Number range CHAPTER

**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

**[MEMORANDUM]{.underline}**

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   365863, 371243, 370491
                                       #s:        
  -------- --------------------------- ---------- ------------------------

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

[**1.0** **Executive Summary** 4](#__RefHeading___Toc165171349)

[**2.0** **Ingredient Profile** 12](#__RefHeading___Toc165171350)

[**2.1** **Summary of Registered/Proposed Uses**
13](#__RefHeading___Toc165171351)

[**2.2** **Structure and Nomenclature**
16](#__RefHeading___Toc165171352)

[**2.3** **Physical and Chemical Properties**
17](#__RefHeading___Toc165171353)

[**3.0** **Hazard Characterization/Assessment**
17](#__RefHeading___Toc165171354)

[**3.1** **Hazard and Dose-Response Characterization**
17](#__RefHeading___Toc165171355)

[**3.1.1** **Dose-response** 18](#__RefHeading___Toc165171356)

[**3.1.2** **FQPA** 21](#__RefHeading___Toc165171357)

[**3.2** **Absorption, Distribution, Metabolism, Excretion (ADME)**
21](#__RefHeading___Toc165171358)

[**3.3** **FQPA Considerations** 22](#__RefHeading___Toc165171359)

[**3.3.1** **Adequacy of the Toxicity Data Base**
23](#__RefHeading___Toc165171360)

[**3.3.2** **Evidence of Neurotoxicity**
23](#__RefHeading___Toc165171361)

[**3.3.3** **Developmental Toxicity Studies**
23](#__RefHeading___Toc165171362)

[**3.3.4** **Reproductive Toxicity Study**
25](#__RefHeading___Toc165171363)

[**3.3.5** **Additional Information from Literature Sources**
26](#__RefHeading___Toc165171364)

[**3.3.6** **Pre-and/or Postnatal Toxicity**
26](#__RefHeading___Toc165171365)

[**3.3.7** **Recommendation for a Developmental Neurotoxicity Study**
27](#__RefHeading___Toc165171366)

[**3.4** **Safety Factor for Infants and Children**
28](#__RefHeading___Toc165171367)

[**3.4.1** **Adequacy of the Exposure Data Base**
28](#__RefHeading___Toc165171368)

[**3.4.2** **Safety Factor Conclusion**
29](#__RefHeading___Toc165171369)

[**3.5** **Hazard Identification and Toxicity Endpoint Selection**
29](#__RefHeading___Toc165171370)

[**3.5.1** **Acute Population Adjusted Dose (aPAD) - General
Population** 29](#__RefHeading___Toc165171371)

[**3.5.2** **Chronic Population Adjusted Dose (cPAD)**
30](#__RefHeading___Toc165171372)

[**3.5.3** **Incidental Oral Exposure (Short- and Intermediate-Term)**
32](#__RefHeading___Toc165171373)

[**3.5.4** **Dermal Absorption** 33](#__RefHeading___Toc165171374)

[**3.5.5** **Dermal Absorption** 34](#__RefHeading___Toc165171375)

[**3.5.6** **Dermal Exposure** 34](#__RefHeading___Toc165171376)

[**3.5.7** **Inhalation Exposure** 35](#__RefHeading___Toc165171377)

[**3.5.8** **Level of Concern for Margin of Exposure**
36](#__RefHeading___Toc165171378)

[**3.5.9** **Recommendation for Aggregate Exposure Risk Assessments**
37](#__RefHeading___Toc165171379)

[**3.3.10** **Classification of Carcinogenic Potential**
37](#__RefHeading___Toc165171380)

[**3.5.11** **Summary of Toxicological Doses and Endpoints for
Imidacloprid for Use in Human Risk Assessments.**
39](#__RefHeading___Toc165171381)

[**3.6** **Endocrine disruption** 40](#__RefHeading___Toc165171382)

[**4.0** **Public Health and Pesticide Epidemiology Data**
41](#__RefHeading___Toc165171383)

[**4.1** **Incident Reports** 41](#__RefHeading___Toc165171384)

[**5.0** **Dietary Exposure/Risk Characterization**
41](#__RefHeading___Toc165171385)

[**5.1** **Pesticide Metabolism and Environmental Degradation**
41](#__RefHeading___Toc165171386)

[**5.1.1** **Metabolism in Primary Crops and Livestock**
41](#__RefHeading___Toc165171387)

[**5.1.2** **Metabolism in Rotational Crops**
41](#__RefHeading___Toc165171388)

[**5.1.3** **Analytical Methodology** 42](#__RefHeading___Toc165171389)

[**5.1.4** **Environmental Degradation**
43](#__RefHeading___Toc165171390)

[**5.1.5** **Comparative Metabolic Profile**
43](#__RefHeading___Toc165171391)

[**5.1.6** **Toxicity Profile of Major Metabolites and Degradates**
44](#__RefHeading___Toc165171392)

[**5.1.7** **Pesticide Metabolites and Degradates of Concern**
45](#__RefHeading___Toc165171393)

[**5.1.8** **Drinking Water Residue Profile**
45](#__RefHeading___Toc165171394)

[**5.1.9** **Food Residue Profile** 45](#__RefHeading___Toc165171395)

[**5.1.10** **International Residue Limits**
50](#__RefHeading___Toc165171396)

[**5.2** **Dietary Exposure and Risk** 50](#__RefHeading___Toc165171397)

[**5.3** **Anticipated Residue and Percent Crop Treated Information**
51](#__RefHeading___Toc165171398)

[**6.0** **Residential (Non-Occupational) Exposure/Risk
Characterization** 53](#__RefHeading___Toc165171399)

[**6.1** **Residential Handler Exposure**
53](#__RefHeading___Toc165171400)

[**6.2.** **Residential Post-application Exposure**
59](#__RefHeading___Toc165171401)

[**6.3** **Combined Residential Exposure**
65](#__RefHeading___Toc165171402)

[**6.4** **Other (Spray Drift, etc.)** 66](#__RefHeading___Toc165171403)

[**7.0** **Aggregate Risk Assessments and Risk Characterization**
66](#__RefHeading___Toc165171404)

[**7.1** **Acute Aggregate Risk** 67](#__RefHeading___Toc165171405)

[**7.2** **Short-Term Aggregate Risk** 67](#__RefHeading___Toc165171406)

[**7.3** **Intermediate-Term Aggregate Risk**
68](#__RefHeading___Toc165171407)

[**7.4** **Long-Term Aggregate Risk** 68](#__RefHeading___Toc165171408)

[**8.0** **Cumulative Risk Characterization/Assessment**
68](#__RefHeading___Toc165171409)

[**9.0** **Occupational Exposure/Risk Pathway**
69](#__RefHeading___Toc165171410)

[**9.1** **Short-/Intermediate-/Long-Term Handler Risk**
69](#__RefHeading___Toc165171411)

[**9.2** **Short-/Intermediate-/Long-Term Post-application Risk**
72](#__RefHeading___Toc165171412)

[**9.3** **Restricted Entry Interval (REI)**
74](#__RefHeading___Toc165171413)

[**10.0** **Data Needs and Label Requirements**
74](#__RefHeading___Toc165171414)

[**10.1** **Toxicology** 74](#__RefHeading___Toc165171415)

[**10.2** **Residue Chemistry** 74](#__RefHeading___Toc165171416)

[**10.3** **Occupational and Residential Exposure**
74](#__RefHeading___Toc165171417)

[**Attachment 1:** **Toxicological Effects Tables**
76](#__RefHeading___Toc165171418)

[**Attachment 2: Structures of Imidacloprid Metabolites**
82](#__RefHeading___Toc165171419)

Number range CHAPTER[]{#__RefHeading___Toc165171349 .anchor}**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.

Number range CHAPTERThe 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               [Dose]{.underline}   [Endpoint]{.underline}   [Effect/Study]{.underline}
  Scenario]{.underline}                                                 

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

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

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

  Short-term inhalation   Oral NOAEL = 10      Target MOE = 100         
                          mg/kg/day            (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 95^th^ 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.

[]{.mark}

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
  -----------------------------------------------------------------------

[]{#__RefHeading___Toc165171350 .anchor}**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).

[]{#__RefHeading___Toc165171351 .anchor}**2.1 Summary of
Registered/Proposed Uses**

