IMIDACLOPRIDRISK CHARACTERIZATION DOCUMENTDIETARY AND DRINKING WATER EXPOSURE

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California Environmental Protection Agency

Department of Pesticide Regulation

February 9, 2006

IMIDACLOPRIDRISK CHARACTERIZATION DOCUMENTDIETARY AND DRINKING WATER EXPOSURE

Health Assessment Section
Medical Toxicology Branch
Department of Pesticide Regulation
California Environmental Protection Agency

February 9, 2006
2

CONTRIBUTORS AND ACKNOWLEDGMENTS

Principal Author:

Svetlana E. Koshlukova, Ph.D., Staff Toxicologist
Health Assessment Section
Medical Toxicology Branch

Scientific Advisor

Nu-may R. Reed, Ph.D., D.A.B.T., Staff Toxicologist
Health Assessment Section
Medical Toxicology Branch

Toxicology Reviewers:

Thomas B. Moore, Ph.D., Staff Toxicologist
Peter Leung, Ph.D., D.A.B.T., Senior Toxicologist
Product Data Review Section
Medical Toxicology BranchCharles N. Aldous, Ph.D., D.A.B.T., Staff Toxicologist
Data Review Section
Medical Toxicology Branch

Dietary Exposure:

Svetlana Koshlukova, Ph.D., Staff Toxicologist
Health Assessment Section
Medical Toxicology Branch

Reviewers:

Keith F. Pfeifer, Ph.D., D.A.B.T., Senior Toxicologist
Joyce F. Gee, Ph.D., Senior Toxicologist
Health Assessment Section
Medical Toxicology Branch
Jay P. Schreider, Ph.D., Primary State Toxicologist
Medical Toxicology Branch
Gary T. Patterson, Ph.D., Branch Chief
Medical Toxicology Branch

The Department of Pesticide Regulation acknowledges the review of this document by thePesticide Epidemiology Unit, Office of Environmental Health Hazard Assessment,
Office of Environmental Health Hazard Assessment
California Environmental Protection AgencyiTABLE OF CONTENTS

Pages
LIST OF ABBREVIATIONS ........................................................................................................ vi
I. SUMMARY.............................................................................................................................. viii
II. INTRODUCTION ...................................................................................................................... 1
A. Mechanism of Action.............................................................................................................. 2
B. Regulatory History .................................................................................................................. 6
C. Technical And Product Formulations ..................................................................................... 7
D. Usage ...................................................................................................................................... 8
E. Illness Reports ......................................................................................................................... 8
F. Physical And Chemical Properties .......................................................................................... 8
G. Environmental Fate ................................................................................................................. 9III. TOXICOLOGY PROFILE ..................................................................................................... 14
A. Pharmacokinetics .................................................................................................................. 14
B. Acute Toxicity....................................................................................................................... 21
C. Subchronic Toxicity .............................................................................................................. 27
D. Chronic Toxicity And Oncogenicity .................................................................................... 35
E. Genotoxicity .......................................................................................................................... 41
F. Reproductive Toxicity ........................................................................................................... 45
G. Developmental Toxicity ....................................................................................................... 46
H. Neurotoxicity ........................................................................................................................ 48
I. Developmental Neurotoxicity................................................................................................ 52
IV. RISK ASSESSMENT............................................................................................................. 55
A. Hazard Identification ............................................................................................................ 55
B. Exposure Assessment............................................................................................................ 67
C. Risk Characterization ............................................................................................................ 84
V. RISK APPRAISAL .................................................................................................................. 87
A. Introduction........................................................................................................................... 87
B. Hazard Identification ............................................................................................................ 87
C. Exposure Assessment............................................................................................................ 89
D. Risk Characterization............................................................................................................ 90
E. Issues Related To The Food Quality Protection Act ............................................................. 91
VI. TOLERANCE ASSESSMENT .............................................................................................. 95
A. Background ........................................................................................................................... 95
B. Acute Exposure ..................................................................................................................... 95
C. Chronic Exposure.................................................................................................................. 98
VII. CONCLUSIONS ……………………………………………………………………………99
VIII.REFERENCES…………………………………………………………………………….100
ATTACHMENT I: DEEM Acute Point Estimate Dietary Exposure Assessment ..................... 115
I.1. Tier 1 Residue Data Files .................................................................................................. 115
I.2. Tier 1 Dietary Exposure and Risk Estimates .................................................................... 122
I.3. Tier 2 Residue Data Files .................................................................................................. 130
I.4. Tier 2 Dietary Exposure and Risk Estimates .................................................................... 138ii

ATTACHMENT II: DEEM Chronic Dietary Exposure Assessment ......................................... 145
II.1. Chronic Residue Data Files .............................................................................................. 145
II.2. Chronic Dietary Exposure and Risk Estimates ................................................................ 153
ATTACHMENT III: Benchmark Dose Modeling. Polynomial Model ...................................... 155
ATTACHMENT IV: Summary of Toxicology Data for Imidacloprid ...................................... 158

iii

LIST OF FIGURES AND TABLESFIGURES
Figure 1. Chemical Structures of Nicotinoid and Neonicotinoid Compounds. .............................. 2
Figure 2. Chemical Structure of Imidacloprid Metabolites Containing the 6-Chloropyridinyl
moiety. .................................................................................................................................... 15
Figure 3. Biotransformation Pathways of Imidacloprid ............................................................... 20
Figure 4. Estimation of the Threshold of the Imidacloprid Acute Oral Toxicity with the BMD
model. ..................................................................................................................................... 58
TABLES
Table 1. Effects of Imidacloprid in Mice After a Single Gavage Dose (Bomann 1989a). .......... 22
Table 2. Acute LD50 and LC50 Values for Imidacloprid and its Metabolite Desnitro-Imidacloprid.
................................................................................................................................................ 25
Table 3. Acute No-Observed-Effect Levels (NOELs) and Lowest-Observed-Effect Levels(LOELs) for Imidacloprid. ..................................................................................................... 26
Table 4. Effects of Imidacloprid in Wistar Rats After 4-Weeks of Inhalation Head/Nose-Only
Exposure (Pauluhn, 1989). ..................................................................................................... 29
Table 5. Effects of Imidacloprid in Beagle Dogs After 4 Weeks of Treatment Through the Diets(Block, 1987). ......................................................................................................................... 33
Table 6. Effects of Imidacloprid in Beagle Dogs After 13 Weeks of Treatment Through the Diets(Ruf, 1990) ............................................................................................................................. 34
Table 7. Imidacloprid-Induced Mineralization of the Colloid of Thyroid Follicles in Ratsa. ...... 37
Table 8. Tumor Incidences from 2-year Dietary Studies with Imidacloprid in Wistar Ratsa. .... 38
Table 9. Mutagenicity Studies with Imidacloprid........................................................................ 43
Table 10. Developmental Toxicity of Imidacloprid in the Rat and Rabbit. ................................. 47
Table 11. Effects of Imidacloprid in Sprague-Dawley Rats After a Single Gavage
Administrationa. ..................................................................................................................... 49
Table 12. Effects of Imidacloprid in Fischer-344 Rats In a 13-Week Feeding Studya. ................ 51
Table 13. Effects of Imidacloprid in Sprague-Dawley Rats in a Developmental Neurotoxicity
Studya. .................................................................................................................................... 53
Table 14. Acute No-Observed_Effect Levels (NOELs) and Lowest-Observed-Effect Levels(LOELs) of Imidacloprid. ...................................................................................................... 56
Table 15. Subchronic No-Observed-Effect Levels (NOELs) and Lowest-Observed-Effect Levels(LOELs) for Imidacloprid. ..................................................................................................... 63
Table 16. Chronic No-Observed Effect Levels (NOELs) and Lowest-Observed-Effect Levels(LOELs) of Imidacloprid. ...................................................................................................... 65
Table 17. Anticipated Imidacloprid Residues From Monitoring Databases Used For Acute And
Chronic Dietary Exposure Assessments ................................................................................ 71iv

Table 18. Imidacloprid Residues from Field Trial Studies Used for Acute and Chronic Dietary
Exposure Assessmentsa. ......................................................................................................... 75
Table 19. Acute Dietary Exposure Estimates for Imidacloprid. ................................................... 81
Table 20. Chronic Dietary Exposure Estimates for Imidacloprid................................................. 83
Table 21. Critical NOELs and Endpoints for the Risk Characterization of Imidacloprid ............ 84
Table 22. Acute (Point Estimate) Dietary Risk Estimates for Imidacloprid................................. 85
Table 23. Chronic Dietary Risk Estimates for Imidacloprid. ....................................................... 86
Table 24. Acute Dietary Risk Estimates for Imidacloprid Residues at the Tolerance Level. ...... 97v

LIST OF ABBREVIATIONS
ACh ……….. Acetylcholine
AChE……… Acetylcholinesterase
AChR……….Acetylcholine receptor
AP…………..Alkaline Phosphatase
ALT…………Alanine Aminotransferase
ATSDR….…. Agency for Toxic Substances and Disease Registry
BEAD……… Biological and Economical Analysis Division
BMD ……… Benchmark DoseBMR……….. Benchmark Response
BR………….. Breathing Rates
CEC……….. Critical Exposure Commodity Analysis
CK…………. Creatin Kinase
CNS…………Central Nervous System
CSFII………. Continuing Survey of Food Intake by Individuals
CYP…………Cytochrome P450
DEEM™…… Dietary Exposure Evaluation Model
DNT………... Developmental Neurotoxicity
DPR ……….. Department of Pesticide Regulation
ED………….. Effective DoseENEL………. Estimated No Effect Level
ERK…………Extracellular Signal-Regulated Kinase
FDA…………Food and Drug Administration
FFDCA …….. Federal Food, Drug, and Cosmetic Act
FIFRA ………Federal Insecticide, Fungicide, and Rodenticide Act
FOB……….. Functional Observational Battery
FQPA………. Food Quality Protection Act
GD…………. Gestation Day
GLDH……….Glutamate Dehydrogenase
GWSS……… Glassy-Winged Sharpshooter
LD50……….. Median Lethal Dose
LC50…………Median Lethal Concentration
LD………….. Lactation Day
LED ………. 95% Confidence Limit of the Effective DoseLOD………. Limit of Detection
LOEL……… Lowest Observed Effect Level
MAPK………Mitogen-Activated Protein Kinase
MFO………...Mixed Function Oxidases
MMAD……...Aerodynamic Droplet Size
MOE ……… Margin of Exposure
MRLs……… Maximum Residue Levels
MTD……….. Maximum Tolerated DosenAChR…….. Nicotinic Acetylcholine Receptor
NCBI……….. National Center for Biotechnology Informationvi

ND………… Non-Detected Residues, Non-Detects
NOEL………. No Observed Effect Level
PCT………… Percent of the Crop Treated
PDP………… Pesticide Data Program
PCPA ……… Pesticide Contamination and Prevention Act of 1985
PND……….. Postnatal Day
ppm………… Part per Million
ppb ………… Part per Billion
RAC…………Raw Agricultural Commodity
RCD…………Risk Characterization Document
RfD …………Reference DoseRPF …………Relative Potency Factor
SB950……….Birth Defect Prevention Act of 1984
SCE………… Sister Chromatid Exchange
SNV…………Specific Numerical Values
TOPE ……….Time to Peak Effect
USDA……….United States Department of Agriculture
USEPA…….. U.S. Environmental Protection Agency
WHO ………. World Health Organizationvii

