Document ID: EPA-HQ-OPP-2006-0968-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-20T04:00Z

SEQ CHAPTER \h \r 1 							

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

							

MEMORANDUM

Date:		5/14/07

Subject:	Amended. Imidacloprid.  Human Health Risk Assessment. Section 3
Requests for Uses on Peanut, Proso Millet, Pearl Millet, Oat, Kava,
Globe Artichoke, Caneberries, Wild Raspberry, and Soybeans.

PP#s	6E7116, 6E7108, & 6F7049

PC Code:	129099	40 CFR:	180.472

DP Num:	337873, 337876, 337879	Decision #s:	365863, 371243, 370491

From:	W. Cutchin, Acting Branch Senior Scientist

	Alternative Risk Integration Assessment Team (ARIA)

	Risk Integration Minor Use and Emergency Response Branch (RIMUERB)

		Registration Division (RD) (7505P)

Through:	PV Shah, Ph.D., Acting Branch Chief

		Registration Action Branch (RAB1)

		Health Effects Division (HED) (7509P)

To:		S. Jackson/D. Rosenblatt, PM Team 05

		RIMUERB/RD (7505P)

The ARIA Team of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that ARIA evaluate hazard and exposure data and
conduct dietary, occupational, residential and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from proposed and registered uses of imidacloprid
[1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-imidazolidinimine] on
peanut, proso millet, pearl millet, oat, kava, globe artichoke,
caneberries, wild raspberry, and soybeans.  A summary of the findings
and an assessment of human risk resulting from the registered and
proposed tolerances for imidacloprid is provided in this document.  The
risk assessment, the residue chemistry data review, and the dietary risk
assessment were provided by W. Cutchin (ARIA), the
occupational/residential exposure assessment by M. Dow (ARIA), and the
drinking water assessment by R. Parker of the Environmental Fate and
Effects Division (EFED).

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc165171349"  1.0	Executive
Summary	  PAGEREF _Toc165171349 \h  4  

  HYPERLINK \l "_Toc165171350"  2.0	Ingredient Profile	  PAGEREF
_Toc165171350 \h  12  

  HYPERLINK \l "_Toc165171351"  2.1	Summary of Registered/Proposed Uses	
 PAGEREF _Toc165171351 \h  13  

  HYPERLINK \l "_Toc165171352"  2.2	Structure and Nomenclature	  PAGEREF
_Toc165171352 \h  16  

  HYPERLINK \l "_Toc165171353"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc165171353 \h  17  

  HYPERLINK \l "_Toc165171354"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc165171354 \h  17  

  HYPERLINK \l "_Toc165171355"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc165171355 \h  17  

  HYPERLINK \l "_Toc165171356"  3.1.1	Dose-response	  PAGEREF
_Toc165171356 \h  18  

  HYPERLINK \l "_Toc165171357"  3.1.2	FQPA	  PAGEREF _Toc165171357 \h 
21  

  HYPERLINK \l "_Toc165171358"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc165171358 \h  21  

  HYPERLINK \l "_Toc165171359"  3.3	FQPA Considerations	  PAGEREF
_Toc165171359 \h  22  

  HYPERLINK \l "_Toc165171360"  3.3.1	Adequacy of the Toxicity Data Base
  PAGEREF _Toc165171360 \h  23  

  HYPERLINK \l "_Toc165171361"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc165171361 \h  23  

  HYPERLINK \l "_Toc165171362"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc165171362 \h  23  

  HYPERLINK \l "_Toc165171363"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc165171363 \h  25  

  HYPERLINK \l "_Toc165171364"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc165171364 \h  26  

  HYPERLINK \l "_Toc165171365"  3.3.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc165171365 \h  26  

  HYPERLINK \l "_Toc165171366"  3.3.7	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc165171366 \h  27  

  HYPERLINK \l "_Toc165171367"  3.4	Safety Factor for Infants and
Children	  PAGEREF _Toc165171367 \h  28  

  HYPERLINK \l "_Toc165171368"  3.4.1	Adequacy of the Exposure Data Base
  PAGEREF _Toc165171368 \h  28  

  HYPERLINK \l "_Toc165171369"  3.4.2	Safety Factor Conclusion	  PAGEREF
_Toc165171369 \h  29  

  HYPERLINK \l "_Toc165171370"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc165171370 \h  29  

  HYPERLINK \l "_Toc165171371"  3.5.1	Acute Population Adjusted Dose
(aPAD) - General Population	  PAGEREF _Toc165171371 \h  29  

  HYPERLINK \l "_Toc165171372"  3.5.2	Chronic Population Adjusted Dose
(cPAD)	  PAGEREF _Toc165171372 \h  30  

  HYPERLINK \l "_Toc165171373"  3.5.3	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc165171373 \h  32  

  HYPERLINK \l "_Toc165171374"  3.5.4	Dermal Absorption	  PAGEREF
_Toc165171374 \h  33  

  HYPERLINK \l "_Toc165171375"  3.5.5	Dermal Absorption	  PAGEREF
_Toc165171375 \h  34  

  HYPERLINK \l "_Toc165171376"  3.5.6	Dermal Exposure	  PAGEREF
_Toc165171376 \h  34  

  HYPERLINK \l "_Toc165171377"  3.5.7	Inhalation Exposure	  PAGEREF
_Toc165171377 \h  35  

  HYPERLINK \l "_Toc165171378"  3.5.8	Level of Concern for Margin of
Exposure	  PAGEREF _Toc165171378 \h  36  

  HYPERLINK \l "_Toc165171379"  3.5.9	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc165171379 \h  37  

  HYPERLINK \l "_Toc165171380"  3.3.10	Classification of Carcinogenic
Potential	  PAGEREF _Toc165171380 \h  37  

  HYPERLINK \l "_Toc165171381"  3.5.11	Summary of Toxicological Doses
and Endpoints for Imidacloprid for Use in Human Risk Assessments.	 
PAGEREF _Toc165171381 \h  39  

  HYPERLINK \l "_Toc165171382"  3.6	Endocrine disruption	  PAGEREF
_Toc165171382 \h  40  

  HYPERLINK \l "_Toc165171383"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc165171383 \h  41  

  HYPERLINK \l "_Toc165171384"  4.1	Incident Reports	  PAGEREF
_Toc165171384 \h  41  

  HYPERLINK \l "_Toc165171385"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc165171385 \h  41  

  HYPERLINK \l "_Toc165171386"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc165171386 \h  41  

  HYPERLINK \l "_Toc165171387"  5.1.1	Metabolism in Primary Crops and
Livestock	  PAGEREF _Toc165171387 \h  41  

  HYPERLINK \l "_Toc165171388"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc165171388 \h  41  

  HYPERLINK \l "_Toc165171389"  5.1.3	Analytical Methodology	  PAGEREF
_Toc165171389 \h  42  

  HYPERLINK \l "_Toc165171390"  5.1.4	Environmental Degradation	 
PAGEREF _Toc165171390 \h  43  

  HYPERLINK \l "_Toc165171391"  5.1.5	Comparative Metabolic Profile	 
PAGEREF _Toc165171391 \h  43  

  HYPERLINK \l "_Toc165171392"  5.1.6	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc165171392 \h  44  

  HYPERLINK \l "_Toc165171393"  5.1.7	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc165171393 \h  45  

  HYPERLINK \l "_Toc165171394"  5.1.8	Drinking Water Residue Profile	 
PAGEREF _Toc165171394 \h  45  

  HYPERLINK \l "_Toc165171395"  5.1.9	Food Residue Profile	  PAGEREF
_Toc165171395 \h  45  

  HYPERLINK \l "_Toc165171396"  5.1.10	International Residue Limits	 
PAGEREF _Toc165171396 \h  50  

  HYPERLINK \l "_Toc165171397"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc165171397 \h  50  

  HYPERLINK \l "_Toc165171398"  5.3	Anticipated Residue and Percent Crop
Treated Information	  PAGEREF _Toc165171398 \h  51  

  HYPERLINK \l "_Toc165171399"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc165171399 \h  53  

  HYPERLINK \l "_Toc165171400"  6.1	Residential Handler Exposure	 
PAGEREF _Toc165171400 \h  53  

  HYPERLINK \l "_Toc165171401"  6.2.	Residential  Post-application
Exposure	  PAGEREF _Toc165171401 \h  59  

  HYPERLINK \l "_Toc165171402"  6.3	Combined Residential Exposure	 
PAGEREF _Toc165171402 \h  65  

  HYPERLINK \l "_Toc165171403"  6.4	Other (Spray Drift, etc.)	  PAGEREF
_Toc165171403 \h  66  

  HYPERLINK \l "_Toc165171404"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc165171404 \h  66  

  HYPERLINK \l "_Toc165171405"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc165171405 \h  67  

  HYPERLINK \l "_Toc165171406"  7.2	Short-Term Aggregate Risk	  PAGEREF
_Toc165171406 \h  67  

  HYPERLINK \l "_Toc165171407"  7.3	Intermediate-Term Aggregate Risk	 
PAGEREF _Toc165171407 \h  68  

  HYPERLINK \l "_Toc165171408"  7.4	Long-Term Aggregate Risk	  PAGEREF
_Toc165171408 \h  68  

  HYPERLINK \l "_Toc165171409"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc165171409 \h  68  

  HYPERLINK \l "_Toc165171410"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc165171410 \h  69  

  HYPERLINK \l "_Toc165171411"  9.1	Short-/Intermediate-/Long-Term
Handler Risk	  PAGEREF _Toc165171411 \h  69  

  HYPERLINK \l "_Toc165171412"  9.2	Short-/Intermediate-/Long-Term
Post-application Risk	  PAGEREF _Toc165171412 \h  72  

  HYPERLINK \l "_Toc165171413"  9.3	Restricted Entry Interval (REI)	 
PAGEREF _Toc165171413 \h  74  

  HYPERLINK \l "_Toc165171414"  10.0	Data Needs and Label Requirements	 
PAGEREF _Toc165171414 \h  74  

  HYPERLINK \l "_Toc165171415"  10.1	Toxicology	  PAGEREF _Toc165171415
\h  74  

  HYPERLINK \l "_Toc165171416"  10.2	Residue Chemistry	  PAGEREF
_Toc165171416 \h  74  

  HYPERLINK \l "_Toc165171417"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc165171417 \h  74  

  HYPERLINK \l "_Toc165171418"  Attachment 1:  Toxicological Effects
Tables	  PAGEREF _Toc165171418 \h  76  

  HYPERLINK \l "_Toc165171419"  Attachment 2:  Structures of
Imidacloprid Metabolites	  PAGEREF _Toc165171419 \h  82  

 

  SEQ CHAPTER \h \r 1 1.0	Executive Summary

Imidacloprid is a systemic insecticide registered to control soil
insects, sucking insects, chewing insects, and termites.  It is
effective against the larval, nymphal and adult stages.  The primary
mode of action is the disruption of the nervous system by acting as an
inhibitor at nicotinic acetylcholine receptors.  Imidacloprid blocks the
signals that are induced by acetylcholine at the post-synaptic membrane,
resulting in nerve function impairment.

The Interregional Research Project No. 4 (IR-4), on behalf of the
Agricultural Experiment Stations of Texas, Missouri, Georgia, Wisconsin,
and Hawaii, has submitted a petition for the use of imidacloprid on
peanuts; proso and pearl millet; oats; kava; globe artichoke; caneberry,
subgroup13A; and wild raspberry.  IR-4 is not requesting a change in the
existing tolerance for globe artichokes; the request is for the addition
of a soil use to the existing foliar use.  Bayer Corp. has also
submitted a petition for the use of imidacloprid on soybeans.

Hazard Assessment

Imidacloprid has low acute toxicity via the dermal and inhalation routes
and moderate acute toxicity via the oral route.  It is not an eye or
dermal irritant and is not a dermal sensitizer.  The nervous system is
the primary target organ of imidacloprid.  Nervous system effects
evidenced as changes in clinical signs and Functional Observation
Battery (FOB) assessments were seen in rat acute and subchronic
neurotoxicity studies.  These effects included decreased motor and
locomotor activities, tremors, gait abnormalities, increased righting
reflex impairments and body temperature, and decreased number of rears
and response to stimuli and decreases in forelimb and hindlimb grip
strength.  Also, in the rat developmental neurotoxicity study, a
decrease in the caudate/putamen width was noted in female pups.  Retinal
atrophy was seen in high-dose females in the rat combined chronic
toxicity/carcinogenicity study.  No nervous system effects were noted in
the mouse carcinogenicity or the reproduction and developmental studies
or in the rabbit dermal or rat inhalation studies.  The dog was less
sensitive to the effects of imidacloprid.  No effects were noted up to
the highest dose tested in the chronic toxicity study.  The rabbit
appeared to be very sensitive as there was increased mortality in the
oral developmental study at the highest dose tested.  Increased
incidence of mineralized particles in the thyroid colloid was noted in
the rat combined chronic toxicity/carcinogenicity study.  Body weight
decrements were noted in the rat and/or mouse chronic and
carcinogenicity studies, the rat subchronic neurotoxicity study, and the
developmental, developmental neurotoxicity and reproduction studies.  No
effects were observed in the rabbit dermal or rat inhalation studies. 
There was no evidence of carcinogenic potential in either the rat
chronic toxicity/carcinogenicity or mouse carcinogenicity studies and no
concern for mutagenicity.  There was no evidence of increased
qualitative or quantitative susceptibility of rats or rabbits to in
utero exposure to imidacloprid and no evidence of qualitative or
quantitative increased susceptibility of rat offspring in the
reproduction study.  There was evidence of an increased qualitative
susceptibility in the rat developmental neurotoxicity study.  At the
highest dose tested, maternal effects consisted largely of slight
decreases in food consumption and body weight gain during early
lactation, while pup effects included decreased body weight; decreased
motor activity; decreased caudate/putamen width, females only [postnatal
days (PNDs) 11 and adult]; and slight changes in performance in the
water maze, males only, at the same dose.

On 11/10/93, the Reference Dose (RfD)/Peer Review Committee classified
imidacloprid as a “Group E” chemical, no evidence of carcinogenicity
for humans, by all routes of exposure based upon lack of evidence of
carcinogenicity in rats and mice.

  SEQ CHAPTER \h \r 1 The HED Hazard Identification Assessment Review
Committee (HIARC) met on 10/8/02 to select endpoints for risk assessment
and to evaluate the potential for increased susceptibility of infants
and children from exposure to imidacloprid according to the February
2002 OPP 10X guidance document.  This was a re-evaluation of the
toxicology database subsequent to the initial evaluation by the HIARC on
9/11/97.  The FQPA Safety Factor (SF) was reduced to 1x based on
toxicological considerations by the HIARC (TXR # 0051292, 10/31/02), the
conservative residue assumptions used in the dietary and residential
exposure risk assessments, and the completeness of the residue chemistry
and environmental fate databases (evaluated by the risk assessment
team).

Risk assessments were conducted for the following specific exposure
scenarios listed below.  The acute Population-Adjusted Dose (aPAD) was
calculated by dividing the acute Point of Departure (aPOD), in this case
the Lowest-Observed-Adverse-Effect-Level (LOAEL) by 300 [10X for
interspecies extrapolation, 10X for intraspecies variation; and 3X
uncertainty factor (UF) for the use of a LOAEL due to the lack of a
No-Observed-Adverse-Effect-Level (NOAEL) in the acute neurotoxicity
study].  The chronic PAD (cPAD) was calculated by dividing the chronic
POD (cPOD), in this case the NOAEL by 100 (10X for interspecies
extrapolation, 10X for intraspecies variation).  Since the FQPA SF has
been reduced to 1X, the aPAD and cPAD are not further adjusted.  Since
oral studies were selected for all durations of dermal and inhalation
exposure, a 7% dermal absorption factor and a 100 % inhalation
absorption factor are used in the route-to-route extrapolation.  The
level of concern for occupational dermal and inhalation exposures are
for Margins of Exposure (MOEs) <100.  For the occupational exposure
assessment, dermal and inhalation exposure estimates can be combined
because the same effects (endpoints) were identified for dermal and
inhalation exposure from an oral study.  The level of concern for
residential oral, dermal and inhalation exposures are for MOEs <100. 
Short-term oral, dermal and inhalation exposure estimates can be
aggregated because of the use of the same toxicity endpoint (decreased
body weight gain) from the same study (oral rat developmental toxicity
study).

Exposure Scenario	Dose	Endpoint	Effect/Study

Acute dietary	LOAEL = 42 mg/kg/day	aPAD  = 0.14 mg/kg/day	Decreased
motor and locomotor activities/Acute neurotoxicity study in rats

Chronic dietary	NOAEL = 5.7 mg/kg/day	cPAD = 0.057 mg/kg/day	Increased
incidence of mineralized particles in the thyroid colloid/Chronic
toxicity study in rats

Short-term incidental oral	Oral NOAEL = 10 mg/kg/day	Target MOE = 100
(residential)	Decreased body weight gain and decreased corrected body
weight gain in maternal animals/ Developmental toxicity study in rats

Short-term dermal	Oral NOAEL = 10 mg/kg/day	Target MOE = 100
(occupational and residential)

	Short-term inhalation	Oral NOAEL = 10 mg/kg/day	Target MOE = 100
(occupational and residential)

	

Exposure Assessment

The petitioners have submitted sample labels for numerous imidacloprid
products.  The uses on peanuts and kava include both an in-furrow spray
on or below seed during or before planting and a foliar use. The peanut
and kava seed uses are for a single application at 0.38 pounds active
ingredient per acre (lb ai/A).  The foliar uses on peanut and kava are
for up to 3 applications for a total 0.13 lb ai/A with pre-harvest
intervals (PHI) of 14 days for peanut and 7 days for kava.  The uses on
millet and oats include commercial seed treatment or below seed during
or before planting at 0.25 or 0.09 lb ai/100lb seed, respectively.  The
use on globe artichoke includes both an in-furrow spray on or below seed
during or before planting at and a foliar use, both at 0.5 lb ai/A with
a 7-day PHI.  The labels for caneberries indicate either a foliar
application at 0.3 lb ai/A with a 3-day PHI or a drench application 0.5
lb ai/A with a 7-day PHI.  Since the previous lower tolerance for
caneberries was based using the drench application at the higher rate,
the use is supported and may remain on the labels.  There is an existing
use of imidacloprid on soybean seeds for protection from damage caused
by seed corn maggot, to reduce feeding damage caused by soybean aphids
and over-wintering bean leaf beetles, and to help suppress the spread of
certain viruses, at 2.0-4.0 fl. oz. per hundredweight of seed.  The
requested foliar use on soybeans is in addition to the current use on
soybean seeds for three applications at 0.047 lb ai/A with a maximum
total application of 0.14 lb ai/A.  

The nature of imidacloprid residues in plants and livestock is
adequately understood.  The residue of concern in plants and livestock
are imidacloprid and its metabolites containing the 6-chloropyridinyl
moiety, all expressed as the parent.  Adequate enforcement methods are
available for determination of imidacloprid residues of concern in plant
(Bayer Gas Chromatography/Mass Spectrometry (GC/MS) Method 00200) and
livestock commodities (Bayer GC/MS Method 00191).  The method is a
common moiety method that uses oxidation of parent and metabolites to
6-chloronicotinic acid (6-CNA) with demonstrated limit of detection
(LOD) and limit of quantitation (LOQ) at 0.01 and 0.05 ppm,
respectively, in plant commodities.  Samples in the submitted peanut
crop field trial and processing studies were for analyzed for combined
residues of imidacloprid and its metabolites containing
6-chloropyridinyl moiety, all expressed as the parent, using a
modification of Bayer GC/MS Method 00200.  The LOD and LOQ were
calculated as 0.03 ppm and 0.076 ppm for nutmeat; 0.01 ppm and 0.033
ppm, for oil; and 0.02 ppm and 0.062 ppm for meal.  For caneberries,
total residues of imidacloprid were determined using a working method
based on Bayer Method 00200.  The lower limit of method validation
(LLMV) of the modified method in this study was reported as 0.05 ppm. 
LODs were estimated as 0.009 ppm, 0.02 ppm and 0.03 ppm for raspberry,
marionberry and boysenberry, respectively.  The total imidacloprid
residue was analyzed in soybean field trial and processing samples by a
common moiety method (oxidation to 6-CNA) and quantitated by liquid
chromatography with tandem mass spectroscopy detection (LC-MS/MS).  The
method in these studies, NT-001-P04-01, is based on an earlier method,
00834.  The LOQ for imidacloprid in soybean forage, hay, and seed was
0.025 ppm, 0.100 ppm, and 0.05 ppm, respectively.  The calculated LODs
for soybean forage, hay, and seed were 0.0111 ppm, 0.0382 ppm, and
0.0136 ppm, respectively.  The data from the soybean processing study
support a method LOQ of 0.050 ppm for each analyte in soybean seed and
processed commodities.  

Another analytical method was used in the caneberry trial designated as
Study No. AAFC03-085R.  The method used quantitation by high performance
liquid chromatography with mass spectroscopy detector (HPLC/MS).  The
LLMV in this study was reported as 0.30 ppm.  The LOD and LOQ were
calculated to be 0.068 ppm and 0.203 ppm, respectively.  However, total
residues of imidacloprid were determined to be below the LLMV (<0.30
ppm) and/or calculated LOQ (<0.203 ppm) at all PHIs.  As the method used
could not be validated at the target LOQ (0.05 ppm), the method LLMV was
unacceptably high and the residues reported at each PHI were below the
LLMV, this residue study is considered scientifically unacceptable. 
Therefore, the results from this trial should not be used to support the
registration of imidacloprid in/on caneberries. 

Residues of imidacloprid have previously been shown to be stable in a
variety of raw agricultural commodities (RACs) for up to 2 years. 
Peanut storage stability testing performed after approximately 4.4 years
of frozen storage showed no appreciable degradation.  There are
sufficient storage stability data to support the submitted residue field
trials and processing studies.  The expected residue levels in the
livestock feed items associated with the subject petition were used to
recalculate the maximum theoretical dietary burden (MTDB) for livestock.
 The newly calculated MTDBs are not greater than those calculated
previously. Therefore, the proposed uses will not require an increase in
livestock tolerances.

Peanut field trials were conducted using a single in-furrow applications
at a rate of approximately 0.375 lb ai/A at planting followed by foliar
applications made 4 to 6 days apart at a rate of approximately 0.044 lb
ai/A for a total of approximately 0.507 lb ai/A.  The results from the
trials show that the maximum combined residues in nutmeat were 0.40 ppm.
 Maximum residues in 14-day and 28-day hay samples were 24 ppm. 
Residues declined in nutmeat to a maximum of 0.14 ppm by 28 days.  The
submitted studies are adequate in number and geographic diversity and
are supported by adequate storage stability data and analytical
methodology.  However, the residue data as analyzed by the
Tolerance/Maximum Residue Limit (MRL) Harmonization Spreadsheet
indicates that the requested tolerances on peanut nutmeat and hay are
not appropriate.  A new Section F requesting imidacloprid tolerances on
peanuts at 0.60 ppm and peanut, hay at 35 ppm is required.

No crop-specific data to support the tolerance requests in conjunction
with the requested uses for proso millet, pearl millet, oats, kava, and
globe artichoke.  Since there are identical seed treatment uses with
tolerances for most of the cereal grain crop group and a tolerance for
indirect or inadvertent residues on the cereal grain crop group,
tolerances can be translated to the seed treatment uses on proso millet
and pearl millet.  ARIA recommends for the proposed tolerances on proso
and pearl millet grain at 0.05 ppm.  In addition, residues would be
expected on the other millet RACs as residues are found on other grain
RACs from the same uses.  A revised Section F is required for proso
millet, forage at 2.0 ppm; proso millet, hay at 6.0 ppm; proso millet,
straw at 3.0 ppm; pearl millet, forage at 2.0 ppm; pearl millet, hay at
6.0 ppm; and pearl millet, straw at 3.0 ppm.  There are already existing
tolerances for the seed treatment use on oats: oats, grain at 0.05 ppm;
oats, forage at 2.0 ppm; oats, hay at 6.0 ppm; oats, straw at 3.0 ppm as
a result of the same proposed seed treatment use as proposed here.  The
request for use and tolerance for imidacloprid on oats is not necessary;
the requested tolerances should be removed from Section F.  Since kava
is projected to be part of the root and tuber vegetable crop group 1 in
the near future and the proposed use is identical to that used for root
and tuber vegetables, ARIA recommends for the proposed imidacloprid
tolerances on kava, leaves at 4.0 ppm and kava, roots at 0.40 ppm.  A
tolerance of 2.5 ppm has already been established for imidacloprid on
globe artichokes as a result of a foliar use.  IR-4 is now requesting a
use either below the seed row before planting, in-furrow during
planting, or by chemigation into the root zone.  Comparisons of data on
foliar vs. limited soil-applied imidacloprid or the two treatments
combined indicate that the foliar treatments clearly drive the magnitude
of the resulting residues.  Any slight additional residues from soil
treatments are expected to be covered by existing tolerances established
to reflect foliar application.  Therefore, it is unlikely that the
residues of imidacloprid from the proposed soil treatment use on globe
artichoke will exceed the existing 2.5 ppm tolerance.  ARIA recommends
for the proposed imidacloprid use on globe artichoke without a change in
the existing tolerance. 

A previous petition for the use of imidacloprid on caneberries as drench
application resulted in a conditional registration and permanent
tolerance.  In the current petition, imidacloprid was applied to
caneberries in three foliar-directed broadcast sprays.  The maximum
residues observed in caneberries were 0.70 ppm in blackberry, 0.96 ppm
in raspberry, 1.7 ppm in marionberry and 1.5 ppm in boysenberry.  The
residue data as analyzed by the Tolerance/MRL Harmonization Spreadsheet
indicates that the requested tolerance on caneberries, crop group 13A at
2.5 ppm is not appropriate.  However, since the databases are small for
blackberries and raspberries, the fruits are essentially the same size
and texture, and in the interest of harmonizing with Canada, ARIA will
consider the entire database for caneberries together.  The
Tolerance/MRL Harmonization Spreadsheet indicates the appropriate
tolerance level for the entire database of caneberry residues should be
2.5 ppm.  Therefore, ARIA recommends for the proposed tolerance for
caneberry, crop group 13A at 2.5 ppm.  The petitioner has requested a
tolerance for wild raspberry.  The wild raspberry is distributed in
tropical northern Queensland in open forests and the rainforest and is
similar to raspberries and other Rubus species.  U.S. growers are
evaluating improved varieties.  ARIA will extend the residue information
to from the caneberry subgroup to wild raspberries; therefore, a
tolerance for the residues of imidacloprid on wild caneberries at 2.5
ppm is appropriate.

Residue filed trials on soybeans were conducted to measure the magnitude
of residues in soybeans resulting from the existing pre-plant seed
treatment followed by three foliar applications of imidacloprid to the
growing soybean plants.  The highest imidacloprid residue on soybean
forage and hay at 0-day PHI was 8.87 ppm and 24.0 ppm, respectively. 
The highest imidacloprid residue on soybean seed at a 21-day PHI was
2.04 ppm.  The total imidacloprid residue was found to decline
significantly on soybean forage with time.  In soybean hay, total
imidacloprid residue was found to decline significantly at one trial but
remained relatively constant at the other.  On soybean seed, total
imidacloprid residue remained constant with time.  The residue data as
analyzed by the Tolerance/MRL Harmonization Spreadsheet indicates that
the requested tolerance on soybean, forage is appropriate at 8.0 ppm. 
However, the requested tolerance levels on the other soybean commodities
are not appropriate.  A new Section F requesting imidacloprid tolerances
on soybean, seed at 3.5 ppm, and soybean, hay at 35 ppm is required.