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    |        |     |      |        |      |     |              |
| S      |        |     |      |        |      |     |              |
| ummary |        |     |      |        |      |     |              |
| of     |        |     |      |        |      |     |              |
| Pr     |        |     |      |        |      |     |              |
| oposed |        |     |      |        |      |     |              |
| Dire   |        |     |      |        |      |     |              |
| ctions |        |     |      |        |      |     |              |
| for    |        |     |      |        |      |     |              |
| Use of |        |     |      |        |      |     |              |
| Imi    |        |     |      |        |      |     |              |
| daclop |        |     |      |        |      |     |              |
| rid.** |        |     |      |        |      |     |              |
+========+========+=====+======+========+======+=====+==============+
| A      | Formu  | A   | Max. | Max.   | RT   | PHI | Use          |
| pplic. | lation | ppl | No.  | Se     | I^1^ |     | Directions   |
| T      |        | ic. | App  | asonal |      | (da | and          |
| iming, | \[EPA  | R   | lic. | A      | (d   | ys) | Limitations  |
| Type,  | Reg.   | ate | per  | pplic. | ays) |     |              |
| and    | No.\]  |     | Se   | Rate   |      |     |              |
| Equip. |        | (lb | ason |        |      |     |              |
|        |        | ai  |      | (lb    |      |     |              |
|        |        | /A) |      | ai/A)  |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| P      |        |     |      |        |      |     |              |
| eanuts |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Apply  | Prov   | 0.  | 3    | 0.13   | 5    | 14  | Use not      |
| as     | ado^®^ | 043 |      |        |      |     | permitted in |
| di     | 70     |     |      |        |      |     | CA           |
| rected | \[264  |     |      |        |      |     |              |
| or     | -823\] |     |      |        |      |     |              |
| bro    |        |     |      |        |      |     |              |
| adcast |        |     |      |        |      |     |              |
| spray  |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Spray  | Gau    | 0   | 1    | 0.38   | NA   | 15  | Spray band   |
| band   | cho^®^ | .38 |      |        |      |     | below seed   |
| below  | 600 SC |     |      |        |      |     | row up to 7  |
| seed   | \[264  |     |      |        |      |     | days before  |
| row    | -828\] |     |      |        |      |     | planting,    |
| before |        |     |      |        |      |     | Use not      |
| pla    |        |     |      |        |      |     | permitted in |
| nting, |        |     |      |        |      |     | CA           |
| in-    |        |     |      |        |      |     |              |
| furrow |        |     |      |        |      |     |              |
| during |        |     |      |        |      |     |              |
| pla    |        |     |      |        |      |     |              |
| nting, |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Apply  | Prov   | 0.  | 3    | 0.13   | 5    | 14  | Use not      |
| as     | ado^®^ | 043 |      |        |      |     | permitted in |
| di     | 1.6    |     |      |        |      |     | CA           |
| rected | Fl     |     |      |        |      |     |              |
| or     | owable |     |      |        |      |     |              |
| bro    | \[3125 |     |      |        |      |     |              |
| adcast | -457\] |     |      |        |      |     |              |
| spray  |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| In-    | Gau    | 0   | 1    | 0.38   | NA   | 15  | Use not      |
| furrow | cho^®^ | .38 |      |        |      |     | permitted in |
| spray  | 550 SC |     |      |        |      |     | CA           |
| on or  | \[264  |     |      |        |      |     |              |
| below  | -827\] |     |      |        |      |     |              |
| seed   |        |     |      |        |      |     |              |
| during |        |     |      |        |      |     |              |
| pla    |        |     |      |        |      |     |              |
| nting, |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| In-    | Adm    | 0   | 1    | 0.38   | NA   | 15  | Use not      |
| furrow | ire^®^ | .38 |      |        |      |     | permitted in |
| spray  | 2      |     |      |        |      |     | CA           |
| on or  | Fl     |     |      |        |      |     |              |
| below  | owable |     |      |        |      |     |              |
| seed   | \[3125 |     |      |        |      |     |              |
| during | -422\] |     |      |        |      |     |              |
| pla    |        |     |      |        |      |     |              |
| nting, |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Millet |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Seed   | Gau    | 0.  | 1    | 0.25/  | NA   |     | Do not graze |
|        | cho^®^ | 25/ |      |        |      |     | or feed      |
| trea   | 480    |     |      | 100 lb |      |     | livestock    |
| tment: | \[7501 |     |      | seed   |      |     | for 45 days  |
| comm   | -155\] |     |      |        |      |     | after        |
| ercial |        |     |      |        |      |     | planting     |
| or at  |        |     |      |        |      |     |              |
| or     |        |     |      |        |      |     |              |
| immed  |        |     |      |        |      |     |              |
| iately |        |     |      |        |      |     |              |
| before |        |     |      |        |      |     |              |
| pl     |        |     |      |        |      |     |              |
| anting |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Seed   | Gau    | 0.  | 1    | 0.25/  | NA   |     | Do not graze |
|        | cho^®^ | 25/ |      |        |      |     | or feed      |
| trea   | 600    | 100 |      | 100 lb |      |     | livestock    |
| tment: | Fl     | lb  |      | seed   |      |     | for 45 days  |
| comm   | owable | s   |      |        |      |     | after        |
| ercial | \[7501 | eed |      |        |      |     | planting     |
| or at  | -173\] |     |      |        |      |     |              |
| or     |        |     |      |        |      |     |              |
| immed  |        |     |      |        |      |     |              |
| iately |        |     |      |        |      |     |              |
| before |        |     |      |        |      |     |              |
| pl     |        |     |      |        |      |     |              |
| anting |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Oat    |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Seed   | Gau    | 0.0 | 1    | 0.     | NA   |     | Do not graze |
|        | cho^®^ | 3-0 |      | 09/100 |      |     | or feed      |
| trea   | 480    | .09 |      | lb     |      |     | livestock    |
| tment: | \[7501 | /   |      | seed   |      |     | for 45 days  |
| comm   | -155\] | 100 |      |        |      |     | after        |
| ercial |        | lb  |      |        |      |     | planting     |
| or at  |        | s   |      |        |      |     |              |
| or     |        | eed |      |        |      |     |              |
| immed  |        |     |      |        |      |     |              |
| iately |        |     |      |        |      |     |              |
| before |        |     |      |        |      |     |              |
| pl     |        |     |      |        |      |     |              |
| anting |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Seed   | Gau    | 0.0 | 1    | 0.     | NA   |     | Do not graze |
|        | cho^®^ | 3-0 |      | 09/100 |      |     | or feed      |
| trea   | 600    | .09 |      | lb     |      |     | livestock    |
| tment: | Fl     |     |      | seed   |      |     | for 45 days  |
| comm   | owable | /   |      |        |      |     | after        |
| ercial | \[7501 | 100 |      |        |      |     | planting     |
| or at  | -173\] | lb  |      |        |      |     |              |
| or     |        | s   |      |        |      |     |              |
| immed  |        | eed |      |        |      |     |              |
| iately |        |     |      |        |      |     |              |
| before |        |     |      |        |      |     |              |
| pl     |        |     |      |        |      |     |              |
| anting |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Vege   |        |     |      |        |      |     |              |
| table, |        |     |      |        |      |     |              |
| root   |        |     |      |        |      |     |              |
| and    |        |     |      |        |      |     |              |
| tuber, |        |     |      |        |      |     |              |
| crop   |        |     |      |        |      |     |              |
| group  |        |     |      |        |      |     |              |
| 1,     |        |     |      |        |      |     |              |
| (      |        |     |      |        |      |     |              |
| except |        |     |      |        |      |     |              |
| sugar  |        |     |      |        |      |     |              |
| beets) |        |     |      |        |      |     |              |
| plus   |        |     |      |        |      |     |              |
| Kava   |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Di     | Prov   | 0.  | 1-3  | 0.044  | 5    | 7   | Not for use  |
| rected | ado^®^ | 044 |      | (r     |      |     | on crops     |
| or     | 70 WG  |     |      | adish) |      |     | grown for    |
| bro    | \[264  |     |      |        |      |     | seed. Use    |
| adcast | -823\] |     |      | 0.13   |      |     | not          |
| foliar |        |     |      | (all   |      |     | permitted in |
| spray  |        |     |      | o      |      |     | CA           |
| and    |        |     |      | thers) |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Spray  | Gau    | 0.2 | 1    | 0.38   | NA   | 21  | Spray band   |
| band   | cho^®^ | 5-0 |      |        |      |     | below seed   |
| below  | 600 SC | .38 |      |        |      |     | row up to 14 |
| seed   | \[264  |     |      |        |      |     | days before  |
| row    | -828\] |     |      |        |      |     | planting.    |
| before |        |     |      |        |      |     | Not for use  |
| pla    |        |     |      |        |      |     | on crops     |
| nting, |        |     |      |        |      |     | grown for    |
| in-    |        |     |      |        |      |     | seed. Use    |
| furrow |        |     |      |        |      |     | not          |
| during |        |     |      |        |      |     | permitted in |
| pla    |        |     |      |        |      |     | CA           |
| nting, |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Di     | Prov   | 0.  | 1-3  | 0.044  | 5    | 7   | Not for use  |
| rected | ado^®^ | 044 |      | (r     |      |     | on crops     |
| or     | 1.6    |     |      | adish) |      |     | grown for    |
| bro    | Fl     |     |      |        |      |     | seed. Use    |
| adcast | owable |     |      | 0.13   |      |     | not          |
| foliar | \[3125 |     |      | (all   |      |     | permitted in |
| spray  | -457\] |     |      | o      |      |     | CA           |
| and    |        |     |      | thers) |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Spray  | Gau    | 0.1 | 1    | 0.38   | NA   | 21  | Spray band   |
| band   | cho^®^ | 6-0 |      |        |      |     | below seed   |
| below  | 550 SC | .38 |      |        |      |     | row up to 14 |
| seed   | \[264  |     |      |        |      |     | days before  |
| row    | -827\] |     |      |        |      |     | planting.    |
| before |        |     |      |        |      |     | Not for use  |
| pla    |        |     |      |        |      |     | on crops     |
| nting, |        |     |      |        |      |     | grown for    |
| in-    |        |     |      |        |      |     | seed. Use    |
| furrow |        |     |      |        |      |     | not          |
| during |        |     |      |        |      |     | permitted in |
| pla    |        |     |      |        |      |     | CA           |
| nting, |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Spray  | Adm    | 0.1 | 1    | 0.38   | NA   | 21  | Spray band   |
| band   | ire^®^ | 6-0 |      |        |      |     | below seed   |
| below  | 2      | .38 |      |        |      |     | row up to 14 |
| seed   | Fl     |     |      |        |      |     | days before  |
| row    | owable |     |      |        |      |     | planting.    |
| before | \[3125 |     |      |        |      |     | Not for use  |
| pla    | -422\] |     |      |        |      |     | on crops     |
| nting, |        |     |      |        |      |     | grown for    |
| in-    |        |     |      |        |      |     | seed. Use    |
| furrow |        |     |      |        |      |     | not          |
| during |        |     |      |        |      |     | permitted in |
| pla    |        |     |      |        |      |     | CA           |
| nting, |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Globe  |        |     |      |        |      |     |              |
| Art    |        |     |      |        |      |     |              |
| ichoke |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Di     | Prov   | 0.0 | 4    | 0.5    | 14   | 7   |              |
| rected | ado^®^ | 5-0 |      |        |      |     |              |
| or     | 70 WG  | .13 |      |        |      |     |              |
| bro    | \[264  |     |      |        |      |     |              |
| adcast | -823\] |     |      |        |      |     |              |
| foliar |        |     |      |        |      |     |              |
| spray  |        |     |      |        |      |     |              |
| and    |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Spray  | Gau    | 0.  | 1    | 0.5    | NA   | 7   | Use not      |
| band   | cho^®^ | 25- |      |        |      |     | permitted in |
| below  | 600 SC | 0.5 |      |        |      |     | CA           |
| seed   | \[264  |     |      |        |      |     |              |
| row    | -828\] |     |      |        |      |     |              |
| before |        |     |      |        |      |     |              |
| pla    |        |     |      |        |      |     |              |
| nting, |        |     |      |        |      |     |              |
| in-    |        |     |      |        |      |     |              |
| furrow |        |     |      |        |      |     |              |
| during |        |     |      |        |      |     |              |
| pla    |        |     |      |        |      |     |              |
| nting, |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Di     | Prov   | 0   | 4    | 0.5    | 14   | 7   |              |
| rected | ado^®^ | .04 |      |        |      |     |              |
| or     | 1.6    | -0. |      |        |      |     |              |
| bro    | Fl     | 125 |      |        |      |     |              |
| adcast | owable |     |      |        |      |     |              |
| foliar | \[3125 |     |      |        |      |     |              |
| spray  | -457\] |     |      |        |      |     |              |
| and    |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Spray  | Gau    | 0.  | 1    | 0.5    | NA   | 7   | Spray band   |
| band   | cho^®^ | 25- |      |        |      |     | below seed   |
| below  | 550 SC | 0.5 |      |        |      |     | row up to 14 |
| seed   | \[264  |     |      |        |      |     | days before  |
| row    | -827\] |     |      |        |      |     | planting.    |
| before |        |     |      |        |      |     | Not for use  |
| pla    |        |     |      |        |      |     | on crops     |
| nting, |        |     |      |        |      |     | grown for    |
| in-    |        |     |      |        |      |     | seed.        |
| furrow |        |     |      |        |      |     |              |
| during |        |     |      |        |      |     |              |
| pla    |        |     |      |        |      |     |              |
| nting, |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Spray  | Adm    | 0.  | 1    | 0.5    | NA   | 7   | Spray band   |
| band   | ire^®^ | 25- |      |        |      |     | below seed   |
| below  | 2      | 0.5 |      |        |      |     | row up to 14 |
| seed   | Fl     |     |      |        |      |     | days before  |
| row    | owable |     |      |        |      |     | planting.    |
| before | \[3125 |     |      |        |      |     | Not for use  |
| pla    | -422\] |     |      |        |      |     | on crops     |
| nting, |        |     |      |        |      |     | grown for    |
| in-    |        |     |      |        |      |     | seed.        |
| furrow |        |     |      |        |      |     |              |
| during |        |     |      |        |      |     |              |
| pla    |        |     |      |        |      |     |              |
| nting, |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Caneb  |        |     |      |        |      |     |              |
| erries |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Chemi  | Adm    | 0.  | 1    | 0.5    | NA   | 7   | Do not apply |
| gation | ire^®^ | 25- |      |        |      |     | pre-bloom or |
| or     | 2      | 0.5 |      |        |      |     | during bloom |
| basal  | Fl     |     |      |        |      |     | or when bees |
| soil   | owable |     |      |        |      |     | are actively |
| d      | \[3125 |     |      |        |      |     | foraging.    |
| rench. | -422\] |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Chemi  | Gau    | 0.  | 1    | 0.5    | NA   | 7   | Do not apply |
| gation | cho^®^ | 25- |      |        |      |     | pre-bloom or |
| or     | 550 SC | 0.5 |      |        |      |     | during bloom |
| basal  | \[264  |     |      |        |      |     | or when bees |
| soil   | -827\] |     |      |        |      |     | are actively |
| d      |        |     |      |        |      |     | foraging.    |
| rench. |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Apply  | Prov   | 0.1 | 1    | 0.3    | 7    | 3   | Do not apply |
| as     | ado^®^ |     |      |        |      |     | during bloom |
| di     | Pro    |     |      |        |      |     | or when bees |
| rected | \[264  |     |      |        |      |     | are actively |
| or     | -858\] |     |      |        |      |     | foraging.    |
| bro    |        |     |      |        |      |     |              |
| adcast |        |     |      |        |      |     |              |
| spray  |        |     |      |        |      |     |              |
| or     |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Apply  | Prov   | 0.1 | 1    | 0.3    | 7    | 3   | Do not apply |
| as     | ado^®^ |     |      |        |      |     | during bloom |
| di     | 70 WG  |     |      |        |      |     | or when bees |
| rected | \[264  |     |      |        |      |     | are actively |
| or     | -823\] |     |      |        |      |     | foraging.    |
| bro    |        |     |      |        |      |     |              |
| adcast |        |     |      |        |      |     |              |
| spray  |        |     |      |        |      |     |              |
| or     |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Apply  | Prov   | 0.1 | 1    | 0.3    | 7    | 3   | Do not apply |
| as     | ado^®^ |     |      |        |      |     | pre-bloom or |
| di     | 1.6    |     |      |        |      |     | during bloom |
| rected | Fl     |     |      |        |      |     | or when bees |
| or     | owable |     |      |        |      |     | are actively |
| bro    | \[3125 |     |      |        |      |     | foraging.    |
| adcast | -457\] |     |      |        |      |     |              |
| spray  |        |     |      |        |      |     |              |
| or     |        |     |      |        |      |     |              |
| chemi  |        |     |      |        |      |     |              |
| gation |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| So     |        |     |      |        |      |     |              |
| ybeans |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Apply  | E      | 0.  | 3    | 0.14   | 7    | 7   | Do not apply |
| as     | ncore™ | 047 |      |        |      |     | through any  |
| di     |        |     |      |        |      |     | type of      |
| rected | \[264  |     |      |        |      |     | irrigation   |
| or     | -783\] |     |      |        |      |     | system or in |
| bro    |        |     |      |        |      |     | enclosed     |
| adcast |        |     |      |        |      |     | structures.  |
| spray. |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+
| Apply  | T      | 0.  | 3    | 0.14   | 7    | 7   | Do not apply |
| as     | rimax™ | 047 |      |        |      |     | through any  |
| di     | Pro    |     |      |        |      |     | type of      |
| rected | \[264  |     |      |        |      |     | irrigation   |
| or     | -855\] |     |      |        |      |     | system or in |
| bro    |        |     |      |        |      |     | enclosed     |
| adcast |        |     |      |        |      |     | structures.  |
| spray. |        |     |      |        |      |     |              |
+--------+--------+-----+------+--------+------+-----+--------------+

^1^ RTI = retreatment interval; PHI = preharvest interval.

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

[]{#__RefHeading___Toc165171352 .anchor}**2.2 Structure and
Nomenclature**

+-------------------+--------------------------------------------------+
| **Table 2.2 Test  |                                                  |
| Compound          |                                                  |
| Nomenclature.**   |                                                  |
+-------------------+--------------------------------------------------+
| Chemical          | ![](media/image1.wmf)                            |
| Structure         |                                                  |
+-------------------+--------------------------------------------------+
| Common Name       | Imidacloprid                                     |
+-------------------+--------------------------------------------------+
| Company           | BAY NTN 33893                                    |
| experimental name |                                                  |
+-------------------+--------------------------------------------------+
| IUPAC name        | (*EZ*)-1-(6-chloro-3-pyr                         |
|                   | idylmethyl)-*N*-nitroimidazolidin-2-ylideneamine |
+-------------------+--------------------------------------------------+
| CAS name          | 1-\[(6-chloro-3-                                 |
|                   | pyridinyl)methyl\]-*N*-nitro-2-imidazolidinimine |
+-------------------+--------------------------------------------------+
| CAS \#            | 138261-41-3                                      |
+-------------------+--------------------------------------------------+
| End-use           | Provado® 1.6F (EPA Reg. No. 264-763)             |
| products/(EP)     |                                                  |
|                   | 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. 264-823)             |
|                   |                                                  |
|                   | Gaucho® 75 ST (EPA Reg. No. 264-959)             |
|                   |                                                  |
|                   | Gaucho® 480 Flowable (EPA Reg. No. 264-957)      |
|                   |                                                  |
|                   | Gaucho® 600 Flowable (EPA Reg. No. 264-968)      |
|                   |                                                  |
|                   | Encore™ (EPA Reg. No. 264-783)                   |
|                   |                                                  |
|                   | Trimax™ Pro (EPA Reg. No. 264-855)               |
+-------------------+--------------------------------------------------+

[]{#__RefHeading___Toc165171353 .anchor}**2.3 Physical and Chemical
Properties**

+------------------------------+-------------------------+-------------+
| **Table 2.3 Physicochemical  |                         |             |
| Properties of the Technical  |                         |             |
| Grade Test Compound.**       |                         |             |
+==============================+=========================+=============+
| **Parameter**                | **Value**               | **          |
|                              |                         | Reference** |
+------------------------------+-------------------------+-------------+
| Melting point                | 144^o^C                 | The         |
|                              |                         | Pesticide   |
|                              |                         | Manual      |
|                              |                         |             |
|                              |                         | Twelfth     |
|                              |                         | Edition     |
|                              |                         | (2000)      |
+------------------------------+-------------------------+-------------+
| pH                           | 5 to 11                 |             |
+------------------------------+-------------------------+-------------+
| Specific gravity             | 1.54 (@ 23^o^C)         |             |
+------------------------------+-------------------------+-------------+
| Water solubility (g/L at     | 0.61                    |             |
| 20^o^C)                      |                         |             |
+------------------------------+-------------------------+-------------+
| Solvent solubility (g/L at   | Dichloromethane: 55,    |             |
| 20^o^C)                      | Isopropanol: 1.2,       |             |
|                              | Toluene: 0.68,          |             |
|                              | n-hexane: \< 0.1        |             |
+------------------------------+-------------------------+-------------+
| Vapor pressure (mPa at       | 4 x 10^-7^              |             |
| 20^o^C)                      |                         |             |
+------------------------------+-------------------------+-------------+
| Octanol/water partition      | 0.57 (21^o^C)           |             |
| coefficient \[Log(K~OW~)\]   |                         |             |
+------------------------------+-------------------------+-------------+
| UV/visible absorption        | Not provided.           |             |
| spectrum                     |                         |             |
+------------------------------+-------------------------+-------------+

Number range CHAPTER[]{#__RefHeading___Toc165171354 .anchor}**3.0 Hazard
Characterization/Assessment**

[]{#__RefHeading___Toc165171355 .anchor}**3.1 Hazard and Dose-Response
Characterization**

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.