I. SUMMARY
I.A. INTRODUCTION
Imidacloprid is a neurotoxic insecticide, which belongs to the class of the neonicotinoid
pesticides. Imidacloprid is registered to control insect pests on agricultural and nursery crops,
structural pests and parasites on companion animals. This risk assessment addresses the potential
human health effects arising from exposure to imidacloprid in the food and drinking water. The
exposures from ambient air, occupational activities and residential uses, as well as aggregate
exposures from various combined scenarios, will be subsequently addressed in an addendum tothis document.
Imidacloprid is an agonist of the nicotinic acetylcholine receptor (nAChR) at the neuronal andneuromuscular junctions in insects and vertebrates. It is structurally and functionally related tonicotine. The toxicity of imidacloprid is largely due to interference of the neurotransmission in
the nicotinic cholinergic nervous system. Prolonged activation of the nAChR by imidacloprid
causes desensitization and blocking of the receptor, and leads to incoordination, tremors,
decreased activity, reduced body temperature and death. Presently, there is no specific antidote,
which acts as an antagonist to the effects imidacloprid.
Imidacloprid represents the new generation of neurotoxic insecticides, which exhibit more
selective toxicity for insects relative to mammals. Since being introduced in the insecticide
market in 1992, the use of imidacloprid has increased yearly. It ranked as one of the top selling
pesticides in the world in 2001-2002. For the most part, it is replacing the acetylcholinesterase
inhibitors, the organophosphorus compounds and methylcarbamates. Imidacloprid is a Category
II acute toxicant, and thus, is classified as a General Use Pesticide. The U.S. Environmental
Protection Agency (USEPA) developed for imidacloprid an oral chronic reference dose (RfD) of
0.057 mg/kg/day.
In the environment, the principal routes of dissipation for imidacloprid are aqueous photolysis,
microbial degradation and uptake by plants. Imidacloprid is currently listed by the DPR as apotential ground water contaminant, based on its high solubility in water, mobility andpersistence in soil. The major degradation product of imidacloprid in the environment isdesnitro-imidacloprid.
I.B. TOXICOLOGICAL PROFILE
Pharmacokinetics- Imidacloprid is quickly absorbed by the oral route and rapidly distributed innearly all organs and tissues. In rats, the oral absorption was estimated as 92-99%. Imidacloprid
degrades to a large number of metabolites formed by multiple pathways. The same, or similar
metabolites are found in rats, goats and hens. Based on structural considerations, the following
metabolites may be of toxicological significance: 6-chloronicotinic acid, imidazolidine 4- and 5hydroxy compounds, olefinic imidacloprid, desnitro-imidacloprid and the nitrosoimine
compound. Metabolites were excreted primarily in the urine as glutathione and glycine
conjugates of mercaptonicotinic acid and hippuric acid. Imidacloprid or its metabolites
penetrated the blood-brain barrier. The parent compound and some of its metabolites have been
detected in milk, meat of goats and hens, and eggs. Pharmacokinetic studies were not available
for a direct determination of the rate of absorption from dermal and inhalation routes.
viiiAcute Toxicity- Acute toxicity of imidacloprid was examined via the oral route in rats and mice,and via the inhalation and dermal routes in rats. Mice appeared to be more sensitive to the acuteoral toxicity of imidacloprid than rats. In mice, the median oral lethal doses (LD50) ranged
between 131-168 mg/kg (Category II oral toxicant). Imidacloprid was classified as Category III
dermal toxicant, Category IV inhalation toxicant and Category IV eye and skin irritant. An acute(single dose) oral exposure of rats and mice to imidacloprid caused clinical signs characteristic
for nicotine intoxication, such as incoordination, tremors, spasms and respiratory difficulties.
Other symptoms included decreased motility and lethargy. The same clinical signs wereobserved in rats following a 4-hour exposure to imidacloprid via the inhalation route.
Subchronic Toxicity- Reduction in body weight was the most common toxic effect observed in
the subchronic oral and inhalation studies in rats, and in oral studies in mice and dogs. The liver
was the principal target organ as demonstrated by the hepatic necrosis or hypertrophy in rats anddogs, elevated activities of serum enzymes, and alteration of clinical chemistry parameters suchas triglycerides, cholesterol and the blood clotting time. Additional morphological effects
included testicular degeneration in rats and dogs; atrophy of thyroid gland and bone marrow, andadvanced involution of the thymus in dogs. Imidacloprid was a potent inducer of the hepatic
mixed-function oxidases. Subchronic exposure of dogs to imidacloprid resulted in severe
tremors.
Chronic Toxicity- Reduction in body weight was the most common toxic effect in the chronicoral studies in rats and mice. The principal morphologic effect was thyroid lesions in rats. Micedeveloped hypersensitivity to anesthesia after chronic treatment with imidacloprid, suggestingthat imidacloprid may reduce the ability of the animals to respond to an additional challenge withxenobiotics.
Genotoxicity- Imidacloprid was negative in a battery of genotoxicity tests, including in vitro
gene mutation tests, in vivo chromosomal aberration tests and tests for DNA damage and repair
capabilities. In mammalian tests in vitro, imidacloprid caused sister chromatid exchange and, at
cytotoxic doses, chromosomal aberrations.
Oncogenicity- In the chronic toxicity/oncogenicity studies there was not sufficient evidence toindicate that imidacloprid was oncogenic to rats and mice.
Reproductive Toxicity- The reported effects of imidacloprid on reproduction included
disproportionally high number of male fetuses in rats, lower fetal body weight in rabbits andtesticular degeneration in rats and dogs.
Developmental Toxicity- The reported imidacloprid-induced developmental effects in rats andrabbits included lower fetal body weight, increased resorptions and skeletal alterations.
Developmental Neurotoxicity- Developmental neurotoxicity study (DNT) revealed decreased
body weights, reduced motor activity level and changes in dimensions of brain structures(reduction in the thickness of corpus callosum and a decreased width of caudate putamen).
I.C. RISK ASSESSMENT
Hazard IdentificationAcute Toxicity: Two acute oral NOELs (No-Observed-Effect Level) were used to address theacute dietary exposure to imidacloprid. The acute NOEL of 9 mg/kg/day was based on decreasesix

in motor activity in adult rats. This NOEL was calculated with the Benchmark Dose (BMD)
approach. It represented the threshold dose LED05, which caused a 5% reduction in the motor
activity of rats. The NOEL of 9 mg/kg/day was utilized in estimating the risk for acute dietary
exposure to imidacloprid to the general population.
The estimated NOEL for developmental neurotoxicity in rats was 5.5 mg/kg/day, based on
significant decreases in the dimensions of brain structures in postnatal day (PND) 11 pups. ThisNOEL was estimated from the LOEL by applying a 10-fold default factor. The ENEL of 5.5
mg/kg/day was pertinent to acute exposures to imidacloprid in women of childbearing age toprotect against fetal exposure
Subchronic Toxicity: The subchronic oral NOEL of 7.3 mg/kg/day was selected to characterize
the risk of subchronic oral exposure of humans to imidacloprid. This NOEL was based onmorphological changes of the liver and the thyroid gland, and tremors in dogs.
Chronic Toxicity: The chronic NOEL of 5.7 mg/kg/day was based on an increase in incidence
and severity of mineralized particles in thyroid gland in rats. This NOEL was employed inestimating the human risk for chronic dietary exposure to imidacloprid.
Exposure Assessment- This document pertains only to the assessment of the dietary exposure toimidacloprid. The exposure from ambient air, the occupational exposure and the exposure fromresidential uses will be addressed subsequently in an addendum to this document.
Dietary and Drinking Water Exposure: The dietary exposure to imidacloprid residues in food andin the drinking water was calculated using the deterministic approach (Point Estimate, Tier 2).
The dietary exposure estimates were based primarily on the maximum allowed residue level(tolerance). The DPR presents the acute Point Estimate exposures at the 95th and 99th percentiles.
At the 95th exposure percentile, the estimated acute exposures to imidacloprid ranged from 15µg/kg/day to 51 µg/kg/day. At the 99th percentile, the exposures ranged from 23 µg/kg/day to 78µg/kg/day. At both, the 95th and 99th percentiles, the population subgroups “Children 1-2 years”
and “All Infants” were identified to receive the highest dietary exposure from imidacloprid. The
high-end exposure mostly reflected residues at the tolerance. Drinking water did not emerge as amajor contributor to the total dietary exposure. The chronic dietary exposures ranged from 1.75
µg/kg/day for Females 13-49 yrs. to 7.41 µg/kg/day for Children 1-2 yrs.
I.D. RISK CHARACTERIZATION AND RISK APPRAISALThe critical NOELs for characterizing the risk from exposure to imidacloprid were derived fromstudies with laboratory animals. The potential risk from exposure to imidacloprid was evaluatedby comparing the MOE (a quotient of the NOEL and the exposure level) to benchmarks. The
benchmark MOE of 100 was generally considered prudent for protection of humans against
imidacloprid toxicity.
Dietary Exposure: The acute dietary MOEs ranged from 175 to 614 at the 95th percentile, andfrom 115 to 394 at the 99th percentile. The high-end exposure mostly reflected residues at thetolerance. Children 1-2 yrs were identified as the most highly exposed population. The chronic
MOEs to imidacloprid were greater than 770 for all of the evaluated population subgroups.

xRisk Appraisal- The main uncertainties with the toxicity of imidacloprid were associated with(i) the use of animal data to evaluate the toxic effects in humans and (ii) the estimation of theNOEL, when a NOEL could not be established from a study. In this respect, evidence from the
DNT study in rats, suggested that imidacloprid may affect the neural development. Significant
decreases in the dimensions of brain structures were observed at the dose of 54.7 mg/kg/day at
PND 11. However, the NOEL for developmental neurotoxicity could not be determined, because
pups from intermediate doses (8–19 mg/kg/day) were not included in the evaluation. Assumingthat the LOEL for DNT is 54.7 mg/kg/day, the NOEL could be estimated (ENEL) as low as 5.5
mg/kg/day by applying a 10-fold default factor. The ENEL of 5.5 mg/kg/day might be applicable
to repeated exposures to imidacloprid to all population subgroups. Because decreases in brain
structures could theoretically result from a single exposure in utero, the ENEL of 5.5 m/kg/day
could be used to estimate the risk of acute exposure to imidacloprid in women of childbearingage.
The uncertainties in the dietary exposure assessment were introduced with the use of thetolerance as surrogate for residue concentration. The uncertainties in the risk characterization
were associated with the default assumptions for the 10-fold interspecies sensitivity and the 10fold variation in the sensitivity within the human population. One specific area of uncertainty is
the use of toxicity thresholds to calculate the acute and chronic MOEs. The chronic dietary
MOEs were estimated based on the chronic NOEL of 5.7 mg/kg/day for thyroid effects in rats.
This chronic NOEL is sufficiently close to the ENEL of 5.5 mg/kg/day for decreases in thicknessof brain structures, and therefore, would be adequate for protection against the potential effects
of imidacloprid on the developing nervous system. The acute MOEs were estimated based on theacute NOEL of 9 mg/kg/day for decreases in motor activity in rats. Using the ENEL of 5.5
mg/kg/day for women of childbearing age to protect against fetal exposure would result in acute
MOEs of 366 and 239 at the 95th and 99th percentiles, respectively.
I.E. TOLERANCE ASSESSMENT
The tolerance assessment was conducted to estimate the point estimate exposure and risk to asingle label-approved commodity with imidacloprid residues at the tolerance. The DPR estimates
the acute tolerance exposure as the sum of the 95th percentile exposure for the commodity ofconcern at the tolerance and a background exposure for all other commodities. The chronic
exposure from total dietary exposures was added as a surrogate for background exposure.
Because of the large number of registered commodities (>270), tolerance assessment was carriedout only for foods with (i) significant impact on the dietary exposure (ii) very high USEPA
tolerances (i.e., >5 ppm), (iii) major uses in California and (iv) high consumption foods for
infants and children. The MOEs were at or above the benchmark of 100 for all of the evaluatedpopulation subgroups for all of the analyzed foods. The lowest MOEs were 170, 175 and 196 forChildren 1-2 yrs and Infants, who consumed tomato paste, spinach and broccoli with tolerance
levels of imidacloprid.