There are many processed commodities of regulatory interest associated
with these petitions among which are millet flour, oat flour, and rolled
oats.  It has been determined that imidacloprid residues do not
concentrate in grain processed commodities; therefore, no imidacloprid
tolerances are required on millet and oat processed commodities.  The
submitted peanut processing study indicates that imidacloprid residues
do not concentrate in peanut oil.  The average concentration factor from
the two processing studies is higher than the theoretical maximum.  The
highest average field trial (HAFT) of 0.32 ppm times the theoretical
maximum of 2.2X yields an expected residue of 0.704 ppm in peanut meal. 
Therefore, the requested tolerance is not appropriate; a revised Section
F requesting an imidacloprid tolerance on peanut, meal at 0.75 ppm is
required.  The submitted processing study indicates that imidacloprid
residues do not concentrate in soybean meal, hulls, or oil.  Therefore,
a separate tolerance for imidacloprid residues in soybean meal, hulls,
or oil is not required.  The processing study indicates that
imidacloprid residues will concentrate in aspirated grain fractions. 
The expected residue is 240 ppm in aspirated grain fractions. The
requested tolerance level for imidacloprid residues in aspirated grain
fractions is appropriate.  However, the Agency does not differentiate
soybean from other aspirated grain fractions; therefore, a revised
Section F for aspirated grain fractions at 240 ppm is required.

EFED provided revised, Tier 1 estimated drinking water concentrations
(EDWCs) for surface water (using FQPA Index Reservoir Screening Tool
(FIRST)) for imidacloprid and its degradates (imidacloprid urea,
imidacloprid guanidine, and imidacloprid olefin).  Revised ground water
EDWCs were not estimated because these values have been shown previously
to be substantially lower in magnitude than the surface water
concentrations.  The revised surface water EDWCs for the proposed uses
do not exceed the EDWCs provided by EFED in conjunction with the 3/14/03
HED risk assessment for imidacloprid (DP Num: 271770, M. Barrett,
2/25/03).  Therefore, the overall highest surface and ground water EDWCs
were used in the current risk assessment (DP Num: 311925, R. Parker,
5/16/06).  Water residues were incorporated in the DEEM-FCID into the
food categories “water, direct, all sources” and “water, indirect,
all sources.”  The surface water values (using FIRST), the acute
(peak) and chronic (annual average) EDWCs, based on the citrus use
pattern, are 36.0 ppb and 17.2 ppb, respectively.

An unrefined, acute dietary exposure assessment using tolerance-level
residues and assuming 100% crop treated (%CT) for all registered and
proposed commodities was conducted for the general U.S. population and
various population subgroups.  Exposure to drinking water was
incorporated directly in the dietary assessment using the acute (peak)
concentration for surface water generated by the FIRST model, 36.0 ppb. 
This assessment indicates that the acute dietary exposure estimates are
below HED’s level of concern, <100% aPAD, at the 95th exposure
percentile for the general U.S. population and all other population
subgroups.  The acute dietary exposure is estimated for the U.S.
population at 28% of the aPAD and the most highly exposed population
subgroup, children 1-2 years old, at 70% of the aPAD.  

A partially refined, chronic dietary exposure assessment (using
tolerance-level residues for all registered and proposed commodities,
and %CT information for some commodities) was conducted for the general
U.S. population and various population subgroups.  Exposure to drinking
water was incorporated directly into the dietary assessment using the
chronic (annual average) concentration for surface water generated by
the FIRST model, 17.2 ppb.  This assessment concludes that the chronic
dietary exposure estimates are below HED’s level of concern (<100%
cPAD) for the general U.S. population and all population subgroups.  The
chronic dietary exposure is estimated for the U.S. population at 13% of
the cPAD and the most highly exposed population subgroup, children 1-2
years old, at 38% of the cPAD.

Residential

Imidacloprid is registered for indoor as well as outdoor residential
uses on ornamental lawns and turf as well as for use on golf courses,
ornamental plantings (i.e. , flowering plants, foliage plants,
herbaceous perennial plants, and woody plant, shrubs and trees), and as
a pre- and post-construction termiticide.  Residential handlers may also
be exposed to imidacloprid via the use of spot-on treatments for dogs or
cats for flea control.  ARIA believes that residential pesticide
handlers (i.e., persons who might mix, load and, or apply a pesticide
material) could be exposed to several formulations that contain
imidacloprid.  ARIA expects that residential handler exposures will be
short-term (i.e., 1-30 days) based upon the pest spectra, sites of
application, methods of application, formulations and the retreatment
intervals.  The pet-treatment scenario resulted in the highest combined
MOE for adults (MOE = 400; handler and post-application) and children
(MOE = 260; post-application).  The turf-treatment scenario resulted in
much lower exposures for both adults (MOE = 15,000; handler and
post-application) and children (MOE = 1,500; post-application).  These
MOEs are below HED’s level of concern.

Aggregate Risk Exposure

The acute aggregate risk assessment takes into account exposure
estimates from dietary consumption of imidacloprid (food and drinking
water).  The acute dietary exposure estimates, which included food and
water, are below HED’s level of concern (<100% aPAD) at the 95th
exposure percentile for the general U.S. population (28% of the aPAD)
and all other population subgroups.  The most highly-exposed population
subgroup is children 1-2 years old, at 70% of the aPAD.  Therefore, the
acute aggregate risk associated with the proposed use of imidacloprid
does not exceed HED’s level of concern for the general U.S. population
or any population subgroup.

Short-term aggregate risk assessments are required for adults as there
is potential for both dermal and inhalation handler exposure, and dermal
post-application exposure from the residential uses of imidacloprid on
turf and pets.  In addition, short-term aggregate risk assessments are
required for children/toddlers because there is a potential for oral and
dermal post-application exposure resulting from the residential uses of
imidacloprid on turf and pets.  The pet-treatment scenario resulted in
the lowest combined MOE for adults (MOE = 400; handler and
post-application) and children (MOE = 260; post-application).  The
turf-treatment resulted in much lower exposures for both adults (MOE =
15,000; handler and post-application) and children (MOE = 1,500;
post-application).  Therefore, the pet-treatment exposure estimates were
aggregated with the chronic dietary (food and water) to provide a
worst-case estimate of short-term aggregate risk for the U.S. population
and children 1-2 years old (the child population subgroup with the
highest estimated chronic dietary food exposure).  As the resulting MOEs
are greater than 100, the short-term aggregate risks are below HED's
level of concern.

 

An assessment of the intermediate-term aggregate risk for exposure to
imidacloprid is not required since, based on the current use patterns,
ARIA does not expect exposure durations that would result in
intermediate-term exposures.

The chronic aggregate risk assessment takes into account average
exposure estimates from dietary consumption of imidacloprid (food and
drinking water) and residential uses.  However, due to the use patterns,
no chronic residential exposures are expected.  The chronic dietary
exposure estimates, which included food and water, are below HED’s
level of concern (<100% cPAD) for the general U.S. population (13% of
the cPAD) and all population subgroups.  The most highly exposed
population subgroup is children 1-2 years old, at 38% of the cPAD. 
Therefore, the chronic aggregate risk associated with the proposed use
of imidacloprid does not exceed HED’s level of concern for the general
U.S. population or any population subgroups.

An assessment of the cancer risk for exposure to imidacloprid is not
required.

Occupational Exposure

Imidacloprid products are registered to control aphids, leafhoppers,
whiteflies and rednecked cane borer.  Some imidacloprid products are not
limited to soil applications and may have repeat applications.  None of
the products may be applied pre-bloom, during bloom or when bees are
actively foraging.  All of the product labels require applicators and
other handlers to wear personal protective equipment (PPE) consisting of
long-sleeved shirt, long pants, shoe plus socks and chemical-resistant
gloves made of any waterproof material such as barrier laminate, butyl
rubber, nitrile rubber, neoprene rubber, natural rubber, polyethylene,
polyvinylchloride or viton.  

Based primarily on the proposed new use patterns, commercial and private
(i.e., grower operators) pesticide handlers are typically expected to
have short-term exposures (i.e., 1-30 days).  The proposed new use
pattern indicates that the most highly exposed occupational pesticide
handlers are likely to be mixer/loaders using open-pour loading of
liquids or granules, and applicators using airblast sprayers,
ground-boom sprayers, high-pressure hand-wand sprayers, backpack
sprayers and aircraft.  In some cases, HED believes that certain
individuals (private growers versus commercial applicators) may perform
all three handler activities, that is, mix, load, and apply the
material.  A MOE of 100 is adequate to protect occupational pesticide
handlers from exposures to imidacloprid.  All of the pesticide handler
exposure scenarios from the proposed new use patterns are above an MOE
of 100 and therefore do not exceed HED’s level of concern.

Typically there is the possibility for agricultural workers to
experience post-application exposures to dislodgeable pesticide
residues.  Post-application worker exposure is estimated using HED
procedure that assumes 20% of the application rate is available as
dislodgeable foliar residue on the day of treatment.  ARIA does not
expect post-application exposures to exceed short-term exposure. 
Therefore, only short-term exposures are assessed.  These estimates are
considered to be screening level estimates i.e., conservative
(protective).  HED’s level of concern for dermal exposure is for MOEs
<100.  In this case, all the MOEs are greater than 100; therefore,
post-application dermal exposure is not of concern for agricultural
workers.  Post-application inhalation exposure is expected to be
negligible.

Recommendation

Provided revised Section Fs are submitted as specified in Section 10.2,
the residue chemistry and hazard databases support the establishment of
the permanent tolerances for the combined residues of imidacloprid and
its metabolites containing the 6-chloropyridinyl moiety, all expressed
as the parent, in/on the RACs listed below.

Commodity	Recommended Tolerance (ppm)

Peanut	0.60

Peanut, hay	35

Peanut, meal	0.75

Millet, proso, grain	0.05

Millet, proso, forage 	2.0

Millet, proso, hay 	6.0

Millet, proso, straw 	3.0

Millet, pearl, grain	0.05

Millet, pearl, forage	2.0

Millet, pearl, hay	6.0

Millet, pearl, straw	3.0

Kava, roots	0.40

Kava, leaves	4.0

Caneberry, subgroup 13A	2.5

Wild raspberry	2.5

Soybean, seed	3.5

Soybean, forage	8.0

Soybean, hay	35

Aspirated grain fractions	240

2.0	Ingredient Profile

 tc "2.0	Ingredient Profile" 

Imidacloprid is an insecticide registered for uses on a variety of crops
for the control of many insects, including aphids, cucumber beetles and
whiteflies (including sweet potato or silverleaf whitefly). 
Imidacloprid is a member of the pyridylmethylamine class of compounds. 
Its mode of action is the disruption of the nervous system by acting as
an inhibitor at nicotinic acetylcholine receptors.  Imidacloprid blocks
the signals that are induced by acetylcholine at the post-synaptic
membrane, resulting in normal nerve function impairment.

Imidacloprid is also currently registered for use on residential
ornamental lawns, golf courses, and ornamental plantings (i.e.,
flowering plants, foliage plants, herbaceous perennial plants, and woody
plant, shrubs and trees).  In addition to the outdoor uses, imidacloprid
is also registered for use indoors.  It should be noted that
imidacloprid is registered as a pre- and post-construction termiticide. 
However, due to the low volatility and short half-life of imidacloprid,
coupled with the fact that it is used pre- and post-construction only,
HED does not expect there to be potential for long-term exposure to
imidacloprid from this use.  Therefore, long-term exposure assessment is
not warranted.

Tolerances are currently established for the combined residues of
imidacloprid and its metabolites containing the 6-chloropyridinyl
moiety, all expressed as the parent, under 40 CFR §180.472 in/on
various plant and livestock commodities.  Section 18 Emergency Exemption
tolerances with expiration/revocation dates are established in/on plant
commodities under 40 CFR §180.472(b), and indirect or inadvertent
tolerances are established as a result of application of the pesticide
to growing crops and other non-food crops under 40 CFR §180.472(d).

2.1	Summary of Registered/Proposed Uses 

 tc "2.1	Summary of Registered/Proposed Uses " \l 2 

Tolerances are currently established for the combined residues of
imidacloprid and its metabolites containing the 6-chloropyridinyl
moiety, all expressed as the parent, under 40 CFR §180.472 in/on
various plant and livestock commodities.  Section 18 Emergency Exemption
tolerances with expiration/revocation dates are established in/on plant
commodities under 40 CFR §180.472(b), and indirect or inadvertent
tolerances are established as a result of application of the pesticide
to growing crops and other non-food crops under 40 CFR §180.472(d).

Table 2.1 Summary of Proposed Directions for Use of Imidacloprid.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

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

(lb ai/A)	RTI1

(days)	PHI

(days)	Use Directions and Limitations

Peanuts

Apply as directed or broadcast spray	Provado® 70 [264-823]	0.043	3	0.13
5	14	Use not permitted in CA

Spray band below seed row before planting, in-furrow during planting,
chemigation	Gaucho® 600 SC [264-828]	0.38	1	0.38	NA	15	Spray band below
seed row up to 7 days before planting, Use not permitted in CA

Apply as directed or broadcast spray	Provado® 1.6 Flowable [3125-457]
0.043	3	0.13	5	14	Use not permitted in CA

In-furrow spray on or  below seed during planting, chemigation	Gaucho®
550 SC  [264-827]	0.38	1	0.38	NA	15	Use not permitted in CA

In-furrow spray on or  below seed during planting, chemigation	Admire®
2 Flowable [3125-422]	0.38	1	0.38	NA	15	Use not permitted in CA

Millet

Seed

treatment: commercial or at or immediately before planting 	Gaucho® 480
[7501-155]	0.25/ 	1	0.25/

100 lb seed	NA

Do not graze or feed livestock for 45 days after planting

Seed

treatment: commercial or at or immediately before planting	Gaucho® 600
Flowable [7501-173]	0.25/ 100 lb seed	1	0.25/

100 lb seed	NA

Do not graze or feed livestock for 45 days after planting

Oat

Seed

treatment: commercial or at or immediately before planting	Gaucho® 480
[7501-155]	0.03-0.09 /100 lb seed	1	0.09/100 lb seed	NA

Do not graze or feed livestock for 45 days after planting

Seed

treatment: commercial or at or immediately before planting	Gaucho® 600
Flowable [7501-173]	0.03-0.09

/100 lb seed	1	0.09/100 lb seed	NA

Do not graze or feed livestock for 45 days after planting

Vegetable, root and tuber, crop group 1, (except sugarbeets) plus Kava

Directed or broadcast foliar spray and chemigation	Provado® 70 WG
[264-823]	0.044	1-3	0.044 (radish)

0.13 (all others)	5	7	Not for use on crops grown for seed. Use not
permitted in CA

Spray band below seed row before planting, in-furrow during planting,
chemigation	Gaucho® 600 SC [264-828]	0.25-0.38	1	0.38	NA	21	Spray band
below seed row up to 14 days before planting. Not for use on crops grown
for seed. Use not permitted in CA

Directed or broadcast foliar spray and chemigation	Provado® 1.6
Flowable [3125-457]	0.044	1-3	0.044 (radish)

Encore™

[264-783] 	0.047	3	0.14	7	7	Do not apply through any type of irrigation
system or in enclosed structures.

Apply as directed or broadcast spray.	Trimax™ Pro [264-855]	0.047	3
0.14	7	7	Do not apply through any type of irrigation system or in
enclosed structures.

1 RTI = retreatment interval; PHI = preharvest interval.

The proposed use directions, including rotational crop restrictions, are
all adequate.

2.2	Structure and Nomenclature  tc "2.2	Structure and Nomenclature " \l
2 

Common Name	Imidacloprid

Company experimental name	BAY NTN 33893

IUPAC name
(EZ)-1-(6-chloro-3-pyridylmethyl)-N-nitroimidazolidin-2-ylideneamine

CAS name	1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-imidazolidinimine

CAS #	138261-41-3

End-use products/(EP)	Provado® 1.6F (EPA Reg. No. 264-763)

Provado® Pro (EPA Reg. No. 264-858)

Admire® 2F (EPA Reg. No. 264-758)

Gaucho® 550 SC (EPA Reg. No. 264-827)

Gaucho® 600 SC (EPA Reg. No. 264-828)

Provado® 70WG (EPA Reg.
No.㈠㐶㠭㌲ഩ慇捵潨₮㔷匠⁔䔨䅐删来‮潎‮㘲ⴴ㔹⤹
䜍畡档깯㐠〸䘠潬慷汢⁥䔨䅐删来‮潎‮㘲ⴴ㔹⤷䜍畡
档깯㘠〰䘠潬慷汢⁥䔨䅐删来‮潎‮㘲ⴴ㘹⤸

Encore™ (EPA Reg. No. 264-783)

Trimax™ Pro (EPA Reg. No. 264-855)

2.3	Physical and Chemical Properties  tc "2.3	Physical and Chemical
Properties " \l 2 

Table 2.3 Physicochemical Properties of the Technical Grade Test
Compound.  

Parameter	Value	Reference

Melting point	144oC	The Pesticide Manual

Twelfth Edition (2000)

pH	5 to 11

	Specific gravity	1.54 (@ 23oC)

	Water solubility (g/L at  20oC)	0.61

	Solvent solubility (g/L at 20oC)	Dichloromethane: 55, Isopropanol: 1.2,
Toluene: 0.68, n-hexane: < 0.1

	Vapor pressure (mPa at 20oC)	4 x 10-7

	Octanol/water partition coefficient [Log(KOW)]	0.57 (21oC)

	UV/visible absorption spectrum	Not provided.

	

  SEQ CHAPTER \h \r 1 3.0	Hazard Characterization/Assessment

3.1	Hazard and Dose-Response Characterization  tc "3.1	Hazard and
Dose-Response Characterization " \l 2 

Imidacloprid has low acute toxicity via the dermal and inhalation routes
and moderate acute toxicity via the oral route.  It is not an eye or
dermal irritant and is not a dermal sensitizer.  The nervous system is
the primary target organ of imidacloprid.  Nervous system effects
evidenced as changes in clinical signs and FOB assessments were seen in
rat acute and subchronic neurotoxicity studies.  These effects included
decreased motor and locomotor activities, tremors, gait abnormalities,
increased righting reflex impairments and body temperature, and
decreased number of rears and response to stimuli and decreases in
forelimb and hindlimb grip strength.  Also, in the rat developmental
neurotoxicity study, a decrease in the caudate/putamen width was noted
in female pups.  Retinal atrophy was seen in high-dose females in the
rat combined chronic toxicity/carcinogenicity study.  No nervous system
effects were noted in the mouse carcinogenicity or the reproduction and
developmental studies or in the rabbit dermal or rat inhalation studies.
 The dog was less sensitive to the effects of imidacloprid.  No effects
were noted up to the highest dose tested in the chronic toxicity study. 
The rabbit appeared to be very sensitive as there was increased
mortality in the oral developmental study at the highest dose tested. 
Increased incidence of mineralized particles in the thyroid colloid was
noted in the rat combined chronic toxicity/carcinogenicity study.  Body
weight decrements were noted in the rat and/or mouse chronic and
carcinogenicity studies, the rat subchronic neurotoxicity study, and the
developmental, developmental neurotoxicity and reproduction studies.  No
effects were observed in the rabbit dermal or rat inhalation studies. 
There was no evidence of carcinogenic potential in either the rat
chronic toxicity/carcinogenicity or mouse carcinogenicity studies and no
concern for mutagenicity.  There was no evidence of increased
qualitative or quantitative susceptibility of rats or rabbits to in
utero exposure to imidacloprid and no evidence of qualitative or
quantitative increased susceptibility of rat offspring in the
reproduction study.  There was evidence of an increased qualitative
susceptibility in the rat developmental neurotoxicity study.  At the
highest dose tested, maternal effects consisted largely of slight
decreases in food consumption and body weight gain during early
lactation, while pup effects included decreased body weight; decreased
motor activity; decreased caudate/putamen width, females only [PNDs 11
and adult]; and slight changes in performance in the water maze, males
only, at the same dose.

On 11/10/93, the RfD/Peer Review Committee classified imidacloprid as a
“Group E” chemical, no evidence of carcinogenicity for humans, by
all routes of exposure based upon lack of evidence of carcinogenicity in
rats and mice.

3.1.1	Dose-response  tc "3.1.1	Dose-response " \l 3 

Acute Dietary Endpoint:  The rat acute neurotoxicity study was used to
select the dose and endpoint for establishing the aPAD of 0.14 mg/kg/day
for the general U.S. population.  The LOAEL of 42 mg/kg was based upon
the decrease in motor and locomotor activities observed in females. 
This aPAD is applicable to the general population, including infants and
children, and is also protective of developmental effects which may
occur in females of reproductive age.  The maternal and developmental
effects in the rabbit study, though severe, occurred at higher doses,
and this endpoint is adequately protective of those effects.  A 300-fold
uncertainty factor (3x UFL; and 10x for interspecies extrapolation and
10x for intraspecies variation) was incorporated in the aPAD.  A 3X
uncertainty factor for the use of a LOAEL was judged to be adequate (as
opposed to a 10X) because: 1) the LOAEL (42 mg/kg) is comparable to the
LOAELs seen in adults in the developmental rat study (30 mg/kg/d) and
the two-generation reproduction study [47/52 mg/kg/d (male/female)] and
in the offspring in the DNT study (55 mg/kg/d); 2) the extrapolated
NOAEL of 14 mg/kg (42/3 = 14) is comparable to the NOAEL of 20 mg/kg/d
established in the offspring in the DNT; and, 3) the neurotoxic effects
in this study showed a good dose response which resulted in minimal
effects on motor activity and locomotor activity at the LOAEL.  The FQPA
SF of 1x is applicable for the acute dietary risk assessment.  Thus, the
aPAD is 0.14 mg/kg.

Chronic Dietary Endpoint:  The rat combined chronic
toxicity/carcinogenicity study was used to select the dose and endpoint
for establishing the cPAD of 0.057 mg/kg/day for the general U.S.
population.  The NOAEL of 5.7 mg/kg/day was based upon an increased
incidence of mineralized particles in the thyroid colloid in males at
the LOAEL of 16.9 mg/kg/day.  The mineralized particles are interpreted
to be the result of imidacloprid selectively localizing in the thyroid
colloid, resulting in increased clumping and basophilia of the colloid. 
The clumping may result in a decrease in the uptake of organic iodine
which can cause a decrease in the production of thyroid hormones (T3 and
T4).  In addition, this may result in a decrease in the ability of the
follicular cells to phagocytize the colloid and release active thyroid
hormones.  These observations are the best available indicator of
thyroid organ toxicity since T3, T4 and TSH were not measured in the rat
combined chronic toxicity/carcinogenicity study.  A 100-fold uncertainty
factor (10x for interspecies extrapolation and 10x for intraspecies
variation) was incorporated into the cPAD.  The FQPA SF of 1x is
applicable for the chronic dietary risk assessment.  Thus, the cPAD is
0.057 mg/kg/day.

Carcinogenicity:  The RfD/Peer Review Committee classified imidacloprid
as a “Group E” (no evidence of carcinogenicity for humans) chemical
based on adequate studies in two animal species; therefore, a cancer
risk assessment is not required.

Short-Term Incidental Oral Endpoint:  A short-term incidental oral
endpoint was selected from the rat developmental toxicity study.  The
maternal NOAEL of 10 mg/kg/day was chosen based upon decreased body
weight gain and decreased corrected body weight gain at the LOAEL of 30
mg/kg/day.  This study and endpoint are appropriate for the population
of concern (infants and children) and the route and duration of
exposure.

Intermediate-Term Incidental Oral Endpoint:  An intermediate-term
incidental oral endpoint was selected from the rat subchronic
neurotoxicity study.  The NOAEL of 9.3 mg/kg/day was chosen based upon
decreased body weight gain at the LOAEL of 63.3 mg/kg/day.  This study
and endpoint are appropriate for the population of concern (infants and
children) and for the route and duration of exposure.

Dermal Penetration:  Dermal Absorption Factor: 7.2% (this value was
rounded to 7% for risk assessment purposes).  No dermal absorption study
was submitted.  The rabbit dermal NOAEL is 1000 mg/kg/day with no
systemic effects noted in the 28-day dermal toxicity study.  In the
developmental toxicity study, the rabbit maternal NOAEL/LOAEL (based on
maternal deaths and decreased maternal absolute body weights, body
weight gains, and food consumption) is 24/72 mg/kg/day.  An upper-bound
estimate of dermal absorption (7.2%) was calculated by comparing the
maternal LOAEL from the rabbit developmental study (870.3700b) with the
NOAEL from the rabbit dermal study (870.3250).

Short-Term Dermal Endpoint:  A short-term dermal endpoint was selected
from the rat developmental toxicity study.  The maternal NOAEL of 10
mg/kg/day was chosen based upon decreased body weight gain and decreased
corrected body weight gain at the LOAEL of 30 mg/kg/day.  A 21-day
dermal study in rabbits was submitted with no systemic effects noted up
to 1000 mg/kg/day; however, the dermal study did not evaluate FOB and
other neurological parameters.  Since there are neurotoxic effects noted
in both adult and offspring rats via the oral route that were not
evaluated in the dermal study, the HIARC chose an oral endpoint for this
risk assessment to adequately protect against neurotoxicity via dermal
exposure.  The chosen endpoint is from a study of the appropriate
duration of exposure and is at a comparable dose where neurotoxic signs
were noted in the rat acute neurotoxicity study.  A dermal absorption
factor of 7% was applied for route-to-route extrapolation.  This
dose/endpoint is appropriate for short-term exposure risk assessment.

Intermediate-term Dermal Endpoint:  An intermediate-term dermal endpoint
was selected from the rat subchronic neurotoxicity study.  The NOAEL of
9.3 mg/kg/day was chosen based upon decreased body weight gain at the
LOAEL of 63.3 mg/kg/day.  A 21-day dermal study in rabbits was submitted
with no systemic effects noted up to 1000 mg/kg/day; however, the dermal
study did not evaluate FOB and other neurological parameters.  Since
there are neurotoxic effects noted in both adult and offspring rats via
the oral route that were not evaluated in the dermal study, the HIARC
chose an oral endpoint for this risk assessment to adequately protect
against neurotoxicity via dermal exposure.  The chosen endpoint is from
a study of the appropriate duration of exposure and is at a comparable
dose where neurotoxic signs were noted in the rat acute neurotoxicity
study.  A dermal absorption factor of 7% was applied for route-to-route
extrapolation.  This dose/endpoint is appropriate for intermediate-term
exposure risk assessment.

Long-term Dermal Endpoint:  A long-term dermal endpoint was selected
from the rat combined chronic toxicity/carcinogenicity study.  The NOAEL
of 5.7 mg/kg/day was based upon an increased incidence of mineralized
particles in the thyroid colloid in males at the LOAEL of 16.9
mg/kg/day.  No long-term dermal study was submitted.  A dermal
absorption factor of 7% was applied for route-to-route extrapolation. 
This dose/endpoint is appropriate for long-term exposure risk
assessment.

Short-term Inhalation Endpoint:  A short-term inhalation endpoint was
chosen from the rat developmental study.  The maternal NOAEL of 10
mg/kg/day was chosen based upon decreased body weight gain and decreased
corrected body weight gain at the LOAEL of 30 mg/kg/day.  The submitted
28-day inhalation study (MRID 42273001) did not test up to the limit
dose and no systemic toxicity was observed up to the highest dose tested
0.191 mg/L.  Also FOB and other neurological parameters were not
evaluated.  An inhalation absorption factor of 100% should be applied. 
This dose/endpoint is appropriate for short-term exposure risk
assessment.