[]{#__RefHeading___Toc165171356 .anchor}**3.1.1 Dose-response**

*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 UF~L~; 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 (T~3~
and T~4~). 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 T~3~, T~4~ 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:]{.underline} 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).

[]{#__RefHeading___Toc165171357 .anchor}**3.1.2 FQPA**

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).

[]{#__RefHeading___Toc165171358 .anchor}**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 \[methylene-^14^C\] imidacloprid and
\[imidazolidine-4,5-^14^C\] 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 \[methylene-^14^C\] 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.

Number range CHAPTER

[]{#__RefHeading___Toc165171359 .anchor}**3.3 FQPA Considerations**

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 UF~L~; 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).

[]{#__RefHeading___Toc165171360 .anchor}**3.3.1 Adequacy of the Toxicity
Data Base**

Number range CHAPTER

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

[]{#__RefHeading___Toc165171361 .anchor}**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

    []{#__RefHeading___Toc165171362 .anchor}**3.3.3 Developmental
    Toxicity Studies**

    **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).

[]{#__RefHeading___Toc165171363 .anchor}**3.3.4 Reproductive Toxicity
Study**

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 F~0~ males, 0, 8.8, 22.1, or 62.8 mg/kg bw/day,
respectively, for F~0~ females, 0, 6.4, 16.5, or 47.3 mg/kg bw/day,
respectively, for F~1~ males, and 0, 7.2, 18.9, or 52.3 mg/kg bw/day,
respectively, for F~1~ 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 F~1~ 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, F~0~ males and females had decreased body weight gains
during premating (10 and 12% less than controls, respectively), and F~1~
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
F~1A~, F~1B~, F~2A~, and F~2B~ 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 F~1~ 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 F~0~ males and
females and F~1~ females and decreased gestational weight gain by F~1~
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: F~1A~ pups on lactations days (LD) 7 and 21
(91 and 87% of controls, respectively); F~1B~ pups on LD 21 (90% of
controls); F~2A~ pups on LD 21 (91% of controls); and F~2B~ 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).

[]{#__RefHeading___Toc165171364 .anchor}**3.3.5 Additional Information
from Literature Sources**

There was no additional relevant information from the published
literature.

[]{#__RefHeading___Toc165171365 .anchor}**3.3.6 Pre-and/or Postnatal
Toxicity**

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**

> 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** **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.

[]{#__RefHeading___Toc165171366 .anchor}**3.3.7 Recommendation for a
Developmental Neurotoxicity Study**

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.

[]{#__RefHeading___Toc165171367 .anchor}**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.

Number range CHAPTER

[]{#__RefHeading___Toc165171368 .anchor}**3.4.1 Adequacy of the Exposure
Data Base**

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.

[]{#__RefHeading___Toc165171369 .anchor}**3.4.2 Safety Factor
Conclusion**

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.

[]{#__RefHeading___Toc165171370 .anchor}**3.5 Hazard Identification and
Toxicity Endpoint Selection**

[]{#__RefHeading___Toc165171371 .anchor}**3.5.1 Acute Population
Adjusted Dose (aPAD) - General Population**

[Study Selected:]{.underline} Acute Neurotoxicity Study - Rat OPPTS
870.6200a

[MRID No.:]{.underline} 43170301

[Executive Summary:]{.underline} 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:]{.underline} 42 mg/kg (LOAEL),
based upon the decreased in motor and locomotor activities observed in
females.

[Uncertainty Factor (UF)]{.underline}: 300

[Comments about Study/Endpoint/Uncertainty Factor:]{.underline} 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]{.underline} = 0.14 mg/kg

> 300

[]{#__RefHeading___Toc165171372 .anchor}**3.5.2 Chronic Population
Adjusted Dose (cPAD)**

[Study Selected]{.underline}: Combined Chronic
Toxicity/Carcinogenicity - Rat OPPTS 870.4300

[MRID No.:]{.underline} 42256331

[Executive Summary:]{.underline} 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:]{.underline} 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):]{.underline} 100

[Comments about Study/Endpoint/Uncertainty Factor:]{.underline} 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]{.underline} = 0.057 mg/kg
>
> 100

[]{#__RefHeading___Toc165171373 .anchor}**3.5.3 Incidental Oral Exposure
(Short- and Intermediate-Term)**

[Study Selected:]{.underline} Developmental Toxicity Study - Rat OPPTS
670.3700a

[MRID No.:]{.underline} 42256338

[Executive Summary:]{.underline} 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:]{.underline} 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:]{.underline} The endpoint of concern is
appropriate for the population of concern (infants and children) and the
duration of exposure.

[]{#__RefHeading___Toc165171374 .anchor}**3.5.4 Dermal Absorption**

[Study Selected:]{.underline} Subchronic Neurotoxicity Study - Rat OPPTS
870.6200b

[MRID No.:]{.underline} 43286401

[Executive Summary:]{.underline} 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:]{.underline} 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:]{.underline} 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.

[]{#__RefHeading___Toc165171375 .anchor}**3.5.5 Dermal Absorption**

[Dermal Absorption Factor:]{.underline} 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]{.underline} = [72 mg/kg/day]{.underline} = 7.2%

> Dermal Tox. NOAEL 1000 mg/kg/day

[]{#__RefHeading___Toc165171376 .anchor}**3.5.6 Dermal Exposure**

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

> [Study Selected:]{.underline} Developmental Toxicity Study - Rat OPPTS
> 670.3700a
>
> [MRID No.:]{.underline} 42256338
>
> [Executive Summary:]{.underline} See Short-term Incidental Oral
>
> [Dose and Endpoint for Risk Assessment]{.underline}: 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:]{.underline} 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:]{.underline} Subchronic Neurotoxicity Study - Rat
> OPPTS 870.6200b
>
> [MRID No]{.underline}.: 43286401
>
> [Executive Summary]{.underline}: See Intermediate-term Incidental Oral
>
> [Dose and Endpoint for Risk Assessment:]{.underline} 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:]{.underline} 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]{.underline}: Combined Chronic
> Toxicity/Carcinogenicity -- Rat OPPTS 870.4300
>
> [MRID No]{.underline}.: 42256331
>
> [Executive Summary]{.underline}: See Chronic PAD
>
> [Dose and Endpoint for Risk Assessment:]{.underline} 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:]{.underline} 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.

[]{#__RefHeading___Toc165171377 .anchor}**3.5.7 Inhalation Exposure**

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

> [Study Selected:]{.underline} Developmental Toxicity Study - Rat OPPTS
> 670.3700a
>
> [MRID No.:]{.underline} 42256338
>
> [Executive Summary:]{.underline} See Short-term Incidental Oral
>
> [Dose and Endpoint for Risk Assessment]{.underline}: 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:]{.underline} 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[)]{.underline}
Exposure**

> [Study Selected:]{.underline} Subchronic Neurotoxicity Study - Rat
> OPPTS 870.6200b
>
> [MRID No]{.underline}.: 43286401
>
> [Executive Summary]{.underline}: See Intermediate-term Incidental Oral
>
> [Dose and Endpoint for Risk Assessment:]{.underline} 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:]{.underline} 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]{.underline}: Combined Chronic
> Toxicity/Carcinogenicity -- Rat OPPTS 870.4300
>
> [MRID No]{.underline}.: 42256331
>
> [Executive Summary]{.underline}: See Chronic PAD
>
> [Dose and Endpoint for Risk Assessment:]{.underline} 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:]{.underline} 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.

[]{#__RefHeading___Toc165171378 .anchor}**3.5.8 Level of Concern for
Margin of Exposure**

+-----------------------+-----------+-----------------+--------------+
| **Table 3.5.8 Summary |           |                 |              |
| of Levels of Concern  |           |                 |              |
| for Risk              |           |                 |              |
| Assessment.**         |           |                 |              |
+-----------------------+-----------+-----------------+--------------+
| **Route**             | **Sho     | **Inte          | *            |
|                       | rt-Term** | rmediate-Term** | *Long-Term** |
|                       |           |                 |              |
|                       | **(1-30   | **(1 - 6        | **(\> 6      |
|                       | Days)**   | Months)**       | 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          |
+-----------------------+-----------+-----------------+--------------+

[]{#__RefHeading___Toc165171379 .anchor}**3.5.9 Recommendation for
Aggregate Exposure Risk Assessments**

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).

[]{#__RefHeading___Toc165171380 .anchor}**3.3.10 Classification of
Carcinogenic Potential**

**3.3.10.1 Combined Chronic Toxicity/Carcinogenicity Study in Rats**

> [MRID No.]{.underline} 42256331
>
> [Executive Summary:]{.underline} See Chronic RfD
>
> [Discussion of Tumor Data]{.underline} At the doses tested, there was
> no treatment related increase in tumor incidence when compared to
> controls.
>
> [Adequacy of the Dose Levels Tested]{.underline} 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.]{.underline} 42256335
>
> [Executive Summary]{.underline}: 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]{.underline} At the doses tested, there was
> no treatment related increase in tumor incidence when compared to
> controls.
>
> [Adequacy of the Dose Levels Tested]{.underline} 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).

Number range CHAPTER[]{#__RefHeading___Toc165171381 .anchor}**3.5.11
Summary of Toxicological Doses and Endpoints for Imidacloprid for Use in
Human Risk Assessments.**

