in line with present OPP policy for a late
season foliar use, a statement should be added to both the 30SG and 70WP
labels prohibiting addition of adjuvants for application to grapes.  If
use of an adjuvant is desired then one should be used in side-by-side
testing.

The PHI for clover harvested for hay should be increased to 56 days on
the 30SG and 70WP labels.

Tolerances:

HED recommends tolerances for acetamiprid be established as specified in
Appendix C.  The tolerance expression should be revised as stated in
Section 1.1.

The final tolerances for subgroup 13-07F should reflect the correct
commodity definition as specified in Appendix C.  A revised Section F is
not needed for this minor change.  The established individual tolerance
for grape at 0.20 ppm should be concomitantly removed with establishment
of the subgroup 13-07F tolerance.

Conditional Data:

Two clover field trials reflecting the same use pattern utilized in the
submitted studies.

  SEQ CHAPTER \h \r 1 Submittal of Analytical Reference Standards:

Analytical standards for the IM-2-1 and IM-2-1-amide metabolites are not
available at the Repository and should be supplied.  The reference
standards should be sent to the Analytical Chemistry Lab, which is
located at Fort Meade, to the attention of Theresa Cole at the following
address:

	USEPA

	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

	701 Mapes Road

	Fort George G. Meade, MD  20755-5350

(Note that the mail will be returned if the extended zip code is not
used.)

References:  TC \l1 "References: 

Acetamiprid.  Request for Label Amendments for New Uses on Clover; Small
Vine Climbing Fruits, except Kiwifruit, Subgroup 13-07F (amending grape
use); Greenhouse-grown Tomatoes; and a Regional Registration for Tea. 
Summary of Analytical Chemistry and Residue Data.  D364833, 10/14/09, D.
McNeilly.

Acetamiprid.  Acute and Chronic Dietary Exposure Assessments to Support
Section 3 Registration of Uses on Clover, Small Vine Climbing Fruits,
except Kiwifruit, Subgroup 13-07F, Greenhouse Grown Tomatoes and Tea. 
D369019, D. McNeilly, Dec 1, 2009.

Acetamiprid: Occupational and Residential Exposure Assessment for the
New Uses on Clover and Greenhouse Grown Tomatoes and for Increasing the
Application Rate on Grapes.  D366701, S. Oonnithan, 10/9/09.

Acetamiprid: Occupational/Residential Exposure and Risk Assessment for
Proposed Use on Indoor/Outdoor Household Pest Control.  12/1/08, Z.
Figueroa.

Tier I Drinking Water Assessment for Acetamiprid Proposed Uses on Red
Clover (Grown for Seed Only), Grape and Tomato (Greenhouse).  David
Lieu, June 10, 2009.

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.

Acetamiprid.  Human Health Risk Assessment for a Proposed Label
Amendment Allowing Food/Feed Use on Vegetable Transplants.  D352925,
11/25/08, W. Drew. 

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

	

Acetamiprid: Aggregate Risk Assessment Associated with the Proposed Use
on Indoor/Outdoor Household Pest Control.  12/12/08, Christina Swartz.

	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.  10/25/07, T. Moriarity.

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. Drew; D328216.



Appendix A:	Occupational Exposure and Risk Tables   TC \l1 "Appendix A:
Occupational Exposure and Risk Tables  

Table A.1.  Acetamiprid: Potential Short-term Exposure Scenarios
Resulting from Its Use on Clover, Grape, and Greenhouse Grown Tomatoes.

Crop	Formulation 1	Scen. No.	Appl. equipment 	Handler	Comments 2

Clover	Assail®  70WP and WP/WSB 	1	foliar/aerial, fixed wing	M/L

	2	 "	 "	applicator

	3	 "	 "	flagger

	4	foliar/ground boom	M/L

	5	 "	 "	applicator

Assail®  30SG	6	foliar/aerial, fixed wing 	M/L

	7	 "	 "	applicator	same as # 2

8	 "	 "	flagger	same as # 3

9	foliar/ground boom	M/L

	10	 "	 "	applicator	same as # 5

Grape	Assail®  70WP and WP/WSB 	11	foliar/aerial, fixed wing 	M/L

	12	 "	 "	applicator

	13	 "	 "	flagger

	14	foliar/air blast	M/L

	15	 "	 "	applicator

Assail® 30SG	16	foliar/aerial, fixed wing 	M/L

	17	 "	 "	applicator	same as # 12

18	 "	 "	flagger	same as # 13

19	foliar/air blast	M/L

	20	 "	 "	applicator	same as # 15

Tomatoes grown in green- house	TriStar® 30SG	21	drip/micro irrigation
M/L/A	no unit exposures