Intermediate-term Inhalation Endpoint:  An intermediate-term inhalation
endpoint was chosen from the rat subchronic neurotoxicity study.  The
NOAEL of 9.3 mg/kg/day was chosen based upon decreased body weight gain
at the LOAEL of 63.3 mg/kg/day.  This dose and endpoint are appropriate
for the duration of exposure.  The submitted 4-week inhalation study
(MRID 42273001) did not test up to the limit dose and no systemic
toxicity was observed up to the highest dose tested 0.191 mg/L.  Also,
FOB and other neurological parameters were not evaluated.  An inhalation
absorption factor of 100% should be applied.  This dose/endpoint is
appropriate for intermediate-term exposure risk assessment.

Long-term Inhalation Endpoint:  A long-term inhalation endpoint was
selected from the rat combined chronic toxicity/carcinogenicity study. 
The NOAEL of 5.7 mg/kg/day was based upon an increased incidence of
mineralized particles in the thyroid colloid in males at the LOAEL of
16.9 mg/kg/day.  No long-term inhalation study was submitted.  An
inhalation absorption factor of 100% should be applied.  This
dose/endpoint is appropriate for long-term exposure risk assessment.

MOE for Occupational/Residential Risk Assessments:  A MOE of 100 is
required for short-, intermediate-, and long-term occupational risk
assessments for both dermal and inhalation routes of exposure.  A MOE of
100 is required for residential risk assessments for all routes of
exposure for any duration.  For short-/intermediate-/long-term oral,
dermal and inhalation exposures, the following route-to-route
extrapolation was followed:  the inhalation (using 100% absorption) and
dermal (using 7% absorption) exposures were converted to equivalent oral
doses, combined, and then compared to their respective oral NOAELs since
all of the dermal and inhalation endpoints are based on oral
equivalents.

As per FQPA, 1996, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  The toxicity
endpoints selected for these routes of exposure may be aggregated as
follows:  For short-term exposure, oral and dermal and inhalation
endpoints can be aggregated because of the use of oral equivalents and a
common endpoint (decreased body weight gain).

	

3.1.2	FQPA  tc "3.1.2	FQPA " \l 3  

On 10/08/2002, the HED HIARC evaluated the potential for increased
susceptibility of infants and children from exposure to imidacloprid
according to the February 2002 OPP 10X guidance document.  The HIARC
concluded that the toxicology database was complete for FQPA purposes
and that there are no residual uncertainties for pre-/post-natal
toxicity (TXR NO. 0051292, D. Nixon, 10/31/02).  Based on the hazard
data, the HIARC recommended the FQPA SF be reduced to 1x.  The
imidacloprid risk assessment team evaluated the quality of the exposure
data; and, based upon these data, recommended that the FQPA SF be
reduced to 1x (DP Num: 286101, J. Tyler, 3/4/03).

3.2	Absorption, Distribution, Metabolism, Excretion (ADME) 

Methylene-labeled imidacloprid was rapidly absorbed with approximately
90% of the administered dose being eliminated within 24 hours and 96%
within 48 hours.  There were no biologically significant differences
between sexes, dose levels, or route of administration.  Urinary
excretion was the major route of elimination (70-80% of recovered
radioactivity), with a lesser amount eliminated in feces (17-25% of
recovered radioactivity).  Biliary excretion was a major contributor to
fecal radioactivity (36.6% vs. 4.8% of recovered radioactivity in
bile-fistulated animals).  Total tissue burden after 48 hours accounted
for only approximately 0.5% of the recovered radioactivity, with major
sites of accumulation being the liver, kidney, lung, skin, and plasma
and minor sites being the brain and testes.  Maximum plasma
concentration occurred between 1.1 and 2.5 hours, and elimination
half-lives (calculated from two exponential terms) were 3 and 26-118
hours.  There were two major evident routes of biotransformation.  The
first included an oxidative cleavage of the parent compound to give
6-CNA and its glycine conjugate.  Dechlorination of this metabolite
formed the 6-hydroxynicotinic acid and its mercapturic acid derivative. 
The second included the hydroxylation of imidazolidine followed by
elimination of water of the parent compound to give NTN 35884.

In a comparison between [methylene-14C] imidacloprid and
[imidazolidine-4,5-14C] imidacloprid, the rates of excretion were
similar; however, the renal portion was higher with the
imidazolidine-labeled test material (90% vs. 75% of recovered
radioactivity for methylene-labeled test material.  The
imidazolidine-labeled test material also demonstrated higher
accumulation in the tissues (approximately 1% of recovered
radioactivity), with the major sites of accumulation being the liver,
kidney, lung, and skin, and the minor sites being brain and muscle.  

In a comparison between [methylene-14C] imidacloprid and WAK 3839 (a
metabolite of imidacloprid), there were no significant differences in
the absorption, distribution, and excretion of the total radioactivity. 
More radioactivity was found in the tissues of the animals receiving
imidacloprid at the 1.0 and 150.0 dose levels (respectively 0.9% and
3.4% vs. 0.2% of administered radioactivity for the WAK 3839 group). 
The major sites of accumulation of WAK 3839 included lung, renal fat,
liver, and kidney, with minor sites being the testis and brain.  WAK
3839 was formed during pretreatment (chronic oral dosing) of
imidacloprid; however, the proposed metabolic pathways of the two
compounds were different.

  SEQ CHAPTER \h \r 1 

3.3	FQPA Considerations  tc "3.3	FQPA Considerations " \l 2 

On 10/08/2002, the HED HIARC evaluated the potential for increased
susceptibility of infants and children from exposure to imidacloprid
according to the February 2002 OPP 10X guidance document.  The HIARC
concluded that the toxicology database was complete for FQPA purposes
and that there are no residual uncertainties for pre-/post-natal
toxicity (TXR NO. 0051292, D. Nixon, 10/31/02).  Based on the hazard
data, the HIARC recommended the FQPA SF be reduced to 1x.  The
imidacloprid risk assessment team evaluated the quality of the exposure
data; and, based upon these data, recommended that the FQPA SF be
reduced to 1x (DP Num: 286101, J. Tyler, 3/4/03).

The 300-fold UF (3x UFL; and 10x for interspecies extrapolation and 10x
for intraspecies variation) was incorporated in the aPAD.  A 3X
uncertainty factor for the use of a LOAEL was judged to be adequate (as
opposed to a 10X) because: 1) the LOAEL (42 mg/kg) is comparable to the
LOAELs seen in adults in the developmental rat study (30 mg/kg/d) and
the two-generation reproduction study [47/52 mg/kg/d (male/female)] and
in the offspring in the DNT study (55 mg/kg/d); 2) the extrapolated
NOAEL of 14 mg/kg (42/3 = 14) is comparable to the NOAEL of 20 mg/kg/d
established in the offspring in the DNT; and, 3) the neurotoxic effects
in this study showed a good dose response which resulted in minimal
effects on motor activity and locomotor activity at the LOAEL (DP Num:
286101, J. Tyler, 3/4/03).

3.3.1	Adequacy of the Toxicity Data Base  tc "3.3.1	Adequacy of the
Toxicity Data Base " \l 3 

  SEQ CHAPTER \h \r 1 

The HIARC concluded that the toxicology database for imidacloprid is
complete. 

3.3.2	Evidence of Neurotoxicity 

The HIARC concluded that there is a concern for neurotoxicity resulting
from exposure to imidacloprid.  The following studies are available:

Two developmental toxicity studies - Rat and Rabbit

Two-generation reproduction toxicity study - Rat

Acute neurotoxicity study - Rat

Subchronic neurotoxicity study - Rat

Developmental neurotoxicity study - Rat

3.3.3	Developmental Toxicity Studies  tc "3.3.3	Developmental Toxicity
Studies " \l 3 

3.3.3.1	Rat

In a developmental toxicity study (MRID 42256338) NTN 33893 Technical
(Imidacloprid; 94.2% ai, batch# PT. 17001/87) was administered to 25
mated female HSD(SD) rats/dose by gavage at dose levels of 0, 10, 30, or
100 mg/kg bw/day from gestation days (GD) 6 through 15, inclusive.  On
GD 21, dams were sacrificed and subjected to cesarean section, and all
fetuses were weighed, sexed, and examined externally.  Approximately
one-half of the fetuses were examined for visceral alterations, and the
remaining one-half of the fetuses were examined for skeletal
alterations.   

There were no deaths or treatment-related clinical signs.  At the 10
mg/kg bw/day treatment level, body weight gain was transiently decreased
during GD 6-11 (81% of controls; n.s), then increased during GD 11-16
and 16-21 (8 and 10%, respectively; n.s.).  At the 30 mg/kg bw/day
treatment level, body weight gains were decreased for the GD 6-11 and
6-16 intervals (76 and 89% of controls, respectively; n.s.).  At the 100
mg/kg bw/day treatment level, body weight gains were decreased
throughout dosing and for the post-dosing interval as well (57 and 87%
of controls, respectively; n.s.).  The mean corrected (for gravid
uterine weight) GD 6-21 body weight gains of the mid- and high-dose
groups were also decreased (71 and 53% of controls, respectively; p<0.01
for the high-dose group only).  Food consumption (g/animal/day)  by the
high-dose group was decreased throughout treatment and increased during
the post-dosing interval (27.2% less than controls, 20.5% greater than
controls, respectively), while food consumption by the low- and mid-dose
groups were decreased only during GD 6-11 (9.5 and 10.0% less than
controls, respectively; p<0.01); however, the decreases noted for the
low- and mid-dose groups were not considered treatment-related because
similar decreases were not present when food consumption was evaluated
on a g/kg bw/day basis.  There were no treatment-related effects on
intrauterine parameters.  The maternal toxicity LOAEL for imidacloprid
in HSD(SD) rats is 30 mg/kg bw/day, based on decreased body weight gain
and decreased corrected body weight gain.  The maternal toxicity NOAEL
is 10 mg/kg/day.

There were no treatment-related effects on fetal deaths or resorptions,
numbers of viable fetuses per litter, or fetal weights, sex ratios, or
external or visceral structural alterations.  Wavy ribs were observed in
2/158 (1/25), 1/155 (1/25), 0/153 (0/24), and 7/149 (4/25) fetuses
(litters) of the control, low-, mid-, and high-dose groups,
respectively, and were considered treatment-related.  The developmental
toxicity LOAEL for imidacloprid in HSD(SD) rats is 100 mg/kg bw/day,
based on a slight increase in the incidence of wavy ribs.  The
developmental toxicity NOAEL is 30 mg/kg bw/day.

The developmental toxicity study in the rat is classified
Acceptable/Guideline and satisfies the guideline requirements for a
developmental toxicity study in the rat (OPPTS 870.3700a; OECD 414).

3.3.3.2	Rabbit

In a developmental toxicity study (MRID 42256339) NTN 33893 Technical
(Imidacloprid; 95.3% ai, batch # PT. 17001/87) was administered to 16
mated female Chinchilla (Chbb: CH Hybrids, SPF quality) rabbits/dose in
distilled water with 0.5% Cremophor EL (BASF) by gavage at dose levels
of 0, 8, 24, or 72 mg/kg bw/day from gestation days (GD) 6 through 18. 
On GD 28, does were sacrificed and necropsied.  All fetuses were
weighed, sexed, and examined for external, visceral, and skeletal
alterations.   

At 72 mg/kg bw/day, two pregnant females died, one each on GDs 18 and
19, and one of these females had white mucoid feces for three days prior
to dying.  Another high-dose female aborted on GD 26, and two additional
high-dose females had total litter resorptions.  Mean absolute body
weights of the high-dose animals were decreased during GD 17-21 (10-11%
less than controls; p<0.01).  Decreased body weight gains were
reportedly noted during treatment at 24 and 72 mg/kg bw/day (up to 9.2%
less than controls for the high-dose group; n.s.).  Mean food
consumption of the high-dose animals was decreased during treatment
(34-58% of controls; p<0.01), then increased during the post-dosing
interval (112-183% of controls).  Mean food consumption of the mid-dose
animals was transiently decreased during GD 6-11 only (84% of controls;
p<0.05); however, the original reviewer did not consider this difference
treatment-related because it was transient and because there were no
other treatment-related effects noted at this dose level.  The maternal
toxicity LOAEL for imidacloprid in Chinchilla (Chbb: CH Hybrids, SPF
quality) rabbits is 72 mg/kg bw/day, based on maternal deaths and
decreased maternal absolute body weights, body weight gains, and food
consumption.  The maternal toxicity NOAEL is 24 mg/kg bw/day.

One high-dose female aborted on GD 26, and two additional high-dose
females had total litter resorptions.  Postimplantation loss of the
high-dose females was increased compared to controls both with the data
from the females with total litter resorptions included (32.5% vs. 4.2%
for controls; p<0.01) and without it (10.8% greater than controls;
p<0.05), and this increase was due to increased late resorptions (6.5%
vs. 0.7% of implantations for controls, data from dams with total litter
resorptions included; p<0.01).  There was a corresponding decrease in
this group’s number of live fetuses per litter (31% less than
controls; n.s. due to a high S.D.).  At 72 mg/kg bw/day, mean litter
weights and mean fetal weights were both decreased (9.7 and 9.9% less
than controls, respectively; p<0.05 and p<0.01, respectively), and these
differences were primarily due to decreased weights of female fetuses
rather than males (12 and 8% less than controls, respectively; p<0.01,
p<0.05, respectively).  Several skeletal malformations not present in
the 136 fetuses (16 litters) of the control group were noted in a total
of 5/83 fetuses (3/11 litters) of the 72 mg/kg bw/day group, and
included the following: fused sternebrae in 2 (2), asymmetric sternebrae
in 3 (2), missing sternebrae in 2 (1), abnormally ossified sternebrae in
4 (2), and shortened tail in 1fetus (1 litter).  These skeletal
alterations were considered treatment-related by the original reviewer. 
The developmental toxicity LOAEL for imidacloprid in Chinchilla (Chbb:
CH Hybrids, SPF quality) rabbits is 72 mg/kg bw/day, based on abortion,
total litter resorptions, increased postimplantation loss due to
increased late resorptions, decreased fetal weights (more pronounced in
female fetuses), and very low incidences of skeletal alterations,
including fused, asymmetric, missing, and/or abnormally ossified
sternebrae, and/or shortened tail.  The developmental NOAEL is 24 mg/kg
bw/day. 

This developmental toxicity study in the rabbit is classified
acceptable/guideline and satisfies the guideline requirements for a
developmental toxicity study in the rabbit (OPPTS 870.3700b; OECD 414).

3.3.4	Reproductive Toxicity Study  tc "3.3.4	Reproductive Toxicity Study
" \l 3 

In a 2-generation reproduction study (MRID 42256340) NTN 33893 Technical
(Imidacloprid; 95.3% ai, batch# Mischpartie 180587) was administered to
26 or 30 Wistar/HAN rats/sex/dose in the diet at concentrations of 0,
100, 250, or 700 ppm.  Two litters were produced by each generation. 
Premating test compound intakes were 0, 8.1, 20.1, or 56.7 mg/kg bw/day,
respectively, for F0 males, 0, 8.8, 22.1, or 62.8 mg/kg bw/day,
respectively, for F0 females, 0, 6.4, 16.5, or 47.3 mg/kg bw/day,
respectively, for F1 males, and 0, 7.2, 18.9, or 52.3 mg/kg bw/day,
respectively, for F1 females.  Parental animals were administered test
or control diet for 84 or 105 days prior to the first mating, throughout
mating, gestation, and lactation, and until necropsy.  In addition,
blood was collected from 10/26 F1 animals/sex/dose for hematological and
clinical chemistry evaluations, and liver samples were taken from these
same animals to measure triglycerides, cytochrome P-450, and O- and
N-demethylase activity.

There were no treatment-related deaths or clinical signs.  At the 700
ppm treatment level, F0 males and females had decreased body weight
gains during premating (10 and 12% less than controls, respectively),
and F1 females had decreased body weight gains during premating and
their first and second gestations (10, 9, and 12% less than controls,
respectively).  High-dose females of both generations had increased
weight gains during both lactations (19, 42, 38, and 66% greater than
controls for the F1A, F1B, F2A, and F2B litters, respectively). 
Decreased food consumption was also noted at the highest dose level and
reportedly followed a similar pattern to body weight gains; however,
food consumption data were not included in the DER.  There were no
treatment-related effects on organ weights, or gross and microscopic
pathology of either sex of either generation.  There were no
treatment-related effects on hematology or clinical chemistry parameters
of the F1 animals.  At the 700 ppm treatment level, cytochrome p450
content was increased in males, and demethylase activity was increased
in both sexes; however, these changes are considered an adaptive
response to a xenobiotic agent rather than a toxicological response. 
The parental systemic toxicity LOAEL for imidacloprid in Wistar/Han rats
is 700 ppm (47.3-56.7 mg/kg bw/day in males, 52.3-62.8 mg/kg bw/day in
females), based on decreased premating weight gain by F0 males and
females and F1 females and decreased gestational weight gain by F1
females.  The parental systemic NOAEL is 250 ppm (16.5-20.1 mg/kg bw/day
in males, 18.9-22.1 mg/kg bw/day, in females). 

At the 700 ppm treatment level, the pup weights of both litters from
both generations were significantly decreased (p<0.05) at one or more
intervals during lactation: F1A pups on lactations days (LD) 7 and 21
(91 and 87% of controls, respectively); F1B pups on LD 21 (90% of
controls); F2A pups on LD 21 (91% of controls); and F2B pups on LD 0, 7,
and 21 (90, 91, and 91% of controls, respectively).  Pup survival, mean
number of pups born, and sex ratios at birth were similar between the
treated and control groups of both generations.  There were no abnormal
clinical signs, external abnormalities, or behavioral abnormalities
noted in any litter of either generation.  The offspring LOAEL is 700
ppm, based on decreased pup body weights in both litters of both
generations.  The offspring NOAEL is 250 ppm. 

There were no treatment-related effects on mating, gestation, or
fertility indices or mean gestation lengths.  The reproductive LOAEL is
undetermined, and the reproductive NOAEL is greater than or equal to 700
ppm.

This study is classified as acceptable/guideline and satisfies the
guideline requirement for a 2-generation reproductive study in the rat
(OPPTS 870.3800; OECD 416).

3.3.5	Additional Information from Literature Sources  tc "3.3.5
Additional Information from Literature Sources " \l 3 

There was no additional relevant information from the published
literature.

3.3.6	Pre-and/or Postnatal Toxicity  tc "3.3.6	Pre-and/or Postnatal
Toxicity " \l 3 

The HIARC concluded that there is low concern for pre- and/or postnatal
toxicity resulting from exposure to imidacloprid.

3.3.6.1	Determination of Susceptibility  tc "3.3.6.1	Determination of
Susceptibility " \l 4 

There is no quantitative or qualitative evidence of increased
susceptibility of rat and rabbit fetuses to in utero exposure in
developmental studies.  There is no quantitative or qualitative evidence
of increased susceptibility of rat offspring in the multi-generation
reproduction study.

There is evidence of an increased qualitative susceptibility in the rat
developmental neurotoxicity study.  At the highest dose tested (750
ppm), maternal effects consisted largely of slight decreases in food
consumption and body weight gain during early lactation, while pup
effects included decreased body weight, decreased motor activity,
decreased caudate/putamen width, females only (PNDs 11 and adult), and
slight changes in performance in the water maze, males only, at the same
dose.

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties  tc
"3.3.6.2	Degree of Concern Analysis and Residual Uncertainties " \l 4 
for Pre and/or Post-natal Susceptibility

Since there is no evidence of increased susceptibility of rat and rabbit
fetuses to in utero exposure, there is no concern and no residual
uncertainties for pre-natal toxicity.  There is also no concern and no
residual uncertainties for pre-/post-natal toxicity in the rat
multi-generation reproduction study.

There is evidence of increased qualitative susceptibility in the rat
developmental neurotoxicity study, but the concern is low since: 1) the
effects in pups are well-characterized with a clear NOAEL; 2) the pup
effects occur in the presence of maternal toxicity with the same NOAEL
for effects in pups and dams; and, 3) the doses and endpoints selected
for regulatory purposes are protective of the pup effects noted at
higher doses in the developmental neurotoxicity study.  Therefore, there
are no residual uncertainties for pre-/post-natal toxicity in this
study.

3.3.7	Recommendation for a Developmental Neurotoxicity Study  tc "3.3.7
Recommendation for a Developmental Neurotoxicity Study " \l 3 

A developmental neurotoxicity study in the rat has been submitted,
reviewed and classified as acceptable/nonguideline.

In a developmental neurotoxicity study (MRID 45537501), imidacloprid
(98.2-98.4% ai, batch # 803-0273) was administered to 30 parent female
Wistar rats/group in the diet at concentrations of 0, 100, 250 or 750
ppm from gestation day 0 through PND 21.  The average daily intake of
Imidacloprid was 0, 8.0-8.3, 19.4-19.7, and 54.7-58.4 mg/kg/day during
gestation and 0, 12.8-19.5, 30.0-45.4, and 80.4-155.0 mg/kg/day during
lactation, for the 0, 100, 250, and 750 ppm groups, respectively.  A FOB
was performed on all dams on gestation days 6, 13, and 20 and on 10
dams/dose on lactation days 4, 11, and 21.  On postnatal day 4, litters
were culled to yield four males and four females (as closely as
possible).  Offspring, representing at least 20 litters/dose, were
allocated for detailed clinical observations (abbreviated FOB),
assessment of motor activity, assessment of auditory startle response
habituation, assessment of learning and memory, and ophthalmology. 
Neural tissues were also collected from selected offspring (10/sex/dose
representing 20 litters) on PND 11 and at study termination (75 days of
age).  Pup physical development was assessed by bodyweight, day of
surface righting, auditory startle, eye opening, pupillary constriction,
vaginal patency in females and balanopreputial separation in males. 

Treatment-related effects for maternal animals were limited to a 9%
decrease (not significant) in food consumption for dams in the high dose
group compared to controls during the third week of gestation and 14%
decrease (p<0.05) for high-dose animals during week 1 of lactation. 
There was also a slight decrease in body weight gain (67% of controls)
during lactation day 0-7.  The maternal LOAEL for Imidacloprid in rats
is 55-58 mg/kg/day in the diet based on decreased food consumption and
decreased body weight gain during lactation.  The maternal NOAEL is 20
mg/kg/day in the diet.

Treatment-related effects for offspring were limited to the high dose
group. Body weights of high-dose males and females were significantly
(p<0.05) decreased 9-13% prior to weaning, and from 3-11% after weaning,
with recovery: in females to control levels by PND 50; and in males to a
4% difference that persisted to study termination.  Body weight gains
were also decreased 12-23% during lactation, with recovery by PND 17.
Overall motor activity was decreased (not statistically significantly)
on PND 17 in high-dose males (38%) and females (31%) and in PND 21
females (37%).  High dose females at study termination had a
statistically significant (p <0.03; t test) decrease in thickness of the
caudate/putamen in comparison to controls (3.7504 vs 3.6774 mm (-2%). 

The offspring LOAEL for Imidacloprid in rats is 55-58 mg/kg/day in the
diet, based on decreased body weight and body weight gain, decreased
motor activity, and decreased caudate/putamen width in females.  The
offspring NOAEL is 20 mg/kg/day.

This study is classified acceptable/ non-guideline and does not satisfy
the guideline requirement for a developmental neurotoxicity study in
rats (OPPTS 870.6300, §83-6); OECD 426 (draft).  The study may be
upgradable upon submission of (1) complete analytical data; (2)
morphometric measurements for caudate/putamen for females at
intermediate dose levels; and (3) additional positive control data, as
described below.

No evidence of neurotoxicity was noted in any other oral toxicity
studies submitted.

3.4	Safety Factor for Infants and Children 

The FQPA SF can be reduced to 1x since there are no residual
uncertainties for pre-/post-natal toxicity.

HIARC recommended the FQPA SF assuming 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 for infants and children.

  SEQ CHAPTER \h \r 1 

3.4.1	Adequacy of the Exposure Data Base  tc "3.4.1	Adequacy of the
Exposure Data Base " \l 3 

The imidacloprid risk assessment team evaluated the quality of the
exposure data; and, based on these data, recommended that the special
FQPA SF be reduced to 1x.  The recommendation is based on the following:

The dietary food exposure assessment utilizes proposed tolerance level
or higher residues and 100% CT information for all commodities.  By
using these screening-level assessments, exposures/risks will not be
underestimated. 

The dietary drinking water assessment (Tier 1 estimates) utilizes values
generated by model and associated modeling parameters which are designed
to provide conservative, health protective, high-end estimates of water
concentrations. 

The residential exposure assessment utilizes: activity specific transfer
coefficients and chemical-specific turf transferable residue (TTR)
studies for the post-application scenario.  The refined residential
assessment is based on reliable data and is unlikely to underestimate
exposure/risk.

3.4.2	Safety Factor Conclusion  tc "3.4.2	Conclusion " \l 3 

There is a complete toxicity database for imidacloprid and exposure data
are complete or are estimated based on data that reasonably accounts for
potential exposures.  There is no evidence of susceptibility following
in utero and/or postnatal exposure in the developmental toxicity studies
in rats or rabbits, and in the 2-generation rat reproduction study. 
There are no residual uncertainties concerning pre- and postnatal
toxicity and no neurotoxicity concerns.  The assessments are based on
reliable data and will not underestimate exposure/risk.  Based on these
data and conclusions, the FQPA SF can be reduced to 1X.

3.5	Hazard Identification and Toxicity Endpoint Selection  tc "3.5
Hazard Identification and Toxicity Endpoint Selection " \l 2 

3.5.1	Acute Population Adjusted Dose (aPAD) - General Population 

Study Selected:  Acute Neurotoxicity Study - Rat		OPPTS 870.6200a

MRID No.: 43170301

Executive Summary: In an acute neurotoxicity study (MRIDs 43170310,
43285801), groups of Sprague-Dawley rats (18/sex/dose) were given a
single oral administration of imidacloprid (97.6% ai) in 0.5%
methylcellulose with 0.4% Tween 80 in deionized water at 0, 42, 151 or
307 mg/kg.  Parameters evaluated included: clinical pathology
(6/sex/dose); Functional Observation Battery (FOB) measurements
(12/sex/dose); and neuropathology (6/sex/dose).  FOB measurements were
made approximately 90 minutes post-dosing, and on days 7 and 14.  Motor
activity measurements were made at approximately 2.5 hours post-dosing.

At 307 mg/kg, 4/18 males and 10/18 females died and both sexes of rats
at this dose exhibited decreased number of rears, grip strength
(forelimb and hindlimb) and response to stimuli (auditory, touch, or
tail pinch) as well as increased gait abnormalities and righting reflex
impairments and body temperatures.  These symptoms regressed by day 5. 
At 151 mg/kg, cage side FOB assessments revealed tremors in one male and
one female and red nasal staining in one male.  On the day of dosing, a
dose-related decrease in total session motor activity was observed in
males at 151 mg/kg (25% decrease) and 307 mg/kg (73% decrease) and in
females at all dose levels with the decreases (25, 48 and 81%,
respectively at 42, 151 and 307 mg/kg) reaching statistical significance
(p<0.05) at 151 and 307 mg/kg dose levels.  Decreases in motor activity
was seen at all time intervals.  Total session locomotor activity was
also decreased to about the same percentage difference but statistical
significance were not reported.  On days 7 and 14, decreases (not
statistically significant) were still observed in motor and locomotor
activity in surviving high-dose males.  The LOAEL was 42 mg/kg based
upon the decrease in motor and locomotor activities observed in females;
a NOAEL was not established.