+------------+------------+---------------+--------------------------+
| **Table    |            |               |                          |
| 3.5.11     |            |               |                          |
| Summary of |            |               |                          |
| Tox        |            |               |                          |
| icological |            |               |                          |
| Dose and   |            |               |                          |
| Endpoints  |            |               |                          |
| for        |            |               |                          |
| Im         |            |               |                          |
| idacloprid |            |               |                          |
| for Use in |            |               |                          |
| Human      |            |               |                          |
| Health     |            |               |                          |
| Risk       |            |               |                          |
| Assess     |            |               |                          |
| ment^1^.** |            |               |                          |
+============+============+===============+==========================+
| **         | **Dose     | **\*FQPA SF   | **Study and              |
| Exposure** | Used in    | and Level of  | Toxicological Effects**  |
|            | Risk       | Concern for   |                          |
| **         | Ass        | Risk          |                          |
| Scenario** | essment,** | Assessment**  |                          |
|            |            |               |                          |
|            | **UF**     |               |                          |
+------------+------------+---------------+--------------------------+
| Acute      | LOAEL = 42 | FQPA SF = 1X  | Acute neurotoxicity -    |
| Dietary    | mg/kg/day  |               | rat                      |
|            |            | **aPAD** =    |                          |
| [all       | UF =       | [aPOD         | LOAEL = 42 mg/kg, based  |
| popu       | 300^2^     | ]{.underline} | upon the decrease in     |
| lations]{. |            |               | motor and locomotor      |
| underline} | **Acute    | FQPA SF       | activities observed in   |
|            | PAD** =    |               | females.                 |
|            | 0.14 mg/kg | = 0.14 mg/kg  |                          |
+------------+------------+---------------+--------------------------+
| Chronic    | NOAEL =    | FQPA SF = 1X  | Combined chronic         |
| Dietary    | 5.7        |               | tox/carcinogenicity -    |
|            | mg/kg/day  | **cPAD** =    | rat                      |
| [all       |            | [cPOD         |                          |
| popu       | UF = 100   | ]{.underline} | LOAEL = 16.9 mg/kg/day,  |
| lations]{. |            |               | based upon increased     |
| underline} | **Chronic  | FQPA SF       | incidence of mineralized |
|            | PAD** =    |               | particles in thyroid     |
|            | 0.057      | = 0.057       | colloid in males.        |
|            | mg/kg/day  | mg/kg/day     |                          |
+------------+------------+---------------+--------------------------+
| Short-Term | oral study | **LOC for     | Developmental toxicity - |
| Oral       | NOAEL = 10 | MOE** = 100   | rat                      |
|            | mg/kg/day  | (Residential, |                          |
| (1-30      |            | includes the  | Maternal LOAEL = 30      |
| days)      |            | FQPA SF)      | mg/kg/day, based upon    |
|            |            |               | decreased body weight    |
|            |            |               | gain and corrected body  |
|            |            |               | weight gain.             |
+------------+------------+---------------+--------------------------+
| Interme    | oral study | **LOC for     | Subchronic               |
| diate-Term | NOAEL =    | MOE** = 100   | neurotoxicity - rat      |
| Oral       | 9.3        | (Residential, |                          |
|            | mg/kg/day  | includes the  | LOAEL = 63.3 mg/kg/day,  |
| (1- 6      |            | FQPA SF)      | based upon decreased     |
| months)    |            |               | body weight gain.        |
+------------+------------+---------------+--------------------------+
| Short-Term | oral study | **LOC for     | Developmental toxicity - |
| Dermal     | NOAEL = 10 | MOE** = 100   | rat                      |
|            | mg/kg/day  | (             |                          |
| (1-30      |            | Occupational) | Maternal LOAEL = 30      |
| days)      | (dermal    |               | mg/kg/day, based upon    |
|            | absorption | **LOC for     | decreased body weight    |
|            | rate =     | MOE** = 100   | gain and corrected body  |
|            | 7.2%)^3^   | (Residential, | weight gain.             |
|            |            | includes the  |                          |
|            |            | FQPA SF)      |                          |
+------------+------------+---------------+--------------------------+
| Interme    | oral study | **LOC for     | Subchronic               |
| diate-Term | NOAEL =    | MOE** = 100   | neurotoxicity - rat      |
|            | 9.3        | (             |                          |
| Dermal     | mg/kg/day  | Occupational) | LOAEL = 63.3 mg/kg/day,  |
|            |            |               | based upon decreased     |
| (1-6       | (dermal    | **LOC for     | body weight gain.        |
| months)    | absorption | MOE** = 100   |                          |
|            | rate =     | (Residential, |                          |
|            | 7.2%)^3^   | includes the  |                          |
|            |            | FQPA SF)      |                          |
+------------+------------+---------------+--------------------------+
| Long-Term  | oral study | **LOC for     | Combined chronic         |
| Dermal     | NOAEL =    | MOE** = 100   | tox/carcinogenicity -    |
|            | 5.7        | (             | rat                      |
| (\> 6      | mg/kg/day  | Occupational) |                          |
| months)    |            |               | LOAEL = 16.9 mg/kg/day,  |
|            | (dermal    | **LOC for     | based upon increased     |
|            | absorption | MOE** = 100   | incidence of mineralized |
|            | rate =     | (Residential, | particles in thyroid     |
|            | 7.2%)^3^   | includes the  | colloid in males.        |
|            |            | FQPA SF)      |                          |
+------------+------------+---------------+--------------------------+
| Short-Term | oral study | **LOC for     | Developmental toxicity - |
| Inhalation | NOAEL = 10 | MOE** = 100   | rat                      |
|            | mg/kg/day  | (             |                          |
| (1-30      |            | Occupational) | Maternal LOAEL = 30      |
| days)      | (          |               | mg/kg/day, based upon    |
|            | inhalation | **LOC for     | decreased body weight    |
|            | absorption | MOE** = 100   | gain and corrected body  |
|            | rate =     | (Residential, | weight gain.             |
|            | 100%)      | includes the  |                          |
|            |            | FQPA SF)      |                          |
+------------+------------+---------------+--------------------------+
| Interme    | oral study | **LOC for     | Subchronic               |
| diate-Term | NOAEL =    | MOE** = 100   | neurotoxicity - rat      |
| Inhalation | 9.3        | (             |                          |
|            | mg/kg/day  | Occupational) | LOAEL = 63.3 mg/kg/day,  |
| (1- 6      |            |               | based upon decreased     |
| months)    | (          | **LOC for     | body weight gain.        |
|            | inhalation | MOE** = 100   |                          |
|            | absorption | (Residential, |                          |
|            | rate =     | includes the  |                          |
|            | 100%)      | FQPA SF)      |                          |
+------------+------------+---------------+--------------------------+
| Long-Term  | oral study | **LOC for     | Combined chronic         |
| Inhalation | NOAEL =    | MOE** = 100   | tox/carcinogenicity -    |
|            | 5.7        | (             | rat                      |
| (\> 6      | mg/kg/day  | Occupational) |                          |
| months)    |            |               | LOAEL = 16.9 mg/kg/day,  |
|            | (          | **LOC for     | based upon increased     |
|            | inhalation | MOE** = 100   | incidence of mineralized |
|            | absorption | (Residential, | particles in thyroid     |
|            | rate =     | includes the  | colloid in males.        |
|            | 100%)      | FQPA SF)      |                          |
+------------+------------+---------------+--------------------------+
| Cancer     | no         | Not           | No evidence of           |
|            | evidence   | applicable    | carcinogenicity in rats  |
| (oral,     | of         |               | and mice.                |
| dermal,    | carci      |               |                          |
| i          | nogenicity |               |                          |
| nhalation) | for humans |               |                          |
+------------+------------+---------------+--------------------------+

^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 UF~L~; 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.

[]{#__RefHeading___Toc165171382 .anchor}**3.6 Endocrine disruption**

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.

[]{#__RefHeading___Toc165171383 .anchor}**4.0 Public Health and
Pesticide Epidemiology Data**

[]{#__RefHeading___Toc165171384 .anchor}**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) \[Personal
Communication from Dr. Jerome Blondell to J. Tyler (e-mail 10/31/02)\].

[]{#__RefHeading___Toc165171385 .anchor}**5.0 Dietary Exposure/Risk
Characterization**

[]{#__RefHeading___Toc165171386 .anchor}**5.1 Pesticide Metabolism and
Environmental Degradation**

[]{#__RefHeading___Toc165171387 .anchor}**5.1.1 Metabolism in Primary
Crops and Livestock**

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.

[]{#__RefHeading___Toc165171388 .anchor}**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).

[]{#__RefHeading___Toc165171389 .anchor}**5.1.3 Analytical Methodology**

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 (KMnO~4~) 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).

[]{#__RefHeading___Toc165171390 .anchor}**5.1.4 Environmental
Degradation**

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).

[]{#__RefHeading___Toc165171391 .anchor}**5.1.5 Comparative Metabolic
Profile**

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 \[methylene-^14^C\] imidacloprid and
\[imidazolidine-4,5-^14^C\] 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.

[]{#__RefHeading___Toc165171392 .anchor}**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

[]{#__RefHeading___Toc165171393 .anchor}**5.1.7 Pesticide Metabolites
and Degradates of Concern**

+--------------+---------------+-------------------+-------------------+
| **Table      |               |                   |                   |
| 5.1.7        |               |                   |                   |
| Summary of   |               |                   |                   |
| Metabolites  |               |                   |                   |
| and          |               |                   |                   |
| Degradates   |               |                   |                   |
| to be        |               |                   |                   |
| included in  |               |                   |                   |
| the Risk     |               |                   |                   |
| Assessment   |               |                   |                   |
| and          |               |                   |                   |
| Tolerance    |               |                   |                   |
| Expression** |               |                   |                   |
+==============+===============+===================+===================+
| > Matrix     |               | Residues included | Residues included |
|              |               | in Risk           | in Tolerance      |
|              |               | Assessment        | Expression        |
+--------------+---------------+-------------------+-------------------+
| Plants       | Primary Crop  | Imidacloprid and  | Imidacloprid and  |
|              |               | its metabolites   | its metabolites   |
|              |               | containing the    | containing the    |
|              |               | 6-chloropyridinyl | 6-chloropyridinyl |
|              |               | moiety            | moiety            |
+--------------+---------------+-------------------+-------------------+
|              | Rotational    |                   |                   |
|              | Crop          |                   |                   |
+--------------+---------------+-------------------+-------------------+
| Livestock    | Ruminant      |                   |                   |
+--------------+---------------+-------------------+-------------------+
|              | Poultry       |                   |                   |
+--------------+---------------+-------------------+-------------------+
| Drinking     |               | Imidacloprid and  | Not Applicable    |
| Water        |               | degadates:        |                   |
|              |               | imidacloprid      |                   |
|              |               | urea,             |                   |
|              |               | imidacloprid      |                   |
|              |               | guanidine, and    |                   |
|              |               | imidacloprid      |                   |
|              |               | olefin            |                   |
+--------------+---------------+-------------------+-------------------+

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

[]{#__RefHeading___Toc165171394 .anchor}**5.1.8 Drinking Water Residue
Profile**

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).

[]{.mark}

+--------------------+------------+-------------------+----------------+
| **Table 5.1.8      |            |                   |                |
| Estimated Tier 1   |            |                   |                |
| Concentrations of  |            |                   |                |
| Imidacloprid in    |            |                   |                |
| Drinking Water.**  |            |                   |                |
+--------------------+------------+-------------------+----------------+
| Chemical           | **Surface  |                   | **Groundwater  |
|                    | Water      |                   | (μg/L)**       |
|                    | (μg/L)**   |                   |                |
+--------------------+------------+-------------------+----------------+
|                    | **Acute**  | **Chronic**       | **Acute and    |
|                    |            |                   | Chronic**      |
+--------------------+------------+-------------------+----------------+
| **Revised          |            |                   |                |
| EDWCs^1^**         |            |                   |                |
+--------------------+------------+-------------------+----------------+
| Imidacloprid total | Tree nuts  | Tree nuts and     | Not provided.  |
| residues^2^        | -- 35.9    | coffee -- 15.3    |                |
+--------------------+------------+-------------------+----------------+
| **Pre              |            |                   |                |
| viously-calculated |            |                   |                |
| EDWCs^3^**         |            |                   |                |
+--------------------+------------+-------------------+----------------+
| Imidacloprid total | Citrus --  | Citrus -- 17.2    | 2.09           |
| residues^2^        | **36.0**   |                   |                |
+--------------------+------------+-------------------+----------------+
| 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.        |            |                   |                |
+--------------------+------------+-------------------+----------------+

[]{#__RefHeading___Toc165171395 .anchor}**5.1.9 Food Residue Profile**

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. Number range CHAPTERImidacloprid
(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 ^14^C-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.

[]{#__RefHeading___Toc165171396 .anchor}**5.1.10 International Residue
Limits**

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.

[]{#__RefHeading___Toc165171397 .anchor}**5.2 Dietary Exposure and
Risk**

[Acute Dietary Exposure Results and Characterization]{.underline}: 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 95^th^ 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.

[]{.mark}

[Chronic Dietary Exposure Results and Characterization]{.underline}: 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        | **Acute       |          | **Chronic  |       |
| Subgroup**          | Dietary^1^**  |          | Di         |       |
|                     |               |          | etary^2^** |       |
|                     | **(95^th^     |          |            |       |
|                     | Percentile)** |          |            |       |
+---------------------+---------------+----------+------------+-------+
|                     | **Dietary     | **%      | **Dietary  | **%   |
|                     | Exposure      | aPAD**   | Exposure** | c     |
|                     | (mg/kg/day)** |          |            | PAD** |
|                     |               |          | **(mg      |       |
|                     |               |          | /kg/day)** |       |
+---------------------+---------------+----------+------------+-------+
| General U.S.        | 0.038846      | 28       | 0.007496   | 13    |
| Population          |               |          |            |       |
+---------------------+---------------+----------+------------+-------+
| All Infants (\< 1   | 0.078728      | 56       | 0.016053   | 28    |
| year old)           |               |          |            |       |
+---------------------+---------------+----------+------------+-------+
| Children 1-2 years  | **0.097610**  | **70**   | **         | *     |
| old                 |               |          | 0.021691** | *38** |
+---------------------+---------------+----------+------------+-------+
| Children 3-5 years  | 0.072724      | 52       | 0.016308   | 29    |
| old                 |               |          |            |       |
+---------------------+---------------+----------+------------+-------+
| Children 6-12 years | 0.046085      | 33       | 0.010058   | 18    |
| old                 |               |          |            |       |
+---------------------+---------------+----------+------------+-------+
| Youth 13-19 years   | 0.029242      | 21       | 0.005972   | 11    |
| old                 |               |          |            |       |
+---------------------+---------------+----------+------------+-------+
| Adults 20-49 years  | 0.026366      | 19       | 0.005890   | 10    |
| old                 |               |          |            |       |
+---------------------+---------------+----------+------------+-------+
| Adults 50+ years    | 0.025495      | 18       | 0.006015   | 11    |
| old                 |               |          |            |       |
+---------------------+---------------+----------+------------+-------+
| Females 13-49 years | 0.026219      | 19       | 0.005652   | 10    |
| old                 |               |          |            |       |
+---------------------+---------------+----------+------------+-------+
| 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.          |               |          |            |       |
+---------------------+---------------+----------+------------+-------+

[]{#__RefHeading___Toc165171398 .anchor}**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                                    
  Imidacloprid^1^**                                       

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

  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).

[]{#__RefHeading___Toc165171399 .anchor}**6.0 Residential
(Non-Occupational) Exposure/Risk Characterization**