22	back-pack sprayer	M/L/A	root zone spray 

23	low-pr. Hand wand	M/L/A	root zone spray 

24	high pr. Hand wand	M/L/A	soil drench

1. Assail 70WP is sold as WP (powder) and as water soluble bags (WSB).

2. Duplicate scenarios (indicated) having identical inputs were not
assessed. 



Table A.2.  Acetamiprid:  Short- and Intermediate-term Occupational
Risks to Handlers Resulting From the Use of Assail 70WP Assail 30SG
Insecticides on Clover.

Crop 	Scen.

No.1	Formulation,            Appl. method                    & Rate 
(AI/A)	Handler 	PPE & Mitigation 2	Acres treated/   day	Unit exposure
(mg/lb AI handled)      and Exposed dose mg/kg/day) 3 	Total exp, 
(mg/kg/ day) 4	Short/Interm.         term MOE 5

Dermal	Inhal.

Clover	1A

	Assail 70WP, Aerial,  0.075  	M/L	Baseline	350	3.7

1.62E-01	0.04342

1.90E-02	0.18087	55

	1B	"	M/L	Baseline + gloves	350	0.17

7.44E-03	0.04342

1.90E-02	0.02643	380

	1C	Assail 70WP/WSB

Aerial, 0.075  	M/L	Baseline	350	0.021

9.19E-04	0.00024

1.05E-04	0.00102	9,800

	2	Assail 70WP                 Aerial, 0.075  	Applic.	Baseline + cl.
Cockpit	350	0.005

2.19E-04	0.00007

3.06E-05	0.00025	40,000

	3	Assail 70WP, Aerial, 0.075  	Flagger	Baseline	350	0.011

4.81E-04	0.00035

1.53E-04	0.00063	16,000

	4A	Assail 70WP Ground boom, 0.075 	M/L	Baseline	80	3.7

3.70E-02	0.04342

4.34E-03	0.04134	240

	4B	"	M/L	Baseline + gloves	80	0.17

1.70E-03	0.04342

4.34E-03	0.00604	1,700

	4C	Assail 70WP/WSB

Aerial, 0.075 	M/L	Baseline	80	0.021

2.10E-04	0.00024

2.40E-05	0.00023	43,000

	5	Assail 70WP, Ground boom, 0.075 	Applic.	Baseline + open cab	80	0.014

1.40E-04	0.00074

7.40E-05	0.00021	47,000

	6	Assail 30SG 

Aerial, 0.075 	M/L	Baseline	350	0.066

2.89E-03	0.00077

3.37E-04	0.00322	3,100

Table A.2 contd …

Clover	7	Assail 30SG 

Aerial, 0.075 	Applic.	same as # 2	-	-	-	-	-

	8	Assail 30SG 

Aerial, 0.075 	Flagger	same as # 3	-	-	-	-	-

	9	Assail 30SG            Ground boom, 0.075 	M/L	Baseline	80	0.066

6.60E-04	0.00077

7.70E-05	0.00074	14,000

	10	Assail 30SG            Ground boom, 0.075 	Applic.	same as # 5	-	-	-
-	-

1. The scenario numbers are from Table A.1.  The Assail 70WP may be sold
as free flowing powder and as water soluble bags (WSB); therefore, both
products were included in the exposure evaluations. 

2. Baseline PPE includes long sleeved shirt, long pants and shoes with
socks. Additional PPE such as gloves, respirators and engineering
controls (open/closed cab/cockpit, etc.) are added if the exposure
exceeds the Agency's LOC (MOE = ≤ 100). 

3. Dermal exposure/day  =  (appl. rate * area treated/day * dermal unit
exp. * dermal absorption (10%) / body wt (60 kg).  Inhalation
exposure/day =  (appl. rate * area treated/day * inhalation unit exp. *
inhalation absorption rate (100%) / body wt (60 kg). 