This study is classified as acceptable/guideline and satisfies the
requirements for an acute neurotoxicity screening battery in rats
(§81-8; 870.6200a).

Dose and Endpoint for Establishing aPAD: 42 mg/kg (LOAEL), based upon
the decreased in motor and locomotor activities observed in females.

Uncertainty Factor (UF): 300

Comments about Study/Endpoint/Uncertainty Factor:  This endpoint is
appropriate, since these effects were seen following a single dose, and
is applicable to the general population, including infants and children
and is also protective of developmental effects which may occur in the
subpopulation females 13-50.  The maternal and developmental effects in
the rabbit study, though severe, occurred at higher doses, and this
endpoint is adequately protective of those effects.  A 3X uncertainty
factor for the use of a LOAEL was judged to be adequate (as opposed to a
10X) because: 1) the LOAEL (42 m/k/d) is comparable to the LOAELs seen
in adults in the developmental rat study (30 m/k/d) and the
two-generation reproduction study [47/52 m/k/d (male/female)] and in the
offspring in the DNT (55 m/k/d); 2) the extrapolated NOAEL of 14 m/k/d
(42/3 = 14) is comparable to the NOAEL of 20 m/k/d established in the
offspring in the DNT; and, 3) the neurotoxic effects in this study
showed a good dose response which resulted in minimal effects on motor
activity and locomotor activity at the LOAEL. 

Acute PAD (gen. pop’n) = 42 (LOAEL) mg/kg = 0.14 mg/kg

  300

3.5.2	Chronic Population Adjusted Dose (cPAD) 

 tc "3.5.2	Chronic Population Adjusted Dose (cPAD) " \l 3 

Study Selected: Combined Chronic Toxicity/Carcinogenicity - Rat 		OPPTS
870.4300

MRID No.: 	42256331

Executive Summary: In a combined chronic toxicity/carcinogenicity study
(MRID 42256331), NTN 33893 Technical (Imidacloprid; 94.3-95.3% ai, batch
#180587) was administered to 50 Bor WISW (SPF Cpb) rats/sex/dose in feed
at concentrations of 0, 100, 300, or 900 ppm (equivalent to 0, 5.7,
16.9, or 51.3 and 0, 7.6, 24.9, or 73.0 mg/kg bw/day for males and
females, respectively) for 24 months.  In a supplementary combined
chronic/carcinogenicity study (MRID 42256332), NTN 33893 Technical
(Imidacloprid; 94.3-95.3% ai, batch #180587) was administered to 50 Bor
WISW (SPF Cpb) rats/sex/dose in feed at concentrations of 0 or 1800 ppm
(equivalent to 0 or 102.6 and 0 or 143.7 mg/kg bw/day for males and
females, respectively) for 24 months.  Both studies included additional
groups of ten rats/sex/dose for interim sacrifice at 12 months.

There were no treatment-related effects on mortality, clinical signs,
food and water consumption, hematology, clinical chemistry,
ophthalmology, or gross pathology.  Mean absolute body weights of both
sexes were decreased throughout the study at the 1800 ppm dose level
(males: up to 12%; females: up to 11% less than controls; p<0.01 for
both sexes).  At 900 ppm, body weights were decreased by up to 5% in
males and 8% in females, and cumulative body weight gains were decreased
in females by 11.2% and 16.2% at 900 and 1800 ppm, respectively,
compared with that of controls.  

The significant decreases in absolute liver weights at 1800 ppm are not
considered adverse since the decreases in relative liver weights were
small and no corroborating gross or histopathologic lesions were noted. 
The small statistically significant changes in absolute and relative
weights of other organs in male and female rats at 12 or 24 months at
900 and 1800 ppm were not accompanied by either gross or microscopic
changes and are not considered adverse.  In the interim sacrifice
groups, increased incidence of a microscopic thyroid lesion described as
mineralized particles in the colloid of isolated follicles were noted in
males at 900 and 1800 ppm [10/10 males (p<0.05) at both doses vs. 3/10
or 5/10 males in the two control groups].  In the main study groups, the
incidence of the same lesion was 12/50, 31/50, 44/50, 46/50 at 100, 300,
900, and 1800 ppm, respectively, in males compared with 2/50 and 12/50
for the two control groups.  The incidence of mineralized particles in
thyroid colloid in females was 27/50 and 38/50 at 900 and 1800 ppm,
respectively, compared with 11/50 and 3/50 for controls (p<0.01).  In
addition, at 1800 ppm colloid aggregation was decreased 100% (p<0.05) in
males at 12 months and decreased 51% (p<0.01) in males and 68% (p<0.01)
in females at 24 months.  At 1800 ppm, a marked decrease occurred in the
incidence of nephropathy in both males and females (65 and 92% less than
controls, respectively; p<0.01), which corresponded to 46-76% (p<0.01)
decreased urine protein in males and up to a 85% decrease in females. 
In females, a 44% (p<0.05) increase in retinal atrophy and a 65%
increase in porphyrin accumulation in the Harderian glands were noted at
1800 ppm.

The LOAEL for NTN 33893 in rats is 300 ppm (16.9 mg/kg bw/day for males,
24.9 mg/kg bw/day for females), based on thyroid toxicity (increased
incidence of mineralized particles in thyroid colloid) in males.  The
NOAEL is 100 ppm (5.7 mg/kg bw/day for males, 7.6 mg/kg bw/day for
females).

At the doses tested, there was no treatment related increase in tumor
incidence when compared to controls.  Dosing was considered adequate
based on thyroid toxicity and decreased body weights in both sexes.

When considered together, these chronic toxicity/carcinogenicity studies
in the rat are classified Acceptable/Guideline and satisfy the guideline
requirements for a chronic toxicity/carcinogenicity study in the rat
[OPPTS 870.4300; OECD 453].

Dose and Endpoint for Establishing cPAD:  5.7 mg/kg/day (NOAEL), based
upon an increased incidence of mineralized particles in the thyroid
colloid in males at the LOAEL of 16.9 mg/kg/day.

Uncertainty Factor(s): 100

Comments about Study/Endpoint/Uncertainty Factor:  This study and
endpoint are appropriate for the route and duration of exposure.  The
NOAEL is the lowest in the database for chronic effects and is
protective of all populations.

Chronic PAD = 5.7 (NOAEL) mg/kg/day = 0.057 mg/kg

100

3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term)  tc "3.5.3
Incidental Oral Exposure (Short and Intermediate Term) " \l 3 

Study Selected:  Developmental Toxicity Study - Rat	OPPTS 670.3700a

MRID No.: 42256338

Executive Summary: In a developmental toxicity study (MRID 42256338) NTN
33893 Technical (Imidacloprid; 94.2% ai, batch# PT. 17001/87) was
administered to 25 mated female HSD(SD) rats/dose by gavage at dose
levels of 0, 10, 30, or 100 mg/kg bw/day from gestation days (GD) 6
through 15, inclusive.  On GD 21, dams were sacrificed and subjected to
cesarean section, and all fetuses were weighed, sexed, and examined
externally.  Approximately one-half of the fetuses were examined for
visceral alterations, and the remaining one-half of the fetuses were
examined for skeletal alterations.   

There were no deaths or treatment-related clinical signs.  At the 10
mg/kg bw/day treatment level, body weight gain was transiently decreased
during GD 6-11 (81% of controls; n.s), then increased during GD 11-16
and 16-21 (8 and 10%, respectively; n.s.).  At the 30 mg/kg bw/day
treatment level, body weight gains were decreased for the GD 6-11 and
6-16 intervals (76 and 89% of controls, respectively; n.s.).  At the 100
mg/kg bw/day treatment level, body weight gains were decreased
throughout dosing and for the post-dosing interval as well (57 and 87%
of controls, respectively; n.s.).  The mean corrected (for gravid
uterine weight) GD 6-21 body weight gains of the mid- and high-dose
groups were also decreased (71 and 53% of controls, respectively; p<0.01
for the high-dose group only).  Food consumption (g/animal/day)  by the
high-dose group was decreased throughout treatment and increased during
the post-dosing interval (27.2% less than controls, 20.5% greater than
controls, respectively), while food consumption by the low- and mid-dose
groups were decreased only during GD 6-11 (9.5 and 10.0% less than
controls, respectively; p<0.01); however, the decreases noted for the
low- and mid-dose groups were not considered treatment-related because
similar decreases were not present when food consumption was evaluated
on a g/kg bw/day basis.  There were no treatment-related effects on
intrauterine parameters.  The maternal toxicity LOAEL for imidacloprid
in HSD(SD) rats is 30 mg/kg bw/day, based on decreased body weight gain
and decreased corrected body weight gain.  The maternal toxicity NOAEL
is 10 mg/kg/day.  

There were no treatment-related effects on fetal deaths or resorptions,
numbers of viable fetuses per litter, or fetal weights, sex ratios, or
external or visceral structural alterations.  Wavy ribs were observed in
2/158 (1/25), 1/155 (1/25), 0/153 (0/24), and 7/149 (4/25) fetuses
(litters) of the control, low-, mid-, and high-dose groups,
respectively, and were considered treatment-related.  The developmental
toxicity LOAEL for imidacloprid in HSD(SD) rats is 100 mg/kg bw/day,
based on a slight increase in the incidence of wavy ribs.  The
developmental toxicity NOAEL is 30 mg/kg bw/day.

The developmental toxicity study in the rat is classified
Acceptable/Guideline and satisfies the guideline requirements for a
developmental toxicity study in the rat (OPPTS 870.3700a; OECD 414).

Dose and Endpoint for Risk Assessment:  10 mg/kg/day (Maternal NOAEL),
based upon decreased body weight gain and decreased corrected body
weight gain at the LOAEL of 30 mg/kg/day.

Comments about Study/Endpoint:  The endpoint of concern is appropriate
for the population of concern (infants and children) and the duration of
exposure.

3.5.4	Dermal Absorption  tc "3.5.4	Dermal Absorption " \l 3 

Study Selected:  Subchronic Neurotoxicity Study - Rat		OPPTS 870.6200b

MRID No.: 43286401

Executive Summary: Four groups of 12/sex Fischer strain rats were dosed
as control, 150, 1000 or 3000 ppm imidacloprid (technical 98% purity,
corresponding to 9.3, 63.3 or 196 in males and 10.5, 69.3 or 213 in
females mg/kg/day imidacloprid) for 13 weeks in a subchronic
neurotoxicity screen study.  6 additional rats/ sex/dose were also
assessed for clinical chemistry and hematology (MRID No.: 43286401).

The LOAEL for neurotoxicity is > 3000 ppm (196/213 mg/kg/day, M/F).

Systemic effects include body weight gain decrease over the first four
weeks for the 1000 (22% males, 18% females) and 3000 (50% males, 25%
females) ppm dose groups and decreased terminal body weight for both
sexes with an associated decrease in forelimb grip strength especially
in males.  The LOAEL for systemic effects is 1000 ppm  (63.3/69.3
mg/kg/day, M/F) based on decreased body weight gain and the NOAEL is 150
ppm (9.3/10.5 mg/kg/day, M/F). 

Classification: MINIMUM.  The study did not demonstrate a LOAEL for
neurotoxicity.  The study satisfies the guideline requirement for a
series 82-7 subchronic neurotoxicity screen study in rodents.

Dose and Endpoint for Risk Assessment:  9.3 mg/kg/day (NOAEL), based
upon decreased body weight gain at the LOAEL of 63.3 mg/kg/day.

Comments about Study/Endpoint: The endpoint of concern is appropriate
for the population of concern (infants and children) and the duration of
exposure.  Also, this study did evaluate neurotoxicity parameters and no
neurotoxicity was noted in the presence of systemic toxicity (decreased
body weight gain) that was observed in other oral studies of similar
duration.

3.5.5	Dermal Absorption 

Dermal Absorption Factor:  No dermal absorption study was submitted.
Using a ratio of the maternal LOAEL from the developmental rabbit study
and the NOAEL from the rabbit dermal toxicity study, one can derive a
dermal absorption factor of 7.2% as an upper-bound estimate.

Dev. Rabbit LOAEL  =    72 mg/kg/day  = 7.2%

Dermal Tox. NOAEL	    1000 mg/kg/day

3.5.6	Dermal Exposure  tc "3.5.7	Dermal Exposure " \l 3 

	3.5.7.1	Dermal Short-Term (1- 30 days) Exposure

Study Selected:  Developmental Toxicity Study - Rat	OPPTS 670.3700a

MRID No.: 42256338

Executive Summary: See Short-term Incidental Oral

Dose and Endpoint for Risk Assessment:  10 mg/kg/day (Maternal NOAEL),
based upon decreased body weight gain and decreased corrected body
weight gain at the LOAEL of 30 mg/kg/day.

Comments about Study/Endpoint: A 21-day dermal study in rabbits was
submitted with no systemic effects noted up to 1000 mg/kg/day; however,
the dermal study did not evaluate FOB and other neurological parameters.
 Since there are neurotoxic effects noted in both adult and offspring
rats via the oral route that were not evaluated in the dermal study, the
HIARC chose an oral endpoint for this risk assessment to adequately
protect against neurotoxicity via dermal exposure.  The chosen endpoint
is from a study of the appropriate duration of exposure.  A dermal
absorption factor of 7.2% should be applied for route-to-route
extrapolation.

	3.5.6.2	Dermal Intermediate-Term (1 - 6 Months) Exposure

Study Selected:  Subchronic Neurotoxicity Study - Rat		OPPTS 870.6200b

MRID No.: 43286401

Executive Summary: See Intermediate-term Incidental Oral

Dose and Endpoint for Risk Assessment: 9.3 mg/kg/day (NOAEL), based upon
decreased body weight gain at the LOAEL of 63.3 mg/kg/day.

Comments about Study/Endpoint:  A 21-day dermal study in rabbits was
submitted with no systemic effects noted up to 1000 mg/kg/day; however,
the dermal study did not evaluate FOB and other neurological parameters.
 Since there are neurotoxic effects noted in both adult and offspring
rats via the oral route that were not evaluated in the dermal study, the
HIARC chose an oral endpoint for this risk assessment to adequately
protect against neurotoxicity via dermal exposure.  The chosen endpoint
is from a study of the appropriate duration of exposure.  A dermal
absorption factor of 7.2% should be applied for route-to-route
extrapolation.

3.5.6.3 Dermal Long-Term (> 6 Months) Exposure

Study Selected:  Combined Chronic Toxicity/Carcinogenicity – Rat OPPTS
870.4300 

MRID No.: 42256331

Executive Summary: See Chronic PAD

Dose and Endpoint for Risk Assessment: 5.7 mg/kg/day (NOAEL), based upon
an increased incidence of mineralized particles in the thyroid colloid
in males at the LOAEL of 16.9 mg/kg/day.

Comments about Study/Endpoint:  No long-term dermal study was submitted.
 The chosen endpoint is from a study of the appropriate duration of
exposure.  A dermal absorption factor of 7.2% should be applied for
route-to-route extrapolation.

3.5.7	Inhalation Exposure  tc "3.5.7	Inhalation Exposure " \l 3 

 	3.5.7.1	Inhalation Short-Term (1- 30 days) Exposure

Study Selected:  Developmental Toxicity Study - Rat	OPPTS 670.3700a

MRID No.: 42256338

Executive Summary: See Short-term Incidental Oral

Dose and Endpoint for Risk Assessment:  10 mg/kg/day (Maternal NOAEL),
based upon decreased body weight gain and decreased corrected body
weight gain at the LOAEL of 30 mg/kg/day.

Comments about Study/Endpoint:  This dose and endpoint are appropriate
for the duration of exposure.  The submitted 28-day inhalation study
(MRID 42273001) did not test up to the limit dose and no systemic
toxicity was observed up to the highest dose tested 0.191 mg/L.  Also
FOB and other neurological parameters were not evaluated.  An inhalation
absorption factor of 100% should be applied.

3.5.7.2	Inhalation Intermediate-Term (1- 6 Months) Exposure

Study Selected:  Subchronic Neurotoxicity Study - Rat		OPPTS 870.6200b

MRID No.: 43286401

Executive Summary: See Intermediate-term Incidental Oral

Dose and Endpoint for Risk Assessment: 9.3 mg/kg/day (NOAEL), based upon
decreased body weight gain at the LOAEL of 63.3 mg/kg/day.

Comments about Study/Endpoint:  This dose and endpoint are appropriate
for the duration of exposure.  The submitted 28-day inhalation study
(MRID 42273001) did not test up to the limit dose and no systemic
toxicity was observed up to the highest dose tested 0.191 mg/L.  Also
FOB and other neurological parameters were not evaluated.  An inhalation
absorption factor of 100% should be applied.

3.5.7.3	Inhalation Long-Term (> 6 Months) Exposure

Study Selected:  Combined Chronic Toxicity/Carcinogenicity – Rat OPPTS
870.4300 

MRID No.: 42256331

Executive Summary: See Chronic PAD

Dose and Endpoint for Risk Assessment: 5.7 mg/kg/day (NOAEL), based upon
an increased incidence of mineralized particles in the thyroid colloid
in males at the LOAEL of 16.9 mg/kg/day.

Comments about Study/Endpoint:  No long-term inhalation study was
submitted.  The chosen endpoint is of the appropriate duration of
exposure.  An inhalation absorption factor of 100% should be applied.

3.5.8	Level of Concern for Margin of Exposure  tc "3.5.9	Level of
Concern for Margin of Exposure " \l 3 

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

Oral	100	100	100

3.5.9	Recommendation for Aggregate Exposure Risk Assessments  tc "3.5.9
Recommendation for Aggregate Exposure Risk Assessments " \l 3 	

		

As per FQPA, 1996, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  The toxicity
endpoints selected for these routes of exposure may be aggregated as
follows:

For short- and intermediate-exposure, oral and dermal and inhalation
endpoints can be aggregated because of the use of oral equivalents and a
common endpoint (decreased body weight gain).

For long-term exposure, oral and dermal and inhalation endpoints can be
aggregated because of the use of oral equivalents and a common endpoint
(thyroid toxicity).

3.3.10	Classification of Carcinogenic Potential tc "3.5.10
Classification of Carcinogenic Potential " \l 3 

3.3.10.1	Combined Chronic Toxicity/Carcinogenicity Study in Rats

MRID No. 42256331

Executive Summary: See Chronic RfD

Discussion of Tumor Data   At the doses tested, there was no treatment
related increase in tumor incidence when compared to controls.

Adequacy of the Dose Levels Tested  Dosing was considered adequate based
on thyroid toxicity and decreased body weights in both sexes.

3.3.10.2	Carcinogenicity Study in Mice

MRID No. 42256335

Executive Summary:  In a carcinogenicity study (MRID 42256335) NTN 33893
Technical (Imidacloprid; 95.0-95.3% ai, batch #180587) was administered
to 50 B6C3F1 mice/sex/dose in the diet at dose levels of 0, 100, 330, or
1000 ppm (equivalent to 0, 20, 66, or 208 mg/kg bw/day for males and 0,
30, 104, or 274 mg/kg bw/day for females) for 24 months.  In a
supplementary study to determine the maximum tolerated dose (MRID
42256336), the same test material was administered to 60 B6C3F1
mice/sex/dose in the diet at dose levels of 0 or 2000 ppm (equivalent to
0 or 414 mg/kg bw/day for males and 0 or 424 mg/kg bw/day for females)
for 24 months.  Both studies included additional groups of 10
animals/sex/dose for evaluation at a 12 month interim sacrifice.

There were no treatment-related deaths in either study.  Increased
incidences of “squeaking or twittering” were noted only at 2000 ppm;
however, the significance of this finding is unclear.  There were no
treatment-related effects on hematological or clinical chemistry
parameters, or gross and histopathology, including tumors.  At 2000 ppm,
absolute body weights were decreased in both sexes from week 13 through
the end of the study (males: 74-87% of controls; females 79-89% of
controls; p<0.01 for both).  Cumulative body weight gain for the first
year of the study was decreased for males and females of the 2000 ppm
group and males of the 1000 ppm group (33, 45, and 85% of their
respective controls).  At 2000 ppm, males had decreased food consumption
on most days throughout the first half of the study and on some days
during the second half as well (63-90% of controls; p<0.05 or p<0.01),
and females had reduced food consumption throughout the entire study
(53-69% of controls; p<0.01), with reduced food efficiency, as well (24%
less than controls).  There were also sporadic non-statistically
significant decreases in food consumption noted at the 1000 ppm dose
level: males during week 104 (87% of controls) and females during weeks
1, 52, 78, and 104 (81-90% of controls).  Water intake was decreased in
females from the 1000 ppm group and both males and females of the 2000
ppm group (10, 29, and 38% less than their respective controls). 
Treatment-related effects on organ weights were noted at 2000 ppm and
included the following: decreased absolute lung, liver, spleen, and
kidney weights, and increased relative brain weight in both sexes at
both interim and final sacrifice; increased relative testes weight at
both interim and final sacrifices; decreased absolute adrenal weight in
both sexes at interim sacrifice and females only at final sacrifice;
decreased relative liver weight in both sexes at interim sacrifice and
females only at terminal sacrifice; decreased absolute ovary weight at
final sacrifice only; increased relative spleen weight in males at
interim sacrifice; and decreased relative spleen weight in females at
interim and final sacrifice.  The organ weight changes were not
considered toxicologically important due to lack of corresponding gross
or microscopic changes.  The systemic toxicity LOAEL for imidacloprid in
B6C3F1 mice is 2000 ppm (equivalent to 414 mg/kg bw/day for males and
424 mg/kg bw/day for females), based on decreased body weights, food
consumption, and water intake.  The NOAEL is 1000 ppm (equivalent to 208
mg/kg/bw/day for males, 274 mg/kg bw/day for females).

At the doses tested, there was no treatment related increase in tumor
incidence when compared to controls.  Dosing was considered adequate
when the two studies were combined, based on decreased body weights,
food consumption, and water intake.

This carcinogenicity study in the mouse is classified
Acceptable/Guideline and satisfies the guideline requirements for a
carcinogenicity study in the mouse (OPPTS 870.4200b; OECD 451).

Discussion of Tumor Data  At the doses tested, there was no treatment
related increase in tumor incidence when compared to controls.

Adequacy of the Dose Levels Tested   Dosing was considered adequate when
the two studies were combined, based on decreased body weights, food
consumption, and water intake in both sexes.

3.5.10.3	Classification of Carcinogenic Potential

Imidacloprid has been classified as a Group E chemical, no evidence of
carcinogenicity for humans, by the HED RfD/Peer Review Committee
(11/10/93).

  SEQ CHAPTER \h \r 1 3.5.11	Summary of Toxicological Doses and
Endpoints for Imidacloprid for Use in Human Risk Assessments.

Table 3.5.11 Summary of Toxicological Dose and Endpoints for
Imidacloprid for Use in Human Health Risk Assessment1.

Exposure

Scenario	Dose Used in Risk Assessment,

UF	*FQPA SF and Level of Concern for Risk Assessment	Study and
Toxicological Effects

Acute Dietary

all populations	LOAEL = 42 mg/kg/day

UF = 3002

Acute PAD = 0.14 mg/kg	FQPA SF = 1X

aPAD = aPOD

              FQPA SF

= 0.14 mg/kg	Acute neurotoxicity - rat

LOAEL = 42 mg/kg, based upon the decrease in motor and locomotor
activities observed in females.

Chronic Dietary

all populations	NOAEL = 5.7 mg/kg/day

UF = 100

Chronic PAD = 0.057 mg/kg/day	FQPA SF = 1X

cPAD = cPOD

             FQPA SF

= 0.057 mg/kg/day	Combined chronic tox/carcinogenicity - rat

LOAEL = 16.9 mg/kg/day, based upon increased incidence of mineralized
particles in thyroid colloid in males.

Short-Term Oral

(1-30 days)

	oral study NOAEL = 10 mg/kg/day	LOC for MOE = 100 (Residential,
includes the FQPA SF)	Developmental toxicity - rat

Maternal LOAEL = 30 mg/kg/day, based upon decreased body weight gain and
corrected body weight gain.

Intermediate-Term Oral

(1- 6 months)	oral study NOAEL = 9.3 mg/kg/day	LOC for MOE = 100
(Residential, includes the FQPA SF)	Subchronic neurotoxicity - rat

LOAEL = 63.3 mg/kg/day, based upon decreased body weight gain.

Short-Term Dermal

(1-30 days)	oral study NOAEL = 10 mg/kg/day

(dermal absorption rate = 7.2%)3	LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF)	Developmental
toxicity - rat

Maternal LOAEL = 30 mg/kg/day, based upon decreased body weight gain and
corrected body weight gain.

Intermediate-Term

Dermal 

(1-6 months)	oral study NOAEL = 9.3 mg/kg/day

(dermal absorption rate = 7.2%)3	LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF)	Subchronic
neurotoxicity - rat

LOAEL = 63.3 mg/kg/day, based upon decreased body weight gain.

Long-Term Dermal

(> 6 months)	oral study NOAEL = 5.7 mg/kg/day

(dermal absorption rate = 7.2%)3	LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF)	Combined chronic
tox/carcinogenicity - rat

LOAEL = 16.9 mg/kg/day, based upon increased incidence of mineralized
particles in thyroid colloid in males.

Short-Term Inhalation

(1-30 days)	oral study NOAEL = 10 mg/kg/day

(inhalation absorption rate = 100%)	LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF)	Developmental
toxicity - rat

Maternal LOAEL = 30 mg/kg/day, based upon decreased body weight gain and
corrected body weight gain.

Intermediate-Term Inhalation

(1- 6 months)	oral study NOAEL = 9.3 mg/kg/day

(inhalation absorption rate = 100%)	LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF)	Subchronic
neurotoxicity - rat

LOAEL = 63.3 mg/kg/day, based upon decreased body weight gain.

Long-Term Inhalation

(> 6 months)	oral study NOAEL = 5.7 mg/kg/day

(inhalation absorption rate = 100%)	LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF)	Combined chronic
tox/carcinogenicity - rat

LOAEL = 16.9 mg/kg/day, based upon increased incidence of mineralized
particles in thyroid colloid in males.

Cancer

(oral, dermal, inhalation)	no evidence of carcinogenicity for humans	Not
applicable	No evidence of carcinogenicity in rats and mice.

1 UF = uncertainty factor, NOAEL = no-observed adverse-effect level,
LOAEL = lowest-observed adverse-effect level, PAD = population-adjusted
dose (a = acute, c = chronic) POD = point of departure, MOE = margin of
exposure, LOC = level of concern.

2 A 300-fold uncertainty factor (3x UFL; and 10x for interspecies
extrapolation and 10x for intraspecies variation) was incorporated in
the aPOD.  A 3X uncertainty factor for the use of a LOAEL was judged to
be adequate (as opposed to a 10X) because: 1) the LOAEL (42 mg/kg) is
comparable to the LOAELs seen in adults in the developmental rat study
(30 mg/kg/d) and the two-generation reproduction study [47/52 mg/kg/d
(male/female)] and in the offspring in the DNT study (55 mg/kg/d); 2)
the extrapolated NOAEL of 14 mg/kg (42/3 = 14) is comparable to the
NOAEL of 20 mg/kg/d established in the offspring in the DNT; and, 3) the
neurotoxic effects in this study showed a good dose response which
resulted in minimal effects on motor activity and locomotor activity at
the LOAEL (DP Num: 286101, J. Tyler, 3/4/03).