xi

I.F. CONCLUSIONSThis health risk assessment for imidacloprid evaluated the risk to 16 population subgroups frompotential residues in food and drinking water. Dietary exposures were estimated under acute andchronic scenarios. The exposure estimates were based primarily on the maximum allowed
residue level (tolerance) as surrogate for residue concentration. The critical NOELs were derived
from studies with laboratory animals; therefore, a MOE of 100 was used as the benchmark to
determine the level of human health protection.
The acute point estimate MOEs ranged from 115 to 614 at the DPR high-end percentiles (95thand 99th), and thus, were greater than the benchmark MOE of 100. Children 1-2 yrs. and Infants
were identified as the most highly exposed population subgroups, with MOEs of 175 and 195 at
the 95th percentile, and 115 and 128 at the 99th percentile. The acute MOEs were estimated basedon the acute NOEL of 9 mg/kg/day for decreases in motor activity in rats.
The risk from acute dietary exposure to imidacloprid in women of childbearing age requires
further consideration. Evidence from the developmental neurotoxicity study in rats, suggested
that imidacloprid may affect the neural development. The estimated NOEL for decreases indimensions of brain structures was 5.5 mg/kg/day. This ENEL might be pertinent to acuteexposures of women of childbearing age to protect for fetal exposure. Based on the ENEL of 5.5
mg/kg/day, the acute dietary MOEs for females 13-49 yrs. would be 366 at the 95th and 239 at
99th percentiles, which exceed the general health protective benchmark MOE of 100.
The MOEs for all of the evaluated population subgroups from chronic dietary exposure weregreater than 770, based on the chronic NOEL of 5.7 mg/kg/day for thyroid effects in rats. ThisNOEL is sufficiently similar to the estimated NOEL for developmental neurotoxicity (5.5mg/kg/day), and thus, would be adequate for protection against potential developmental effects
of imidacloprid.
The acute tolerance exposure was calculated as the sum of the 95th percentile exposure for thecommodity of concern at the tolerance and a background exposure. The MOEs for exposure totolerance level imidacloprid were at or above the benchmark of 100. The lowest MOEs were170-196 for Children 1-2 yrs. and Infants, who consumed tomato paste, spinach and broccoli.
The MOEs in this RCD reflect only the risk form the dietary exposure. The potential human
exposures from ambient air, occupational activities and residential uses of imidacloprid will be
subsequently evaluated in an addendum to this RCD. Aggregate exposures to specific population
subgroups from various combined scenarios will also be determined. These additional exposures
will lead to reductions in the MOEs estimated in this assessment. Dietary exposure may have tobe reevaluated using refinements such as measured residue levels from monitoring studies, whendata become available.

xii

II. INTRODUCTION
Imidacloprid [N-(6-chloropyridin-3-ylmethyl)-2-nitroiminoimidazolidine] is a member of a newclass of pesticides, the neonicotinoid insecticides. It is effective against sucking insects on plants
and companion animals, against turf insects and some beetles. Due to its systemic activity,
imidacloprid is extensively used for soil application, seed and foliar treatment. Like the otherneonicotinoids, imidacloprid shares structural similarity and a common mode of action with thetobacco toxin, nicotine. The toxicity of imidacloprid is based on interference of theneurotransmission in the nicotinic cholinergic nervous system. Imidacloprid binds to thenicotinic acetylcholine receptor (nAChR) at the neuronal and neuromuscular junctions in insects
and vertebrates. The nAChR is an ion channel, which endogenous agonist is the excitatoryneurotransmitter acetylcholine (ACh). The receptor normally exists in a closed state, however,upon ACh binding, the complex opens a pore and becomes permeable for cations. The channel
openings occur in short bursts, which represent the lifetime of the receptor-ligand complex. ACh
is then rapidly degraded by the enzyme acetylcholinesterse (AChE). In contrast, imidacloprid
bound to the nAChR is inactivated very slowly. Prolonged activation of the nAChR byimidacloprid causes desensitization and blocking of the receptor and leads to paralysis and death.
Imidacloprid was the first neonicotinoid registered by the United States Environmental
Protection Agency (USEPA) for use as a pesticide. It possesses selective toxicity for insects
relative to mammals and displays a broad spectrum of useful properties. These properties include
high insecticidal potency, control of insects resistant to the major pesticides (e.g.
organophosphates, carbamates and pyrethroids) and efficacy in soil application due to its
mobility from the roots to the upper parts of plants (Kagubu, 2004). Since being introduced in
the insecticide market in 1992, the use of imidacloprid has increased yearly. It ranked as one of
the top selling pesticides in the world in 2001-2002. For the most part, it is replacing theacetylcholinesterase inhibitors, the organophosphorus compounds and methylcarbamates, whichdisplay higher mammalian toxicity and decreased effectiveness due to pest resistance.
This human health risk assessment for imidacloprid was conducted because adverse effects on
the liver and the thyroid gland were observed following subchronic and chronic exposures. This
Risk Characterization Document (RCD) evaluated the potential health hazard from exposure toimidacloprid residues in the food and drinking water. The exposures from ambient air,occupational activities and residential uses of imidacloprid, as well as aggregate exposures fromvarious combined scenarios, will be subsequently evaluated in an addendum to this RCD. The
toxicological profile was based on studies on file at the DPR, which were submitted for fulfilling
the pesticide registration data requirements under the California Birth Defect Prevention Act of1984 (SB 950). Published experimental data were also used to characterize the imidacloprid
toxicity. Relevant publications were searched from the electronic databases at the National
Center for Biotechnology Information (NCBI, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi;
http://toxnet.nlm.nih.gov/). The most recent database search was conducted in November 2004,
and the document was updated accordingly.

1

II.A. MECHANISM OF ACTION
II.A.1. Imidacloprid and the Neonicotinoids
Imidacloprid was discovered in 1984 at Nihon Bayer Agrochem in Japan by screening novel
synthetic compounds for a high affinity to the insect nicotinic AChRs receptors, but with low
toxicity to vertebrate species (Kagabu, 1997). Its molecule includes the insecticidal N-(3pyridinyl)methyl group of nicotine and a nitroimine moiety (Fig.1). Because of their structuralsimilarity to nicotine, imidacloprid and related insecticides (acetamiprid, thiacloprid,thiamethoxam and nitenpyram) were termed neonicotinoids (Tomizawa and Yamamoto, 1993).
Nicotine possesses only modest insecticidal activity and is not stable for use in the field for crop
protection. Imidacloprid has greater insecticidal activity than nicotine, and its stability is suitablefor field use. Both the neonicotinoids and nicotinoids act as agonists at the nAChR. The principal
differences between the two classes of compounds are that the nicotinoids are ionized at
physiological pH and selective for the mammalian nAChR; whereas the neonicotinoids are notionized and more selective for the insect nAChR. The selectivity of the neonicotinoids toward
insects relative to mammals reflects the fundamental differences in the subunit combination andpharmacological profiles between the nAChR in insects and mammals (for review see Tomizawa
and Casida, 2003).
Figure 1. Chemical Structures of Nicotinoid and Neonicotinoid Compounds.
NH