[]{#__RefHeading___Toc165171400 .anchor}**6.1 Residential Handler
Exposure**

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]{.underline} (*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**    | **Form    | **Appli  | **Number | **Comments**        |
|             | ulation** | cation** | of**     |                     |
|             |           |          |          |                     |
|             |           | **Rate** | **Applic |                     |
|             |           |          | ations** |                     |
+-------------+-----------+----------+----------+---------------------+
| Lawns &     | Granular  | 0.4 lb   | 1/yr     | applied with        |
| Turf        |           | ai/A     |          | broadcast by        |
|             | 0.62 %    |          |          | push-type "drop" or |
| Ornamental  |           |          |          | rotary spreader     |
| Plantings   |           |          |          |                     |
+-------------+-----------+----------+----------+---------------------+
| flowers,    | Ready-to  | "spray   | "as      |                     |
| ground      | Use Pump  | till     | needed"  |                     |
| covers      | Sprayer   | point of |          |                     |
|             | 0.012 %   | run-off" | 7 - 14   |                     |
| shrubs,     |           |          | day      |                     |
| house       | 24 fl.oz. |          | i        |                     |
| plants      |           |          | ntervals |                     |
+-------------+-----------+----------+----------+---------------------+
| Indoor &    | Plant     | one      | eff      | formulation         |
| Outdoor     | "spikes"  | package  | icacious | contains fertilizer |
| Residential |           | will     | for 8    | and Bitrex. Not for |
| Potted      | 0.8 oz    | treat    | weeks    | use on edible       |
| Plants      | (20 g)    | 4-5      |          | plants/herbs etc.   |
|             |           | eight    |          |                     |
|             | 10 two    | inch     |          |                     |
|             | gram      | pots     |          |                     |
|             | spikes    |          |          |                     |
|             |           |          |          |                     |
|             | 2.5 %     |          |          |                     |
+-------------+-----------+----------+----------+---------------------+
| Potting     | 0.015 %   |          | eff      | Used as medium for  |
| medium for  | ready to  |          | icacious | new seedlings or as |
| indoor or   | use       |          | 4 months | additional medium   |
| outdoor     | potting   |          |          | when transplanting  |
| plant       | medium -  |          |          | to larger           |
| containers  | largest   |          |          | containers. Label   |
|             | container |          |          | directs use of      |
|             | 19 lb 3   |          |          | rubber gloves.      |
|             | oz        |          |          | Medium contains     |
|             |           |          |          | sphagnum, bark,     |
|             |           |          |          | perlite,            |
|             |           |          |          | vermiculite,        |
|             |           |          |          | limestone and       |
|             |           |          |          | fertilzers          |
+-------------+-----------+----------+----------+---------------------+
| Lawns,      | liquid    | 0.001098 | "repeat  | For use on          |
| trees,      | co        | lb       | if       | out-door, non-food  |
| shrubs,     | ncentrate | ai/5000  | needed"  | residential plants  |
| flowers     |           | ft^2^    | in       |                     |
|             | 0.70 % 32 |          |          | Assumed applied via |
|             | fl oz     |          | 7 - 14   | compressed air or   |
|             |           |          | days     | garden hose-end     |
|             |           |          |          | sprayer             |
+-------------+-----------+----------+----------+---------------------+
| Trees &     | liquid    | depends  | 1/yr     | Applied to soil by  |
| Shrubs      | co        | on plant |          | pouring dilute from |
|             | ncentrate | stem     |          | a bucket or a       |
|             |           | size.    |          | watering can around |
|             | 2.95 %    | One      |          | bases of plant      |
|             | one       | gallon   |          | "stems"/trunks      |
|             | gallon =  | treats   |          |                     |
|             | largest   | 20       |          |                     |
|             | container | "medium" |          |                     |
|             | size      | trees or |          |                     |
|             |           |          |          |                     |
|             |           | 42       |          |                     |
|             |           | "        |          |                     |
|             |           | average" |          |                     |
|             |           | shrubs   |          |                     |
+-------------+-----------+----------+----------+---------------------+
| Cats & Dogs | ready to  | max rate | 1/mo if  | Packaged in         |
|             | use       | = 5.0 ml | needed   | "dropper" vials.    |
|             | liquid    |          |          | The end cap is      |
|             |           | for dogs |          | removed and one     |
|             | 9.1 %,    | \> 55 lb |          | half the contents   |
|             | max = 5   |          |          | dropped between the |
|             | ml for    |          |          | scapulae and one    |
|             | large     |          |          | half on the         |
|             | dogs \>   |          |          | lumbrosacral        |
|             | 55 lb     |          |          | 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/day~dermal~

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]{.underline}) 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 ft^2^ therefore

0.0000366 lb ai/fl oz \* 6 fl oz/1000 ft^2^ = 0.0002196 lb ai/1000
ft^2^. 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 ft^2^ \* 22,000 ft^2^/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 ft^2^ \* 22,000 ft^2^/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)]{.underline}

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**        | **MOE**   |
|                               |                          |           |
|                               | **mg ai/kg bw/day**      |           |
+-------------------------------+--------------------------+-----------+
| Granular/push-type spreader   | Dermal + inhalation      | 72,150    |
| application                   |                          |           |
|                               | 0.0000139                |           |
+-------------------------------+--------------------------+-----------+
| Ready to Use Trigger Pump     | negligible see hose end  |           |
| Spray                         | spray                    |           |
+-------------------------------+--------------------------+-----------+
| Potted Plant Spikes           | Dermal (inhalation       | 2,600     |
|                               | negligible)              |           |
|                               |                          |           |
|                               | 0.00392                  |           |
+-------------------------------+--------------------------+-----------+
| Plant Potting Medium          | Dermal (inhalation       | 1,000     |
|                               | negligible)              |           |
|                               |                          |           |
|                               | 0.01                     |           |
+-------------------------------+--------------------------+-----------+
| Garden Hose-end Spray         | Dermal + Inhalation      | 185,000   |
|                               |                          |           |
|                               | 0.0000541                |           |
+-------------------------------+--------------------------+-----------+
| Soil Drench - Water           | Dermal + Inhalation      | 14,000    |
| Can/Bucket                    |                          |           |
|                               | 0.0007                   |           |
+-------------------------------+--------------------------+-----------+
| Pet Spot-On                   | Dermal (inhalation       | 400       |
|                               | negligible)              |           |
|                               |                          |           |
|                               | 0.025                    |           |
+-------------------------------+--------------------------+-----------+

[]{#__RefHeading___Toc165171401 .anchor}**6.2. Residential
Post-application Exposure**

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)**   | *      | **       |
|                         |                       | *MOE** | COMBINED |
|                         | **mg ai/kg bw/day**   |        | MOE^1^** |
+-------------------------+-----------------------+--------+----------+
| Toddler oral hand to    | 0.0059                | 1,700  | 1,500    |
| mouth from contacting   |                       |        |          |
| treated turf            |                       |        |          |
+-------------------------+-----------------------+--------+----------+
| Toddler oral -          | 0.12                  | 350    | N/A      |
| ingestion of granules   |                       |        |          |
+-------------------------+-----------------------+--------+----------+
| Toddler incidental oral | 0.02                  | 5      | N/A      |
| ingestion of treated    |                       | 00,000 |          |
| soil                    |                       |        |          |
+-------------------------+-----------------------+--------+----------+
| Toddler incidental oral | 10 min hand wipe data | 3,600  | 255      |
| from contacting treated | = 0.11                |        |          |
| pet                     |                       | 5,200  | 261      |
|                         | 1 hr hand wipe data = |        |          |
|                         | 0.08                  | 23,000 | 271      |
|                         |                       |        |          |
|                         | 12 hr hand wipe data  | 33,000 | 272      |
|                         | = 0.017               |        |          |
|                         |                       |        |          |
|                         | 24 hr hand wipe data  |        |          |
|                         | = 0.012               |        |          |
+-------------------------+-----------------------+--------+----------+
| Toddler dermal - pet    | 0.036                 | 275    | See pet  |
| "hug"/contacting        |                       |        | in       |
| treated pet             |                       |        | cidental |
|                         |                       |        | oral     |
+-------------------------+-----------------------+--------+----------+
| Adult dermal post       | 0.00053               | 19,000 | N/A      |
| applic turf contact     |                       |        |          |
+-------------------------+-----------------------+--------+----------+
| Adult combined dermal   | 0.0000162             | 72150  | 1        |
| exposure =              |                       |        | 5,000^2^ |
| application +           | 0.00053               | 19,000 |          |
| post-application        |                       |        |          |
+-------------------------+-----------------------+--------+----------+
| Toddler dermal post     | 0.001                 | 10,000 | See hand |
| applic turf contact     |                       |        | to mouth |
|                         |                       |        | turf     |
+-------------------------+-----------------------+--------+----------+
| Adult golfer post app   | 0.00016               | 62,500 | N/A      |
| turf contact            |                       |        |          |
+-------------------------+-----------------------+--------+----------+
| Child golfer post app   | 0.000272              | 37,000 | N/A      |
| turf contact            |                       |        |          |
+-------------------------+-----------------------+--------+----------+

^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 cm^2^ for the SR value (2.47E-8 acre/cm^2^ )
>
> CF4 = volume to weight unit conversion factor to convert the volume
> units (cm^3^) to weight units for the SR value (0.67 cm^3^/g soil)

Therefore 0.4 lb ai/A \* 1.0/cm \* (1-0)^0^ \* 4.54 x 10^8^ µg/lb \*
2.47 x 10^-8^ A/cm^2^ \* 0.67 cm^3^/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)]{.underline}

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\*F~AR~)/SA~pet~) \* (1 - DR)^t^ \* SA~hug~ \* (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);
>
> F~AR~ = fraction of the application rate available for dermal contact
> as transferable residue (20%)
>
> SA~pet~ = surface area of a treated dog (5,986cm^2^/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 (1,875cm^2^ contact/hug).
>
> DA = Dermal absorption factor (7%)

In this case actual compound specific study data are used in place of
the expression (AR\*F~AR~) 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]{.underline} 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.

[]{#__RefHeading___Toc165171402 .anchor}**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   |                       |           |      |        |         |
| Exp   |                       |           |      |        |         |
| osure |                       |           |      |        |         |
| Pote  |                       |           |      |        |         |
| ntial |                       |           |      |        |         |
| for   |                       |           |      |        |         |
| Adult |                       |           |      |        |         |
| and   |                       |           |      |        |         |
| Child |                       |           |      |        |         |
| Short |                       |           |      |        |         |
| -term |                       |           |      |        |         |
| Aggr  |                       |           |      |        |         |
| egate |                       |           |      |        |         |
| Risk  |                       |           |      |        |         |
| E     |                       |           |      |        |         |
| stima |                       |           |      |        |         |
| tes** |                       |           |      |        |         |
+=======+=======================+===========+======+========+=========+
| **Exp |                       | *         | **M  | **Co   | **C     |
| osure |                       | *Exposure | OE** | mbined | OMBINED |
| Scena |                       | (Dose)**  |      | Ex     | M       |
| rio** |                       |           |      | posure | OE**^1^ |
|       |                       | **mg      |      | (D     |         |
|       |                       | ai/kg     |      | ose)** |         |
|       |                       | bw/day**  |      |        |         |
|       |                       |           |      | **mg   |         |
|       |                       |           |      | ai/kg  |         |
|       |                       |           |      | bw     |         |
|       |                       |           |      | /day** |         |
+-------+-----------------------+-----------+------+--------+---------+
| Todd  | Oral hand-to-mouth    | 0.0059    | 1    | 0      | 1,500   |
| ler - | post-application      |           | ,700 | .00692 |         |
| Tr    | exposure from         |           |      |        |         |
| eated | contacting treated    |           |      |        |         |
| Turf  | turf                  |           |      |        |         |
+-------+-----------------------+-----------+------+--------+---------+
|       | Incidental oral       | 0.00002   | 500  |        |         |
|       | post-application      |           | ,000 |        |         |
|       | exposure from         |           |      |        |         |
|       | ingestion of treated  |           |      |        |         |
|       | soil                  |           |      |        |         |
+-------+-----------------------+-----------+------+--------+---------+
|       | Dermal                | 0.001     | 10   |        |         |
|       | post-application      |           | ,000 |        |         |
|       | exposure from         |           |      |        |         |
|       | contacting turf       |           |      |        |         |
+-------+-----------------------+-----------+------+--------+---------+
| Todd  | Incidental oral       | 0.00276   | 3    | 0      | 260     |
| ler - | post-application      |           | ,600 | .03876 |         |
| Tr    | exposure from         |           |      |        |         |
| eated | contacting treated    |           |      |        |         |
| Pet   | pet                   |           |      |        |         |
+-------+-----------------------+-----------+------+--------+---------+
|       | Dermal                | 0.036     | 280  |        |         |
|       | post-application      |           |      |        |         |
|       | exposure from pet     |           |      |        |         |
|       | "hug"/ contacting     |           |      |        |         |
|       | treated pet           |           |      |        |         |
+-------+-----------------------+-----------+------+--------+---------+
| Ad    | Handler dermal and    | 0.0000139 | 72   | 0.     | 15,000  |
| ult - | inhalation exposure   |           | ,000 | 000669 |         |
| Tr    | from applying         |           |      |        |         |
| eated | imidacloprid using    |           |      |        |         |
| Turf  | granular/push-type    |           |      |        |         |
|       | spreader              |           |      |        |         |
+-------+-----------------------+-----------+------+--------+---------+
|       | Dermal                | 0.00053   | 19   |        |         |
|       | post-application      |           | ,000 |        |         |
|       | exposure from         |           |      |        |         |
|       | contacting treated    |           |      |        |         |
|       | turf                  |           |      |        |         |
+-------+-----------------------+-----------+------+--------+---------+
| Ad    | Handler dermal and    | 0.025     | 400  |        |         |
| ult - | inhalation exposure   |           | ^2^  |        |         |
| Tr    | from applying         |           |      |        |         |
| eated | imidacloprid to pet   |           |      |        |         |
| Pet   | with pet spot-on      |           |      |        |         |
+-------+-----------------------+-----------+------+--------+---------+
|       | 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).

[]{#__RefHeading___Toc165171403 .anchor}**6.4 Other (Spray Drift,
etc.)**

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.

**Number range CHAPTER**[]{#__RefHeading___Toc165171404 .anchor}**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.

Number range CHAPTER

[]{#__RefHeading___Toc165171405 .anchor}**7.1 Acute Aggregate Risk**

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.