3 A dermal absorption factor of 7% was used for risk assessment
purposes.

3.6	Endocrine disruption  tc "3.6	Endocrine disruption " \l 2 			

EPA is required under the Federal Food Drug and Cosmetic Act (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, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA has authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, imidacloprid 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 

4.1	Incident Reports

According to OPPs Incident Data System there are a number of unconfirmed
incidents regarding imidacloprid.  The State of California sent a report
in 1999 of 56 cases involving imidacloprid the majority of which
involved pesticide mixtures.  In only one case was imidacloprid
considered the cause of the illness (a kennel worker splashed a drop in
his eye which began burning and had a corneal abrasion) [Personal
Communication from Dr. Jerome Blondell to J. Tyler (e-mail 10/31/02)].

5.0	Dietary Exposure/Risk Characterization tc "5.0	Dietary Exposure/Risk
Characterization" 

5.1	Pesticide Metabolism and Environmental Degradation  tc "5.1 
Pesticide Metabolism and Environmental Degradation " \l 2 

5.1.1	Metabolism in Primary Crops and Livestock tc "5.1.1	Metabolism in
Primary Crops " \l 3 

Data concerning the metabolism of imidacloprid in apples, potatoes,
tomatoes, eggplant, cottonseed, field corn, tobacco, ruminants, and
poultry have been submitted and reviewed in conjunction with
PP#3F4169/3H5655 (DP Num: 185148, F. Griffith, 9/20/93; DP Num: 200233,
F. Griffith, 6/8/94; and DP Num: 217632, F. Griffith, 2/29/96).  The
results of the aforementioned plant and livestock metabolism studies
were presented to the HED Metabolism Assessment Review Committee (MARC)
on 6/22/93 (F. Griffith, 6/18/93).  The nature of imidacloprid residues
in plants and livestock is adequately understood.  The residue of
concern in plants and livestock is imidacloprid and its metabolites
containing the 6-chloropyridinyl moiety, all expressed as the parent, as
specified in 40 CFR §180.472.

5.1.2	Metabolism in Rotational Crops

No rotational crop data were submitted in conjunction with the proposed
uses.  The nature of the imidacloprid residue in rotational crops has
been adequately characterized and identified.  The identified residue in
rotational crops is nearly identical to that identified in the primary
crops, and the regulable residues in rotated crops are imidacloprid and
its metabolites containing the 6-chloropyridinyl moiety.  According to
the proposed use labels, treated areas may be replanted with any crop
specified on the labels or with any crop for which a tolerance exists
for imidacloprid.  However, a 12-month plant-back interval should be
observed for crops not listed on the labels and for those crops for
which no tolerances for imidacloprid have been established.  Also, cover
crops for soil building or erosion control may be planted any time, but
do not graze or harvest for food or feed (PP# 6F4682 & 0E6106; DP Num:
224074 & 263729; MRID: 43939401, 43939402, & 45051401; Y. Donovan;
7/12/00).

5.1.3	Analytical Methodology  tc "5.1.4	Analytical Methodology " \l 3 

Adequate enforcement methods are available for determination of
imidacloprid residues of concern in plant (Bayer GC/MS Method 00200) and
livestock commodities (Bayer GC/MS Method 00191).  These methods have
undergone successful EPA petition method validations (PMVs), and the
registrant has fulfilled the remaining requirements for additional raw
data, method validation, independent laboratory validation (ILV), and an
acceptable confirmatory method (high-performance liquid
chromatography/ultraviolet (HPLC/UV) Method 00357) (DP Num: 187911,
6/18/93; DP Num: 202113, 6/1/94; DP Num: 200233, 6/8/94; DP Num: 213252,
6/8/95; and DP Num: 221591, 12/18/95; F. Griffith).  The LOD and LOQ for
the GC/MS Method 00200 are 0.01 and 0.05 ppm, respectively, in plant
commodities.

Bayer GC/MS Method 00200 is a common moiety method that uses a 3:1
methanol/1% sulfuric acid extraction, filtering through Celite/filter
paper, XAD-4 resin column clean-up, oxidation of parent and metabolites
to 6-CNA by refluxing in a 32% sodium hydroxide (NaOH) solution combined
with a 5% potassium permanganate (KMnO4) solution, extracted 3 times
with methyl t-butyl ether, then N-methyl-N-(trimethylsilyl)
trifluroacetamide (MSFTA) derivatization for 1 hour, and determination
by capillary GC/MS selective ion monitoring at m/z 214, 216, 170, and
140. 

Samples in the submitted peanut crop field trial and processing studies
were for analyzed for combined residues of imidacloprid and its
metabolites containing 6-chloropyridinyl moiety, all expressed as the
parent, using a modification of Bayer GC/MS Method 00200.  The LOD and
LOQ were calculated as 0.03 ppm and 0.076 ppm for nutmeat; 0.01 ppm and
0.033 ppm, for oil; and 0.02 ppm and 0.062 ppm for meal.

For caneberries, total residues of imidacloprid (including the
metabolites containing the 6-chloropicolyl moiety) were determined using
working methods based on the gas chromatographic Bayer Method 00200 -
Reformatted (Report Number 102624-R1) with GC/MS.  In IR-4 PR No. 08257,
minor modifications to the reference analytical method did not affect
the validity of the method for the determination of total residues of
imidacloprid in/on caneberries.  The LLMV of the modified method in this
study was reported as 0.05 ppm.  LODs were estimated as 0.009 ppm, 0.02
ppm and 0.03 ppm for raspberry, marionberry and boysenberry,
respectively.  The method is valid for the determination of total
imidacloprid residues in caneberries

Also in the caneberry Study No. AAFC03-085R, the method was modified to
allow quantitation by HPLC/MS.  The LLMV in this study was reported as
0.30 ppm.  The LOD and LOQ were calculated to be 0.068 ppm and 0.203
ppm, respectively.  Concurrent recoveries in raspberry samples ranged
from 60.9% to 86.2% (n=6) when samples were fortified at the LLMV. 
Total residues of imidacloprid were determined to be below the LLMV
(<0.30 ppm) and/or calculated LOQ (<0.203 ppm) at all PHIs.  As the
modified method used could not be validated at the target LOQ (0.05
ppm), the method LLMV was unacceptably high and the residues reported at
each PHI were below the LLMV, this residue study is considered
scientifically unacceptable.  Therefore, the results from this study
should not be used to support the registration of imidacloprid in/on
caneberries. 

The total imidacloprid residue (imidacloprid + des nitro imidacloprid +
hydroxyl imidacloprid+ olefin imidacloprid + 6-chloronicotinic acid) was
analyzed in soybean samples by a common moiety method (oxidation to
6-chloronicotinic acid) and quantitated by using isotopically-labeled
internal standards and LC-MS/MS.  The method in this study,
NT-001-P04-01, is based on an earlier method, 00834.  The LOQ for
imidacloprid in soybean forage, hay, and seed was 0.025 ppm, 0.100 ppm,
and 0.05 ppm, respectively.  The calculated LOD for soybean forage, hay,
and seed were 0.0111 ppm, 0.0382 ppm, and 0.0136 ppm, respectively.  The
data from the soybean processing study support a method LOQ of 0.050 ppm
for each analyte in soybean seed and processed commodities.  The method
is adequate for data collection purposes.

These data indicate that the GC/MS method, Bayer Method 00200, and
HPLC/MS method, NT-001-P04-01, are adequate for determining residues of
imidacloprid and its metabolites containing the 6-chloropyridinyl
moiety, all expressed as the parent, in/on the commodities associated
with the proposed uses.

Bayer Corporation previously submitted adequate multiresidue method
(MRM) recovery data for imidacloprid and the metabolites 5-hydroxy
imidacloprid, imidacloprid olefin, des nitro imidacloprid and 6-CNA
through Food and Drug Administration (FDA) Protocols A through E (DP
Num: 187911, 6/18/93; DP Num: 193027, 7/15/93; DP Num: 200233, 6/8/94;
and 194206, 6/22/94; F. Griffith).  Imidacloprid and its metabolites
were not recoverable by these methods.  The results of the MRM testing
for imidacloprid were forwarded to FDA for inclusion in the Pesticide
Analytical Method Volume I (PAM I) (DP Num: 193005, F. Griffith,
7/15/93).

5.1.4	Environmental Degradation  tc "5.1.4	Environmental Degradation "
\l 3 

In a meeting on 12/18/02, the HED MARC recommended that for surface
water risk assessment, degradates of concern should be parent and the
three degradates: imidacloprid urea, imidacloprid guanidine, and
imidacloprid olefin (DP Num: 28740, J. Tyler, 1/13/03).  

5.1.5	Comparative Metabolic Profile  tc "5.1.5	Comparative Metabolic
Profile " \l 3 

In a rat metabolism study, methylene-labeled imidacloprid was rapidly
absorbed with approximately 90% of the administered dose being
eliminated within 24 hours and 96% within 48 hours.  There were two
major evident routes of biotransformation.  The first included an
oxidative cleavage of the parent compound to give 6-CNA and its glycine
conjugate.  Dechlorination of this metabolite formed the 6-CNA and its
mercapturic acid derivative.  The second included the hydroxylation of
imidazolidine followed by elimination of water of the parent compound to
give NTN 35884.  In a comparison between [methylene-14C] imidacloprid
and [imidazolidine-4,5-14C] imidacloprid, the rates of excretion were
similar; however, the renal portion was higher with the
imidazolidine-labeled test material (90% vs. 75% of recovered
radioactivity for methylene-labeled test material.

Imidacloprid is metabolized in plants by three pathways as follows: 1)
hydroxylation of the dihydroimidazole ring of imidacloprid to form the
4-hydroxy, 5-hydroxy, and dihydroxy imidacloprid followed by the loss of
water to form the olefin; 2) reduction and loss of the nitro group on
the dihydroimidazole ring to form the nitrosimino imidacloprid, then the
guanidine imidacloprid, and finally the urea imidacloprid; and 3) bridge
cleavage of the C-N bond to form the 6-chloropicolyl alcohol (6-CPA)
which rapidly forms the glucoside and the 6-CNA, and dihydroimidazole. 
All residues are determined as 6-CNA, then converted to imidacloprid
equivalents.

Imidacloprid is metabolized in ruminants by 3 pathways as follows: 1)
hydroxylation of the dihydroimidazole ring of imidacloprid to form
4-hydroxy, 5-hydroxy, plus the glucuronide conjugates of each
monohydroxy metabolite, and the dihydroxy imidacloprid followed by the
loss of water to form the olefin imidacloprid; 2) reduction and loss of
the nitro group on the dihydroimidazole ring to form aminoguanidine
imidacloprid, then the guanidine imidacloprid and finally the urea
imidacloprid; and 3) opening of the dihydroimidazole ring with loss of
the ethyl group and subsequent oxidation.  The first step is forming the
nitroguanidine imidacloprid, next the ring open guanidine which can also
form both the guanidine imidacloprid and the dihydroxy guanidine
imidacloprid.  This metabolite can form picolylic urea, and picolylic
amine which is oxidized to 6-CNA which then can conjugate with glycine. 
The identified residues in ruminants are imidacloprid and its
metabolites that contain the 6-chloropyridinyl moiety.  All residues are
determined as 6-CNA, then converted to imidacloprid equivalents.

Imidacloprid is metabolized in poultry by 3 pathways as follows: 1)
hydroxylation of the dihydroimidazole ring of imidacloprid to form
4-hydroxy, 5-hydroxy and the dihydroxy imidacloprid followed by loss of
water to form the olefin; 2) reduction and loss of the nitro group on
the dihydroimida-zole ring to form the dihydroxyguanidine imidacloprid;
and 3) opening of the dihydroimidazole ring with the loss of the ethyl
group and subsequent oxidation.  The first step is forming the
nitroguanidine imidacloprid, next the ring open guanidine imidacloprid
which can also form from both the dihydroxy guanidine imidacloprid and
the guanidine imidacloprid.  This metabolite can form picolylic amine
which is oxidized to 6-CNA.  The identified residues in poultry are
imidacloprid and its metabolites which contain the 6-chloropyridinyl
moiety.  All residues are determined as 6-CNA, then converted to
imidacloprid equivalents.

5.1.6	Toxicity Profile of Major Metabolites and Degradates 

Little information is available on the toxicity of the major
imidacloprid metabolites.  The 6-CNA metabolite formed in plants and
animals appears to be also formed in the rat, and is, therefore, part of
the total toxic exposure for these animals.  It is unlikely to be more
toxic than the parent

5.1.7	Pesticide Metabolites and Degradates of Concern  tc "5.1.7
Pesticide Metabolites and Degradates of Concern " \l 3 

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	Imidacloprid and its metabolites containing the
6-chloropyridinyl moiety	Imidacloprid and its metabolites containing the
6-chloropyridinyl moiety

	Rotational Crop

Livestock

	Ruminant

	Poultry

Drinking Water

	Imidacloprid and degadates: imidacloprid urea, imidacloprid guanidine,
and imidacloprid olefin	Not Applicable

The structures of imidacloprid metabolites can be seen in Attachment 2.

5.1.8	Drinking Water Residue Profile  tc "5.1.8	Drinking Water Residue
Profile " \l 3 

In a meeting on 12/18/02, the HED MARC recommended that for surface
water risk assessment, degradates of concern should be parent and the
three degradates: imidacloprid urea, imidacloprid guanidine, and
imidacloprid olefin (DP Num: 28740, J. Tyler, 1/13/03).  EFED provided
revised, Tier 1 EDWCs for surface water (using FIRST) for imidacloprid
and its degradates (imidacloprid urea, imidacloprid guanidine, and
imidacloprid olefin) for the proposed uses only.  Revised ground water
EDWCs were not estimated because these values have been shown previously
to be substantially lower in magnitude than the surface water
concentrations.  The revised surface water EDWCs for the proposed uses
do not exceed the EDWCs provided by EFED in conjunction with the 3/14/03
HED risk assessment for imidacloprid (DP Num: 271770, M. Barrett,
2/25/03).  Therefore, the overall highest surface and ground water EDWCs
were used in the current risk assessment (DP Num: 311925, R. Parker,
5/16/06).

Table 5.1.8  Estimated Tier 1 Concentrations of Imidacloprid in Drinking
Water.

Chemical	Surface Water (μg/L)	Groundwater (μg/L)

	Acute	Chronic	Acute and Chronic

Revised EDWCs1

Imidacloprid total residues2	Tree nuts – 35.9	Tree nuts and coffee –
15.3	Not provided.

Previously-calculated EDWCs3

Imidacloprid total residues2	Citrus – 36.0	Citrus – 17.2	2.09

1.  Memo, R. Parker, 5/16/06; DP# 311925.

2.  Imidacloprid and its degradates (imidacloprid urea, imidacloprid
guanidine, and imidacloprid olefin).

3.  Memo, M. Barrett, 2/25/03; DP# 271770.

5.1.9	Food Residue Profile  tc "5.1.9	Food Residue Profile " \l 3 

IR-4, on behalf of the Agricultural Experiment Stations of Texas,
Missouri, Georgia, Wisconsin, and Hawaii, has submitted a petition for
the use of imidacloprid on peanuts; proso and pearl millet; oats; kava;
globe artichoke; caneberry, subgroup13A; and wild raspberry.  IR-4 is
not requesting a change in the existing tolerance for globe artichokes;
the request is for the addition of a soil use to the existing foliar
use.  Bayer Corp. has also submitted a petition for the use of
imidacloprid on soybeans.    SEQ CHAPTER \h \r 1 Imidacloprid
(1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-imidazolidinimine) is an
insecticide registered for uses on a variety of crops for the control of
aphids, cucumber beetles and whiteflies (including sweet potato or
silverleaf whitefly).  

In conjunction with these petitions, tolerances have been requested for
the combined residues of the insecticide imidacloprid
(1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-imidazolidinimine) and its
metabolites containing the 6-chloropyridinyl moiety, all expressed as
1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-imidazolidinimine.

 

The petitioners have submitted sample labels for numerous imidacloprid
products.  The uses on peanuts and kava include both an in-furrow spray
on or below seed during or before planting and a foliar use.  The peanut
and kava seed use is for a single application at 0.38 pounds active
ingredient per acre (lb ai/A).  The foliar uses on peanut and kava are
for up to 3 applications for a total 0.13 lb ai/A with PHIs of 14 days
for peanut and 7 days for kava.  The uses on millet and oats include
commercial seed treatment or below seed during or before planting at
0.25 or 0.09 lb ai/100lb seed, respectively.  The use on globe artichoke
includes both an in-furrow spray on or below seed during or before
planting at and a foliar use, both at 0.5 lb ai/A with a 7-day PHI. 
These use directions are adequate. 

The labels for caneberries indicate either a foliar application at 0.3
lb ai/A with a 3-day PHI or a drench application 0.5 lb ai/A with a
7-day PHI.  Since the previous lower tolerance for caneberries was based
using the drench application at the higher rate, the use is supported
may remain on the labels.  

There is an existing use of imidacloprid on soybean seeds for protection
from damage caused by seed corn maggot, to reduce feeding damage caused
by soybean aphids and over-wintering bean leaf beetles, and to help
suppress the spread of certain viruses, at 2.0-4.0 fl. oz. per
hundredweight of seed.  The requested foliar use on soybeans is in
addition to the current use on soybean seeds for three applications at
0.047 lb ai/A with a maximum total application of 0.14 lb ai/A.  These
use directions are adequate.

The nature of imidacloprid residues in plants and livestock is
adequately understood.  The residue of concern in plants and livestock
is imidacloprid and its metabolites containing the 6-chloropyridinyl
moiety, all expressed as the parent.  

Adequate enforcement methods are available for determination of
imidacloprid residues of concern in plant (Bayer GC/MS Method 00200) and
livestock commodities (Bayer GC/MS Method 00191).  These methods have
undergone successful EPA PMVs.  Bayer GC/MS Method 00200 is a common
moiety method that uses oxidation of parent and metabolites to 6-CNA
with demonstrated LOD and LOQ at 0.01 and 0.05 ppm, respectively, in
plant commodities.  Previously submitted MRM recovery data for
imidacloprid and the metabolites 5-hydroxy imidacloprid, imidacloprid
olefin, des nitro imidacloprid and 6-CNA indicate that these residues
were not recoverable by these methods.  

Samples in the submitted peanut crop field trial and processing studies
were for analyzed for combined residues of imidacloprid and its
metabolites containing 6-chloropyridinyl moiety, all expressed as the
parent, using a modification of Bayer GC/MS Method 00200.  The LOD and
LOQ were calculated as 0.03 ppm and 0.076 ppm for nutmeat; 0.01 ppm and
0.033 ppm, for oil; and 0.02 ppm and 0.062 ppm for meal.

For caneberries, total residues of imidacloprid were determined using a
working method based on Bayer Method 00200.  The LLMV of the modified
method in this study was reported as 0.05 ppm.  LODs were estimated as
0.009 ppm, 0.02 ppm and 0.03 ppm for raspberry, marionberry and
boysenberry, respectively.  Another analytical method was used in the
caneberry trial designated as Study No. AAFC03-085R.  The method used
quantitation by high performance liquid chromatography with mass
spectroscopy detector (HPLC/MS).  The LLMV in this study was reported as
0.30 ppm.  The LOD and LOQ were calculated to be 0.068 ppm and 0.203
ppm, respectively.  However, total residues of imidacloprid were
determined to be below the LLMV (<0.30 ppm) and/or calculated LOQ
(<0.203 ppm) at all PHIs.  As the method used could not be validated at
the target LOQ (0.05 ppm), the method LLMV was unacceptably high and the
residues reported at each PHI were below the LLMV, this residue study is
considered scientifically unacceptable.  Therefore, the results from
this trial should not be used to support the registration of
imidacloprid in/on caneberries. 

The total imidacloprid residue was analyzed in soybean field trial and
processing samples by a common moiety method (oxidation to 6-CNA) and
quantitated by LC-MS/MS.  The method in these studies, NT-001-P04-01, is
based on an earlier method, 00834.  The LOQ for imidacloprid in soybean
forage, hay, and seed was 0.025 ppm, 0.100 ppm, and 0.05 ppm,
respectively.  The calculated LODs for soybean forage, hay, and seed
were 0.0111 ppm, 0.0382 ppm, and 0.0136 ppm, respectively.  The data
from the soybean processing study support a method LOQ of 0.050 ppm for
each analyte in soybean seed and processed commodities.  The method is
adequate for data collection purposes.

Residues of imidacloprid have previously been shown to be stable in a
variety of RACs for up to 2 years.  In addition, analysis of samples
from the 14C-imidacloprid plant metabolism studies for corn, cotton,
apples, and potatoes showed no loss of imidacloprid and its major
metabolites during a period of 2 years of frozen storage.  The maximum
storage interval for field-treated samples in the peanut studies was
approximately 4 years (1489 days for nutmeat, 1506 days for oil, 1662
days for hay, and 1534 days for meal).  Storage stability testing
performed after approximately 4.4 years of frozen storage (1600 days for
both nutmeat and oil, 1609 days for hay, and 1595 days for meal) showed
no appreciable degradation.  Caneberries were stored frozen for up to 87
days.  Concurrent storage stability studies with marionberries indicated
that residues were stable when frozen for up to 75 days.  The soybean
field trial samples analyzed in this study were held in frozen storage
for a maximum of 15 months (450 days) prior to extraction.  Soybean
aspirated grain fractions and the processed commodities of soybean seed
were analyzed within 3.1 months (95 days) of production.  

The expected residue levels in the livestock feed items associated with
the subject petition were used to recalculate the MTDB for livestock. 
The newly calculated MTDBs are not greater than those calculated
previously.  Therefore, the proposed uses will not require an increase
in livestock tolerances.

Twelve peanut field trials were conducted using a single in-furrow
applications at a rate of approximately 0.375 lb ai/A at planting
followed by foliar applications made 4 to 6 days apart at a rate of
approximately 0.044 lb ai/A for a total of approximately 0.507 lb ai/A. 
In addition to peanuts and hay harvested 13 to 15 days PHI, each
commodity was harvested at 21 and 28 days at the 98-TX17 trial for
decline determination.  The results from the trials show that the
maximum combined residues in nutmeat were 0.40 ppm.  Maximum residues in
14-day and 28-day hay samples were 24 ppm.  Residues declined in nutmeat
to a maximum of 0.14 ppm by 28 days. The submitted studies are adequate
in number and geographic diversity and are supported by adequate storage
stability data and analytical methodology.  However, the residue data as
analyzed by the Tolerance/MRL Harmonization Spreadsheet indicates that
the requested tolerances on peanut nutmeat and hay are not appropriate. 
A new Section F requesting imidacloprid tolerances on peanuts at 0.60
ppm and peanut, hay at 35 ppm is required.

No crop-specific data to support the tolerance requests in conjunction
with the requested uses for proso millet, pearl millet, and oats.  There
are existing tolerances for residues of imidacloprid on barley, grain;
corn, field, grain; corn, pop, grain; corn, sweet, kernel plus cob with
husks removed; oats, grain; rye, grain; sorghum, grain; and wheat, grain
all at 0.05 ppm.  In addition, there is a tolerance for indirect or
inadvertent combined residues of imidacloprid on grain, cereal, group 15
also at 0.05 ppm.  Since there are identical seed treatment uses with
tolerances for most of the cereal grain crop group and a tolerance for
indirect or inadvertent residues on the cereal grain crop group,
tolerances can be translated to the seed treatment uses on proso millet
and pearl millet.  ARIA recommends for the proposed tolerances on proso
and pearl millet grain at 0.05 ppm.  In addition, residues would be
expected on the other millet RACs as residues are found on other grain
RACs from the same uses.  A revised Section F is required for proso
millet, forage at 2.0 ppm; proso millet, hay at 6.0 ppm; proso millet,
straw at 3.0 ppm; pearl millet, forage at 2.0 ppm; pearl millet, hay at
6.0 ppm; and pearl millet, straw at 3.0 ppm. 

As noted above, there are already existing tolerances for the seed
treatment use on oats: oats, grain at 0.05 ppm; oats, forage at 2.0 ppm;
oats, hay at 6.0 ppm; oats, straw at 3.0 ppm as a result of the same
proposed seed treatment use as proposed here.  The request for use and
tolerance for imidacloprid on oats is not necessary; the requested
tolerances should be removed from Section F.  

No crop-specific data were submitted to support the tolerance requests
in conjunction with the requested use for kava.  Since kava is projected
to be part of the root and tuber vegetable crop group 1 in the near
future and the proposed use is identical to that used for root and tuber
vegetables, ARIA recommends for the proposed imidacloprid tolerances on
kava, leaves at 4.0 ppm and kava, roots at 0.40 ppm. 

  

No new crop-specific data to support the tolerance requests in
conjunction with the requested use on globe artichoke.  A tolerance of
2.5 ppm has already been established for imidacloprid on globe
artichokes as a result of a foliar use.  IR-4 is now requesting a use
either below the seed row before planting, in-furrow during planting, or
by chemigation into the root zone. Comparisons of data on foliar vs.
limited soil-applied imidacloprid or the two treatments combined
indicate that the foliar treatments clearly drive the magnitude of the
resulting residues.  Any slight additional residues from soil treatments
are expected to be covered by existing tolerances established to reflect
foliar application.  Therefore, it is unlikely that the residues of
imidacloprid from the proposed soil treatment use on globe artichoke
will exceed the existing 2.5 ppm tolerance.  ARIA recommends for the
proposed imidacloprid use on globe artichoke without a change in the
existing tolerance. 

A previous petition for the use of imidacloprid on caneberries as drench
application 0.5 lb ai/A with a 7-day PHI resulted in a conditional
registration and permanent tolerance at 0.05 ppm.  The registration was
conditional until the submission of additional crop field trial data. 
Residue data have now been submitted.  A total of ten trials were
conducted in the U.S. and Canada.  Imidacloprid was applied to
caneberries in three foliar-directed broadcast sprays at a rate of 0.10
to 0.11 lb ai/A/application at 6 to 11-day retreatment intervals (RTIs)
for total application rates of 0.30 to 0.31 lb ai/A.  Crops were
harvested 2-4 days after the last application (DALA).  The maximum
residues observed in caneberries were 0.70 ppm in blackberry, 0.96 ppm
in raspberry, 1.7 ppm in marionberry and 1.5 ppm in boysenberry.  The
residue data as analyzed by the Tolerance/MRL Harmonization Spreadsheet
indicates that the requested tolerance on caneberries, crop group 13A at
2.5 ppm is not appropriate.  The commodities blackberry, marionberry,
and boysenberry are considered cultivars of blackberries while
raspberries are separate.  The Tolerance/MRL Harmonization Spreadsheet
indicates appropriate tolerance levels of 3.5 ppm and 1.3 ppm for
blackberries and raspberries, respectively.  However, since the
databases are small for blackberries and raspberries, the fruits are
essentially the same size and texture, and in the interest of
harmonizing with Canada, ARIA will consider the entire database for
caneberries together.  The Tolerance/MRL Harmonization Spreadsheet
indicates the appropriate tolerance level for the entire database of
caneberry residues should be 2.5 ppm.  Therefore, ARIA recommends for
the proposed tolerance for caneberry, subgroup 13A at 2.5 ppm. 