N
N

nicotine

N
CH3

Cl

N

N

imidacloprid

NO2

N
Cl

N

NH
NH

desnitro-imidacloprid

II.A.2. Nicotinic ACh Receptors (nAChRs) as Target for Imidacloprid
The nAChRs are cation selective ligand-gated ion channels, which are involved in thephysiological responses to acetylcholine. All nAChRs are transmembrane oligomers. They are
made up of homologous subunits, which are encoded by a large multigene family. Most havesignificant calcium permeabilities, enabling them to regulate Ca2+-dependent processes. The
functions and pharmacological properties of the nAChRs depend on the subunit composition andcellular and subcellular distribution.
Vertebrate nAChRs. The vertebrates nAChRs are assembled from five identical or different
subunits. In mammals, the nAChRs are expressed at the neuromuscular junction (muscle
nAChRs), within the central and peripheral nervous system (neuronal nAChRs); and also on
some non-neuronal cells. Subunit composition of these pentameric channels varied between
muscle and brain. In neurons, most nAChRs contain two α and three β subunits. The α1, β1, γ, δand ε subunits make up heteropentamers in muscle cells (Le Novere and Changeux, 1995; Le
Novere et al, 2002). Nicotine is the typical agonist of nAChRs; bungarotoxin, tubocurarine,
pancuronium and hexamethonium are antagonists for the ganglionic and neuromusculartransmission. Residues contributing to ACh binding site in vertebrates have been identified and2referred to as loops. Loop F, designated as a negative subsite, is considered to interact with thequaternary nitrogen atom of ACh and nicotine (Corringer et al., 2000). Imidacloprid has no such
nitrogen (Fig.1). Structural studies predicted that the electron deficient nitrogen atom of theimidazolidine group of imidacloprid corresponds to the positively charged, protonated form of
nicotine and is likely to interact with the mammalian nicotinic receptors (Matsuda et al., 2000).
At the vertebrate neuromuscular junction and autonomic ganglia, each postsynaptic nAChR
binds two molecules of ACh to form a ligand-receptor complex. This complex then undergoes a
conformational change to open an ion channel, which is permeable to extracellular Na+ and Ca2+
and promotes efflux of intracellular K+. At the cellular level, the immediate impact on nAChRs
activation is a cation influx and membrane depolarization (Berg and Conroy, 2002). The mostimportant long-term consequence of the synaptic signaling is transcriptional regulation. The
nAChR-mediated transcription requires calcium influx and calcium release from internal stores
to initially activate Ca2+/calmodulin-dependent protein kinases (CaMKII/IV) and then mitogenactivated protein kinases (MAPK; Liu and Berg, 1999). These enzymes, in turn, activatetranscription factor CREB, which alter expression of genes involved in transmitter synthesis(Chang and Berg, 2001; Gueorguiev et al., 2000).
Although nAChRs are expressed in the mammalian CNS, it relies on glutamatergic transmission
as its primary form of excitatory signaling. Current evidence suggests that the physiological rolefor nAChRs in the CNS is not as mediators of rapid chemical transmission, but rather as
modulators of synaptic signaling (Sharma and Vijayaraghavan, 2002). In the CNS, the neuronalnAChRs appear to be involved in complex central functions, including control of voluntary
motion, memory and attention, sleep and wakefulness, reward and pain, and anxiety (CorderoErausquin et al., 2000). In mammals, the acute neurotoxicity of imidacloprid is largely due toaction at the α4β2 and the homomeric α7 receptors in the brain(Tomizawa et al., 2001; Shimomura et al., 2002). The CNS effects cause excessive stimulation,
convulsions, seizures then depression and coma. The action of imidacloprid in the brain is very
complex due to its biotransformation to a large number of metabolites with varying stability andtoxicity. One of these metabolites, desnitro-imidacloprid (Fig. 1), is of particular interest,
because it has a nicotinic-type action that prefers mammalian versus insect nAChRs (Tomizawa
and Casida, 1999; Tomizawa and Casida, 2000).
Neuronal-type nAChRs are now being discovered in many non-neuronal cells such as
keratinocytes, bronchial epithelial cells, lymphocytes, chondrocytes, glial cells and astrosytes(for review see Sharma and Vijayaraghavan, 2002). In some of these cell systems additional
components of the cholinergic signaling have been found, including AChE, ACh and choline
acetyltransferase; but synapses have not yet been identified (Grando, 2001). Calcium appears tobe the major mediator of the nAChR activation and the consequences of receptor activation arelikely to be cell-type specific. Recent findings suggest that nAChRs on non-excitable cells might
regulate cellular functions like cell death and cell migration, in addition to the modulation ofcellular signaling. The presence of nAChRs in non-excitable cells implies a broader scope forimidacloprid actions, which needs to be considered when assessing its toxicity to humans.
Several human neuropathologies have been linked to genetic alterations of nAChRs genes or
autoimmune disruption of the receptor proteins, including congenital myasthenia, autosomal
dominant frontal lobe nocturnal epilepsy and possibly a schizophrenic syndrome (for review see
Lindstrom, 2002). These receptors are also involved at various degrees in several
neuropathologies such as Parkinson and Alzheimer’s diseases, and Gilles de la Tourette’s
3syndrome. Autoimmune responses to specific neuronal nAChR subunits have been found in theskin disease pemphigus, in which cells of the epidermis lose adherence. However, the mostwidespread human pathology associated with neuronal nAChRs is the addiction to nicotine(Mansvelder and McGehee, 2002).
The physiological role of nAChRs has been investigated in vivo by gene inactivation oroverexpression. Knockout mice of α3 or both β2 and β4 subunits developed a perinatal-lethal
dysautonomia (Xu et al., 1999a,b). Knockin mice with high levels of expression of α4 subunits
died near birth; but at lower levels of expression displayed increased anxiety and poor motor
activity. These phenotypes resulted from hyperactivity of nAChRs in some neurons and death ofother neurons and resembled toxic signs seen after chronic exposures to nicotine andimidacloprid.
Insect nAChRs. Invertebrates possess a variable number of genes encoding nAChR subunits(Gundelfinger and Schulz, 2000; Marshall et al., 1990; Eastham et al., 1998). Putative nAChR
subunits have been purified from Drosophila, Musca, Schistocerca and Periplaneta (Tomizawa
et al., 1996; Hanke and Breer, 1986). All known nAChR sequences are of neuronal type, butdiffer significantly from the vertebrate neuronal receptors. Novel insect nAChR subunits havebeen predicted from the Drosophila genome data (Littleton and Ganetzky, 2000). It is presently
unknown which subunits of the insect nAChR bind imidacloprid.
High affinity [3H]-imidacloprid binding sites were detected in a broad range of insects, including
green peach aphid, cowpea aphid, glassy-winged sharpshooter, whitefly, cockroach, migratory
locust, tobacco hornworm, fruit fly and housefly (Zhang et al., 2000; Tomizawa and Casida,2003). Both in insects and mammals, imidacloprid appears to act on multiple nAChRs subtypes
with differential sensitivity. The prolonged activation of these receptors by imidacloprid results
in toxicity, typical for cholinergic hyperactivity, e.g. uncoordinated abdominal quivering, wingflexing, tremor and violent whole body shaking, followed by prostration and death (Schroeder
and Flattum, 1984).
II.A.3. Imidacloprid Binding Affinity, Agonist Potency and Intracellular Signaling
The potency of imidacloprid for insect brain nAChRs is substantially higher than for mammalianbrain channels. For example, the binding affinity of imidacloprid to Drosophila nAChRs is over
550-fold greater than the affinity to the mammalian α4β2; and imidacloprid is about 900-foldmore toxic to houseflies than to mice (see LD50 values in Table 1; Tomizawa et al., 2000; 2001).
The current model postulates that, unlike the anionic ACh-binding subsite in vertebrates, thesubsite in the insect nAChRs consists of cationic amino acids, which interact with the negatively
tipped nitro group of imidacloprid (Tomizawa et al., 2003). Consistent with this model, minor
structural changes in imidacloprid molecule, such as replacing the = NNO2 group with = NH
(desnitro-imidacloprid, Fig. 1), drastically increases the specificity for the mammalian nAChR
subtypes (Tomizawa and Casida, 1999). The imino group of desnitro-imidacloprid is readily
protonated and the resulting positive charge may improve the fit into the mammalian negative
ACh subsite (Matsuda et al., 2000).
The binding affinity and agonist potency of imidacloprid have been reported for several
vertebrate species. Imidacloprid inhibited [3H]-α-Bgt binding and displayed weak agonist effects
in muscle type nAChR from Torpedo electric organ (Tomizawa et al., 1995; Tomizawa andCasida, 1999). It was an agonist of the nAChRs in mouse N1E-115 neuroblastoma and BC3H1
muscle cells (Zwart et al., 1992; 1994). Imidacloprid activated the rat α4β2 and α7 ion channels
4expressed in Xenopus oocytes, albeit with much lower potency than ACh (Yamamoto et al.,1998); and displayed a partial agonistic activity with the recombinant chick α4β2 and α7
receptors (Matsuda et al., 1998; 2000). Imidacloprid bound with lower affinity to α1, α3, α4 andα7 nicotinic AChR subtypes compared to its desnitro metabolite (Chao and Casida, 1997;
Tomizawa and Casida, 1999). The reported safety of imidacloprid as an insecticide wasattributed to its high potency on insect AChRs, but poor interaction with vertebrate neuronal
receptors. Clearly, this observation is based on only the toxicity of the parent compound.
Chronic nicotine treatment in vivo is known to cause an increase in the number (up-regulation) of
nicotinic AChRs in mammalian brain, based on radioligand binding. It has been proposed thatthe up-regulation is related to receptor desensitization (Marks et al., 1992; Pauly et al., 1996).
Imidacloprid and its metabolite desnitro-imidacloprid also up-regulated the α4β2 nicotinic
AChR subtype, which represent more than 90% of the high affinity [3H]nicotine binding sites inmammalian brain. Exposure of α4β2-expressing mouse fibroblast M10 cells for 3 days toimidacloprid and desnitro-imidacloprid caused up to 8 fold increase of [3H]nicotine binding(Tomizawa and Casida, 2000). The potency of desnitro-imidacloprid was similar to nicotine,whereas a 300-fold higher concentration of imidacloprid was required to induce this level of upregulation. The active concentrations of nicotine, desnitro-imidacloprid and imidacloprid, whichcaused a half-maximal increase in [3H]nicotine binding sites in M10 cells, were 760 nM, 870 nM
and 70,000 nM. The potency order for receptor up-regulation correlated with the in vitro binding
affinities (IC50 of 7 nM, 8.2 nM and 2600 nM for nicotine, desnitro-imidacloprid andimidacloprid, respectively). The correlation between the up-regulation and binding potencies of
the agonists indicated that binding to the α4β2 channels initiated the increase in the receptor
number. Experimental data support the hypothesis that the increased number of receptors is due
to prevention of AChR degradation, rather than an adaptive mechanism to compensate for theloss of channel function. The biological consequences of the imidacloprid and desnitroimidacloprid-induced up-regulation of neuronal AChRs are not known. However, it has beenshown that mice chronically treated with nicotine became tolerant to its acute effects on
locomotor activity and body temperature (Marks et al., 1992; Salminen and Ahtee, 2000).
Electrophysiological studies revealed that imidacloprid induced multiple conductance states ofsingle channel currents in rat phaeochromocytoma PC12 cells (Nagata et al., 1996; 1998). The
main conductance and subconductance of these currents were similar to those caused by ACh.
Unlike ACh, which evoked currents mainly in the main conductance state, imidacloprid induced
predominantly currents in the subconductance state. Furthermore, imidacloprid acted as a partial
agonist of the nAChRs in these cells. An interesting model was proposed to explain thesefindings. Imidacloprid may bind to two different sites on the neuronal nAChRs. One is theagonist-binding site and the other is the blocking site, which may be located at or near thechannel pore. Imidacloprid may bind to the agonist site and compete with other agonists,
including ACh and nicotine. The binding of imidacloprid to the agonist site generates the main
conductance current. The binding of imidacloprid to the blocking site interferes with ion
permeation, resulting in a partial suppression of the ACh-induced currents. The possible dual
action of imidacloprid as an agonist and antagonist of the mammalian nAChRs needs further
experimental verification.
Neuronal nAChRs activate complex downstream signaling pathways, which are initiated with anincrease in the level of intracellular calcium (Berg and Conroy, 2002). One of the key
components participating in the nAChR signaling is the extracellular signal-regulated kinase
5