[]{#__RefHeading___Toc165171406 .anchor}**7.2 Short-Term Aggregate
Risk**

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    |       |        |         |           |         |           |
| Shor   |       |        |         |           |         |           |
| t-Term |       |        |         |           |         |           |
| Agg    |       |        |         |           |         |           |
| regate |       |        |         |           |         |           |
| Risk   |       |        |         |           |         |           |
| Calcul |       |        |         |           |         |           |
| ations |       |        |         |           |         |           |
| for    |       |        |         |           |         |           |
| Imi    |       |        |         |           |         |           |
| daclop |       |        |         |           |         |           |
| rid.** |       |        |         |           |         |           |
+--------+-------+--------+---------+-----------+---------+-----------+
| Popu   | Short |        |         |           |         |           |
| lation | -Term |        |         |           |         |           |
|        | Sce   |        |         |           |         |           |
| Sub    | nario |        |         |           |         |           |
| groups |       |        |         |           |         |           |
+--------+-------+--------+---------+-----------+---------+-----------+
|        | NOAEL | Level  | Max     | Average   | Resi    | Aggregate |
|        |       | of     | Expo    | Dietary   | dential | MOE       |
|        | (     | Conc   | sure^2^ | Exposure  | Expo    |           |
|        | mg/kg | ern^1^ |         |           | sure^3^ | (dietary  |
|        | /day) |        | (mg/    | (m        |         | and       |
|        |       |        | kg/day) | g/kg/day) | (mg/    | reside    |
|        |       |        |         |           | kg/day) | ntial)^4^ |
+--------+-------+--------+---------+-----------+---------+-----------+
| US     | 10    | 100    | 0.1     | 0.007496  | 0.025   | 310       |
| Popu   |       |        |         |           |         |           |
| lation |       |        |         |           |         |           |
+--------+-------+--------+---------+-----------+---------+-----------+
| Ch     | 10    | 100    | 0.1     | 0.021691  | 0.03876 | 170       |
| ildren |       |        |         |           |         |           |
| 1-2    |       |        |         |           |         |           |
| years  |       |        |         |           |         |           |
| old    |       |        |         |           |         |           |
+--------+-------+--------+---------+-----------+---------+-----------+
| ^1^    |       |        |         |           |         |           |
| The    |       |        |         |           |         |           |
| level  |       |        |         |           |         |           |
| of     |       |        |         |           |         |           |
| c      |       |        |         |           |         |           |
| oncern |       |        |         |           |         |           |
| (      |       |        |         |           |         |           |
| target |       |        |         |           |         |           |
| MOE)   |       |        |         |           |         |           |
| in     |       |        |         |           |         |           |
| cludes |       |        |         |           |         |           |
| 10X    |       |        |         |           |         |           |
| for    |       |        |         |           |         |           |
| inters |       |        |         |           |         |           |
| pecies |       |        |         |           |         |           |
| e      |       |        |         |           |         |           |
| xtrapo |       |        |         |           |         |           |
| lation |       |        |         |           |         |           |
| and    |       |        |         |           |         |           |
| 10X    |       |        |         |           |         |           |
| for    |       |        |         |           |         |           |
| intras |       |        |         |           |         |           |
| pecies |       |        |         |           |         |           |
| vari   |       |        |         |           |         |           |
| ation. |       |        |         |           |         |           |
|        |       |        |         |           |         |           |
| ^2^    |       |        |         |           |         |           |
| M      |       |        |         |           |         |           |
| aximum |       |        |         |           |         |           |
| Ex     |       |        |         |           |         |           |
| posure |       |        |         |           |         |           |
| (mg/k  |       |        |         |           |         |           |
| g/day) |       |        |         |           |         |           |
| =      |       |        |         |           |         |           |
| NOAEL/ |       |        |         |           |         |           |
| Target |       |        |         |           |         |           |
| MOE    |       |        |         |           |         |           |
|        |       |        |         |           |         |           |
| ^3^    |       |        |         |           |         |           |
| Resid  |       |        |         |           |         |           |
| ential |       |        |         |           |         |           |
| Ex     |       |        |         |           |         |           |
| posure |       |        |         |           |         |           |
| =      |       |        |         |           |         |           |
| \[Oral |       |        |         |           |         |           |
| expo   |       |        |         |           |         |           |
| sure + |       |        |         |           |         |           |
| Dermal |       |        |         |           |         |           |
| expo   |       |        |         |           |         |           |
| sure + |       |        |         |           |         |           |
| Inha   |       |        |         |           |         |           |
| lation |       |        |         |           |         |           |
| Expos  |       |        |         |           |         |           |
| ure\]. |       |        |         |           |         |           |
| The    |       |        |         |           |         |           |
| p      |       |        |         |           |         |           |
| et-tre |       |        |         |           |         |           |
| atment |       |        |         |           |         |           |
| sc     |       |        |         |           |         |           |
| enario |       |        |         |           |         |           |
| re     |       |        |         |           |         |           |
| sulted |       |        |         |           |         |           |
| in the |       |        |         |           |         |           |
| lowest |       |        |         |           |         |           |
| co     |       |        |         |           |         |           |
| mbined |       |        |         |           |         |           |
| resid  |       |        |         |           |         |           |
| ential |       |        |         |           |         |           |
| MOE    |       |        |         |           |         |           |
| for    |       |        |         |           |         |           |
| adults |       |        |         |           |         |           |
| (h     |       |        |         |           |         |           |
| andler |       |        |         |           |         |           |
| and    |       |        |         |           |         |           |
| post-  |       |        |         |           |         |           |
| applic |       |        |         |           |         |           |
| ation) |       |        |         |           |         |           |
| and    |       |        |         |           |         |           |
| ch     |       |        |         |           |         |           |
| ildren |       |        |         |           |         |           |
| (      |       |        |         |           |         |           |
| post-a |       |        |         |           |         |           |
| pplica |       |        |         |           |         |           |
| tion). |       |        |         |           |         |           |
| The    |       |        |         |           |         |           |
| co     |       |        |         |           |         |           |
| mbined |       |        |         |           |         |           |
| MOEs   |       |        |         |           |         |           |
| for    |       |        |         |           |         |           |
| the    |       |        |         |           |         |           |
| p      |       |        |         |           |         |           |
| et-use |       |        |         |           |         |           |
| sc     |       |        |         |           |         |           |
| enario |       |        |         |           |         |           |
| were   |       |        |         |           |         |           |
| used   |       |        |         |           |         |           |
| to     |       |        |         |           |         |           |
| cal    |       |        |         |           |         |           |
| culate |       |        |         |           |         |           |
| the    |       |        |         |           |         |           |
| shor   |       |        |         |           |         |           |
| t-term |       |        |         |           |         |           |
| risk   |       |        |         |           |         |           |
| \[see  |       |        |         |           |         |           |
| Table  |       |        |         |           |         |           |
| 11 of  |       |        |         |           |         |           |
| HED    |       |        |         |           |         |           |
| human  |       |        |         |           |         |           |
| health |       |        |         |           |         |           |
| risk   |       |        |         |           |         |           |
| asse   |       |        |         |           |         |           |
| ssment |       |        |         |           |         |           |
| dated  |       |        |         |           |         |           |
| 3/4/03 |       |        |         |           |         |           |
| (Memo, |       |        |         |           |         |           |
| J.     |       |        |         |           |         |           |
| Tyler  |       |        |         |           |         |           |
| *et    |       |        |         |           |         |           |
| al.*;  |       |        |         |           |         |           |
| D2861  |       |        |         |           |         |           |
| 01)\]. |       |        |         |           |         |           |
|        |       |        |         |           |         |           |
| ^4^    |       |        |         |           |         |           |
| Agg    |       |        |         |           |         |           |
| regate |       |        |         |           |         |           |
| MOE =  |       |        |         |           |         |           |
| \      |       |        |         |           |         |           |
| [NOAEL |       |        |         |           |         |           |
| ÷ (Avg |       |        |         |           |         |           |
| D      |       |        |         |           |         |           |
| ietary |       |        |         |           |         |           |
| Expo   |       |        |         |           |         |           |
| sure + |       |        |         |           |         |           |
| Resid  |       |        |         |           |         |           |
| ential |       |        |         |           |         |           |
| Expos  |       |        |         |           |         |           |
| ure)\] |       |        |         |           |         |           |
+--------+-------+--------+---------+-----------+---------+-----------+

[]{#__RefHeading___Toc165171407 .anchor}**7.3 Intermediate-Term
Aggregate Risk**

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

[]{#__RefHeading___Toc165171408 .anchor}**7.4 Long-Term Aggregate Risk**

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**

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

[]{#__RefHeading___Toc165171409 .anchor}**8Number range CHAPTER.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
[[http://www.epa.gov/pesticides/cumulative/.]{.underline}](http://www.epa.gov/pesticides/cumulative/.)

[]{#__RefHeading___Toc165171410 .anchor}**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**            | **          | **     | **Appli  | **A    |
|                        | Application | Prehar | cation** | pplica |
|                        | Rate lb     | vest** |          | tion** |
|                        | ai/A**      |        | **       |        |
|                        |             | **Inte | Method** | **Inte |
|                        |             | rval** |          | rval** |
+------------------------+-------------+--------+----------+--------+
| Admire^®^ 2 Flowable   | 0.25 - 0.5  | 7 days | che      | NA     |
| Insecticide; Reg. No.  |             |        | migation |        |
| 264-758; 2.0 lb ai/gal | (maximum    |        | or       |        |
| liquid flowable        | 0.5 lb      |        |          |        |
|                        | a           |        | basal    |        |
|                        | i/A/season) |        | soil     |        |
|                        |             |        | drench   |        |
+------------------------+-------------+--------+----------+--------+
| Gaucho^®^ 550 SC       | 0.25-0.5    | 7 days | che      | NA     |
| Insecticide; Reg. No.  |             |        | migation |        |
| 264-827; 4.6 lb ai/gal | (maximum    |        | or basal |        |
| soluble concentrate    | 0.5 lb      |        | soil     |        |
| liquid                 | a           |        | drench   |        |
|                        | i/A/season) |        |          |        |
+------------------------+-------------+--------+----------+--------+
| Provado^®^ Pro         | 0.1         | 3 days | foliar   | 7 days |
| Insecticide; Reg. No.  |             |        |          |        |
| 264-858; 1.6 lb ai/gal | (maximum    |        |          |        |
| liquid                 | 0.3 lb      |        |          |        |
|                        | a           |        |          |        |
|                        | i/A/season) |        |          |        |
+------------------------+-------------+--------+----------+--------+
| Provado^®^ 70 WG       | 0.1         | 3 days | foliar   | 7 days |
| Insecticide; Reg. No.  |             |        |          |        |
| 264-823; 70 % ai water | (maximum    |        |          |        |
| dispersible granule    | 0.3 lb      |        |          |        |
|                        | a           |        |          |        |
|                        | i/A/season) |        |          |        |
+------------------------+-------------+--------+----------+--------+
| Provado^®^ 1.6         | 0.1         | 3 days | foliar   | 7 days |
| Flowable Insecticide;  |             |        |          |        |
| Reg. No. 264-763; 1.6  | (maximum    |        |          |        |
| lb ai/gal flowable     | 0.3 lb      |        |          |        |
| liquid                 | a           |        |          |        |
|                        | i/A/season) |        |          |        |
+------------------------+-------------+--------+----------+--------+

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).

[]{#__RefHeading___Toc165171411 .anchor}**9.1
Short-/Intermediate-/Long-Term Handler Risk**

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           |   | Applic.  | Units     | Average Daily | CO  |     |
| Exposure^1^    |   | Rate^2^  | T         |               | MBI |     |
|                |   |          | reated^3^ | Dose^4^       | NED |     |
| mg ai/lb       |   |          |           |               |     |     |
| handled        |   |          | Per Day   | mg ai/kg      | MOE |     |
|                |   |          |           | bw/day        | ^5^ |     |
+----------------+---+----------+-----------+---------------+-----+-----+
|                |   |          |           |               | ST  | IT  |
+----------------+---+----------+-----------+---------------+-----+-----+
| Mixer/Loader - |   |          |           |               |     |     |
| Liquid - Open  |   |          |           |               |     |     |
| Pour           |   |          |           |               |     |     |
+----------------+---+----------+-----------+---------------+-----+-----+
| Dermal:        |   | 0.5 lb   | 350 A     | Dermal:       | NG  | NG  |
|                |   | ai/A     |           |               |     |     |
| SLNG 2.9 HC    |   |          |           | No Gloves     | 20  | 18  |
|                |   |          |           | 0.51          |     |     |
| SLWG 0.023 HC  |   |          |           |               | WG  | WG  |
|                |   |          |           | With Gloves   |     |     |
| Inhal 0.0012   |   |          |           | 0.004         | 1   | 1   |
| HC             |   |          |           |               | 400 | 300 |
|                |   |          |           | Inhal 0.003   |     |     |
+----------------+---+----------+-----------+---------------+-----+-----+
| Mixer/Loader - |   |          |           |               |     |     |
| Open Pour -    |   |          |           |               |     |     |
| Granules       |   |          |           |               |     |     |
+----------------+---+----------+-----------+---------------+-----+-----+
| Dermal:        |   | 0.1 lb   | 350 A     | Dermal:       | NG  | NG  |
|                |   | ai/A     |           |               |     |     |
| SLNG 0.0084 LC |   |          |           | No Gloves     | 8   | 8   |
|                |   |          |           | 0.00029       | 800 | 200 |
| SLWG 0.0069 MC |   |          |           |               |     |     |
|                |   |          |           | With Gloves   | WG  | WG  |
| Inhal 0.0017   |   |          |           | 0.00024       |     |     |
| HC             |   |          |           |               | 9   | 8   |
|                |   |          |           | Inhal 0.00085 | 200 | 500 |
+----------------+---+----------+-----------+---------------+-----+-----+
| Applicator -   |   |          |           |               |     |     |
| Aerial (Pilots |   |          |           |               |     |     |
| not required   |   |          |           |               |     |     |
| to wear        |   |          |           |               |     |     |
| protective     |   |          |           |               |     |     |
| gloves)        |   |          |           |               |     |     |
+----------------+---+----------+-----------+---------------+-----+-----+
| Dermal:        |   | 0.5 lb   | 350       | Dermal:       | NG  | NG  |
|                |   | ai/A     |           |               |     |     |
| SLNG 0.005 HC  |   |          |           | No Gloves     | 9   | 8   |
|                |   |          |           | 0.00088       | 500 | 900 |
| Inhal 0.000068 |   |          |           |               |     |     |
| MC             |   |          |           | Inhal 0.00017 |     |     |
+----------------+---+----------+-----------+---------------+-----+-----+
| Applicator -   |   |          |           |               |     |     |
| Ground-boom -  |   |          |           |               |     |     |
| Open-cab       |   |          |           |               |     |     |
+----------------+---+----------+-----------+---------------+-----+-----+
| Dermal:        | 0 |          | 80 A      | Dermal:       | NG  | NG  |
|                | \ |          |           |               |     |     |
| SLNG 0.014 HC  | . |          |           | NG 0.00056    | 10, | 9   |
|                | 5 |          |           |               | 000 | 500 |
| SLWG 0.014 MC  | l |          |           | WG 0.00056    |     |     |
|                | b |          |           |               | WG  | WG  |
| Inhal 0.00074  | a |          |           | Inhal 0.00042 |     |     |
| HC             | i |          |           |               | 10  | 9   |
|                | / |          |           |               | 000 | 500 |
|                | A |          |           |               |     |     |
+----------------+---+----------+-----------+---------------+-----+-----+
| Applicator -   |   |          |           |               |     |     |
| Air-blast -    |   |          |           |               |     |     |
| Open Cab       |   |          |           |               |     |     |
+----------------+---+----------+-----------+---------------+-----+-----+
| Dermal:        |   | 0.5 lb   | 40 A      | Dermal:       | NG  | NG  |
|                |   | ai/A     |           |               |     |     |
| SLNG 0.36 HC   |   |          |           | No Gloves     | 1   | 1   |
|                |   |          |           | 0.0072        | 200 | 100 |
| SLWG 0.24 HC   |   |          |           |               |     |     |
|                |   |          |           | With Gloves   | WG  | WG  |
| Inhal 0.0045   |   |          |           | 0.0048        |     |     |
| HC             |   |          |           |               | 1   | 1   |
|                |   |          |           | Inhal 0.0013  | 600 | 500 |
+----------------+---+----------+-----------+---------------+-----+-----+
| Mix/Loa        |   |          |           |               |     |     |
| d/Applicator - |   |          |           |               |     |     |
| High Pressure  |   |          |           |               |     |     |
| Hand-wand      |   |          |           |               |     |     |
+----------------+---+----------+-----------+---------------+-----+-----+
| Dermal         |   | 0.5 lb   | 20 A      | Dermal:       | NG  | NG  |
|                |   | ai/A     |           |               |     |     |
| SLNG no data   |   |          |           | No Gloves no  | no  | no  |
|                |   |          |           | data          | d   | d   |
| SLWG 2.5 LC    |   |          |           |               | ata | ata |
|                |   |          |           | Wit Gloves    |     |     |
| Inhal 0.12 LC  |   |          |           | 0.025         | WG  | WG  |
|                |   |          |           |               |     |     |
|                |   |          |           | Inhal 0.017   | 240 | 220 |
+----------------+---+----------+-----------+---------------+-----+-----+
| Mixer/Loade    |   |          |           |               |     |     |
| r/Applicator - |   |          |           |               |     |     |
| Backpack -     |   |          |           |               |     |     |
| Liquid - Open  |   |          |           |               |     |     |
| Pour           |   |          |           |               |     |     |
+----------------+---+----------+-----------+---------------+-----+-----+
| Dermal:        |   | 0.5 lb   | 1 A       | Dermal:       | NG  | NG  |
|                |   | ai/A     |           |               |     |     |
| SLNG no data   |   |          |           | No Gloves -   | no  | no  |
|                |   |          |           | no data       | d   | d   |
| SLWG 2.5 LC    |   |          |           |               | ata | ata |
|                |   |          |           | With Gloves   |     |     |
| Inhal 0.03 LC  |   |          |           | 0.0013        | WG  | WG  |
|                |   |          |           |               |     |     |
|                |   |          |           | Inhal 0.00021 | 6   | 6   |
|                |   |          |           |               | 600 | 200 |
+----------------+---+----------+-----------+---------------+-----+-----+