The petitioner has requested a tolerance for wild raspberry.  The wild
raspberry is distributed in tropical northern Queensland in open forests
and the rainforest and is similar to raspberries and other Rubus
species.  U.S. growers are evaluating improved varieties.  ARIA will
extend the residue information to from the caneberry subgroup to wild
raspberries; therefore, a tolerance for the residues of imidacloprid on
wild caneberries at 2.5 ppm is appropriate

Bayer Corp. submitted a total of 21 crop residue field trials on
soybeans.  The trials were conducted to measure the magnitude of
residues in soybeans resulting from the existing pre-plant seed
treatment followed by three foliar applications of imidacloprid to the
growing soybean plants.  The soybean seeds were treated at a nominal
rate of 0.125 lb ai/100 lb seed prior to planting.  The growing soybean
plants were subsequently treated with three foliar broadcast
applications of imidacloprid at a target rate of 0.047 lb ai/A.  Total
imidacloprid application rates (seed + foliar) ranged from 0.201 to
0.275 lb ai/A.  The highest imidacloprid residue on soybean forage and
hay at 0-day PHI was 8.87 ppm and 24.0 ppm, respectively.  The highest
imidacloprid residue on soybean seed at a 21-day PHI was 2.04 ppm.  The
total imidacloprid residue was found to decline significantly on soybean
forage with time.  In soybean hay, total imidacloprid residue was found
to decline significantly at one trial but remained relatively constant
at the other.  On soybean seed, total imidacloprid residue remained
constant with time.  The residue data as analyzed by the Tolerance/MRL
Harmonization Spreadsheet indicates that the requested tolerance on
soybean, forage is appropriate at 8.0 ppm.  However, the requested
tolerance levels on the other soybean commodities are not appropriate. 
A new Section F requesting imidacloprid tolerances on soybean, seed at
3.5 ppm, and soybean, hay at 35 ppm is required.

There are many processed commodities of regulatory interest associated
with these petitions among which are millet flour, oat flour, and rolled
oats.  It has been determined that imidacloprid residues do not
concentrate in grain processed commodities; therefore, no imidacloprid
tolerances are required on millet and oat processed commodities.

The submitted peanut processing study indicates that imidacloprid
residues do not concentrate in peanut oil.  Therefore, a separate
tolerance for imidacloprid residues in peanut oil is not required.  The
average of the two processing studies indicates that imidacloprid
residues will concentrate at 2.5X in peanut meal ((1.9+3.1)/2). 
However, this is higher than the theoretical maximum of 2.2X.  The HAFT
of 0.32 ppm times the theoretical maximum of 2.2X yields an expected
residue of 0.704 ppm in peanut meal.  Therefore, the requested tolerance
for imidacloprid residues in peanut meal at 0.9 ppm is not appropriate. 
ARIA recommends for the establishment of an imidacloprid tolerance on
peanut, meal at 0.75 ppm.  A revised Section F requesting an
imidacloprid tolerance on peanut, meal at 0.75 ppm is required. 

The submitted processing study indicates that imidacloprid residues do
not concentrate in soybean meal, hulls, or oil.  Therefore, a separate
tolerance for imidacloprid residues in soybean meal, hulls, or oil is
not required.  The processing study indicates that imidacloprid residues
will concentrate at 160X in aspirated grain fractions.  The HAFT of 1.50
ppm for soybean seed at the proposed application rate and PHI times the
empirical concentration value of 160X yields an expected residue of 240
ppm in aspirated grain fractions. The requested tolerance for
imidacloprid residues in aspirated grain fractions is appropriate. 
However, the Agency does not differentiate soybean from other aspirated
grain fractions; therefore, a revised Section F for aspirated grain
fractions at 240 ppm is required.

5.1.10	International Residue Limits  tc "5.2.10	International Residue
Limits " \l 3 

There are no established Canadian or Mexican MRLs for the proposed uses.
 There is an established Codex MRLs for the sum of imidacloprid and its
metabolites containing the 6-chloropyridinyl moiety, expressed as
imidacloprid, in/on cereal grain at 0.05 ppm.  Therefore, there are no
harmonization issues for these petitions.

5.2	Dietary Exposure and Risk  tc "5.2  Dietary Exposure and Risk " \l 2

Acute Dietary Exposure Results and Characterization:  An unrefined,
acute dietary exposure assessment using tolerance-level residues and
assuming 100 %CT for all registered and proposed commodities was
conducted for the general U.S. population and various population
subgroups.  Exposure to drinking water was incorporated directly in the
dietary assessment using the acute (peak) concentration for surface
water generated by the FIRST model.  This assessment indicates that the
acute dietary exposure estimates are below HED’s level of concern,
<100% aPAD, at the 95th exposure percentile for the general U.S.
population and all other population subgroups.  The acute dietary
exposure is estimated for the U.S. population at 28% of the aPAD and the
most highly exposed population subgroup, children 1-2 years old, at 70%
of the aPAD.  

Chronic Dietary Exposure Results and Characterization:  A partially
refined, chronic dietary exposure assessment (using tolerance-level
residues for all registered and proposed commodities, and %CT
information for some commodities) was conducted for the general U.S.
population and various population subgroups.  Exposure to drinking water
was incorporated directly into the dietary assessment using the chronic
(annual average) concentration for surface water generated by the FIRST
model.  This assessment concludes that the chronic dietary exposure
estimates are below HED’s level of concern (<100% cPAD) for the
general U.S. population and all population subgroups.  The chronic
dietary exposure is estimated for the U.S. population at 13% of the cPAD
and the most highly exposed population subgroup, children 1-2 years old,
at 38% of the cPAD.

Table 5.2.  Summary of Dietary Exposure and Risk for Imidacloprid

Population Subgroup	Acute Dietary1

(95th Percentile)	Chronic Dietary2

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

(mg/kg/day)	% cPAD

General U.S. Population	0.038846	28	0.007496	13

All Infants (< 1 year old)	0.078728	56	0.016053	28

Children 1-2 years old	0.097610	70	0.021691	38

Children 3-5 years old	0.072724	52	0.016308	29

Children 6-12 years old	0.046085	33	0.010058	18

Youth 13-19 years old	0.029242	21	0.005972	11

Adults 20-49 years old	0.026366	19	0.005890	10

Adults 50+ years old	0.025495	18	0.006015	11

Females 13-49 years old	0.026219	19	0.005652	10

1.  aPAD of 0.14 mg/kg/day applies to the general U.S. population and
all population subgroups.

2.  cPAD of 0.057 mg/kg/day applies to the general U.S. population and
all population subgroups.

5.3	Anticipated Residue and Percent Crop Treated Information 

No anticipated residue information was used in the dietary exposure
assessments.  The %CT information used in the chronic assessment is
presented in Table 5.3

Table 5.3  Screening Level Estimates of Agricultural Uses of
Imidacloprid1

Crop	Pounds of Active Ingredient	Percent of Crop Treated	Maximum Percent
of Crop Treated

Apples	10,000	30	45

Artichokes	<500	5	15

Beans, Green	2,000	5	10

Beets (NCFAP '97)	<500	15	-

Blueberries	<500	10	15

Broccoli	9,000	35	55

Brussels Sprouts *	<500	55	60

Cabbage	3,000	20	25

Cantaloupes	8,000	30	50

Carrots	<500	<1	<2.5

Cauliflower	4,000	40	60

Celery	1,000	5	15

Cherries	<500	5	7

Chicory *	<500	-	-

Collards	<500	10	15

Corn	100,000	<1	<2.5

Cotton	30,000	5	10

Cucumbers	1,000	5	7

Eggplant	<500	45	50

Grapefruit	2,000	5	10

Grapes	20,000	30	35

Greens, Turnip	<500	10	15

Honeydew	1,000	10	15

Hops (NCFAP '97)	4,000	90	-

Kale	<500	30	35

Lemons	1,000	<1	5

Lettuce	40,000	60	80

Nectarines *	<500	-	-

Olives *	<500	-	-

Onions	1,000	<1	<2.5

Oranges	10,000	5	10

Parsley (NCFAP '97)	<500	35	-

Peaches	<500	5	25

Pears	2,000	10	20

Pecans	9,000	10	15

Peppers	9,000	25	35

Potatoes	60,000	35	40

Pumpkins	1,000	5	15

Sod (NCFAP '97)	<500	5	-

Spinach	1,000	20	30

Squash	2,000	10	25

Strawberries	2,000	10	15

Sugar Beets	<500	<1	<2.5

Sweet Corn	<500	<1	<2.5

Tangerines	<500	10	15

Tobacco	10,000	20	25

Tomatoes	20,000	15	35

Walnuts	<500	<1	<2.5

Watermelons	4,000	10	10

1  Checking our available usage databases, we found no usage data for
the following crops: dairy cattle for milk, limes, mustard greens,
wheat, soybeans, apricots, plums, dry beans, snap beans, and processed
and green peas.  For your calculations, you may use <1%, for each crop,
for both typical average and likely maximum (DP Num: 311925, R. Parker,
5/16/06).

6.0	Residential (Non-Occupational) Exposure/Risk Characterization tc
"6.0	Residential (Non-Occupational) Exposure/Risk Characterization" 

6.1	Residential Handler Exposure 

 tc "6.1	Residential Handler Exposure " \l 2 

Imidacloprid is registered for use on residential ornamental lawns and
turf as well as for use on golf courses.  It is registered for use on
ornamental plantings (i.e., flowering plants, foliage plants, herbaceous
perennial plants, and woody plant, shrubs and trees).  It is registered
for indoor as well as outdoor residential uses.  It is registered as a
pre- and post-construction termiticide.  

The Office of Pesticide Programs’ Reference Files System (REFS) (7 MAY
02) indicates that there are 82 registered products (excluding Section
18 registrations) that contain imidacloprid. With the use of the
Pesticide Product Label System (PPLS), HED determined the use patterns
of each product in terms of pesticide handlers.  HED believes that
residential pesticide handlers (i.e., persons who might mix, load,
and/or apply a pesticide material) could be exposed to several
formulations that contain imidacloprid.  See Table 6.1 for a summary of
residential handler use patterns.  HED expects that residential handlers
will be exposed to short-term (i.e., 1-30 days) exposures based upon the
pest spectra, sites of application, methods of application, formulations
and the RTI intervals, if applicable.

Table 6.1  Summary of Residential “Handler” Use Patterns

Site	

Formulation	

Application

Rate	

Number of

Applications	

Comments

Lawns & Turf

Ornamental Plantings	

Granular

0.62 %	

0.4 lb ai/A	

1/yr	

applied with broadcast by push-type “drop” or rotary spreader

flowers, ground covers

shrubs, house plants	

Ready-to Use Pump Sprayer 0.012 %

24 fl.oz.	

“spray till point of run-off”	

“as needed”

7 - 14 day intervals	

Indoor & Outdoor Residential Potted Plants	

Plant “spikes”

0.8 oz (20 g)

10 two gram spikes

2.5 %	

one package will treat 4-5 eight inch pots	

efficacious for 8 weeks	

formulation contains fertilizer and Bitrex.  Not for use on edible
plants/herbs etc.

Potting medium  for indoor or outdoor plant containers	

0.015 % ready to use potting medium - largest container 19 lb 3 oz	

	

efficacious 4 months

	

Used as medium for new seedlings or as additional medium when
transplanting to larger containers.  Label directs use of rubber gloves.
 Medium contains sphagnum, bark, perlite, vermiculite, limestone and
fertilzers

Lawns, trees, shrubs, flowers	

liquid concentrate

0.70 % 32 fl oz	

0.001098 lb ai/5000 ft2	

“repeat if needed” in

 7 - 14 days	

For use on out-door, non-food residential plants

Assumed applied via compressed air or garden hose-end sprayer

Trees & Shrubs	

liquid concentrate

2.95 % one gallon = largest container size	

depends on plant stem size.  One gallon treats 20 “medium” trees or

42 “average” shrubs	

1/yr	

Applied to soil by pouring dilute from a bucket or a watering can around
bases of plant “stems”/trunks

Cats & Dogs	

ready to use liquid

9.1 %,  max = 5 ml for large dogs > 55 lb	

max rate = 5.0 ml

for dogs > 55 lb	

1/mo if needed	

Packaged in “dropper” vials.  The end cap is removed and one half
the contents dropped between the scapulae and one half on the
lumbrosacral region.

No rubbing or other contact is directed.

There are numerous granular products that contain imidacloprid alone or
with some combination of lawn/garden fertilizer.   An example is Merit®
0.62 G Insecticide (EPA Reg No 3125-416) which contains 0.62 %
imidacloprid.  The maximum rate of application for these products is 0.4
lb ai/A.

There are one or two Ready-To-Use products that contain imidacloprid
alone or in combination with another active.  Merit® RTU (EPA Reg No
3125-501) is the single active product and contains 24 fluid ounces of
product of which 0.012% is imidacloprid.  

Another formulation that might be handled by a residential handler is
potted plant spikes that contain 2.5 % imidacloprid.  A product is
Merit® 2.5 PR (EPA Reg No 3125-531).

There is a potting medium mixture for use with indoor or outdoor potted
plants.  Merit® PM plus fertilizer (EPA Reg No 3125-532) is an example
and contains 0.015 % imidacloprid.

Imidacloprid is formulated alone or in combination with other actives as
a concentrate for dilution and use in either pump sprayers or garden
hose-end sprayers.  Merit® + Tempo concentrate (EPA Reg No 3125-505) is
a product that contains 2.94 % imidacloprid.

Merit® 2.94 TLC (EPA Reg No3125-554) is designed to be used as a soil
drench application using a bucket or watering can to pour the diluted
product around trees or shrubs.  It also contains 2.94 % active
ingredient.

And finally, residential handlers may be exposed to imidacloprid via the
use of one of the Advantage® products such as Advantage® 110 (EPA Reg.
No 11556-121) which are spot-on treatments for dogs or cats for flea
control.  

The various types of products intended for residential use (i.e.,
application) as discussed above, are intended for control of different
pests.  Therefore, HED believes that it is highly unlikely that a
residential handler would be concurrently exposed to more than one
formulation containing imidacloprid at any given time (i.e., apply a
granular, then apply a topical flea control product, then apply a RTU
product).  

There are numerous products such as gel baits for cockroach control,
numerous products intended for commercial ornamental, lawn and turf pest
control, commercially applied products for ant control, products used as
preservatives for wood products, building materials, textiles and
plastics.  All of these types of products are intended for use by
commercial applicators of one type or other; and, therefore, will not be
addressed in terms of residential pesticide handler.

There are termiticide products.  Since termiticide applications are done
by professional applicators, residential “handler” assessment is not
necessary.  Further, since the pre and post-construction use as a
termiticide is subsoil and since the vapor pressure of imidacloprid is
1.5 x 10-9 mm Hg at 20(C, HED believes there is no residential
post-application inhalation exposure.

 

6.1.1	Resident-applicator Granular Push-type Spreader

The resident-applicator using push-type spreader to apply granules is
assessed using HED’s SOPs for Residential Exposure Assessments (81 DEC
97) in conjunction with unit exposures developed by the Outdoor
Residential Exposure Task Force (ORETF) and cited as HED Science
Advisory Council for Exposure (ExpoSAC) policy in a memorandum by G.
Bangs (Memo, G. Bangs, MRID 449722-01, 30 APRIL 01).  The dermal unit
exposure for an applicator wearing short pants and short-sleeved shirt
plus shoes and socks = 0.68 mg ai/lb handled.  The inhalation unit
exposure is 0.00091 mg ai/lb handled.  Dermal absorption is 7%.  The
rate of application is taken from Merit® 0.62 G insecticide (Reg. No.
3125-416).  Therefore:

0.68 mg ai/lb handled * 0.4 lb handled/A * 0.5 A/day * 0.07 ( 70 kg bw =
0.000136 mg ai/kg bw/daydermal

0.00091 mg ai/lb handled * 0.4 lb handled/A * 0.5 A/day ( 70 kg bw =
0.0000026 mg ai/kg bw/day inhalation

Dermal + Inhalation exposure = 0.000139 mg ai/kg bw/day

MOE = NOAEL/Dose = 10 mg ai/kg bw/day/0.000139 mg ai/kg bw/day = 72,150.

6.1.2	Resident-applicator Ready To Use

Merit® RTU is 0.012 % imidacloprid in a 24 fl. oz. trigger pump spray
bottle.  Exposure is not formally assessed here.  HED expects that
exposure from use of the entire contents (i.e., 24 fl.oz.) will not
exceed the exposure associated with the use of a garden hose-end sprayer
and which is assessed later in this document.  

6.1.3	Resident-applicator Potted Plant Spikes

Merit® 2.5 PR consists of 10 two gram “spikes” of which 2.5 % is
imidacloprid.  Plant “spikes” are actually semi-solid cylindrically
shaped objects about the diameter of a lead pencil and about an inch
long.  They are composed of a mixture of imidacloprid, fertilizers/plant
nutrients and decomposable bonding materials.  There are no specific
unit exposure data relative to this use pattern therefore HED uses the
PHED “hand” unit exposure for an applicator applying granular bait
by hand.  HED believes that use of the hand applied granular unit
exposure overestimates the exposure actually experienced from the use of
plant “spikes.”  Essentially only the tips of one or two fingers and
one thumb are necessary to push “spikes” into potting soil.  HED
assumes that the entire package is used at one time.  One package of 10
“spikes” will treat 4 - 5 eight inch plant pots.  The label directs
a user to “push spikes down into the soil...”  Since the vapor
pressure of imidacloprid is 1.5 x 10-9 mm Hg at 20(C, HED believes
inhalation exposure in this case is negligible.  So, 10 two gram
“spikes” equal 20 g product of which 2.5% is imidacloprid  = 0.5 g
ai (0.5 g ai ( 453.6 g/lb = 0.0011 lb ai).  The unit exposure for the
hand is 356 mg ai/lb handled and is for a “gloved” (i.e.,
“protected”) hand.  The unit exposure is back-calculated to account
for 90% protection of a gloved hand and the ungloved unit exposure is
3,560 mg ai/lb handled.  Exposure is then estimated as:

3,560 mg ai/lb handled * 0.0011 lb ai handled/day * 7% Derm. Abs. ( 70
kg bw = 0.00392 mg ai/kg bw/day.  MOE = NOAEL/DOSE ( 10 mg ai/kg bw/day
( 0.00392 mg ai/kg bw/day = 2,600 which is believed to be a conservative
(i.e., highly protective) estimate of risk.

6.1.4	Resident-applicator/Plant Potting Medium

Merit® PM plus fertilizer (Reg. No. 3125-532) is a plant potting medium
for use in indoor or outdoor containers.  It contains 0.015%
imidacloprid.  The largest container net weight is 19.19 lb of which
0.015% is imidacloprid = 0.00288 lb ai.  HED assumes that one large
container is used per day.  As with the assessment of plant “spikes”
above, HED utilizes the SOP unit exposure value for hands for
residential applicator applying granular bait by hand.  The hand unit
exposure is corrected to equate to an “ungloved” (i.e.,
“unprotected”) hand.   Estimated exposure is:

3,560 mg ai/lb handled * 0.00288 lb handled/day * 7% D.A. ( 70 kg bw =
0.01 mg ai/kg bw/day.

MOE = NOAEL/DOSE ( 10 mg ai/kg bw/day ( 0.1 mg ai/kg bw/day = 1,000.  

6.1.5	Resident-applicator using Garden Hose-end Sprayer

Merit® Concentrate Insecticide (Reg. No. 3125-500) contains 2.94%
imidacloprid and is a liquid concentrate for dilution and use in pump up
sprayers or garden hose-end sprayers.  HED policy indicates a larger
area per day may be treated with a hose-end sprayer which results in
possible contact with more active ingredient per day.  Therefore,
exposure from a hose-end sprayer is assessed versus that of a compressed
air sprayer.  

The unit density of this product is 1.6 g/ml (pers. comm. D. Kenny,
Registration Division, 25 OCT 02).  Using a conversion factor (Oil &
Colour Chemists Assoc. www.occa.org.uk) g/ml are converted to lb/gal by
multiplying by 0.09978.   Thus, 1.6 g/ml * 0.09978 = 0.1596 lb/gal of
which 2.94 % is imidacloprid or 0.00469 lb/gal imidacloprid.

0.00469 lb/gal ( 128 fl oz/gal = 0.0000366 lb ai/fl oz.  The maximum
rate of application is 6 fl oz/1000 ft2 therefore

0.0000366 lb ai/fl oz * 6 fl oz/1000 ft2 = 0.0002196 lb ai/1000 ft2. 
HED SOPs assume 0.5 acre treated per day (rounded to 22,000 square feet
treated per day); therefore, 0.0048312 lb ai will be applied per day. 
The unit exposure value for a residential handler using open-pour
mixing/loading for a garden hose-end sprayer is 11 mg/lb handled
(dermal) and 0.013 mg/lb handled (inhalation) (Memo, G. Bangs, MRID
449722-01; 30 APR 01; Summary of HED’s Reviews of ORETF Chemical
Handler Exposure Studies).  Thus, exposure is estimated as:

11.0 mg ai/lb handled * 0.0002196 lb ai/1000 ft2 * 22,000 ft2/day * 7%
dermal absorption ( 

70 kg bw = 0.000053 mg ai/kg bw/day for dermal.

0.016 mg ai/lb handled * 0.0002196 lb ai/1000 ft2 * 22,000 ft2/day ( 70
kg bw = 0.0000011 mg ai/kg bw/day.

Dermal + inhalation = 0.0000541 mg ai/kg bw/day.   MOE = NOAEL/Dose (

10 mg ai/kg bw/day ( 0.0000541 mg ai/kg bw/day = 185,000

6.1.6	Resident-applicator/Soil Drench Using Bucket or Watering Can

Merit® 2.94 TLC is a liquid concentrate intended for use as a systemic
soil drench application using a pale or watering can.  The largest
product container is 3.78 liter and HED assumes that equates to 3780
grams of which 2.94% is imidacloprid, or 111 g ai.  HED assumes the
contents of one container are used per day which will treat 20 medium
trees or 42 average-sized shrubs.  The total 111 g ai = 0.245 lb ai. 
The unit exposures are taken from the Residential SOPs with dermal = 2.9
mg/lb handled and inhalation = 0.0012 mg/lb handled.  The unit exposures
are for a residential handler using liquid, open pour mixing.  Exposure
is estimated as:

2.9 mg ai/lb handled * 0.245 lb handled/day * 7% dermal absorption ( 70
kg bw 

= 0.0007 mg ai/kg bw/day (dermal)

0.0012 mg ai/lb handled * 0.245 lb handled/day ( 70 kg bw = 0.0000042 mg
ai/kg bw/day.

Dermal + inhalation = 0.0007 and with MOE = NOAEL/DOSE, 10 mg ai/kg
bw/day ( 0.0007 = 14,000.

 The MOE is > 100 therefore this use is not of concern to HED.

6.1.7	Resident-applicator of Pet Spot-On

HED believes that imidacloprid applied as label directed will result in
negligible handler exposure.  A handler uses a dropper to deliver 2.5 ml
to two spots (total volume = 5 ml, equal to 500 mg/dog) on a dog’s
back.  There should be no contact with any material and if there is
contact, HED believes it would be minimal.  There are neither chemical
specific data nor any applicable surrogate data with which to assess
this method of application.  There is an unpublished study (see
residential post-application exposure to treated pets [Fichtel, M. and
R. Krebber. 27 MAR 1996, Imidacloprid (Bay t 7391) - Stroke Test in Dogs
after Topical Application of Imidacloprid Spot-on 10%; Bayer Animal
Health Development AH-D ID: 16051]) designed to measure possible
post-application exposure.  Data were collected from 15 beagle dogs
which were each treated with 500 mg of Imidacloprid 10% Spot-on per
animal.  The study used cotton-glove dosimeter hand-wipes of the treated
areas over 24 hours.  Summary data are:

(mg imidacloprid/glove +/- SEM)

10 min        24.9 +/- 6.4

1 hr             17.3 +/- 3.3

12 hr             3.9 +/- 1.1

24 hr             2.7 +/- 0.7

The total dose from the four sampling times over 24 hours is 48.8 mg
imidacloprid.  This is derived from purposeful stroking of a treated
animal, on the treatment loci.  HED herein uses the data from sampling
at ten minutes post-application and assumes that a pesticide handler
would not receive a greater dose if applied according to label
directions than what was measured via cotton glove dosimetry from
purposeful stroking of treatment loci.  Cotton glove dosimeters are
highly sorbent and in this case, dermal absorption is 7%.  Therefore, an
estimate of exposure is:

24.9 mg ai/day * 7% dermal absorption ( 70 kg bw = 0.025 mg ai/kg bw/day

MOE = NOAEL/DOSE where 10 mg ai/kg bw/day ( 0.025 mg ai/kg bw/day = 400

Since MOEs for residential handlers are > 100 they do not exceed HED’s
level of concern.	

Table 6.1.7  Summary of Residential Handler Exposures and Risks

Activity	

Exposure/Dose

mg ai/kg bw/day	

MOE

Granular/push-type spreader application	

Dermal + inhalation

0.0000139	

72,150

Ready to Use Trigger Pump Spray	

negligible see hose end spray	

Potted Plant Spikes	

Dermal (inhalation negligible)

0.00392	

2,600

Plant Potting Medium	

Dermal (inhalation negligible)

0.01	

1,000

Garden Hose-end Spray	

Dermal + Inhalation

0.0000541	

185,000

Soil Drench - Water Can/Bucket	

Dermal + Inhalation

0.0007	

14,000

Pet Spot-On	

Dermal (inhalation negligible)

0.025	

400

6.2.	Residential  Post-application Exposure  tc "6.2.	Residential 
Post-application Exposure " \l 2 

As noted earlier, HED conducted a “Non-Occupational/Residential
Exposure Assessment for Imidacloprid - Turf and Pet Uses” (Memo, Y.
Donovan, DP 268562, 22 JAN 01).  The 22 JAN 01 memo by Donovan, cites an
HED review of a study (“memo of 11/14/96, L. Lasota, DP Barcode
D223275, MRID# 43923901") of imidacloprid foliar dislodgeable residues
from turf as well as passive monitoring of dermal and inhalation
exposure measured during the course of prescribed “jazzercise”
activities.  The accepted study provides compound specific turf
transferable residue data as well as dermal transfer factors relative
for use in assessing non-occupational, post-application, dermal
exposures.  The 2001 Donovan memo did not utilize the study data as no
dermal or inhalation toxicological endpoints were identified at that
time.  In the current assessment, where applicable, data and information
from the 1996 LaSota memo are utilized to estimate dermal,
post-application exposures.  The half life of imidacloprid at the three
study locations was 2.0 day in Florida, 0.9 day in New Jersey, and 1.1
day in Kansas.  Due to residential application practices and the
half-lives observed in the turf transferable residue study, HED believes
post-application exposures will be short-term (1-30 days) and therefore
assessment of intermediate-term residential post-application exposure is
not necessary and not presented here.  See Table 6.2 for a summary of
residential post-application exposures and risks.

Table 6.2  Summary Residential Post-Application Exposures and Risks

Activity	

Exposure (Dose)

mg ai/kg bw/day	

MOE	

COMBINED MOE1

Toddler oral hand to mouth from contacting treated turf	

0.0059	

1,700	

1,500

Toddler oral - ingestion of granules	

0.12	

350	

N/A

Toddler incidental oral ingestion of treated soil	

0.02	

500,000	

N/A

Toddler incidental oral from contacting treated pet	

10 min hand wipe data = 0.11

1 hr hand wipe data = 0.08

12 hr hand wipe data = 0.017

24 hr hand wipe data = 0.012	

3,600

5,200

23,000

33,000	

255

261

271

272

Toddler dermal - pet “hug”/contacting treated pet	

0.036	

275	

See pet incidental oral

Adult dermal post applic turf contact	

0.00053	

19,000	

N/A

Adult combined dermal exposure = application + post-application	

0.0000162

0.00053	

72150

19,000	

15,0002

Toddler dermal post applic turf contact	

0.001	

10,000	

See hand to mouth turf

Adult golfer post app turf contact	

0.00016	

62,500	

N/A

Child golfer post app turf contact	

0.000272	

37,000	

N/A

1 Combined MOEs are presented for toddler oral + dermal exposure to
treated turf, and oral + dermal exposure to a treated pet.  Combined
MOEs are expressed as: 1/ ((1/MOE DERMAL) + (1/MOE ORAL))

2 Combined MOEs are presented for an adult who applies the material to
his/her lawn and then experiences post-application exposure.   MOEs
combined from different sources of exposure (i.e., application +
post-application) are expressed as: 1/ ((1/ MOE applicator) + (1/ MOE
post-application))

Children’s short-term oral hand-to-mouth turf exposure was assessed by
Donovan (JAN 01) using HED standard operating procedures.  The oral
daily dose estimated was 0.0059 mg ai/kg bw/day.  MOE = NOAEL ( Average
Daily Dose.  Using the short-term incidental oral NOAEL identified by
the HIARC (10 August 02) of 10 mg ai/kg bw/day, the MOE for short-term
oral hand-to-mouth (i.e., incidental oral exposure from contacting
treated turf grass) is 10 mg ai/kg bw/day ( 0.0059 mg ai/kg bw/day =
1700.