(ERK), also known as mitogen-activated protein kinase (MAPK; Schaeffer and Webber, 1999).
ERK pathway is a necessary intermediate in the signaling from the nAChR toward gene
expression (Chang and Berg, 2001). In neurons, ERK/MAPK cascades regulate important
physiological processes such as cell differentiation, growth and survival, memory processing andsynaptic plasticity (Grewal et al., 1999). The current model for ERK activation is that the
nicotinic cholinergic stimulation triggers an initial cytosolic influx of sodium, creating
membrane depolarization and a subsequent increase in the intracellular calcium concentrations.
Depending on the cell type, calcium serves as a second messenger to activate protein kinase C(PKC) or protein kinase A (PKA), which in turn trigger the ERK/MAPK cascade to activate thetranscription factor CREB and expression of specific genes (Cox and Parsons, 1997; DajasBailador et al., 2002). In mouse neuroblastoma N1E cells, imidacloprid, desnitro-imidacloprid
and nicotine activated the ERK cascade. The stimulation of α4β2 receptor was coupled to thephosphorylation of ERK in a Ca2+ and PKC-dependent manner (Tomizawa and Casida, 2003)
Both, desnitro-imidacloprid and nicotine induced phosphorylation of ERK at 1 µM, whereas 100
fold higher concentration was required for imidacloprid to activate the kinase. The potencies of
the three nicotinic agonists in inducing ERK phosphorylation were consistent with their binding
affinities and toxicity. The principal finding of this study was that low concentrations ofimidacloprid and its metabolite affected neuronal functions. The importance of the insecticideinduced changes in the nAChR signal transduction at the organismal level remains to beevaluated.
Imidacloprid binding to neuronal nAChRs may be dependent on the phosphorylated state of thereceptors. According to a proposed model for cockroach neurons, the nAChRs can exist either ina phosphorylated or dephosphorylared form (Courjaret and Lapied, 2001). Increased cAMP via a
calcium/calmodulin (CaM)-sensitive adenylyl cyclase activates PKA, which in turn
phosphorylates and maintains the nAChR in a functional form. In contrast, dephosphorylation,
which is catalyzed by a CaM kinase-regulated protein phosphatase, renders the receptor
nonfunctional. Imidacloprid preferentially bound and activated the phosphorylated form of thechannel. These results indicated that conditions, which alter the nAChR
phosphorylation/dephosphorylation mechanisms, may significantly affect the toxicity ofimidacloprid.
II.B. REGULATORY HISTORY
Imidacloprid was first registered in the Unites States by the USEPA in 1994 as Merit®
insecticide for use on turf and ornamentals (USEPA 1994). Subsequently, it was registered with
the USEPA for use on various food and feed crops, tobacco, ornamentals, buildings for termite
control and on cats and dogs for flea control. Currently, as a Category II acute toxicant, it isclassified as a General Use Pesticide. USEPA has developed for imidacloprid an oral chronic
reference dose (RfD) of 0.057 mg/kg/day. Imidacloprid is classified as a “Group E” carcinogen,indicating “no evidence of carcinogenicity in humans” (USEPA 1999a,b; 2003).
USEPA has evaluated the human risk from aggregate exposure to imidacloprid (USEPA, 2003).
The aggregate exposures included dietary exposure to establish tolerances on food commodities,
exposure from drinking water and in residential settings. An occupational exposure assessment
has not been conducted. The USEPA utilized imidacloprid residue levels at the tolerance for its
acute and chronic dietary exposure assessments. The main conclusion from these assessments
was that the aggregate exposure to imidacloprid of the US population, infants and children would
6not result in harm. Consequently, tolerances for the combined residues of imidacloprid and its
metabolites containing the 6-chloropyridinyl moiety were established on a large number of raw
agricultural commodities, meat, milk, poultry and eggs (CFR 2003a). There are no CODEX
Maximum Residue Levels (MRLs) for residues of imidacloprid. There are currently Canadianand Mexican MRLs for imidacloprid on potato, but these MRLs are not equivalent to the USrecommended tolerance level.
In California, the Department of Pesticide Regulation (DPR) completed a health risk assessment
for imidacloprid in 1993, which evaluated imidacloprid for emergency use on cotton under theSection 18 of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA; Lewis et al.,1993). Based on this risk assessment, the emergency registration of imidacloprid for use on
cotton was approved. Subsequently, in 1997 imidacloprid was registered to control aphids andwhiteflies on cotton.
Imidacloprid has played a significant role in reducing the populations of the glassy-winged
sharpshooter (GWSS, Homalodisca coagulata) in California. GWSS can feed and reproduce onover 70 species of crop and ornamental plants. This insect is a new pest for California and posesa serious threat to the vineyards, due to its ability to spread Xylella fastidiosa, the bacterium thatcauses the Pierce’s disease in grapes. Vines develop Pierce’s disease when X. fastidiosaovergrow the water conducting system of the plants (xylem) and blocks the flow of water to theaffected leaves (Bentley et al., 2004). Because of its systemic properties, imidacloprid iscurrently one of the few effective insecticides, which is registered to control GWSS in vineyards,
citrus orchards and stone fruit in California.
II.C. TECHNICAL AND PRODUCT FORMULATIONS
Imidacloprid is effective against piercing-sucking and some chewing insect pests of agricultural
crops and pets. It is available as granular and wettable powders, liquid forms and flowableformulations. It is more efficient as a systemic pesticide (e.g. within the plant) via soil
application or seed treatment, however it is also used as a foliar spray. In the US, Bayer
Agricultural Products is the main producer of the trade name imidacloprid.
As of March 2004, the following products containing imidacloprid were registered in California
for use on food and feed crops: Admire™ 2 Flowable (21.4% a.i.); Merit® Concentrate
Insecticide (75% a.i.), Merit® 0.5 Insecticide (0.5% a.i.), Merit® 1G Greenhouse and Nursery
Insecticidal (75% a.i.), Merit® 2 Insecticide (21.4% a.i.), Merit® 75 Wettable Powder andMerit® 75 Solupack Wettable Powder (75% a.i.); Gaucho® 480 Flowable (40.7% a.i.),
Gaucho® 600 Flowable (48.7% a.i.), Gaucho® 75 St Insecticide and Gaucho® 75 ST FS
Insecticide (75% a.i.); Provado® 1.6 Flowable (17.4% a.i.), Provado® 75 Solupack Wettable
Powder (75% a.i.); Leverage™ 2.7 (17% a.i.); Marathon® 1% Granular, Marathon® 60
Wettable Powder (60% a.i.) and Marathon II Greenhouse and Nursery Insecticide 21.4% a.i.).
The food commodities on which imidacloprid formulations can be applied are presented inTables 17 and 18. In addition, a special local need registration (SLN) of Admire™ 2 Flowable(21.4% a.i.) was obtained for the use on grape. The product Gaucho TOPS-MZ Potato SeedPiece Treatment contains imidacloprid (1.25%) in combination with the fungicide pesticide
mancozeb (6%).
Imidacloprid is currently registered for use on the following residential non-dietary sites:
Granular products for application to lawns and ornamental plants; Ready-to-use spray for7

application to flowers, shrubs and house plants; Plant spikes for application to indoor andoutdoor residential potted plants; Ready-to-use potting medium for indoor and outdoor plantcontainers; Liquid concentrate for application to lawns, trees, shrubs and flowers; Ready-to-use
liquid for directed spot application to cats and dogs (Advantage® 9.1% a.i.). The formulation K9Advantix™ is used to control ticks, mosquitoes and fleas on pets and contains imidacloprid(8.8% a.i.) in combination with permethrin (44 % a.i.).
In addition, there are numerous registered products intended for use by commercial applicators toresidential sites. These include: gel baits for cockroach control (Pre-Empt® cockroach gel bait,
2.5% a.i.), products for commercial ornamental, lawn and turf pest control (Pointer™
Insecticide, 5% a.i.); products for ant and fly control (Pre-Empt liquid ant bait, 0.005 a.i.;
Quickbayt Fly Bait 0.5% a.i.); and products used as preservatives for wood products, building
materials, textiles and plastics (Premise® 2 Insecticide 21.4% a.i.; Premise® 75 Insecticide,
Premise® 75% a.i.; Premise® 0.5 SC, 5.6% a.i., and Preventol™ Preservative Insecticide, 21.4
% a.i.).
II.D. USAGE
From 1996 to 2001, over 510,000 pounds of imidacloprid were used in California. The amounts
applied in 1996, 1997, 1998, 1999 and 2000 were 70,685; 80,036; 62,882; 102,323; 101,409 and
98,000 pounds, respectively. The major usages of imidacloprid include: lettuce (53 %), structural
pest control (16.9%), cotton (17%), grapes (11%), melons (9.7%), broccoli (5%), landscapemaintenance (5.3%), cauliflower (4%), tomato (2.3%) and peppers (1.8%). Other uses accounted
for less than 1% (DPR 2002d; http://www.cdpr.ca.gov/docs/pur/pur01rep/chmrpt01.pdf).
II.E. ILLNESS REPORTS
In California, 118 cases of illnesses were linked to imidacloprid from 1995 to 2001 (DPR,
2001b). The health effects attributed to exposure to imidacloprid alone, or in combination withother pesticides, were rated as definite (3 cases), probable (65 cases) or possible (50 cases). Twoof the illnesses identified as “definite”, were caused by imidacloprid applications to grapes andbroccoli. The clinical signs of the workers included eye irritation, blurred vision, tearing and pain
in both eyes. The third “definite “ case was reported for a kennel worker who had imidacloprid
splashed into the eyes. The clinical signs were burning and corneal abrasion in the eye. The
majority of the illnesses “probably” caused by imidacloprid were reported for agricultural
workers, which applied a pesticide mixture of imidacloprid, methamidophos and oxydemetonmethyl on broccoli. The most common clinical signs included: rash, breathing difficulty,
headache, tearing eyes, nausea, itching, dizziness, increased salivation, vomiting, numbness anddry mouth.
II.F. PHYSICAL AND CHEMICAL PROPERTIES
Chemical name:
CAS Registry number:
Common name(s):Trade names:

1-(6-chloro-3-pyridin-3-ylmethyl)-N-nitroimidazolidin-2ylidenamine
13826-41-3
Imidacloprid
Admire, Acidor (Agro Chemical Industries), Gaucho, Genesis,
Prescribe (Gustafson LLC); Marathon (Olympic Horticultural

8

Molecular formula:

Products); Confidate, Imadate (The Arab Pesticides&Veterinary
Drugs Mfg.Co.); ( Farm Chem. Handbook, 2002)
C9H10ClN5O2

Molecular weight:

255.66NH

N
Cl

Structural Formula
Physical appearance:
Solubility:
Melting point:
Vapor pressure:
Density:
Henry’s Constant

N

N

NO2

light yellow powder
0.58 g/l water at 20°C. Soluble in acetone, acetonitrile, methylene
chloride and dimethylformamide, DMSO
120-134°C
1.5x10-9 mmHg at 20ºC
1.54 g/cm3 at 23ºC
9.9 x10-13 atm m3g.mol-1 at 20ºC