4. Since the dermal and inhalation endpoints are the same; the dermal
and inhalation exposures were combined. 

5. Short- and intermediate-term MOE =  short- and intermediate-term POD
(10 mg/kg/day) / combined exposure (mg/kg/day).  Since the short- and
intermediate-term dermal and inhalation PODs are the same the short- and
intermediate-term dermal and inhalation MOEs also are the same. The
bolded MOE is of concern and adding gloves to the baseline clothing
reduces the exposure.



Table A.3.  Acetamiprid:  Short- and Intermediate-term Occupational
Risks to Handlers Resulting From the Use of Assail 70WP and Assail 30SG
Insecticides on Grapes.1 

Crop	Scen.Nos.1	Formulation, Appl. equipment & App. rate	Handler 	PPE &
Mitigation 2	Acres     Treated/day	Unit exposure (mg AI/lb handled)

and Exposed dose (mg/kg/day) 3	Total exposure. (mg/kg/day) 4
Short/Interm. term MOE 5

Dermal	Inhal.

Grape	11A	Assail 70WP              Aerial, 0.1 lb AI/A 	M/L	Baseline	350
3.7

2.16E-01	0.04342

2.53E-02	0.2416	41

	11B	Assail 70WP             Aerial, 0.1 lb AI/A  	M/L	Baseline + gloves
350	0.17

9.92E-03	0.04342

2.53E-02	0.03505	280

	11C	Assail 70WP/WSB 

Aerial, 0.1 lb AI/A  	M/L	Baseline	350	0.021

1.23E-03	0.00024

1.40E-04	0.00137	7,300

	12	Assail 70WP,                Aerial (fixed wing),            0.1 lb
AI/A	Applic.	Baseline + closed cockpit	350	0.005

2.92E-04	0.00007

4.08E-05	0.00033	30,000

	13	Assail 70WP                 Aerial, 0.1 lb AI/A	Flagger	Baseline	350
0.011

6.42E-04	0.00035

2.04E-04	0.00085	12,000

	14A	Assail 70WP             Air blast, 0.1 lb AI/A  	M/L	Baseline	40
3.7

2.47E-02	0.04342

2.89E-03	0.02756	360

	14B	Assail 70WP             Air blast, 0.1 lb AI/A  	M/L	Baseline +
gloves	40	0.17

1.13E-03	0.04342

2.89E-03	0.00403	2,500

	14C	Assail 70WP/WSB 

Air blast, 0.1 lb AI/A  	M/L	Baseline	40	0.021

1.40E-04	0.00024

1.60E-05	0.00016	64,000

	15	Assail 70WP, Air blast, 0.1 lb AI/A 	Applic.	Baseline +  open cab	40
0.36

2.40E-03	0.0045

3.00-E04	0.0027	3,700

Table  A.3 contd …..

Grape	16	Assail 30SG, Aerial, 0.1 lb AI/A 	M/L	Baseline	350	0.066

3.85E-03	0.00077

4.49E-04	0.0043	2,300

	17	Assail 30SG, Aerial, 0.1 lb AI/A 	Applic.	same as # 12	-	-	-	-	-

	18	Assail 30SG, Aerial, 0.1 lb AI/A 	Flagger	same as # 13	-	-	-	-	-

	19	Assail 30SG, Air blast 0.1 lb AI/A           	M/L	Baseline	40	0.066

4.40E-04	0.00077

5.13E-05	0.00049	20,000

	20	Assail 30SG          Air blast, 0.1 lb AI/A	Applic.	same as # 15	-	-
-	-	-

1. All the foot notes are the same as in Table A.2.



Table A.4.  Acetamiprid:  Short- and Intermediate-term Occupational
Risks to Handlers Resulting From the Use of TriStar 30SG Insecticide on
Tomatoes Grown in Greenhouse.1

Scen.

Nos.1	Formulation, &          Appl. equipment	Handler 	PPE & Mitigation
2	Total Area ** treated/day 	Unit exposure (mg AI/lb handled) and
Exposed dose (mg/kg/day) 3	Total exposure  (mg/kg/ day) 4	MOE 5

	Dermal	Inhal.