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.

[]{#__RefHeading___Toc165171412 .anchor}**9.2
Short-/Intermediate-/Long-Term Post-application Risk**

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 cm^2^/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.

PDR~t~ = DFR~t~ \* CF1 \* Tc \* ET where:

PDR~t~ = potential dose rate on day "t" (mg/day)

DFR~t~ = dislodgeable foliar residue on day "t" (µg/cm^2^)

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 (cm^2^/hr) (In this case 1,100 cm^2^/hr;
ExpoSAC Policy 003.1 Rev. 7 Aug. 2000; amended 7 August 2003 ExpoSAC
meeting Notes).

ET = Exposure Time (hrs) (8)

and

DFR~t~ = 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
(ft^2^) in the application rate to cm^2^ for the DFR value (1.08E-3
ft^2^/cm^2^ or 2.47E-8 acre/cm^2^ 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/cm^2^ = 1.121 µg/cm^2^

PDR = 1.121 µg/cm^2^ \* 0.001 mg/µg \* 1,100 cm^2^/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.

[]{#__RefHeading___Toc165171413 .anchor}**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.

[]{#__RefHeading___Toc165171414 .anchor}**10.0 Data Needs and Label
Requirements**

[]{#__RefHeading___Toc165171415 .anchor}**10.1 Toxicology**

None.

[]{#__RefHeading___Toc165171416 .anchor}**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.

[]{#__RefHeading___Toc165171417 .anchor}**10.3 Occupational and
Residential Exposure**

None.

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

[]{#__RefHeading___Toc165171418 .anchor}**Attachment 1:**
**Toxicological Effects Tables**

+--------+----------------+----------+-----------------+--------------+
| *      |                |          |                 |              |
| *Table |                |          |                 |              |
| A.1    |                |          |                 |              |
| Acute  |                |          |                 |              |
| To     |                |          |                 |              |
| xicity |                |          |                 |              |
| of     |                |          |                 |              |
| Im     |                |          |                 |              |
| idaclo |                |          |                 |              |
| prid** |                |          |                 |              |
+--------+----------------+----------+-----------------+--------------+
| Gui    | Study Type     | MRID     | Results         | Toxicity     |
| deline |                | #(s)     |                 | Category     |
|        |                |          |                 |              |
| No.    |                |          |                 |              |
+--------+----------------+----------+-----------------+--------------+
| 81-1   | Acute Oral     | 42055331 | LD~50~ = 424    | II           |
|        |                |          | mg/kg (M)       |              |
|        |                |          |                 |              |
|        |                |          | LD~50~ \> 450   |              |
|        |                |          | mg/kg (F)       |              |
+--------+----------------+----------+-----------------+--------------+
| 81-2   | Acute Dermal   | 42055332 | LD~50~ \> 5000  | IV           |
|        |                |          | mg/kg           |              |
+--------+----------------+----------+-----------------+--------------+
| 81-3   | Acute          | 42256317 | LC~50~ \> 5.33  | IV           |
|        | Inhalation     |          | m/L             |              |
+--------+----------------+----------+-----------------+--------------+
| 81-4   | Primary Eye    | 42055334 | Not an eye      | IV           |
|        | Irritation     |          | irritant        |              |
+--------+----------------+----------+-----------------+--------------+
| 81-5   | Primary Skin   | 42055335 | Not a dermal    | IV           |
|        | Irritation     |          | irritant        |              |
+--------+----------------+----------+-----------------+--------------+
| 81-6   | Dermal         | 42055336 | Not a dermal    | N/A          |
|        | Sensitization  |          | sensitizer      |              |
+--------+----------------+----------+-----------------+--------------+