Children’s Incidental Oral Ingestion of Granules was assessed by
Donovan (JAN 01) using SOPs and the estimated Average Daily Oral Dose
was 0.12 mg ai/kg bw/day.  Using the LOAEL of 42 mg ai/kg bw/day acute
dietary endpoint identified by HIARC, the MOE for incidental ingestion
of granules is 42 mg ai/kg bw/day ( 0.12 mg ai/kg bw/day = 350.  Use of
a LOAEL to calculate MOE requires an uncertainty factor of 300.   Since
the MOE is 350, this is not a risk of concern to HED.

Children Incidental Oral Ingestion of Pesticide Treated Soil may be
estimated using HED SOPs for Residential Exposure Assessments (18 DEC
97) which state that:  PDRt for incidental ingestion of soil = SRt * IgR
* CF1

where:	PDRt 	= potential dose rate on day "t" (mg/day)

SRt	= soil residue on day "t" (ug/g)

IgR	= ingestion rate of soil (mg/day) (100 mg/day)

CF1	= weight unit conversion factor to convert the ug of residues on the
soil to grams to provide units of mg/day (1E-6 g/ug)

and:	SRt 	= AR * F * (1-D)t * CF2 * CF3 * CF4

where:	AR	= application rate (lb ai/acre) (0.4 lb ai/A)

F	= fraction of ai available in uppermost cm of soil (fraction/cm)
(1.0/cm)

D	= fraction of residue that dissipates daily 

t	= post-application day on which exposure is being assessed (day zero)

CF2	= weight unit conversion factor to convert the lbs ai in the
application rate to ug for the soil residue value (4.54E+8 ug/lb)

CF3    	=  area unit conversion to convert the surface area units (acre)
in the application rate to cm2 for the SR value (2.47E-8 acre/cm2 )

CF4	= volume to weight unit conversion factor to convert the volume
units (cm3) to weight units for the SR value (0.67 cm3/g soil)   

Therefore 0.4 lb ai/A * 1.0/cm * (1-0)0 * 4.54 x 108 µg/lb * 2.47 x
10-8 A/cm2 * 0.67 cm3/g soil = 3.0 µg/g soil and

3.0 µg/g soil * 100 mg/day * 1 x 10-6 g/µg = 0.0003 mg/day ( 15 kg
body wt = 0.00002 mg ai/kg bw/day average daily oral dose from
incidental oral ingestion of pesticide treated soil.

MOE = 10 mg ai/kg bw/day ( 0.00002 mg ai/kg bw/day = 500,000.

Toddler incidental oral ingestion from touching a treated pet may be
assessed using HED SOPs for Residential Exposure Assessments (18 DEC 97)
9.2.2 “Postapplication Potential Dose Among Toddlers from Incidental
Nondietary Ingestion of Pesticide Residues on Pets from Hand-to-Mouth
Transfer.”  The SOPs utilize certain assumptions in lieu of
chemical-specific data.  

In this case, there is an unpublished study (Fichtel, M. and R. Krebber.
27 MAR 1996, Imidacloprid (Bay t 7391) - Stroke Test in Dogs after
Topical Application of Imidacloprid Spot-on 10%; Bayer Animal Health
Development AH-D ID: 16051) which was designed to determine residues
that persons with close physical contact to a treated animal might
experience. UNTIL FORMALLY NOTIFIED OTHERWISE, THE STUDY SHOULD BE
CONSIDERED PROPRIETARY AND SUBJECT TO DATA COMPENSATION.  The study used
cotton gloves as dosimeters.  Sixteen beagle dogs received a 500 mg dose
(as would a dog receiving a maximum treatment dose from Advantage 110
Flea Adulticide (Reg. No. 11556-121), one half of which was administered
between the scapulae (shoulders) and one half on the rump (lumbosacral
region) according to label directions.  Samples were taken from each
treatment site separately (i.e., shoulders separately from rump area)
and consisted of 30 strokes, one per second at about 20 cm per stroke
such as not to overlap the treated areas.  A new dosimeter glove was
used for each “site” change and for each dog.  Residues were
analyzed after extraction with acetonitrile using HPLC with UV detector
(recovery rates of 83-94%).

Summary results:

(mg imidacloprid/glove +/- SEM)

10 min        24.9 +/- 6.4

1 hr             17.3 +/- 3.3

12 hr             3.9 +/- 1.1

24 hr             2.7 +/- 0.7

The dosimetry data are used in conjunction with the SOPs, that is to
say, using the SOPs but substituting measured dislodgeable residues for
the otherwise assumed 20 % of administered dose.  Further, the HED
ExpoSAC believes that it is likely there would be one event per day. 
Therefore the resulting MOEs are calculated as follows:

10 min post-application:  24.9 mg ai/6000 cm² * 0.5 (=50 % saliva
extraction factor) * 20 cm²/event * 1 event/day ( 15 kg bw = 0.00276.  
MOE = NOAEL ( DOSE or 10 mg ai/kg bw/day ( 0.00276mg ai/kg bw/day =
3,600.

1 hr post-application: 17.3 mg ai/6000 cm² * 0.5 (= 50 % saliva
extraction factor) * 20 cm²/event * 1 event/day ( 15 kg bw = 0.0019 mg
ai/kg bw/day.  MOE = NOAEL ( DOSE or 10 mg ai/kg bw/day ( 0.0019mg ai/kg
bw/day = 5,200.

12 hr post-application: 3.9 mg ai/6000 cm² * 0.5 (= 50 % saliva
extraction factor)* 20 cm²/event * 1 event/day ( 15 kg bw = 0.000433 mg
ai/kg bw/day.  MOE = NOAEL ( DOSE or 10 mg ai/kg bw/day ( 0.0004332mg
ai/kg bw/day = 23,000.

24 hr post-application: 2.7 mg ai/6000 cm² * 0.5 (= 50 % saliva
extraction factor)* 20 cm²/event * 1 event/day ( 15 kg bw = 0.0003. 
MOE = NOAEL ( DOSE or 10 mg ai/kg bw/day ( 0.0003mg ai/kg bw/day =
33,000.

The data indicate that imidacloprid rapidly biologically disperses from
the specific application loci.  HED believes it is unlikely that a
toddler would consistently “stroke” a pet exactly on the application
loci.  This assessment addresses the maximum dose that would be applied
to a large dog.  A toddler is expected to more likely touch areas of a
pet to which imidacloprid has not dispersed (immediately upon treatment)
such as the sides of shoulders or flanks.  The use of highly absorbent
cotton gloves as dosimeters, is expected to result in over-estimation of
actual dermal exposure.  In the case of imidacloprid, the dermal
absorption is 7%.   

It is unlikely that a toddler could absorb the “dose” measured by
absorption to a cotton glove purposefully moved directly over the point
of treatment, essentially at the time of treatment.  Cotton is much more
absorptive than human skin and the surface area of an adult hand is much
greater than that of a toddler.

HED believes that the MOEs > 100, based upon the study data, are
conservative i.e., overestimate the actual exposure and risk.  This use
is therefore, not of concern to HED.

Toddler Dermal Exposure From Touching Treated Pet (pet hug) may be
estimated according to the Residential SOPs as follows:

D = (((AR*FAR)/SApet) * (1 - DR)t * SAhug * (1 mg/1000µg)) * DA

where:  

D	= dose from dermal pet contact (mg/day);

AR	= application rate or amount applied to animal in a single treatment
(mg ai/animal);

FAR	=  fraction of the application rate available for dermal contact as
transferable residue (20%)

SApet	=  surface area of a treated dog (5,986cm2/animal);

t	=  time after application (days);

DR	=  fractional dissipation rate per day (5% per day/100); and

SA hug	=  surface area of a child hug (1,875cm2 contact/hug).

DA	=  Dermal absorption factor (7%)

In this case actual compound specific study data are used in place of
the expression (AR*FAR) which is the assumption that 20% of the
application rate is available as dislodgeable residue.  The ExpoSAC
believes it is appropriate to use the dislodgeable residues from the 10
min post-application observations in the dog wipe study.  Therefore, the
estimate of exposure and risk are expressed as:

24.9 mg ai ( 5986 cm²/surface area dog * (1 - DR)0day * 1875
cm²/surface area child hug * 7 % DA ( 15 kg bw = 0.036 mg ai/kg bw/day.
  MOE = NOAEL/DOSE ( 10 mg ai/kg bw/day ( 0.036 mg ai/kg bw/day = 275.

The MOE is > 100 and is therefore does exceed HED’s level of concern.

Adult and toddler dermal post-application exposure to treated turf is
assessed using SOPs which indicate that Potential Dose Rate (PDR) =
Dislodgeable Foliar Residue (DFR) * Transfer Coefficient (TC) *
hours/day * 0.001 mg/µg ( body weight (70 kg for adult, 15 kg for
toddler).  

DFR and TC are utilized from the study reviewed and found acceptable by
L. LaSota (Memo 14 NOV 1996, DP 223276, MRID 439239-01).  The combined
arithmetic mean of imidacloprid transferable residues from three study
locations was 79.8 ng/cm² and was determined using the turf roller
technique.  The study was conducted at an application rate of 0.5 lb
ai/A and the maximum label rate for commercial application to
residential lawns and turf is 0.4 lb ai/A.  Data were collected as soon
as sprays had dried.  The TCs were determined using “inner” and
“outer” whole body dosimeters to simulate the use of a sleeveless
shirt, short pants and shoes and adjusted to simulate 4 hours of foliar
contact/day.  The TC for adults is 3,343 cm²/hr and 1,397 cm²/hr for
toddlers.  

0.064 µg/cm² * 3.343 cm²/hr * 0.001 mg/µg * 2 hr/day * 7 % dermal
absorption ( 70 kg bw = 0.00053 mg ai/kg bw/day for adults.  MOE = 10 mg
ai/kg bw/day ( 0.00053 mg ai/kg bw/day = 23,000 for adults.  

0.064 µg/m² * 1,397 cm²/hr * 0.001 mg/µg * 2 hr/day * 7 % dermal
absorption ( 15 kg bw = 0.001 mg ai/kg bw/day.  MOE = 10 mg ai/kg bw/day
( 0.001 mg ai/kg bw/day = 12,000 for toddlers.

Adult and Adolescent Golfer Post-Application Dermal Exposure may be
estimated using the convention stated in ExpoSAC draft Policy regarding
“Golfer Exposure Assessment For Adults and Children” (24 August
2000).  The draft policy states that adult and adolescent golfer dermal
post-application exposure may be calculated as 

DE(t) (mg ai/kg bw/day) = (TTR(t) (µg/cm²)) * TC (cm²/hr) *
hr/day/1000 µg/mg * BW (body weight (kg)) 

Where:

DE(t)	=  dermal exposure at time (t) attributable to golfing on
previously treated turf (mg ai/kg bw/day).

TTR(t)	=  turf transferable residue at time t (µg/cm²)

TC	=  Transfer Coefficient (500 cm²/hr)

Hr	= exposure period (4 hours)

BW	= body weight (kg) (70 kg for adult; adjusted (multiplied) by a
factor of 1.7 for child golfers)) A BW of 60 kg is utilized if the
toxicological endpoint is derived from a developmental study and there
are fetal effects.

Therefore,

DE = 0.064 µg/cm² * 500 cm²/hr * 4 hr/day/1000µg/mg * 7 % dermal
absorption ( 70 kg bw = 0.00016 mg ai/kg bw/day.  

MOE for adult golfer is 10 mg ai/kg bw/day ( 0.00016 mg ai/kg bw/day =
76,000.

The adult dose level is adjusted by a factor of 1.7 to estimate child
golfer exposure therefore 0.00016 mg ai/kg bw/day * 1.7 = 0.000272 mg
ai/kg bw/day.   

 

MOE for child golfer is 10 mg ai/kg bw/day ( 0.000272 = 42,000

Post-application exposure was estimated for residential handlers who
might apply imidacloprid to a lawn and then experience post-application
exposure.  See Summary Table 6.3 for combined MOE for application
exposure + post-application exposure.  “Residential”
post-application exposure was not assessed for the use of plant spikes
or for the potting medium.  HED believes that it is highly unlikely for
adults and toddlers to experience post-application exposure to plant
spikes or potting medium after their initial use i.e., application.

HED believes that the estimates of exposure and risk that result from
the use of the SOPs are Tier I, screening level estimates.  HED also
believes that whenever appropriate study data are available, the data
should be utilized in lieu of the Tier I estimates based solely on the
SOPs.  The SOPs resulted in MOEs < 100 for 1) Toddler incidental oral
ingestion of granules; 2) for toddler incidental hand-to-mouth oral
ingestion from touching a treated pet; and 3) for toddler dermal
post-application exposure from “hugging” a treated pet.  When study
data are used for assessing exposures from a treated pet, the MOEs are >
100 and are not of concern to HED.  HED suggests that toddler incidental
oral ingestion of granules be compared to all other residential
post-application exposures, to residential handler exposures and to
commercial handler exposures and that it is likely a conservative
over-estimate of risk and therefore not of concern to HED.  All other
residential post-application exposures and risks resulted in MOEs > 100
and are therefore not of concern to HED.

6.3	Combined Residential Exposure

FQPA requires that all exposures that could reasonably be expected to
occur on the same day be combined and compared to the appropriate
toxicity endpoint.  The residential scenarios that can reasonably be
expected to occur on the same day for toddlers/children are listed in
Table 6.3.

Table 6.3  Exposure Potential for Adult and Child Short-term Aggregate
Risk Estimates

Exposure Scenario	

Exposure (Dose)

mg ai/kg bw/day	

MOE	

Combined Exposure (Dose)

mg ai/kg bw/day	

COMBINED MOE1

Toddler - Treated Turf	

Oral hand-to-mouth post-application exposure from contacting treated
turf	

0.0059	

1,700	

0.00692	

1,500

	

Incidental oral post-application exposure from ingestion of treated soil

0.00002	

500,000

	

Dermal post-application exposure from contacting turf	

0.001	

10,000

Toddler - Treated Pet	

Incidental oral post-application exposure from contacting treated pet	

0.00276	

3,600	

0.03876	

260

	

Dermal post-application exposure from pet “hug”/ contacting treated
pet	

0.036	

280

Adult - Treated Turf	

Handler dermal and inhalation exposure from applying imidacloprid using
granular/push-type spreader	

0.0000139	

72,000	

0.000669	

15,000

	

Dermal post-application exposure from contacting treated turf	

0.00053	

19,000

Adult - Treated Pet	

Handler dermal and inhalation exposure from  applying imidacloprid to
pet with pet spot-on	

0.025	

400 2

	

Dermal post-application exposure from contacting treated pet

1  Combined MOEs are presented for toddler oral + dermal exposure to
treated turf, and oral + dermal exposure to a treated pet.  Combined
MOEs are expressed as:  MOE DERMAL +  MOE ORAL.  Combined MOEs are
presented for an adult who applies the material to his/her lawn and then
experiences post-application exposure.   MOEs combined from different
sources of exposure (i.e., application + post-application) are expressed
as:  MOE applicator + MOE post-application.

2.  HED believes handler exposure will be negligible.  However, the
results from an unpublished study (see residential post-application
exposure to treated pets) were use to measure possible post-application
exposure.  HED herein used the data from sampling at ten minutes
post-application and assumes that a pesticide handler would not receive
a greater dose if applied according to label directions than what was
measured via cotton glove dosimetry from purposeful stroking of
treatment loci (see Section 6.1.6 Residential Handler of this risk
assessment).

6.4	Other (Spray Drift, etc.) 

 tc "6.4	Other (Spray Drift, etc.) " \l 2 

Spray drift is often a potential source of exposure to residents nearby
to agricultural spraying operations.  This is particularly the case with
aerial operations, but to a lesser extent, could also be a potential
source of exposure from ground application methods.  As indicated in
this assessment, imidacloprid can be directly applied to residential
turf.   The rates of application to residential turf are generally equal
to or greater than the agricultural rates of application.  The resulting
MOEs are not of concern to HED.  Therefore, based on this assessment,
HED believes that it is unlikely that there is higher potential for risk
of exposure to spray drift from agricultural uses of this chemical than
have been assessed for direct residential applications.  

  SEQ CHAPTER \h \r 1 7.0	Aggregate Risk Assessments and Risk
Characterization

In accordance with the FQPA, ARIA must consider and aggregate (add)
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, ARIA considers both the route and duration of exposure.  In the
case of imidacloprid aggregate risk assessments were performed for acute
(food + drinking water), short-term aggregate exposure (food + drinking
water + residential), and chronic aggregate exposure (food + drinking
water).  Intermediate- and long-term aggregate risk assessments were not
performed because, based on the current and proposed use patterns, ARIA
does not expect residential exposure durations that would result in
intermediate- or long-term exposures.  A cancer aggregate risk
assessment was not performed because imidacloprid is not carcinogenic. 
All potential exposure pathways were assessed in the aggregate risk
assessment. 

Rather than using back-calculated drinking water levels of comparison
(DWLOCs), estimates of pesticide residues in drinking water were
incorporated directly into the dietary exposure analysis to assess
aggregate acute and chronic risk.  In the past, EPA has not directly
combined pesticide exposure estimates from drinking water with pesticide
exposures from food because EPA was concerned that combining high-end
modeling values for drinking water with more realistic food exposure
data might be confusing.  Although EPA retains this concern, it is now
outweighed by the advantages of using EPA’s current aggregate exposure
assessment models, Lifeline™ and DEEM™. Advances in these models
allow EPA to incorporate actual water consumption data and body weight
data in assessing exposure to pesticides in drinking water as well as
conduct probabilistic assessments for food, water, and residential
exposures to pesticides.  These more sophisticated exposure assessments
are not possible under the DWLOC approach.

  SEQ CHAPTER \h \r 1 

7.1	Acute Aggregate Risk  tc "7.1	Acute Aggregate Risk " \l 2 

The acute aggregate risk assessment takes into account exposure
estimates from dietary consumption of imidacloprid (food and drinking
water).  The dermal, inhalation, and incidental oral exposures resulting
from short-term residential applications are assessed separately.  The
acute dietary exposure estimates are below HED’s level of concern
(<100% aPAD) at the 95th exposure percentile for the general U.S.
population (28% of the aPAD) and all other population subgroups (see
Table 5.2).  The most highly-exposed population subgroup is children 1-2
years old, at 70% of the aPAD.  Therefore, the acute aggregate risk
associated with the proposed use of imidacloprid does not exceed HED’s
level of concern for the general U.S. population or any population
subgroups.

7.2	Short-Term Aggregate Risk 

 tc "7.2	Short-Term Aggregate Risk " \l 2 

The short-term aggregate risk assessment estimates risks likely to
result from 1- to 30-day exposure to imidacloprid residues from food,
drinking water, and residential pesticide uses.  High-end estimates of
the residential exposure are used in the short-term assessment, and
average values are used for food and drinking water exposures.

Short-term aggregate risk assessments are required for adults as there
is potential for both dermal and inhalation handler exposure, and dermal
post-application exposure from the residential uses of imidacloprid on
turf and pets.  In addition, short-term aggregate risk assessments are
required for children/toddlers because there is a potential for oral and
dermal post-application exposure resulting from the residential uses of
imidacloprid on turf and pets.  The short-term residential exposure
potential from the turf and pet uses for adults and children/toddlers
can be found in Table 6.2.  The pet-treatment scenario resulted in the
highest combined MOE for adults (MOE = 400; handler and
post-application) and children (MOE = 260; post-application).  The
turf-treatment resulted in much lower exposures for both adults (MOE =
15,000; handler and post-application) and children (MOE = 1,500;
post-application).  Therefore, the pet-treatment exposure estimates were
aggregated with the chronic dietary (food) to provide a worst-case
estimate of short-term aggregate risk for the U.S. population and
children 1-2 years old (the child population subgroup with the highest
estimated chronic dietary food exposure) (see Table 5.2).  As the MOEs
are greater than 100, the short-term aggregate risks are below HED's
level of concern.

 

Table 7.2  Short-Term Aggregate Risk Calculations for Imidacloprid.

Population

Subgroups	Short-Term Scenario

	NOAEL

(mg/kg/day)	Level of Concern1	Max Exposure2

(mg/kg/day)	Average Dietary Exposure

(mg/kg/day)	Residential Exposure3

(mg/kg/day)	Aggregate MOE

(dietary and residential)4

US Population	10	100	0.1	0.007496	0.025	310

Children 1-2 years old	10	100	0.1	0.021691	0.03876	170

1 The level of concern (target MOE) includes 10X for interspecies
extrapolation and 10X for intraspecies variation.

2  Maximum Exposure (mg/kg/day) = NOAEL/Target MOE

3  Residential Exposure = [Oral exposure + Dermal exposure + Inhalation
Exposure].  The pet-treatment scenario resulted in the lowest combined
residential MOE for adults (handler and post-application) and children
(post-application).  The combined MOEs for the pet-use scenario were
used to calculate the short-term risk [see Table 11 of HED human health
risk assessment dated 3/4/03 (Memo, J. Tyler et al.; D286101)].

4  Aggregate MOE = [NOAEL ÷ (Avg Dietary Exposure + Residential
Exposure)]

7.3	Intermediate-Term Aggregate Risk 

An assessment of the intermediate-term aggregate risk for exposure to
imidacloprid is not required.

7.4	Long-Term Aggregate Risk  tc "7.4	Long-Term Aggregate Risk " \l 2 

The chronic aggregate risk assessment takes into account average
exposure estimates from dietary consumption of imidacloprid (food and
drinking water) and residential uses.  However, due to the use patterns,
no chronic residential exposures are expected.  Therefore, the chronic
aggregate risk assessment will consider exposure from food and drinking
water only.  The chronic dietary exposure estimates are below HED’s
level of concern (<100% cPAD) for the general U.S. population (13% of
the cPAD) and all population subgroups (see Table 5.2).  The most highly
exposed population subgroup is children 1-2 years old, at 38% of the
cPAD.  Therefore, the chronic aggregate risk associated with the
proposed use of imidacloprid does not exceed HED’s level of concern
for the general U.S. population or any population subgroups.

7.5	Cancer Risk 

 tc "7.5	Cancer Risk " \l 2 

An assessment of the cancer risk for exposure to imidacloprid is not
required. tc "7.3	Intermediate-Term Aggregate Risk " \l 2 

8  SEQ CHAPTER \h \r 1 .0	Cumulative Risk Characterization/Assessment 

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to imidacloprid and any other
substances and imidacloprid does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this
tolerance action, therefore, EPA has not assumed that imidacloprid 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 released by EPA’s Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism 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 "9.0	Occupational
Exposure/Risk Pathway" 

The current request is for registration of additional formulations
(i.e., end-use products).  They are summarized as follows.  

.

Table 9.0  Summary of Proposed Caneberry Use Pattern

Product	Application Rate lb ai/A	Preharvest

Interval	Application

Method	Application

Interval

Admire® 2 Flowable Insecticide; Reg. No. 264-758; 2.0 lb ai/gal liquid
flowable	0.25 - 0.5

(maximum  0.5 lb ai/A/season)	7 days	chemigation or

basal soil drench	NA

Gaucho® 550 SC Insecticide; Reg. No. 264-827; 4.6 lb ai/gal soluble
concentrate liquid	0.25-0.5

(maximum 0.5 lb ai/A/season)	7 days	chemigation or basal soil drench	NA

Provado® Pro Insecticide; Reg. No. 264-858; 1.6 lb ai/gal liquid	0.1

(maximum 0.3 lb ai/A/season)	3 days	foliar	7 days

Provado® 70 WG Insecticide; Reg. No. 264-823; 70 % ai water dispersible
granule	0.1

(maximum 0.3 lb ai/A/season)	3 days	foliar	7 days

Provado® 1.6 Flowable Insecticide; Reg. No. 264-763; 1.6 lb ai/gal
flowable liquid	0.1

(maximum 0.3 lb ai/A/season)	3 days	foliar	7 days

Admire® and Gaucho® are listed to control aphids, leafhoppers,
whiteflies and rednecked cane borer.  They suppress foliage feeding
thrips.  The 3 Provado® products are listed to control aphids,
leafhoppers and thrips.  The Provado® products are not limited to soil
applications and may have repeat applications.  None of the products may
be applied pre-bloom, during bloom or when bees are actively foraging. 
All of the product labels require applicators and other handlers to wear
PPE consisting of long-sleeved shirt, long pants, shoe plus socks and
chemical resistant gloves made of any waterproof material such as
barrier laminate, butyl rubber, nitrile rubber, neoprene rubber, natural
rubber, polyethylene, polyvinylchloride or viton.  

A number of ORE assessments have been conducted for the proposed uses of
imidacloprid (DP Num: 337875, M. Dow, 4/17/07 & DP Num: 337878, M. Dow,
4/17/07).  The assessment with the worst case occupational exposure is
discussed here (DP Num: 281610, 281612, & 281614, M. Dow, 2/26/07).

9.1	Short-/Intermediate-/Long-Term Handler Risk  tc "9.1
Short-/Intermediate-/Long-Term Handler Risk " \l 2 

 Based primarily on the proposed new use patterns, commercial and
private (i.e., grower operators) pesticide handlers are typically
expected to have short-term exposures (i.e., 1 - 30 days).  The acreages
involved with caneberry crops are relatively small as compared to such
field crops as cotton, corn or soybean.  However, the ExpoSAC asserts
that there is a possibility that commercial handlers might be exposed to
intermediate-term exposures (1-6 months).

The proposed new use pattern indicates that the most highly exposed
occupational pesticide handlers are likely to be mixer/loaders using
open-pour loading of liquids or granules, and applicators using airblast
sprayers, ground-boom sprayers, high-pressure hand-wand sprayers,
backpack sprayers and aircraft.  Chemigation in the form of drip or low
pressure trickle irrigation is also mentioned as a method of
application.  

ARIA believes that a “loader” (i.e., applicator in this sense) for
chemigation will not likely be exposed more than a loader supporting
aerial operations.  Chemigation typically involves preparation of
minibulk containers which have siphon tubes attached to the irrigation
equipment.  An individual preparing irrigation equipment to include
pesticide application is believed to experience exposure similar to that
of a mixer/loader using open-pour loading technique.  Therefore, a
“chemigator” is not assessed, with the assumption that the work
activity is represented by that of a mixer/loader supporting aerial
operations.  Chemigation includes the soil injection and drip irrigation
methods of application used for caneberries.  