Short/Inter. -term	Long-term        

21	TriStar 30SG,   0.075 lb AI/A          micro-irrigation	not assessed
due to lack of appropriate unit exposures	-	-	-	-	-

22	TriStar 30SG,         0.075 lb AI/A, base of plant appl., back-pack 
M/L/A	Baseline + gloves	0.4	2.5

1.25E-4	0.03

1.50E-05	0.00014	71,000	51,000

23	TriStar 30SG,         0.075 lb AI/A, base of plant appl., low
pressure  hand wand	M/L/A	Baseline + gloves	0.4	0.43

2.15E-5	0.03

1.50E-05	0.00004	270,000	190,000

24	TriStar 30SG, 0.075 lb AI/A, base of plant appl., high pressure  hand
wand 	M/L/A	Baseline + gloves	10	2.5

3.13E-03	0.12

1.50E-03	0.00463	2,200	1,500

1. All the foot notes are the same as in Table A.2.  Note that in Table
A.4, the M/L/A unit exposures are for a liquid formulation rather than a
soluble granule product.

** The total area (A) treated/day in the greenhouse was derived as
follows: the spray volume handled/day was taken as 40 gal for back-pack
and low-pressure hand wand  and 1000 gal for high-pressure hand wand
sprayer (root zone drench).  It is assumed that 100 gal of spray would
cover 1.0 A of greenhouse area (L. Venkateshwara, D355232, 11/21/08). 



Table A.5.  Acetamiprid:  Short-term Post-application Dermal Risk to
Workers From the Use of Assail 70WP and Assail 30SG Insecticides on
Grapes.  

Crop         	Max. single appl. rate              (lb Ai/A)	Dislodgeable
foliar residue (µg/cm2) 1	Surrogate                          crop group
Post-treatment activity                                    	Transfer
coefficient (cm2/hr) 2	Dermal absorpt. (%)	ADD  (mg/kg/day) 3	MOE 4

Short/Interm.-term	Long-term

Clover 	0.075	0.168	Field and row crop, forage	irrigation/   scouting
1,500	10	0.0034	3,000	NA

Grape	0.1 	0.224	Vine, trellis	training, scouting	1,000

0.003	3,300	NA

hand harvesting, pruning	5,000

0.015	670

	NA

turning and tying	10,000

0.0299	330	NA

Tomatoes grown in greenhouses	0.075	0.168	Fruiting vegetables	staking,
thinning, training, tying	1,000

0.00224	4,500	3,200

1. Dislodgeable foliar residue (DFR) = max. single appl. rate for the
crop (lb AI/A) * 20% *  4.54 x 108 (µg/lb) * 2.47 x 10-8 (A/cm2). 

2. TC values are from Science Advisory Council for Exposure Policy No.
3.1. 

3. Average daily dose (ADD) = [DFR *  TC for the activity * 8 (hrs/day)
* 0.001 mg/µg * dermal absorp.] / BW (60 kg).

4.  Short/intermediate-term dermal MOE = ADD/ short/intermediate-term
dermal NOAEL (10 mg/kg/day).  Long-term dermal MOE = ADD/ long-term
dermal NOAEL (7.1 mg/kg/day).

Appendix B:	Toxicology Assessment  TC \l1 "Appendix B:	Toxicology
Assessment 

Appendix B.  Toxicity Profile for Acetamiprid:  Subchronic, Chronic, and

 Other Toxicity Studies

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

870.3100

90-Day oral toxicity-rat

(dietary)	44651843 (1997)

Acceptable/guideline

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

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

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

870.3100

90-Day feeding – mouse	44988425 (1997)

Acceptable/guideline

0, 400, 800, 1600, 3200 ppm

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

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

870.3150

90-Day oral toxicity-dog

(Dietary)	44988424 (1998)

Acceptable/guideline 

0, 320, 800, 2000 ppm

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

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

870.3200

21-Day dermal toxicity-rabbit	44651844 (1997)

Acceptable/guideline

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

LOAEL= not determined

Dermal NOAEL= 1000 mg/kg/day

LOAEL= not determined 

870.3700

Developmental toxicity - rat

(gavage)	44651847 (1997)

Acceptable/guideline

0, 5, 16, 50 mg/kg/day

	Maternal:

NOAEL = 16 mg/kg/day

LOAEL = 50 mg/kg/day based on reduced BW & BW gain and food consumption,
increased liver weights

Developmental:

NOAEL = 16 mg/kg/day 

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

870.3700

Developmental toxicity – rabbit

(gavage)	44651848 (1997)

Acceptable/guideline 

0, 7.5, 15, 30 mg/kg/day	Maternal:

NOAEL = 15 mg/kg/day

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

Developmental:

NOAEL = 30 mg/kg/day (HDT) 

LOAEL = not determined

870.3800

Reproduction and fertility effects-rats

(dietary)	44988430 (1999)

Acceptable/guideline

0, 100, 280, 800 ppm

Parental animals

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

F1 animals

0/0, 7.5/8.4, 21.0/23.8, 63.3/72.6 (M/F) mg/kg/day

	Parental/Systemic:

NOAEL = 17.9/21.7 (M/F) mg/kg/day 

LOAEL = 51.0/60.1 (M/F) mg/kg/day based on decreased body weight, body
weight gain and food consumption

Offspring:

NOAEL = 17.9/21.7 (M/F) mg/kg/day 

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

Reproductive:

NOAEL = 17.9/21.7 (M/F) mg/kg/day 

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

870.4100

Chronic toxicity-rat 	Same as Chronic Toxicity/Carcinogenicity- rat see
below (870.4300)	See below (870.4300)

870.4100

Chronic toxicity-dog 

(Dietary)	44651846 (1998)

Acceptable/guideline

0, 240, 600, 1500 ppm

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

LOAEL = 55/61 (M/F) mg/kg/day based on initial BW loss and overall
reduction in BW gain

870.4200

Carcinogenicity-mouse

(dietary)

	44988428, 45245305 (1999) 

Acceptable/guideline

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

LOAEL = 65.6/214.6 (M/F ) mg/kg/day based on decreased BW & BW gain and
amyloidosis in numerous organs (M) and decreased BW and BW gain (F)

Not oncogenic under conditions of study

870.4300

Chronic/

Carcinogenicity-rat 

	44988429, 45245304 (1999)

Acceptable/guideline

0, 160, 400, 1000 ppm

(equivalent to 0/0, 7.1/8.8, 17.5/22.6, 46.4/60.0 (M/F) mg/kg/day)

	NOAEL  = 7.1/8.8 (M/F) mg/kg/day 

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

Evidence of treatment-related increase in mammary tumors

870.5100

Salmonella typhimurium/E. coli

Reverse gene mutation assay	44651849 (1997)

Acceptable/guideline

313 to 5000 µg a.i./plate incubated 65.5 hours with +/- S9	Not
mutagenic under the conditions of the study

870.5300

Mammalian cells in culture

Forward gene mutation assay - CHO cells	44651857 (1998)

Acceptable/guideline

500-4000 ug/mL –S9 or 250-3000ug/mL + S9	Not mutagenic under the
conditions of the study.

870.5375

In vitro mammalian chromosome aberration test- Chinese hamster ovary
(CHO) cells	

44651855 (1997)

Acceptable/guideline

μg/mL - S9 or 338, 675, 1350 ug/mL + S9 (Highest doses slight to
moderately cytotoxic).	

Acetamiprid is a clastogen under the conditions of the study.

870.5385

In vivo mammalian chromosome aberrations - rat bone marrow	44651854
(1998)

Acceptable/guideline

250 mk/kg (maximum tolerated dose)

Bone marrow analyzed at 6, 24, and 48 hours.	Acetamiprid did not induce
a significant increase in chromosome aberrations in bone marrow cells
when compared to the vehicle control group.

970.5395

In vivo mammalian cytogenetics - micronucleus assay in mice	44651852
(1998)

Acceptable/guideline

20, 40, 80 mg/kg

Bone marrow analyzed at 24, 48, or 72 hours	Acetamiprid is not a
clastogen in the mouse bone marrow micronucleus test.

870.5550 

Unscheduled DNA synthesis in primary rat hepatocytes/mammalian cell
culture	44651856 (1998)

Acceptable/guideline

0.5 to 1000 μg/mL	

Acetamiprid tested negatively for UDS in mammalian hepatocytes in vivo.

870.6200a

Acute neurotoxicity screening battery-rats

(gavage)	44651842 (1997) Acceptable/guideline

0, 10, 30, 100 mg/kg	Neurotoxicity:

NOAEL= 10 mg/kg/day

LOAEL = 30 mg/kg based on reduction in locomotor activity

870.6200b

Subchronic neurotoxicity screening battery

(dietary)	44651845 (1997)

Acceptable/guideline

0, 100, 200, 800, 1600 ppm

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

NOAEL= 14.8/16.3 mg/kg/day (M/F)

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

870.6300

Developmental neurotoxicity – rat (gavage)	46255619 (2003)

Acceptable/Non-Guideline

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

Volume: 5 mL/kg

Vehicle: 5% gum Arabic with 0.01% Tween 80 

	Maternal:

NOAEL = 10 mg/kg/day

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

Offspring:

NOAEL = 10 mg/kg/day. 