II.G. ENVIRONMENTAL FATE
Summary: In the environment, the principal routes of dissipation for imidacloprid are aqueous
photolysis, microbial degradation and uptake by plants. Imidacloprid photodegraded rapidly(half-life of 4 hours) in water, compared to soil (half-life of 171 days). It was hydrolyticallystable at pH 5 and 7, but hydrolyzed slowly in sterile alkaline solutions (half-life of 355 days).
The half-life of the imidacloprid degradation in anaerobic soil was 27 days. Imidacloprid was
persistent in aerobic soil under laboratory conditions (half-life of 188 to > 365 days). The
presence of vegetation substantially increased the rate of imidacloprid degradation in the soil
(half-life of 48 days). Studies on the imidacloprid mobility in soil revealed that imidacloprid
residues leached into the 6-12 inch soil depth under field conditions.
Imidacloprid is currently listed by the DPR as a potential ground water contaminant, based on its
high solubility in water, mobility and persistence in soil. The low vapor pressure of imidacloprid
indicates that its volatilization from soil and leaf surfaces may not be a major route ofdissipation. Presently, information on imidacloprid residues in ground and surface water or in air
samples in California is not available.
The major degradation product of imidacloprid in the environment is desnitro-imidacloprid.
Other products, which have been found in laboratory studies, included 5-hydroxy-imidacloprid,imidacloprid-urea, 6-chloronicotinic acid and carbon dioxide. Additional discussion on the fateof imidacloprid in the environment is presented in Volume II, Environmental Fate (Bacey 2001,
http://www.cdpr.ca.gov/docs/empm/pubs/fatememo/imid.pdf).
II.G.1. Hydrolysis
The hydrolysis of imidacloprid was investigated in sterile aqueous buffered solutions at 25ºC for
30 days (Yoshida, 1989). Pyridine-labeled 14C-imidacloprid (5 ppm) was hydrolytically stable at9pH 5 and 7. It hydrolyzed very slowly at pH 9 with an estimated half-live of 355 days. In
alkaline solutions the major metabolite (7% of the total radioactivity) could not be identified.
The other hydrolysis product was imidacloprid urea (1.7% of the total radioactivity).
II.G.2. Photolysis or Photodegradation
The photodegradation of [pyridinyl-14C-methyl]imidacloprid was studied in sterile water, under
the conditions of maximum hydrolytic stability (pH 7 at 23ºC). Imidacloprid (5.4 mg/l) was
continuously irradiated with a sunlight-simulating xenon lamp. The half-life of thephotodegradation was 57 min. Based on this half-life, the environmental half-life was estimatedat about 4.2 hours. Similarly, imidacloprid was degraded quickly (~ 4h) under natural sunlight in
the greenhouse. The major photodegradation products were desnitro-imidacloprid (17.2%) andimidacloprid urea (10 % of the applied radioactivity, Anderson 1991).
The photodegradation of [pyridinyl-14C]imidacloprid was investigated on sandy loam soil.
[Pyridinyl-14C] imidacloprid was applied at a concentration of 48.5 mg/kg onto the soil layer. It
was the continuously irradiated with a sunlight-simulating xenon lamp for 15 days at 25ºC.
Imidacloprid degraded with a half-life of 38.9 days under the experimental conditions. The
calculated environmental half-live was 171 days. The major photodegradate was 5-hydroxyimidacloprid (Yoshida 1990).
II.G.3. Microbial Degradation
The anaerobic metabolism of imidacloprid was investigated in microbially active water and theaccompanying sediment, which were obtained from a pond. Imidacloprid was applied to thewater at an application rate of 0.6 mg/l and incubated for 358 days. This dose rate was about 1.5
fold higher that the actual field use rate (0.5 lb a.i./acre). Under these conditions, [pyridinyl-14Cmethyl]-imidacloprid degraded with a half-life of 27 days. Desnitro-imidacloprid was identified
as the only major metabolite. After 60 days, large amounts of this metabolite were bound to thesediment. At the end of the incubation period, imidacloprid degraded to less than 0.1 % in both,water and sediment. The final degradation product was carbon dioxide (Fritz and Hellpointer,1991).
The aerobic metabolism of imidacloprid was studied on microbially active, sandy loam soil inthe dark, at 20ºC. [Pyridinyl-14C-methyl]-imidacloprid was applied to the soil at a dose rate of
0.33 mg/kg soil. After 366 days of incubation, imidacloprid accounted for more than 60% of theapplied radioactivity. The extrapolated half-life of its degradation was greater than 1 year. Sevenmetabolites were observed at the end of the incubation period, but they represented less than 2%of the applied parent compound. The degradation of imidacloprid in soil was proposed to be via
denitrification, oxidation and cleavage of the dihydro-imidazole ring to yield 6-cloronicotinicacid and ultimately carbon dioxide (Anderson et al., 1991).
Additional aerobic metabolism studies of imidacloprid were conducted on microbially active,
flooded sandy loam soil BBA 2.2, Hoefchen silt and Monheim 1 sandy loam in the dark at 20ºC.
The application rates were 0.33 mg/kg (BBA 2.2 and Monheim 1 soils) and 0.36 mg/kg(Hoefchen silt) and the incubation period was 100 days. Under the experimental conditions, theradiolabeled imidacloprid degraded with estimated half-lives of approximately 188, 248 and 100
days, respectively. (Anderson et al., 1990; Anderson and Fritz, 1990; Anderson and Fritz, 1991).
The effect of growing vegetation on the degradation of imidacloprid in soils was investigated in
BBA 2.2 loamy soil. The soil was fertilized to maintain a nutrient supply for the plants.
[Pyridinyl-14C-methyl]-imidacloprid was applied at 0.23 mg a.i./kg soil and grass was then10planted as vegetation. The samples were incubated in the greenhouse at 17-20ºC for 274 days.
The half-life of imidacloprid degradation in samples with vegetation was 48 days, whereas insamples without vegetation the degradation was significantly slower (half-life 190 days). Under
vegetation, the main metabolite was desnitro-imidacloprid, whereas 5-hydroxy-imidacloprid was
the major degradate in the soil without growing vegetation. The grass absorbed about 10% of theapplied radioactivity. Therefore, the accelerated degradation of imidacloprid could not be
attributed solely to the uptake by the vegetation (Scholz, 1992).
II.G.4. Mobility and Field Dissipation
II.G.4.a. Soil
A soil adsorption/desorption study was carried out to characterize the mobility of imidacloprid insoil (Fritz, 1988). Aqueous solutions of [pyridinyl-14C-methyl]-imidacloprid were equilibrated
for 48 h at 25ºC with four different soil types – sandy loam, slit loam, low-humus sandy soil andsilty clay. The highest tested concentration of imidacloprid was approximately 290 mg/l. The soil
to water ratio was 1:4. Based on the soil-carbon sorption constant (Koc), the mobility ofimidacloprid could be classified as high in silt (Koc of 132) and medium in low-humus sandy
soil, silty clay and sandy loam (Koc of 157, 212 and 256, respectively).
In a subsequent study, aqueous solutions of [pyridinyl-14C-methyl]-imidacloprid were incubatedat 25ºC with four different soil types – sand, loamy sand, slit loam and loam. The mobility ofimidacloprid was classified as medium (Koc of 277-411; Williams et al, 1992).
A soil adsorption/desorption study was carried out to characterize the sorption properties of the
major metabolite of imidacloprid, desnitro-imidacloprid. Aqueous solutions of [14C]-desnitroimidacloprid were equilibrated at 25ºC with four different soil types – sand, loamy sand, slit
loam and loam. The highest tested concentration of desnitro-imidacloprid was approximately 250
ppm. The soil to water ratio was 1:3 for sand, loamy sand and 1:5 for slit loam. Desnitroimidacloprid had a stronger sorption affinity for soil than the parent compound. Based on the Koc
values, it can be classified as a medium mobility compound in sand (Koc 327) and low mobility
compound in loamy sand, slit loam and loam (Koc of 833, 942 and 866, respectively). Therefore,
desnitro-imidacloprid is less likely to leach through the soil than the parent chemical (Dyer et al.,1992).
II.G.4.b. Ambient Air
Preliminary ambient air monitoring studies were conducted in Santa Clara, Imperial and Butte
Counties, California (DPR 2001a; 2002 a,b,c). Ground applications of imidacloprid foliar spray
were used in residential properties, businesses, commercial parking lots, curbsides and publicparks in Cupertino (Santa Clara county), Imperial Spa (Imperial County) and Chico (Butte
County), which were infested with GWSS. A total of 8 air samples from the treated areas wereanalyzed at the time of application, 24 and 48 h post application. Information on the geographic
relationship between the location of the monitoring and the application site was not provided.
There were no imidacloprid detections in the air. The detection limit was 0.5 µg/sample.
II.G.4.c. Ground Water
The California Pesticide Contamination and Prevention Act (PCPA) of 1985 established a set ofdata requirements for identifying potential ground water contaminants. Pesticides withparameters exceeding Specific Numerical Values (SNVs) established by DPR, are considered topose a risk to ground water (Kollman and Guo, 2000). The SNVs include: Solubility (SNV>311ppm), Koc (SNV<1900 cm3/g), Hydrolysis (SNV>14 days), Aerobic Metabolism (SNV>610
days) and Anaerobic Metabolism (SNV>9 days). DPR identified imidacloprid as a potential
ground water contaminant based on its high water solubility (514 ppm), low Koc (262 cm3/g),long hydrolysis half-life (t1/2= 30 days), long aerobic soil metabolism (t1/2= 997 days) and longanaerobic soil metabolism (t1/2= 27 days). Recently, DPR developed analytical methods for
detection of imidacloprid residues to perform actual screening for imidacloprid and its
metabolites in the water of the California wells.
II.G.4.d. Surface Water
Preliminary surface water monitoring studies were conducted in Santa Clara, Imperial and Butte
Counties, California. Imidacloprid was applied via soil injection or foliar spray in areas infested
with GWSS (DPR 2001a; 2002 a,b,c). A total of 11 surface water samples were collected at fivecreeks and at a fishpond. The location of the monitoring sites was generally indicated as
upstream or downstream of the application area, however, more specific information was notprovided. Imidacloprid residues were not detected in any of these samples. The detection limit
was 0.05 ppb.
II.G.5. Field Dissipation
A series of field dissipation studies were performed at different sites (Georgia, Minnesota andCalifornia) with various soil types to evaluate the degradation and mobility of imidacloprid
under actual field conditions. Imidacloprid formulation 240FS (23.3% a.i. liquid suspension) wasapplied to the soil at the highest recommended rate of 0.5 lb a.i./acre. Soil core samples wereanalyzed for imidacloprid immediately post-application through 18 months. Each core wassectioned into 6-inch segments.
The half-life for imidacloprid dissipation in loamy sand and sandy loam was 12 days.
Imidacloprid applied to a field planted with corn had a half-life of 7 days. Residues at or above
the detection limit (10 ppb) were not detected below 0-6-inch soil depth (Rice et al., 1991a,b).
Imidacloprid applied to a tomato plot dissipated with a half-life of 53 days. Residues above thedetection limit (10 ppb) were detected below the 6-inch soil depth, indicating that the pesticide
had leached into the 6-12 inch soil dept (Rice et al., 1991c). The half-life for imidacloprid
dissipation in the turf grass was 61-107 days with no leaching below the 0-6 inch soil depth(Rice et al., 1992a,b).
The field dissipation studies revealed that imidacloprid had a shorter half-life under field
conditions (7 to 146 days), when compared to the half-life observed under aerobic laboratory
conditions (greater than 1 year, Anderson et al., 1991). This difference in the imidacloprid
stability was attributed to the combined effect of various dissipation pathways under field
conditions, including photolysis, hydrolysis, chemical and microbial degradation and plant
uptake.
II.G.6. Plant /Metabolism
Accumulation Studies on Rotational crops: [Pyridinyl-14C-methyl]-imidacloprid was applied to
sandy loam at an application rate of 454 g a.i./ha (Vogeler et al., 1992). The rotational crops red
beet, Swiss chard and wheat were planted after 30 days (first rotation), 120 days (second
rotation) and after 271 days (third rotation) after application of the pesticide. The plant parts,
which were analyzed for radioactivity included: wheat forage, wheat straw, wheat grain, Swiss
chard foliage, red beet leaves and red beet roots. The samples were analyzed from 0 to 412 days
post-application. The concentration of imidacloprid in the soil decreased from 0.36 mg/kg at day
12