In some cases, HED believes that certain individuals (private growers
versus commercial applicators) may perform all three handler activities,
that is, mix, load, and apply the material.  The available exposure data
for combined mixer/loader/applicator scenarios are limited in comparison
to the monitoring of these two activities separately.  These exposure
scenarios are outlined in the PHED Surrogate Exposure Guide (August
1998).  HED has adopted a methodology to present the exposure and risk
estimates separately for the job functions in some scenarios and to
present them as combined in other cases.  Most exposure scenarios for
hand-held equipment (such as hand wands, backpack sprayers, and
push-type granular spreaders) are assessed as a combined job function. 
With these types of hand held operations, all handling activities are
assumed to be conducted by the same individual.  The available
monitoring data support this and HED presents them in this way. 
Conversely, for equipment types such as fixed-wing aircraft, groundboom
tractors, or air-blast sprayers, the applicator exposures are assessed
and presented separately from those of the mixers and loaders.  By
separating the two job functions, HED determines the most appropriate
levels of PPE for each aspect of the job without requiring an applicator
to wear unnecessary PPE that may be required for a mixer/loader (e.g.,
chemical-resistant gloves may only be necessary during the pouring of a
liquid formulation).  

On 8 October 2002, the HIARC met to discuss the adequacy of the
toxicological database relative to imidacloprid.  During that meeting a
number of toxicological endpoints relative to the current assessment
were identified.  Short and intermediate term dermal and inhalation
endpoints were identified as well as short and intermediate term
incidental oral endpoints.  The short-term dermal, inhalation and
incidental oral endpoints are 10 mg ai/kg bw/day based on a
developmental rat study. The effects were reduced body weight gains. 
The intermediate-term dermal, inhalation and incidental oral endpoints
are 9.3 mg ai/kg bw/day and were identified from a sub-chronic
neurotoxicity study in the rat.  The effects were reduced body weight
gains.  The HIARC identified a 7% dermal absorption factor for use in
assessing dermal exposures.  An MOE ( than 100 is adequate to protect
pesticide handlers.  Table 9.1 contains a summary of estimated exposures
and risks to occupational pesticide handlers from the proposed use
patterns.  

Table 9.1 Estimated Handler Exposure and Risk from the Proposed New Use
Patterns for Imidacloprid

Unit Exposure1

mg ai/lb handled	

Applic. Rate2	

Units Treated3

Per Day	

Average Daily

Dose4

mg ai/kg bw/day	

COMBINED

MOE5

ST	

IT

Mixer/Loader - Liquid - Open Pour

Dermal:

SLNG       2.9    HC

SLWG      0.023 HC	

Inhal         0.0012 HC	

0.5 lb ai/A	

350 A	

Dermal:

No Gloves      0.51

With Gloves   0.004

Inhal               0.003	

NG

20

WG

1400	

NG

18

WG

1300

Mixer/Loader - Open Pour - Granules 

Dermal:

SLNG       0.0084 LC

SLWG      0.0069 MC	

Inhal         0.0017 HC	

0.1 lb ai/A	

350 A	

Dermal:

No Gloves      0.00029

With Gloves   0.00024

Inhal               0.00085	

NG

8800

WG

9200	

NG

8200

WG

8500

Applicator - Aerial (Pilots not required to wear protective gloves)

Dermal:

SLNG       0.005 HC

Inhal         0.000068 MC	

0.5 lb ai/A	

350	

Dermal:

No Gloves      0.00088

Inhal               0.00017	

NG

9500

	

NG

8900

Applicator - Ground-boom - Open-cab

Dermal:

SLNG       0.014 HC

SLWG      0.014 MC

Inhal         0.00074 HC	

0. 5 lb ai/A	

80 A	

Dermal:

NG    0.00056

WG   0.00056

Inhal  0.00042	

NG 

10,000

WG 

10000	

NG

9500

WG

9500

Applicator - Air-blast - Open Cab

Dermal:

SLNG       0.36 HC

SLWG      0.24 HC

Inhal         0.0045 HC	

0.5 lb ai/A	

40 A	

Dermal:

No Gloves      0.0072

With Gloves   0.0048

Inhal               0.0013	

NG 

1200

WG

1600	

NG

1100

WG

1500

Mix/Load/Applicator - High Pressure Hand-wand

Dermal

SLNG       no data

SLWG      2.5 LC

Inhal         0.12 LC	

0.5 lb ai/A	

20 A	

Dermal:

No Gloves    no data

Wit Gloves     0.025

Inhal               0.017	

NG 

no data

WG

240	

NG

no data

WG

220

Mixer/Loader/Applicator - Backpack - Liquid - Open Pour

Dermal:

SLNG       no data

SLWG       2.5 LC

Inhal          0.03 LC	

0.5 lb ai/A	

1 A	

Dermal:

No Gloves - no data

With Gloves    0.0013

Inhal                0.00021	

NG

 no data

WG 

6600	

NG

no data

WG

6200

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.   SLNG = Dermal Single Layer Work
Clothing No Gloves; SLWG = Dermal Single Layer  Work Clothing With
Gloves;  Inhal. = Inhalation.  Units = mg ai/pound of active ingredient
handled.  Data Confidence: LC = Low Confidence, MC = Medium Confidence,
HC = High Confidence.

2.  Applic. Rate. = Taken from Sections A & B (proposed labeling) of
IR-4 submission

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP No. 9.1.   Science Advisory Council for
Exposure;  Revised 5 July 2000;  Policy 9.1 indicates a worker may spray
40 gallons/day with a backpack sprayer.  The labeling for tree nuts
indicates 50 gal/A by ground equipment.   It is assumed that a  backpack
sprayer might treat 1 acre/day.   From previous assessments it was
assumed that a high-pressure handwand can treat 20 A/day.

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated *
0.07 (7 % dermal absorption) ( Body Weight (70 kg).  

5.  MOE = Margin of Exposure = No Observable Adverse Effect Level
(NOAEL)  ( ADD.   Short-term dermal and inhalation NOAEL = 10 mg ai/kg
bw/day and are identified from developmental study in the rat where 
maternal effects ((body weight gain) were observed.  MOEs are
“combined” that is,  Dermal + Inhalation, since the toxicological
effects are the same and are identified from the same study. 
Intermediate-term NOAEL = 9.3 mg ai/kg bw/day.     ST = Short-term
combined MOE; IT = Intermediate-term combined MOE.  NG = No gloves.  WG
= With gloves.

 A MOE of 100 is adequate to protect occupational pesticide handlers
from exposures to imidacloprid.  Therefore, the proposed new use
patterns do not exceed HED’s level of concern.

9.2	Short-/Intermediate-/Long-Term Post-application Risk  tc "9.2
Short-/Intermediate-/Long-Term Post-application Risk " \l 2 

Typically there is the possibility for agricultural workers to
experience post-application exposures to dislodgeable pesticide
residues.  There were no chemical-specific data with which to estimate
post-application exposure of agricultural workers to dislodgeable
residues of imidacloprid.  Therefore, theoretical estimates of exposure,
based on surrogate studies, have been conducted.  The ExpoSAC (SOP
003.1, Rev. 7 Aug. 2000, Regarding Agricultural Transfer Coefficients;
Amended ExpoSAC Meeting notes - 13 Sept 01) lists a number of possible
post-application agricultural activities relative to caneberries that
might result in pesticide exposure to agricultural workers.  TCs
expressed as cm²/hr are identified for each of the post-application,
agricultural activities.  The TCs are derived from data in surrogate
exposure studies conducted during the various activities listed.

The highest (i.e., most conservative) TC relative to caneberries is
1,100 cm2/hr (personal communication J. Dawson, ExpoSAC meeting minutes
7 August 2003).  The transfer coefficients used in this assessment are
from an interim transfer coefficient SOP developed by HED’s ExpoSAC
using proprietary data from the Agricultural Re-Entry Task Force (ARTF)
database (policy # 3.1).  It is the intention of HED’s ExpoSAC that
this SOP will be periodically updated to incorporate additional
information about agricultural practices in crops and new data on
transfer coefficients.  Much of this information will originate from
exposure studies currently being conducted by the ARTF, from further
analysis of studies already submitted to the Agency, and from studies in
the published scientific literature.

Post-application worker exposure is estimated using HED procedure that
assumes 20% of the application rate is available as dislodgeable foliar
residue on the day of treatment.  HED does not expect post-application
exposures to exceed short term exposure.  Therefore, only short term
exposures are assessed. 

However, the HED ExpoSAC directs that there may be intermediate-term
exposures (1-6 months) to agricultural workers.  The following
convention is used to estimate post-application exposures to
agricultural workers.

PDRt  =  DFRt * CF1 * Tc * ET where:

PDRt  =  potential dose rate on day “t” (mg/day)

DFRt  = dislodgeable foliar residue on day “t” (µg/cm2)

CF1   =   weight unit conversion factor to convert µg units in DFR
value to mg for the daily dose     (0.001 mg/µg)

Tc     =  transfer coefficient (cm2/hr) (In this case 1,100 cm2/hr;
ExpoSAC Policy 003.1 Rev. 7 Aug. 2000; amended 7 August 2003 ExpoSAC
meeting Notes). 

ET     = Exposure Time (hrs) (8)

and

DFRt = AR * F * (1-D)t * CF2 * CF3 where:

AR  = Application rate (lb ai/A) (0.5 lb ai/A)

F     = fraction of ai on foliage available as dislodgeable residue
(unitless) (20.0 %)

D     = fraction of residue that dissipates daily (unitless) (10.0 %)

t      = post-application day on which exposure is being assessed

CF2 = weight unit conversion factor to convert the lbs ai in the
application rate to µg for the DFR value (4.54E8 µg/lb)

CF3 = Area unit conversion factor to convert the surface area units
(ft2) in the application rate to cm2 for the DFR value (1.08E-3 ft2/cm2
or 2.47E-8 acre/cm2 if the application rate is per acre).

( DFR = 0.5 lb ai/A * 0.20 * (1-0)0 * 4.54E8 µg ai/lb * 2.47E-8A/cm2 =
1.121 µg/cm2

PDR = 1.121 µg/cm2 * 0.001 mg/µg * 1,100 cm2/hr * 8 hr/day = 9.86 mg
ai/day * 0.07 (% dermal absorption) ( 70 kg bw = 0.00986 mg ai/kg bw/day

MOE = NOAEL ( PDR 

( 10 mg ai/kg bw/day ( 0.00986 mg ai/kg bw/day = 1014 = Short Term MOE 

and 9.3 mg ai/kg bw/day ( 0.0269 mg ai/kg bw/day = 943 = Intermediate
Term MOE.

These estimates are considered to be screening level estimates i.e.,
conservative (protective).   ARIA’s level of concern for dermal
exposure is for MOEs <100.  In this case, MOEs are greater than 100
therefore post-application dermal exposure is not of concern for
agricultural workers.    Post-application inhalation exposure is
expected to be negligible.

9.3	Restricted Entry Interval (REI)

Imidacloprid is classified in Toxicity Category IV for acute dermal,
acute inhalation, primary eye irritation and primary skin irritation
therefore the interim Worker Protection Standard REI of 12 hours is
sufficient to protect workers from excessive exposure.

10.0	Data Needs and Label Requirements

10.1	Toxicology  tc "10.1	Toxicology " \l 2 			

None.

10.2	Residue Chemistry 

A new Section F requesting imidacloprid tolerances on peanuts at 0.60
ppm and peanut, hay at 35 ppm is required.

The request for use and tolerance for imidacloprid on oats is not
necessary; the request should be removed from Section F. 

A revised Section F is required for proso millet, forage at 2.0 ppm;
proso millet, hay at 6.0 ppm; proso millet, straw at 3.0 ppm; pearl
millet, forage at 2.0 ppm; pearl millet, hay at 6.0 ppm; and pearl
millet, straw at 3.0 ppm.

A revised Section F requesting an imidacloprid tolerance on peanut, meal
at 0.75 ppm is required.

A revised Section F requesting imidacloprid tolerances on soybean, seed
at 3.5 ppm, and soybean, hay at 35 ppm is required.

A revised Section F for aspirated grain fractions at 240 ppm is
required.

10.3	Occupational and Residential Exposure  tc "10.3	Occupational and
Residential Exposure " \l 2 

None.

References: tc "References\:" 

HIARC, TXR NO. 0051292, D. Nixon, 10/31/02

MARC, DP Num: 28740, J. Tyler, 1/13/03

Dietary Exposure: DP Num: 337874, 337877, & 337880, W. Cutchin, 4/2/07

Chemistry Chapter: DP Num: 332757, 333517, & 334153, W. Cutchin, 4/11/07

ORE: DP Num: 281610, 281612, & 281614, M. Dow, 2/26/07

EFED Water: DP Num: 311925, R. Parker, 5/16/06

DP Num: 337875, M. Dow, 4/17/07

DP Num: 337878, M. Dow, 4/17/07

PP#s: 3E6564, 3E6561, 3E6738, 3E6760, 5E6920, 5E6921, 5E6922, & 5E6923,
DP Num:  322225, 322249, 322250, 322251, 322253, 322257, 322255, &
322260, J. Tyler, 6/15/06

PP#s: 2E6409, 1E6254, 2E6506, 2E6406, 2E6435, 0E6203, 2E6414, 1E6237,
2E6458, 1E6074, 1E6225, 1E6268, 2E6421, 2E6417, & 2E6403,  DP Num:
286101, 284746, 282414, 280766, 278760, 286722, 280447, & 285741, J.
Tyler, 3/4/03 

PP#s: 3F4169 & 3H5655; DP Num: 185148, F. Griffith, 9/20/93; DP Num:
200233, F. Griffith, 6/8/94; and DP Num: 217632, F. Griffith, 2/29/96

PP# 6F4682 & 0E6106; DP Num: 224074 & 263729; MRID: 43939401, 43939402,
& 45051401; Y. Donovan; 7/12/00



Attachment 1:  Toxicological Effects Tables

Table A.1  Acute Toxicity of Imidacloprid

Guideline

 No.	

Study Type	

MRID #(s)	

Results	

Toxicity Category

81-1	

Acute Oral	

42055331	

LD50 = 424 mg/kg (M)

LD50 > 450 mg/kg (F)	

II

81-2	

Acute Dermal	

42055332	

LD50 > 5000 mg/kg	

IV

81-3	

Acute Inhalation	

42256317	

LC50 > 5.33 m/L	

IV

81-4	

Primary Eye Irritation	

42055334	

Not an eye irritant	

IV

81-5 	

Primary Skin Irritation	

42055335	

Not a dermal irritant	

IV

81-6	

Dermal Sensitization	

42055336	

Not a dermal sensitizer	

N/A

Table A.2 Toxicity Profile of Imidacloprid Technical. 

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day oral toxicity rodents (rats)	

NA	

NA

870.3150

90-Day oral toxicity (nonrodents)	

NA	

NA

870.3200

21/28-Day dermal toxicity

(rabbits)	

42256329 (1990)

Acceptable/guideline

0 or 1000 mg/kg/day 

6 hr/day, 5 d/week	

NOAEL = 1000 mg/kg/day (HDT)

LOAEL = not identified

870.3250

90-Day dermal toxicity	

NA	

NA

870.3465

4-Week inhalation toxicity

(rat)	

42273001 (1989) Acceptable/guideline

0, 0.0055, 0.035, or 0.191 mg/L/day, 6 hr/day,

5 d/week for 4 weeks	

NOAEL = 0.191 mg/L/day (HDT)

LOAEL = not identified

870.3700a

Prenatal developmental toxicity (rats)	

42256338 (1992)

Acceptable/guideline 

F: 0, 10, 30, or 100 mg/kg/day	

Maternal NOAEL = 10 mg/kg/day

LOAEL = 30 mg/kg/day based on decreased body weight gain and decreased
corrected body weight gain.

Developmental NOAEL = 30 mg/kg/day

LOAEL = 100 mg/kg/day based on a slight increase in the incidence of
wavy ribs.

870.3700b

Prenatal developmental toxicity (rabbits)	

42256339 (1992)

Acceptable/guideline

F: 0, 8, 24, or 72 mg/kg/day	

Maternal NOAEL = 24 mg/kg/day

LOAEL = 72 mg/kg/day based on maternal deaths and decreased maternal
absolute body weights, body weight gains, and food consumption.

Developmental NOAEL = 24 mg/kg/day

LOAEL = 72 mg/kg/day based on abortion, total litter resorptions,
increased postimplantation loss due to increased late resorptions,
decreased fetal weights, and very low incidences of skeletal
alterations.

870.3800

Reproduction and fertility effects (rats)	

42256340 (1990)

Acceptable/guideline

0, 100, 250, or 700 ppm

F0 (M/F): 0, 8.1/8.8, 20.1/22.1, or 56.7/62.8 mg/kg/day

F1 (M/F): 0, 6.4/7.2, 16.5/18.9, or 47.3/52.3 mg/kg/day	

Parental/Systemic NOAEL = 16.5 mg/kg/day

LOAEL = 47.3 mg/kg/day based on decreased premating weight gain by F0
males and females and F1 females and decreased gestational weight gain
by F1 females.

Reproductive NOAEL = 47.3 mg/kg/day (HDT)

LOAEL = not identified

Offspring NOAEL = 16.5 mg/kg/day

LOAEL = 47.3 mg/kg/day based on decreased pup body weights in both
litters of both generations.

870.4100a

Chronic toxicity (rodents)	

NA; see 870.4300	

NA

870.4100b

Chronic toxicity (dogs)	

42273002 (1989)

Acceptable/guideline

0, 200, 500, or 1250/2500 ppm

M/F: 0, 6.1, 15, or 41(first 16 wks.), then 72 mg/kg/day	

NOAEL = 72 mg/kg/day (HDT)

LOAEL = not identified

870.4200a

Carcinogenicity (rats)	

NA; see 870.4300	

NA

870.4200b

Carcinogenicity (mice)	

42256335 (1991)

Acceptable/guideline with 42256336

0, 100, 330, or 1000 ppm

M: 0, 20, 66, or 208 mg/kg/day

F: 0, 30, 104, or 274 mg/kg/day

42256336 (1991)

0 or 2000 ppm

M: 0 or 414; F: 0 or 424 mg/kg/day	

NOAEL = Males: 208 mg/kg/day; Females: 274 mg/kg/day

LOAEL = Males: 414 mg/kg/day; Females: 424 mg/kg/day based on decreased
body weights, food consumption and water intake.

No evidence of carcinogenicity.

870.4300

Combined Chronic/carcinogenicity (rats)	

42256331 (1989)

Acceptable/guideline with 42256332

0, 100, 300, or 900 ppm

M: 0, 5.7, 16.9, or 51.3 mg/kg/day

F: 0, 7.6, 24.9, or 73.0 mg/kg/day

42256332 (1991)

0 or 1800 ppm

M: 0 or 102.6; F: 0 or 143.7 mg/kg/day	

NOAEL = Males: 5.7 mg/kg/day; Females: 7.6 mg/kg/day

LOAEL = Males: 16.9 mg/kg/day; Females: 24.9 mg/kg/day based on thyroid
toxicity (increased incidence of mineralized particles in thyroid
colloid) in males.

No evidence of carcinogenicity.

870.5100

Bacterial reverse mutation	

 42256341

Acceptable/guideline	

Negative for inducing reverse mutation in bacteria exposed to doses up
to 5000 ug/plate.

870.5100

Bacterial reverse mutation	

42256343

Acceptable/guideline	

Negative up to 12,500 ug/plate.

870.5100

Bacterial reverse mutation	

42256363

Acceptable/guideline	

Negative up to 5500 ug/plate.

870.5300

In vitro mammalian cell gene mutation	

42256342

Acceptable/guideline	

Negative for inducing forward mutation in Chinese Hamster Ovary (CHO)
(mammalian) cells treated up to 1222 ug/mL.

870.5300

In vitro mammalian cell gene mutation	

42256364

Acceptable/guideline	

Negative up to 2000 ug/mL.

870.5300

In vitro mammalian cell gene mutation	

42256365

Acceptable/guideline	

Negative up to 2000 ug/mL.

870.5375

In vitro mammalian chromosome abberation (HL)	

42256345

Acceptable/guideline	

Positive at 500 ug/mL - S9 and 

1300 ug/mL +S9, both cytotoxic doses

870.5375

In vitro mammalian chromosome abberation (CHV79)	

42256370

Acceptable/guideline	

Negative up to 1000 ug/mL.

870.5375

In vitro mammalian chromosome abberation (CHO)	

42256371

Acceptable/guideline	

Negative up to 1000 ug/mL.

870.5380

Mammalian germ cell chromosome abberation (mouse)	

42256348

Unacceptable/guideline	

Negative, but only tested up to 80 mg/ml.

870.5385

Mammalian bone marrow chromosome aberration (chinese hamster)	

42256344

Acceptable/guideline	

Negative for chromosome breakage up to 2000 ug/mL.

870.5395

Mammalian micronucleus (mouse)	

42256347

Unacceptable/guideline	

Negative, but only tested up to 80 mg/kg.

870.5395

Mammalian micronucleus (mouse)	

42256366

Acceptable/guideline	

Negative up to 50 mg/kg IP, toxic dose.

870.5395

Mammalian micronucleus (mouse)	

42256367

Unacceptable/guideline	

Negative up to 80 mg/kg IP, a non-toxic dose.

870.5395

Mammalian micronucleus (mouse)	

42256368

Unacceptable/guideline	

Negative up to 100 mg/kg PO, a non-toxic dose.

870.5395

Mammalian micronucleus (mouse)	

42256369

Acceptable/guideline	

Negative up to 160 mg/kg PO, toxic dose.

870.5500

DNA damage/repair REC assay	

41156351

Acceptable/guideline	

Negative up to 5000 ug/disc, the limit of solubility, with or without
activation.

870.5550

Unscheduled DNA synthesis (RPH)	

42256352

Acceptable/guideline	

Negative up to 750 ug/mL, a cytotoxic dose.

870.5575

Mitotic gene conversion	

42256353

Acceptable/guideline	

Negative for crossing-over in yeast cells exposed with/without
activation to precipitating levels of test article (5,000-10,000 ug/mL).

870.5550

Unscheduled DNA synthesis (RPH)	

42256372

Acceptable/guideline	

Negative up to cytotoxic doses (1333 ug/mL).

870.5900

In vitro sister chromatid exchange (CHO)	

42256349

Acceptable/guideline	

Positive at 500 ug/mL -S9 and 2000 ug/mL +S9, both cytotoxic doses.

870.5900

In vitro sister chromatid exchange (CHO)	

47256350

Acceptable/guideline	

Negative at cytotoxic doses of 400 ug/mL -S9 and 1250 ug/mL +S9.

870.59.15

In vivo sister chromatid exchange (chinese hamster bone marrow)	

42256346

Acceptable/guideline	

Negative up to 2000 mg/kg.

870.6200a

Acute neurotoxicity screening battery

rat	

43170301 (1994)

43285801 (1994)

Acceptable/guideline

0, 42, 151, or 307 mg/kg	

NOAEL = not identified.

LOAEL = 42 mg/kg based on decreased motor and locomotor activities
observed in females.

870.6200b

Subchronic neurotoxicity screening battery

rat	

43286401 (1994)

Minimum

0, 150, 1000, or 3000 ppm

M: 0, 9.3, 63.3, or 196 mg/kg/day

F: 0, 10.5, 69.3, or 213 mg/kg/day	

NOAEL = 9.3 mg/kg/day.

LOAEL = 63.3 mg/kg/day based on decreased body weight gain.

870.6300

Developmental neurotoxicity

(rat)	

45537501 (2001)

Acceptable/non-guideline

0, 100, 250, or 750 ppm

Gest.: 0, 8.0-8.3, 19.4-19.7, or 54.7-58.4 mg/kg/day

Lact.: 0, 12.8-19.5, 30.0-45.4, or 80.4-155.0 mg/kg/day	

Maternal NOAEL = 20 mg/kg/day.

LOAEL = 55 mg/kg/day based on decreased food consumption and body weight
gain during lactation.

Offspring NOAEL = 20 mg/kg/day.

LOAEL = 55 mg/kg/day based on decreased body weight and body weight
gain, decreased motor activity and decreased caudate/putamen width in
females.

870.7485

Metabolism and pharmacokinetics

rat	

42256354 (1990)

42256356 (1987)

M&F: 1.0 or 20.0 mg/kg (labeled) as single oral dose or

1.0 mg/kg unlabeled orally followed by 1.0 mg/kg single oral dose
(labeled) or

1.0 mg/kg (labeled) single dose IV

M: 20.0 mg/kg single oral dose or 1.0 mg/kg single duodenal dose

42256357 (1991)

M&F: 1.0 mg/kg single oral dose

M: 1.0 or 150 mg/kg single oral dose

42256373 (1990)

M: 1.0 or 150 mg/kg single oral dose or

80.0 mg/kg single oral dose after 1 year 1800 ppm 

42256355 (1987)

M: 1.0 mg/kg single oral or IV dose

42256358 (1990)

42256359 (1990)

Acceptable/guideline

	

Methylene-labeled imidacloprid was rapidly absorbed with approximately
90% of the administered dose being eliminated within 24 hours and 96%
within 48 hours.  There were no biologically significant differences
between sexes, dose levels, or route of administration.  Urinary
excretion was the major route of elimination (70-80% of recovered
radioactivity), with a lesser amount eliminated in feces (17-25% of
recovered radioactivity).  Biliary excretion was a major contributor to
fecal radioactivity (36.6% vs. 4.8% of recovered radioactivity in
bile-fistulated animals).  Total tissue burden after 48 hours accounted
for only approximately 0.5% of the recovered radioactivity, with major
sites of accumulation being the liver, kidney, lung, skin, and plasma
and minor sites being the brain and testes.  Maximum plasma
concentration occurred between 1.1 and 2.5 hours, and elimination
half-lives (calculated from two exponential terms) were 3 and 26-118
hours.  There were two major evident routes of biotransformation.  The
first included an oxidative cleavage of the parent compound to give
6-CNA and its glycine conjugate.  Dechlorination of this metabolite
formed the 6-hydroxynicotinic acid and its mercapturic acid derivative. 
The second included the hydroxylation of imidazolidine followed by
elimination of water of the parent compound to give NTN 35884.

In a comparison between [Methylene-14C] Imidacloprid and
[Imidazolidine-4,5-14C] Imidacloprid, the rates of excretion were
similar; however, the renal portion was higher with the
imidazolidine-labeled test material.  The imidazolidine-labeled test
material also demonstrated higher accumulation in the tissues, with the
major sites of accumulation being the liver, kidney, lung, and skin, and
the minor sites being brain and muscle.  

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In a comparison between [Methylene-14C] Imidacloprid and WAK 3839, there
were no significant differences in the absorption, distribution, and
excretion of the total radioactivity.  More radioactivity was found in
the tissues of the animals receiving imidacloprid at the 1.0 and 150.0
dose levels.  The major sites of accumulation of WAK 3839 included lung,
renal fat, liver, and kidney, with minor sites being the testis and
brain.  WAK 3839 was formed during pretreatment (chronic oral dosing) of
imidacloprid; however, the proposed metabolic pathways of the two
compounds were different.

870.7600

Dermal penetration	

NA	

NA

Attachment 2:  Structures of Imidacloprid Metabolites 

 Name	

Structure

Imidacloprid urea

1-[(6-chloro-3-pyridinyl)methyl]-2-imidazolidinoe

	

Imidacloprid hydroxy

(WAK 4103)	

Imidacloprid guanidine

(WAK 4140)

1-[(6-chloro-3-pyridinyl)methyl]-4,5-dihydro-1H-imidazol-2-amine

	

Imidacloprid olefin

(WAK 3745)

1-[(6-chloro-3-pyridinyl)methyl]-4,5-dihydro-1H-imidazol-2H-imidazol-2-i
mine

	

6-CNA 

6-chloronicotinic acid	

6-hydroxynicotinic acid	

WAK 3839	

	  PAGE  12  of   NUMPAGES  82