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

870.7485

Metabolism and pharmacokinetics-rats	44988503-7 (1997)

Acceptable/guideline

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

15-day repeated doses study with 1 mg/kg (gavage); Biliary excretion
study with 1 mg/kg (gavage)

	Extensively and rapidly metabolized.  Metabolites 79-86% of
administered dose.  Profiles similar for males and females for both oral
and intravenous dosing.  Thirty-seven percent of dose recovered in urine
and feces as unchanged test article.  Urinary and fecal metabolites from
15-day repeat dose experiment only showed minor differences from
single-dose test.   Initial Phase I biotransformation: demethylation of
parent.  6-chloronicotinic acid was the most prevalent metabolite. Phase
II metabolism shown by the increase in glycine conjugate.

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, an overall NOAEL of 10
mg/kg (threshold) and LOAEL of 20 mg/kg could be estimated for a single
dose by various exposure routes.

870.7600

Dermal penetration	44651844 (1997)

Acceptable/guideline

0, 100, 500, 1000 mg/kg/day

Applied 6 hours/day for 5 days/week over a 21 day period

NOAEL > 1000 mg/kg/day	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).

	44651858 (1997)

Acceptable/non-guideline 

1.09, 9.53, 90.2 ug/cm2

	Absorption was highest at the mid-dose and increased with duration
(4.07% at 10 after 10 hours and 6.34% after 24 hours).  Residue
remaining in the skin at 24 hours is 25.0%.  In addition to absorbed
dose (6.34%), total absorption is estimated at 30%.

N/A

28-Day Range-finding Study – dog

(dietary)	45245306

Non-guideline

0, 125, 250, 500, 1000 mg/kg/day

	NOAEL = 16.7/19.1 (M/F) mg/kg/day 

LOAEL =  28.0/35.8 (M/F) mg/kg/day based on reduced BW gain

Appendix C:	Tolerance Summary  TC \l1 "Appendix C:	Tolerance Summary 

Appendix C.   Tolerance Summary for Acetamiprid.

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

Clover, forage	0.10	0.10	Recommended tolerances are for regional
registration.

Clover, hay	0.01	0.01

	Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F
0.35	0.35	Pending label revision to prohibit use of a spreader,
methylated seed oil or crop oil.   Correct term is Fruit, small, vine
climbing, except fuzzy kiwifruit, subgroup 13-07F

„@

^„@

	

A

B

N

p

q

±

²

¸

¹

Ù

ë

í

î

ï

	

$

D

E

q

˜

²

¸

Ø

ï

ð

ò

	

	

 

!

A

£

摧枻_ༀ!

;

<

=

>

?

@

A

B

C

_

`

a

b

‚

ƒ

ž

Ÿ

 

¡

¢

£

¤

¥

Á

Â

Ã

Ä

á

â

ã

ý

þ

j

"þ

ÿ

ô

@

jÝ

j`

jÑ

jT

@

j

h‡m

 hE

hE

! hE

hE

- hE

hE

 hE

h

h

h

0

h

 h

h˜

萏Ũ葞Ũ摧僾¹

$

0

h˜

h˜

h˜

h˜

h˜

h˜

将

\

\

0

1

q

.

/

0

1

?

q

r

É

Ê

è

é

ê

ñ

ô

õ

愀Ĥ摧⦪ÿ

愀Ĥ摧⦪ÿ

Ԁõ

ø

ù

ü

ý

þ

愀Ĥ摧⦪ÿ

愀Ĥ摧⦪ÿ

愀Ĥ摧⦪ÿ

愀Ĥ摧⦪ÿ

ô

摧໺W

摧䮾H

㄀Ĥ摧羌)

 h

 h

瑹䲶ü

㐀ۖĀ̊e攃昀Ĵ瑹䲶ü

摧䲶ü

摧䲶ü

㐀ۖĀ̊e攃昀Ĵ瑹䲶ü

摧䲶ü

摧䲶ü

 h

 h

 h

kd

 h

Ff

 h

h±

 h

 hÏ5

K

 h

 h

䀀Ħ摧㠮

h›

 hæ	

h›

hY

hƒ

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

愀Ĥ摧習?