+------------------+-------------+-------------------------------------+
| **Table A.2      |             |                                     |
| Toxicity Profile |             |                                     |
| of Imidacloprid  |             |                                     |
| Technical.**     |             |                                     |
+==================+=============+=====================================+
| **Guideline No./ | **MRID No.  | **Results**                         |
| Study Type**     | (year)/     |                                     |
|                  | Cla         |                                     |
|                  | ssification |                                     |
|                  | /Doses**    |                                     |
+------------------+-------------+-------------------------------------+
| 870.3100         | NA          | NA                                  |
|                  |             |                                     |
| 90-Day oral      |             |                                     |
| toxicity rodents |             |                                     |
| (rats)           |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.3150         | NA          | NA                                  |
|                  |             |                                     |
| 90-Day oral      |             |                                     |
| toxicity         |             |                                     |
| (nonrodents)     |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.3200         | 42256329    | NOAEL = 1000 mg/kg/day (HDT)        |
|                  | (1990)      |                                     |
| 21/28-Day dermal |             | LOAEL = not identified              |
| toxicity         | Acceptabl   |                                     |
|                  | e/guideline |                                     |
| (rabbits)        |             |                                     |
|                  | 0 or 1000   |                                     |
|                  | mg/kg/day   |                                     |
|                  |             |                                     |
|                  | 6 hr/day, 5 |                                     |
|                  | d/week      |                                     |
+------------------+-------------+-------------------------------------+
| 870.3250         | NA          | NA                                  |
|                  |             |                                     |
| 90-Day dermal    |             |                                     |
| toxicity         |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.3465         | 42273001    | NOAEL = 0.191 mg/L/day (HDT)        |
|                  | (1989)      |                                     |
| 4-Week           | Acceptabl   | LOAEL = not identified              |
| inhalation       | e/guideline |                                     |
| toxicity         |             |                                     |
|                  | 0, 0.0055,  |                                     |
| (rat)            | 0.035, or   |                                     |
|                  | 0.191       |                                     |
|                  | mg/L/day, 6 |                                     |
|                  | hr/day,     |                                     |
|                  |             |                                     |
|                  | 5 d/week    |                                     |
|                  | for 4 weeks |                                     |
+------------------+-------------+-------------------------------------+
| 870.3700a        | 42256338    | **Maternal** NOAEL = 10 mg/kg/day   |
|                  | (1992)      |                                     |
| Prenatal         |             | LOAEL = 30 mg/kg/day based on       |
| developmental    | Acceptabl   | decreased body weight gain and      |
| toxicity (rats)  | e/guideline | decreased corrected body weight     |
|                  |             | gain.                               |
|                  | F: 0, 10,   |                                     |
|                  | 30, or 100  | **Developmental** NOAEL = 30        |
|                  | mg/kg/day   | mg/kg/day                           |
|                  |             |                                     |
|                  |             | LOAEL = 100 mg/kg/day based on a    |
|                  |             | slight increase in the incidence of |
|                  |             | wavy ribs.                          |
+------------------+-------------+-------------------------------------+
| 870.3700b        | 42256339    | **Maternal** NOAEL = 24 mg/kg/day   |
|                  | (1992)      |                                     |
| Prenatal         |             | LOAEL = 72 mg/kg/day based on       |
| developmental    | Acceptabl   | maternal deaths and decreased       |
| toxicity         | e/guideline | maternal absolute body weights,     |
| (rabbits)        |             | body weight gains, and food         |
|                  | F: 0, 8,    | consumption.                        |
|                  | 24, or 72   |                                     |
|                  | mg/kg/day   | **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         | 42256340    | **Parental/Systemic** NOAEL = 16.5  |
|                  | (1990)      | mg/kg/day                           |
| Reproduction and |             |                                     |
| fertility        | Acceptabl   | LOAEL = 47.3 mg/kg/day based on     |
| effects (rats)   | e/guideline | decreased premating weight gain by  |
|                  |             | F~0~ males and females and F~1~     |
|                  | 0, 100,     | females and decreased gestational   |
|                  | 250, or 700 | weight gain by F~1~ females.        |
|                  | ppm         |                                     |
|                  |             | **Reproductive** NOAEL = 47.3       |
|                  | F~0~ (M/F): | mg/kg/day (HDT)                     |
|                  | 0, 8.1/8.8, |                                     |
|                  | 20.1/22.1,  | LOAEL = not identified              |
|                  | or          |                                     |
|                  | 56.7/62.8   | **Offspring** NOAEL = 16.5          |
|                  | mg/kg/day   | mg/kg/day                           |
|                  |             |                                     |
|                  | F~1~ (M/F): | LOAEL = 47.3 mg/kg/day based on     |
|                  | 0, 6.4/7.2, | decreased pup body weights in both  |
|                  | 16.5/18.9,  | litters of both generations.        |
|                  | or          |                                     |
|                  | 47.3/52.3   |                                     |
|                  | mg/kg/day   |                                     |
+------------------+-------------+-------------------------------------+
| 870.4100a        | NA; see     | NA                                  |
|                  | 870.4300    |                                     |
| Chronic toxicity |             |                                     |
| (rodents)        |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.4100b        | 42273002    | NOAEL = 72 mg/kg/day (HDT)          |
|                  | (1989)      |                                     |
| Chronic toxicity |             | LOAEL = not identified              |
| (dogs)           | Acceptabl   |                                     |
|                  | e/guideline |                                     |
|                  |             |                                     |
|                  | 0, 200,     |                                     |
|                  | 500, or     |                                     |
|                  | 1250/2500   |                                     |
|                  | ppm         |                                     |
|                  |             |                                     |
|                  | M/F: 0,     |                                     |
|                  | 6.1, 15, or |                                     |
|                  | 41(first 16 |                                     |
|                  | wks.), then |                                     |
|                  | 72          |                                     |
|                  | mg/kg/day   |                                     |
+------------------+-------------+-------------------------------------+
| 870.4200a        | NA; see     | NA                                  |
|                  | 870.4300    |                                     |
| Carcinogenicity  |             |                                     |
| (rats)           |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.4200b        | 42256335    | NOAEL = Males: 208 mg/kg/day;       |
|                  | (1991)      | Females: 274 mg/kg/day              |
| Carcinogenicity  |             |                                     |
| (mice)           | Acceptabl   | LOAEL = Males: 414 mg/kg/day;       |
|                  | e/guideline | Females: 424 mg/kg/day based on     |
|                  | with        | decreased body weights, food        |
|                  | 42256336    | consumption and water intake.       |
|                  |             |                                     |
|                  | 0, 100,     | **No evidence of carcinogenicity.** |
|                  | 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   |                                     |
+------------------+-------------+-------------------------------------+
| 870.4300         | 42256331    | NOAEL = Males: 5.7 mg/kg/day;       |
|                  | (1989)      | Females: 7.6 mg/kg/day              |
| Combined         |             |                                     |
| Chronic          | Acceptabl   | LOAEL = Males: 16.9 mg/kg/day;      |
| /carcinogenicity | e/guideline | Females: 24.9 mg/kg/day based on    |
| (rats)           | with        | thyroid toxicity (increased         |
|                  | 42256332    | incidence of mineralized particles  |
|                  |             | in thyroid colloid) in males.       |
|                  | 0, 100,     |                                     |
|                  | 300, or 900 | **No evidence of carcinogenicity.** |
|                  | 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   |                                     |
+------------------+-------------+-------------------------------------+
| 870.5100         | 42256341    | Negative for inducing reverse       |
|                  |             | mutation in bacteria exposed to     |
| Bacterial        | Acceptabl   | doses up to 5000 ug/plate.          |
| reverse mutation | e/guideline |                                     |
+------------------+-------------+-------------------------------------+
| 870.5100         | 42256343    | Negative up to 12,500 ug/plate.     |
|                  |             |                                     |
| Bacterial        | Acceptabl   |                                     |
| reverse mutation | e/guideline |                                     |
+------------------+-------------+-------------------------------------+
| 870.5100         | 42256363    | Negative up to 5500 ug/plate.       |
|                  |             |                                     |
| Bacterial        | Acceptabl   |                                     |
| reverse mutation | e/guideline |                                     |
+------------------+-------------+-------------------------------------+
| 870.5300         | 42256342    | Negative for inducing forward       |
|                  |             | mutation in Chinese Hamster Ovary   |
| *In vitro*       | Acceptabl   | (CHO) (mammalian) cells treated up  |
| mammalian cell   | e/guideline | to 1222 ug/mL.                      |
| gene mutation    |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5300         | 42256364    | Negative up to 2000 ug/mL.          |
|                  |             |                                     |
| *In vitro*       | Acceptabl   |                                     |
| mammalian cell   | e/guideline |                                     |
| gene mutation    |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5300         | 42256365    | Negative up to 2000 ug/mL.          |
|                  |             |                                     |
| *In vitro*       | Acceptabl   |                                     |
| mammalian cell   | e/guideline |                                     |
| gene mutation    |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5375         | 42256345    | Positive at 500 ug/mL - S9 and      |
|                  |             |                                     |
| *In vitro*       | Acceptabl   | 1300 ug/mL +S9, both cytotoxic      |
| mammalian        | e/guideline | doses                               |
| chromosome       |             |                                     |
| abberation (HL)  |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5375         | 42256370    | Negative up to 1000 ug/mL.          |
|                  |             |                                     |
| *In vitro*       | Acceptabl   |                                     |
| mammalian        | e/guideline |                                     |
| chromosome       |             |                                     |
| abberation       |             |                                     |
| (CHV79)          |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5375         | 42256371    | Negative up to 1000 ug/mL.          |
|                  |             |                                     |
| *In vitro*       | Acceptabl   |                                     |
| mammalian        | e/guideline |                                     |
| chromosome       |             |                                     |
| abberation (CHO) |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5380         | 42256348    | Negative, but only tested up to 80  |
|                  |             | mg/ml.                              |
| Mammalian germ   | Unacceptabl |                                     |
| cell chromosome  | e/guideline |                                     |
| abberation       |             |                                     |
| (mouse)          |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5385         | 42256344    | Negative for chromosome breakage up |
|                  |             | to 2000 ug/mL.                      |
| Mammalian bone   | Acceptabl   |                                     |
| marrow           | e/guideline |                                     |
| chromosome       |             |                                     |
| aberration       |             |                                     |
| (chinese         |             |                                     |
| hamster)         |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5395         | 42256347    | Negative, but only tested up to 80  |
|                  |             | mg/kg.                              |
| Mammalian        | Unacceptabl |                                     |
| micronucleus     | e/guideline |                                     |
| (mouse)          |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5395         | 42256366    | Negative up to 50 mg/kg IP, toxic   |
|                  |             | dose.                               |
| Mammalian        | Acceptabl   |                                     |
| micronucleus     | e/guideline |                                     |
| (mouse)          |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5395         | 42256367    | Negative up to 80 mg/kg IP, a       |
|                  |             | non-toxic dose.                     |
| Mammalian        | Unacceptabl |                                     |
| micronucleus     | e/guideline |                                     |
| (mouse)          |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5395         | 42256368    | Negative up to 100 mg/kg PO, a      |
|                  |             | non-toxic dose.                     |
| Mammalian        | Unacceptabl |                                     |
| micronucleus     | e/guideline |                                     |
| (mouse)          |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5395         | 42256369    | Negative up to 160 mg/kg PO, toxic  |
|                  |             | dose.                               |
| Mammalian        | Acceptabl   |                                     |
| micronucleus     | e/guideline |                                     |
| (mouse)          |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5500         | 41156351    | Negative up to 5000 ug/disc, the    |
|                  |             | limit of solubility, with or        |
| DNA              | Acceptabl   | without activation.                 |
| damage/repair    | e/guideline |                                     |
| *REC* assay      |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5550         | 42256352    | Negative up to 750 ug/mL, a         |
|                  |             | cytotoxic dose.                     |
| Unscheduled DNA  | Acceptabl   |                                     |
| synthesis (RPH)  | e/guideline |                                     |
+------------------+-------------+-------------------------------------+
| 870.5575         | 42256353    | Negative for crossing-over in yeast |
|                  |             | cells exposed with/without          |
| Mitotic gene     | Acceptabl   | activation to precipitating levels  |
| conversion       | e/guideline | of test article (5,000-10,000       |
|                  |             | ug/mL).                             |
+------------------+-------------+-------------------------------------+
| 870.5550         | 42256372    | Negative up to cytotoxic doses      |
|                  |             | (1333 ug/mL).                       |
| Unscheduled DNA  | Acceptabl   |                                     |
| synthesis (RPH)  | e/guideline |                                     |
+------------------+-------------+-------------------------------------+
| 870.5900         | 42256349    | Positive at 500 ug/mL -S9 and 2000  |
|                  |             | ug/mL +S9, both cytotoxic doses.    |
| *In vitro*       | Acceptabl   |                                     |
| sister chromatid | e/guideline |                                     |
| exchange (CHO)   |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.5900         | 47256350    | Negative at cytotoxic doses of 400  |
|                  |             | ug/mL -S9 and 1250 ug/mL +S9.       |
| *In vitro*       | Acceptabl   |                                     |
| sister chromatid | e/guideline |                                     |
| exchange (CHO)   |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.59.15        | 42256346    | Negative up to 2000 mg/kg.          |
|                  |             |                                     |
| *In vivo* sister | Acceptabl   |                                     |
| chromatid        | e/guideline |                                     |
| exchange         |             |                                     |
| (chinese hamster |             |                                     |
| bone marrow)     |             |                                     |
+------------------+-------------+-------------------------------------+
| 870.6200a        | 43170301    | NOAEL = not identified.             |
|                  | (1994)      |                                     |
| Acute            |             | LOAEL = 42 mg/kg based on decreased |
| neurotoxicity    | 43285801    | motor and locomotor activities      |
| screening        | (1994)      | observed in females.                |
| battery          |             |                                     |
|                  | Acceptabl   |                                     |
| rat              | e/guideline |                                     |
|                  |             |                                     |
|                  | 0, 42, 151, |                                     |
|                  | or 307      |                                     |
|                  | mg/kg       |                                     |
+------------------+-------------+-------------------------------------+
| 870.6200b        | 43286401    | NOAEL = 9.3 mg/kg/day.              |
|                  | (1994)      |                                     |
| Subchronic       |             | LOAEL = 63.3 mg/kg/day based on     |
| neurotoxicity    | Minimum     | decreased body weight gain.         |
| screening        |             |                                     |
| battery          | 0, 150,     |                                     |
|                  | 1000, or    |                                     |
| rat              | 3000 ppm    |                                     |
|                  |             |                                     |
|                  | M: 0, 9.3,  |                                     |
|                  | 63.3, or    |                                     |
|                  | 196         |                                     |
|                  | mg/kg/day   |                                     |
|                  |             |                                     |
|                  | F: 0, 10.5, |                                     |
|                  | 69.3, or    |                                     |
|                  | 213         |                                     |
|                  | mg/kg/day   |                                     |
+------------------+-------------+-------------------------------------+
| 870.6300         | 45537501    | **Maternal** NOAEL = 20 mg/kg/day.  |
|                  | (2001)      |                                     |
| Developmental    |             | LOAEL = 55 mg/kg/day based on       |
| neurotoxicity    | Ac          | decreased food consumption and body |
|                  | ceptable/no | weight gain during lactation.       |
| (rat)            | n-guideline |                                     |
|                  |             | **Offspring** NOAEL = 20 mg/kg/day. |
|                  | 0, 100,     |                                     |
|                  | 250, or 750 | LOAEL = 55 mg/kg/day based on       |
|                  | ppm         | decreased body weight and body      |
|                  |             | weight gain, decreased motor        |
|                  | Gest.: 0,   | activity and decreased              |
|                  | 8.0-8.3,    | caudate/putamen width in females.   |
|                  | 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   |                                     |
+------------------+-------------+-------------------------------------+
| 870.7485         | 42256354    | Methylene-labeled imidacloprid was  |
|                  | (1990)      | rapidly absorbed with approximately |
| Metabolism and   |             | 90% of the administered dose being  |
| pharmacokinetics | 42256356    | eliminated within 24 hours and 96%  |
|                  | (1987)      | within 48 hours. There were no      |
| rat              |             | biologically significant            |
|                  | M&F: 1.0 or | differences between sexes, dose     |
|                  | 20.0 mg/kg  | levels, or route of administration. |
|                  | (labeled)   | Urinary excretion was the major     |
|                  | as single   | route of elimination (70-80% of     |
|                  | oral dose   | recovered radioactivity), with a    |
|                  | or          | lesser amount eliminated in feces   |
|                  |             | (17-25% of recovered                |
|                  | 1.0 mg/kg   | radioactivity). Biliary excretion   |
|                  | unlabeled   | was a major contributor to fecal    |
|                  | orally      | radioactivity (36.6% vs. 4.8% of    |
|                  | followed by | recovered radioactivity in          |
|                  | 1.0 mg/kg   | bile-fistulated animals). Total     |
|                  | single oral | tissue burden after 48 hours        |
|                  | dose        | accounted for only approximately    |
|                  | (labeled)   | 0.5% of the recovered               |
|                  | or          | radioactivity, with major sites of  |
|                  |             | accumulation being the liver,       |
|                  | 1.0 mg/kg   | kidney, lung, skin, and plasma and  |
|                  | (labeled)   | minor sites being the brain and     |
|                  | single dose | testes. Maximum plasma              |
|                  | IV          | concentration occurred between 1.1  |
|                  |             | and 2.5 hours, and elimination      |
|                  | M: 20.0     | half-lives (calculated from two     |
|                  | mg/kg       | exponential terms) were 3 and       |
|                  | single oral | 26-118 hours. There were two major  |
|                  | dose or 1.0 | evident routes of                   |
|                  | mg/kg       | biotransformation. The first        |
|                  | single      | included an oxidative cleavage of   |
|                  | duodenal    | the parent compound to give 6-CNA   |
|                  | dose        | and its glycine conjugate.          |
|                  |             | Dechlorination of this metabolite   |
|                  | 42256357    | formed the 6-hydroxynicotinic acid  |
|                  | (1991)      | and its mercapturic acid            |
|                  |             | derivative. The second included the |
|                  | M&F: 1.0    | hydroxylation of imidazolidine      |
|                  | mg/kg       | followed by elimination of water of |
|                  | single oral | the parent compound to give NTN     |
|                  | dose        | 35884.                              |
|                  |             |                                     |
|                  | M: 1.0 or   | In a comparison between             |
|                  | 150 mg/kg   | \[Methylene-14C\] Imidacloprid and  |
|                  | single oral | \[Imidazolidine-4,5-14C\]           |
|                  | dose        | Imidacloprid, the rates of          |
|                  |             | excretion were similar; however,    |
|                  | 42256373    | the renal portion was higher with   |
|                  | (1990)      | the imidazolidine-labeled test      |
|                  |             | material. The imidazolidine-labeled |
|                  | M: 1.0 or   | test material also demonstrated     |
|                  | 150 mg/kg   | higher accumulation in the tissues, |
|                  | single oral | with the major sites of             |
|                  | dose or     | accumulation being the liver,       |
|                  |             | kidney, lung, and skin, and the     |
|                  | 80.0 mg/kg  | minor sites being brain and muscle. |
|                  | single oral |                                     |
|                  | dose after  | In a comparison between             |
|                  | 1 year 1800 | \[Methylene-14C\] Imidacloprid and  |
|                  | ppm         | WAK 3839, there were no significant |
|                  |             | differences in the absorption,      |
|                  | 42256355    | distribution, and excretion of the  |
|                  | (1987)      | total radioactivity. More           |
|                  |             | radioactivity was found in the      |
|                  | M: 1.0      | tissues of the animals receiving    |
|                  | mg/kg       | imidacloprid at the 1.0 and 150.0   |
|                  | single oral | dose levels. The major sites of     |
|                  | or IV dose  | accumulation of WAK 3839 included   |
|                  |             | lung, renal fat, liver, and kidney, |
|                  | 42256358    | with minor sites being the testis   |
|                  | (1990)      | and brain. WAK 3839 was formed      |
|                  |             | during pretreatment (chronic oral   |
|                  | 42256359    | dosing) of imidacloprid; however,   |
|                  | (1990)      | the proposed metabolic pathways of  |
|                  |             | the two compounds were different.   |
|                  | Acceptabl   |                                     |
|                  | e/guideline |                                     |
+------------------+-------------+-------------------------------------+
| 870.7600         | NA          | NA                                  |
|                  |             |                                     |
| Dermal           |             |                                     |
| penetration      |             |                                     |
+------------------+-------------+-------------------------------------+

[]{#__RefHeading___Toc165171419 .anchor}**Attachment 2: Structures of
Imidacloprid Metabolites**

+------------------------------+---------------------------------------+
| **Name**                     | **Structure**                         |
+==============================+=======================================+
| Imidacloprid urea            | ![](media/ima                         |
|                              | ge2.png){width="1.9722222222222223in" |
| 1-\[(6-chloro-3-pyridin      | height="0.7895833333333333in"}        |
| yl)methyl\]-2-imidazolidinoe |                                       |
+------------------------------+---------------------------------------+
| Imidacloprid hydroxy         | ![](media/ima                         |
|                              | ge3.png){width="1.4993055555555554in" |
| (WAK 4103)                   | height="0.5763888888888888in"}        |
+------------------------------+---------------------------------------+
| Imidacloprid guanidine       | ![](media/ima                         |
|                              | ge4.png){width="1.9270833333333333in" |
| (WAK 4140)                   | height="0.7895833333333333in"}        |
|                              |                                       |
| 1-\[(6-chl                   |                                       |
| oro-3-pyridinyl)methyl\]-4,5 |                                       |
| -dihydro-1H-imidazol-2-amine |                                       |
+------------------------------+---------------------------------------+
| Imidacloprid olefin          | !                                     |
|                              | [](media/image5.png){width="1.9375in" |
| (WAK 3745)                   | height="0.7791666666666667in"}        |
|                              |                                       |
| 1-\[(6-chloro-3-pyridi       |                                       |
| nyl)methyl\]-4,5-dihydro-1H- |                                       |
| imidazol-2H-imidazol-2-imine |                                       |
+------------------------------+---------------------------------------+
| 6-CNA                        | ![](media/ima                         |
|                              | ge6.png){width="1.4986111111111111in" |
| 6-chloronicotinic acid       | height="1.0263888888888888in"}        |
+------------------------------+---------------------------------------+
| 6-hydroxynicotinic acid      | ![](media/ima                         |
|                              | ge7.png){width="1.4993055555555554in" |
|                              | height="1.0090277777777779in"}        |
+------------------------------+---------------------------------------+
| WAK 3839                     | ![](media/image8.png){width="1.5in"   |
|                              | height="0.7354166666666667in"}        |
+------------------------------+---------------------------------------+