0 to 0.13 mg/kg at day 412. The half-life for imidacloprid dissipation in soil was 179 days. The
major metabolite in the soil was 5-hydroxy imidacloprid (4.7% of the total applied radioactivity).
The residual radioactivity in plants and plant parts ranged from 0.07 mg/kg to 0.5 mg/kg in crop
I. The residual radioactivity in straw was higher (2.5 mg/kg in crop I), due to the process ofdehydration of green wheat. The decrease in radioactivity was the most in the wheat straw 2.5
mg/kg (crop I) to 0.9 mg/kg (crop III). Imidacloprid, taken up by the crops, was further
metabolized to several major products including desnitro-imidacloprid, 5-hydroxy imidacloprid
and 6-chloronicotinic acid. The rotational studies revealed that the plant uptake of imidacloprid
is one of its major dissipation pathways in the soil (Vogeler et al., 1992).
Rotational crop studies with imidacloprid were conducted in Massachusetts, Kansas andCalifornia, after a single soil application of imidacloprid (2.5% granular formulation) at a rate of
0.29-0.32 lb/acre (Minor, 1994). Cereal grain crops (wheat and sorghum), root crops (turnips)
and leafy vegetable crops (spinach and mustard green) were planted at 1, 4, 8 and 11- monthrotational intervals, which are typically used in the normal practice. Imidacloprid residues were
measured as 6-chloronicotinic acid. The highest residue level (1.81 ppm) was detected in cereal
forage and straw in California at the 1-month interval, which declined to 0.12 ppm at the 8month plant-back interval. Based on the rate of residue decline, the concentration of imidacloprid
in all rotational crops was calculated to be lower than 0.05 ppm at the 11-month interval after theapplication of the pesticide.

13

III. TOXICOLOGY PROFILE
III.A. PHARMACOKINETICS
Summary: Five pharmacokinetic studies with [14C]-imidacloprid in Wistar rats (strain
BOR:WISW SPF Cpb) were submitted to the DPR (Klein 1987, 1990a and 1990b; Klein andKarl 1990; and Klein and Brauner 1991a). There were two pharmacokinetic studies in laying
hens and two studies in lactating goats (Klein and Brauner 1990, 1991b; Klein, 1992 and Karl etal., 1991). All studies were performed at the Bayer AG Laboratory in Germany.
In the rat, imidacloprid was quickly and well absorbed from the gastrointestinal tract, rapidly
distributed in nearly all organs and tissues, and quickly passed through the body. The oral
absorption was estimated as 92-99%, based on the urinary recovery after oral and intravenous
dosing. Imidacloprid underwent degradation to a large number of metabolites formed by multiple
pathways, both alternative and sequential. The same, or similar metabolites were found in rats,
goats and hens. Based on structural considerations or potency relative to the parent compound,the following metabolites may be of toxicological significance: 6-chloronicotinic acid,imidazolidine 4- and 5- hydroxy compounds, olefinic imidacloprid, desnitro-imidacloprid andthe nitrosoimine compound. Metabolites were excreted primarily in the urine as glutathione andglycine conjugates of mercaptonicotinic acid and hippuric acid. Pharmacokinetic studies were
not available for a direct determination of the rate of absorption from dermal and inhalationroutes.
III.A.1. Absorption
III.A.1.a. Oral Absorption
To investigate the oral absorption of imidacloprid, Wistar rats (5/sex/dose) received a single
intravenous (i.v.) dose of 1 mg/kg or single oral doses of 1 and 20 mg/kg of 14C-imidacloprid(methylene-labeled, 150.7 μCi/mg; Klein, 1987; Klein and Karl, 1990). These doses
corresponded to 0.2% and 5% of the rat oral LD50 (424 mg/kg, Table 1) and did not cause toxic
signs. In parallel experiments, rats were pre-loaded for 14 days with non-radiolabeledimidacloprid (1 mg/kg) and then received single oral doses of 1 mg/kg or 20 mg/kg 14Cimidacloprid. Additional tests were carried out to measure the radioactivity in the expired CO2 in
5 male rats, which received a single oral dose of 20 mg/kg 14C-imidacloprid. To characterize thebile excretion, five more rats were bile-fistulated, prior to receiving intraduodenally a single doseof 1 mg/kg 14C-imidacloprid (Klein, 1987).
In the above studies, imidacloprid was labeled with 14C in the methylene moiety. Because nearly
half of the identified metabolites did not contain the imidazolidine moiety, a comparative study
was conducted, using imidacloprid labeled with 14C in the 4- and 5- position of the imidazolidine
moiety (Klein and Brauner, 1991a). In the later experiments, radiolabeled imidacloprid wasgiven as a single oral dose to 5 male and female rats at 1 mg/kg; or to 5 male rats at 150 mg/kg.
There were no major differences in the behavior of the total radioactivity between the methyleneand imidazolidine-radiolabeled imidacloprid.
The absorption of orally administered 14C-imidacloprid was rapid as evidenced by the calculated
lag-time of less than 2.5 min. The average half-life of absorption was estimated as about 35 min(for both sexes and all dose-groups). After oral administration of 1 mg/kg or 20 mg/kg [14C]imidacloprid, the plasma concentrations reached maximum between 1.1 h and 2.5 h at; and at 4 h
14

after 150 mg/kg (Klein, 1987; Klein and Brauner, 1991a). Approximately 90-98% of theadministered radioactivity was recovered within 24 h. Adjusted for 100% mass balance, theaverage radioactivity recovered in the urine within 48 h was 78% (males) and 74% (females) at 1
mg/kg imidacloprid. At 20 mg/kg imidacloprid, these values were and 77% and 82% for males
and females, respectively. The urinary recovery after 14 day-preloading was in the same range(74% for the males and 75% for the females (Klein and Karl, 1990). Adjusted for 100%
recovery, the 48-hour radioactivity in the feces was 18-26% of the administered activity.
The major urinary metabolites were 6-chloronicotinic acid and its glycine conjugate (WAK3583), which represented about 30% of the recovered radioactivity (Klein and Karl, 1990; Fig.
2). Additional urinary metabolites included 5-OH-imidacloprid (WAK 4103, 15-18%), the parent
compound (9-15%) and olefinic imidacloprid (NTN 35884, 8-13%). Metabolites identified in thefeces included a glycine conjugate of 6-methylmercaptonicotinc acid, imidacloprid, olefinic
imidacloprid and desnitro-imidacloprid (all at 2-3%).
Figure 2. Chemical Structure of Imidacloprid Metabolites Containing the 6-Chloropyridinyl
moiety.

NH

N
Cl

NH

N

N

N

Cl

NO2

Imidacloprid (NTN 33893)

N

NH

Desnitro-imidacloprid (Guanidine, NTN 33823)
HO

NH

N
Cl

N

N

Cl
NO2

Olefinic-imidacloprid (NTN 35884)

Cl

N

N

N

N

NO2

5-OH-imidacloprid (WAK 4103)

NH

N

NH

N

COOH
Cl

NO

Nitrosoimine-imidacloprid (WAK 3839)

N

6-Cl-nicotinic acid (WAK 3583)

15

Experiments with bile-fistulated rats confirmed that the absorption of imidacloprid was nearlycomplete (Klein, 1987). After intraduodenal dose of 1 mg/kg, the total radioactivity recovered in
the urine and in the bile was about 95%. Less than 1% of the radioactivity was left in the carcass
after 48 h. Very little radioactivity (< 0.2%) was recovered in the expired air in males, which
received 1 mg/kg imidacloprid. The oral absorption can also be estimated by comparing theurinary recovery from oral and from i.v. dosing. In rats, which received 1mg/kg 14Cimidacloprid, the estimated oral absorption was 92-99%. Together, these results demonstrated
that imidacloprid was completely (100%) absorbed via the oral route in rats.
The absorption of imidacloprid was studied in Caco-2 cell line, derived from a human colon
adenocarcinoma (Brunet et al., 2004). Caco-2 cells are commonly used as an in vitro model topredict the intestinal absorption of drugs and chemicals in humans, because they have properties
similar to the intestinal mucosa (Yamashita et al., 2000). The apical and basolateral sides of
Caco-2 cells represent the luminal and blood sides, respectively, of the gastrointestinal tract invivo. For a large number of model compounds a correlation has been established between
permeability in the Caco-2 system and the fraction absorbed in humans (Artursson et al., 2001).
In the Caco-2 system, imidacloprid crossed the trans-epithelial layer very quickly at 37°C. Basedon the apparent permeability coefficient (22x10-6 cm/s) imidacloprid could be classified as ahighly absorbed compound, presenting 100% efficiency of in vivo absorption in humans. Both,the uptake and the efflux of imidacloprid were energy-dependent and sensitive to pretreatment of
the cell surface with trypsin. These results suggested that imidacloprid may be absorbed in vivo
by inward and outward active transport systems.
III.A.1.b. Dermal and Inhalation Absorption
There were no pharmacokinetic studies to determine the rate and extent of imidacloprid
absorption upon inhalation exposure or via the dermal route. In the absence of data for inhalation
uptake, both the DPR and the USEPA assume a default of 100%. The dermal absorption could be
estimated by comparing the oral and dermal LD50. The ratio between the oral and dermal LD50
for rats was 8.5% (see Table 1 and studies by Bomann, 1989b and Krotlinger, 1989). An oral
developmental toxicity study and a 28-Day subchronic dermal toxicity study in rabbits were theonly available studies to compare the oral and dermal thresholds. The developmental toxicity
study established a maternal LOEL of 72 mg/kg/day (Becker and Biedermann, 1992; Section
III.G.2. under DEVELOPMENTAL TOXICITY). A LOEL could not be determined from the 28day dermal study in rabbits, because no toxicity was observed at the only tested dose of 1000
mg/kg/day (Flucke, 1990, Section III.C.4 under SUBCHRONIC TOXICITY). A dermal
absorption of 7.3% could be calculated from the oral LOEL of 72 mg/kg/day and from a dermal
NOEL of 1000. However, this dataset may not provide a reliable estimate of the dermal
absorption, because a dermal toxicity threshold was not clearly defined in the 28-day dermal
study.
III.A.2. Distribution
III.A.2.a. Tissues and Organs
Analysis of the basic pharmacokinetic parameters revealed that imidacloprid was widely andrapidly distributed in the rat body. This was evidenced by (i) the large apparent distribution
volume (Vc), which accounted for about 84% of the total body volume distribution volume and(ii) by the short half-life for distribution of the radioactivity after an i.v. administration (3 h). The
same half-lives for distribution of the radioactivity (2.6-3.6 h) were calculated after single oral
16