kd

hƒ

@

@

@

@

hƒ

hƒ

@

@

䀀逋 ࠞ耥䀆

䀀逋 ࠞ耥䀆

䀀逋 ࠞ耥䀆

hý

hý

hý

hŠK

1

q

r

‘

š

í

ï

'

(

‹

‘

–

ê

ë

ù

ú

Ø	@

옍)

옍)

옍)

㄀Ĥ摧䌿S

옍)

̀

l	¤

 h

l	¤

l	¤

 

 h

 h

 h

š

옍)

摧ፖ

瑹ፖ咊

摧ፖ

摧ፖ

摧ፖ

摧ፖ

摧ፖ

摧ፖ

摧ፖ

瑹ፖ咊

摧ፖ

摧ፖ

摧ፖ

瑹ፖ咊

옍)

rape at 0.20 ppm should be concomitantly removed upon establishment of
the subgroup 13-07F tolerance.

Grape	0.20	Remove	Grapes will be covered under the subgroup 13-07F
tolerance.

Tea, dried	50.0	50.0	Tolerance without a U.S. registration.

Appendix D:	INTERNATIONAL RESIDUE LIMIT STATUS   TC \l1 "Appendix D:
International Residue Limit Status 

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:	

Common Name:

Acetamiprid	

X Proposed tolerance

( Reevaluated tolerance

( Other	

Date:  07/06/2009

Updated: Oct 5, 2009 with the tea MRL information.

Codex Status (Maximum Residue Limits)	

U. S. Tolerances

X No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested	

Petition Number:  9E7544

DP Barcode:  D364833

Other Identifier:  

Residue definition (step 8/CXL): N/A	

Reviewer/Branch:  Dennis McNeilly/RAB2

	

Residue definition:  acetamiprid
[N1-[(6-chloro-3-pyridyl)methyl]-N2-cyano-N1-methylacetamidine]

Crop (s)	

MRL (mg/kg)	

Crop(s) 	

Tolerance (ppm)

	

	Clover, forage	0.10 

	

	Clover, hay	0.01

	

	Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F
0.35

	

	Tea	

50.0

Limits for Canada	

Limits for Mexico

( No Limits

( No Limits for the crops requested	

( No Limits

X No Limits for the crops requested

Residue definition: (E )-N-[(6-chloro-3-pyridinyl)methyl]-N’
-cyano-N-methylethanimidamide

	

Residue definition: acetamiprid

Crop(s)	

MRL (mg/kg)	

Crop(s)	

MRL (mg/kg)

Grapes	

0.2	

	

	

	

	

Notes/Special Instructions:

S. Funk, 07/07/2009.  Note:  There are no MRLs for acetamiprid in Codex.
 There is no MRL for acetamiprid on tea in Australia.  There is no MRL
for acetamiprid on tea in Canada.  Japan has a 50 ppm MRL for tea.

Acetamiprid		                 DP No.: 369474

Pa敧ጠ倠䝁⁅㈔ᔴ漠⁦–啎偍䝁卅ᐠ㌶ക഍഍捁瑥浡灩
楲।楄瑥牡⁹硅潰畳敲䄠獳獥浳湥ॴ偄丠⹯›〳㜹〴倍
⁃潃敤›㤰〹〵उ慐敧›
漠⁦–啎偍䝁卅尠‪牡扡捩尠‪䕍䝒䙅剏䅍⁔㘔ᔳ഍഍
഍഍倍条⁥–䅐䕇ᐠ㘲―景ጠ丠䵕䅐䕇⁓㘔ᔳ഍捁瑥浡
灩楲।楄瑥牡⁹硅潰畳敲䄠獳獥浳湥ॴ偄丠⹯›〳㜹〴
倍⁃潃敤›㤰〹〵उ慐敧›
漠⁦–啎偍䝁卅尠‪牡扡捩尠‪䕍䝒䙅剏䅍⁔㘔ᔳ഍഍
഍഍慐敧ጠ倠䝁⁅㘔ᔲ漠⁦–啎偍䝁卅ᐠ㌶ക഍