doses of 1 and 20 mg/kg or after multiple doses of 1 mg/kg. To quantify the radioactivity in thebody, male rats were sacrificed at 1-48 h (5 animals/ time point) after oral administration of 20
mg/kg 14C-imidacloprid. Imidacloprid had a high ability to permeate tissues, as radioactivity was
detected in all of the 13 tested tissues and organs. All tested organs contained the highest
radioactivity at 40 min to 1.5 h after dosing. The highest concentrations were measured in thegastrointestinal tract, liver, kidney, lung and heart. The respective concentrations (P) 1 of theradioactivity in these tissues normalized to dose were 4 (GI), 1.3-1.7 (liver and kidney), 0.9(lung) and 0.74 (heart). The brain, which is a presumed target for imidacloprid, was not among
the tissues and organs analyzed for radioactivity. Overall, the results from the distribution studies
indicated that there was no dependence on dose, sex or pretreatment.
The whole body autoradiography confirmed the findings from the quantitative pharmacokinetic
studies. In these experiments, one male rat was injected intravenously with 20 mg/kg methylenelabeled 14C-imidacloprid and sacrificed 5 min later (Klein, 1987). Six more male rats received
the same dose orally and were sacrificed in a period of 1-to 48 h. Sections from the fixed rats
were then prepared for autoradiography. Five min after an i.v. injection, the concentration of theradioactivity in the blood was lower than in many of the organs such as liver, kidney, muscle andthyroid, thus indicating a fast turnover of imidacloprid. One hour after an oral administration,
imidacloprid was readily absorbed from the gastrointestinal tract, as the radioactivity was foundin nearly all organs and tissues. The high labeling of the liver and over the entire kidney was
indicative of an ongoing biotransformation and renal excretion. Other tissues with increased
radioactivity included the glandular organs (adrenal, thyroid and salivary glands) and connective
tissues associated with the skin, walls of aorta and spinal cord. The intensive labeling over thekidney at 4 and 8 h was consistent with the high rate of renal excretion estimated in thequantitive pharmacokinetic study (about 60% at 8 h). Radioactivity was also found in the CNS,
thus indicating that imidacloprid and its metabolites penetrated the blood-brain barrier. However,of all analyzed organs and tissues, the fatty tissues and the CNS had the lowest labeling.
III.A.2.b. Milk, Meat and Eggs
The USEPA has established tolerances for imidacloprid and its metabolites containing the 6chloropyridinyl moiety on milk (0.1 ppm), meat (0.3 ppm) and eggs (0.02 ppm; CFR 2003a).
Tolerances are the highest level of residues permitted in agricultural commodities. Four residue
studies with methylene-labeled-14C-imidacloprid in hens and goats were available on file in the
DPR.
Goat: [14C-methylene]Imidacloprid was administered to one 41 kg lactating goat by intubation inthree consecutive daily doses of 10 mg/kg. The goat was sacrificed 2 h after the last dose (Karl etal, 1991; Klein, 1992). The highest plasma concentration of 3.98 mg/ml was measured after 2 hof last dosing. The highest radioactivity of 3.16-3.65 µg/g in the milk was determined 8 h after
the first dose and 2 hours after the third dose; the concentration in the milk prior to second
dosing was 2.77 µg/g. Assuming a daily milk production of about 2 liters, the radioactivity in themilk was about 0.4% of the total administered radioactivity. The total residue in the edible
tissues and organs measured two hours after the third dose was about 5% of the administeredradioactivity. The respective residual radioactivity in the edible tissues was 1.3% (liver), (0.1%)

1

P, Relative concentration defined as:
P=Radoactivity (grams) of tissue/radioactivity administered (grams) of body weight
17

kidney, (3%) muscles and 0.4% (fat). The main compounds in the milk and the edible tissues
were imidacloprid, olefinic imidacloprid (NTN 35884) and 4- and 5-OH-imidacloprid.
Hens: Five laying hens were intubated with 10 mg/kg methylene-labeled- 14C-imidacloprid for 3
days (Klein and Brauner 1990, 1991b). The highest radioactivity of 0.34 µg/ml in the plasma
was measured at 0.5 h after the third dosing. At that time, the total residue in the edible tissues
and organs was about 3% of the total dose. The highest radioactivity of 1.347 µg/g in eggs wasfound 2 h after the last dose. This level was less than 0.2% of the total administered radioactivity.
The main metabolite in the eggs was the olefine-imidacloprid. Olefine- and desnitroimidacloprid were detected in muscle and kidney tissues.
III.A.3. Metabolism
Based on the profile of the metabolites, two major routes were proposed for the imidacloprid
metabolism in the rat (Fig. 3, Klein and Karl, 1990; Thyssen and Machmer, 1999). In the firstroute, imidacloprid undergoes oxidative cleavage to imidazolidine and 6-chloronicotinic acid.
The imidazolidine is directly excreted via the urine. The nicotinic moiety is detoxified via
glutathione conjugation to a derivative of mercapturic acid and then to mercaptonicotinic acid.
The mercaptonicotinic acid is, in turn, conjugated with glycine to hippuric acid-conjugate forexcretion. The second route involves hydroxylation in the imidazolidine ring, followed byelimination of water and formation of an unsaturated metabolite (olefinic imidacloprid NTN
35884). The metabolism in hens and goats was similar to that in rats (Klein and Brauner,
1991a,b; Karl et al., 1991; Klein 1992).
Studies with recombinant human isozymes of CYP450 have suggested that a single isozyme,
CYP3A4, both oxidizes and reduces imidacloprid at the imidazolodine and nitroimine moieties(Schulz-Jander and Casida, 2002). A major metabolite upon incubation of imidacloprid with thehuman microsome-NADPH system was tentatively identified as a derivative of hydrazone (the=N-NO2 moiety becomes = N-NH2 or desnitro-imidacloprid). Based on these results, a yetunidentified microsomal NADPH-nitro reductase was implicated to bioactivate imidacloprid inhumans into the more toxic metabolite desnitro-imidacloprid (Schulz-Jander et al., 2002).
In rats, there were no sex differences in the metabolic profile at the lower dose (1 mg/kg
imidacloprid (Klein and Karl, 1990). However, male rats showed an increased ability tometabolize higher doses of imidacloprid (20 mg/kg), resulting in significantly lower amount of
the parent compound and an increased level of the metabolite olefinic imidacloprid. The
formation of other biotransformation products was similar in males and females.
From a toxicological point of view, the formation of the metabolite desnitro-imidacloprid (NTN
33823) in rats is of particular interest, because of the following considerations: (i) this metabolite
displayed a nicotinic-type action with a markedly higher toxicity to mammals than imidacloprid,(ii) desnitro-imidacloprid was identified as the major degradation product of imidacloprid in theenvironment (i.e. the major photodegradate and the major product of microbial and plant
metabolism) and (iii) desnitro-imidacloprid was a major metabolite produced in vitro withhuman liver microsomes. In rats, desnitro-imidacloprid was identified only in the feces andrepresented a relatively small amount of the total recovered radioactivity (about 2-3%, Klein,
1987). In hens, desnitro-imidacloprid was detected in eggs, muscle and fat tissues (5-12%, Klein
and Brauner 1990, 1991b).
An additional biotransformation product of imidacloprid, the nitrosoimine metabolite WAK
3839, was identified in the urine of chronically fed rats and mice (1 year, 1800 ppm, Klein,18

1990b). WAK 3839 represented about 9% of total urinary radioactivity. Since this metabolite
was not found after a single dosage of up to 150 mg/kg, it was proposed that the reduction of theNO2-moiety of imidacloprid takes place only if the enzymes catalyzing other biotransformation
reactions (e.g. oxidative cleavage to 6-chloronicotinic acid) are saturated by chronic “flooding”
of the liver with imidacloprid. In rats, the acute toxicity of WAK 3839 was about 5-fold lower
than that of imidacloprid (Kaoru, 1991).
The toxicity of the major metabolites of imidacloprid in rats, (6-chloronicotinic acid 4- or 5-OHimidacloprid and olefinic imidacloprid) has not been evaluated in mammals. Studies ininvertebrates showed that the olefinic- and hydroxy- compounds had similar acute toxicity to theparent compound, whereas the 6-chloronicotinic acid did not act as a nicotinic agonist (Nauen, etal., 2001a,b). All of these compounds contain the 6-chloropyridinyl moiety and are included in
the tolerances established for the imidacloprid residues (Fig. 2).
III.A.4. Excretion
The half-lives for excretion of the radiolabeled imidacloprid were calculated in rats after a single
i.v. dose of 1 mg/kg, after single oral doses of 1 and 20 mg/kg or after multiple doses of 1 mg/kg
Klein, 1987). The excretion half-life values varied greatly (from 26 h to 118 h), but the variation
was not dose-, sex-, or route-dependent. In all dose groups, less than 1% of the radioactivity wasleft in the body after 48 h of dosing. The results from the whole body autoradiography
confirmed that within 24-48 h the radioactivity was nearly eliminated from the body, with skin,nasal mucosa, liver, kidney and the thyroid being the only tissues with residual radioactivity.
Altogether, these data indicated that imidacloprid did not significantly accumulate in the rat
body.
III.A.5. Chemical Interactions and Toxicity Variation
Metabolic modifiers and other pharmaceutical drugs have been shown to modify the toxicity ofimidacloprid. The CYP450-inhibiting piperonyl butoxide synergized the toxicity of imidacloprid(Liu et al., 1993). In subchronic and chronic feeding studies, mice developed hypersensitivity toether, which was used as anesthesia during procedures such as blood withdrawal and tattooing(Eiben, 1988b, Watta-Gebert, 1991). These animals exhibited dyspnea, respiratory failure andspasms and died shortly after administration of ether. The specific mechanism of theimidacloprid-induced hypersensitivity to ether is presently unknown. This effect needs to beconsidered when assessing the toxicity of imidacloprid to humans, since it may reduce the abilityof the body to respond to an additional challenge with xenobiotics.

19

Figure 3. Biotransformation Pathways of Imidacloprid

Cl

N

NH

N

NH

N

Cl

NH
Desnitro-Imidacloprid
NTN 33823

N

N

Imidacloprid

NO2

HO
Mercapturic acidderivative of
6-Cl-nicotinic acid

COOH

COOH
S

OH

N

N

6-Hydroxynicotinic acid

CH2

COOH
Cl

NO2

COOH

Cl

+ Cl

N

N

N

NO2

Olefinic Imidacloprid
NTN 35884

O
C

NH

N
Cl

NHCH2COOH

N(From Thyssen and Machmer, 1999)
20

NO2

4-OH-Imidacloprid

NHCH2COOH

WAK 3583

Glycine conjugate of
6-mercaptonicotic acidN

WAK 4103

N

N

NH

N

O
C

H2CS

N

5-OH-Imidacloprid

COOH

H2CS

N

6-chloronicotinic acid

HCNHAcMetylmercaptonicotinic acid

NH

N
Cl

N

OH

III.B. ACUTE TOXICITY
Summary: Acute toxicological studies are conducted to establish the median lethal dose (LD50)
or concentration (LC50), which in turn are used to determine the toxicity category of the technicalgrade and the formulations. Depending on the dose range used in the test, it may be possible toestablish an acute NOEL (No-Observed-Effect Level) from these limited studies. In risk
assessment, the NOEL is commonly used to define the threshold dose for non-oncogenic effects.
The NOEL is the experimentally determined highest dose at which no effects were observed.
In acute toxicological studies with two rodent species, imidacloprid caused clinical signs
characteristic for nicotine intoxication, such as incoordination, tremors, spasms and respiratory
difficulties. Other symptoms included decreased motility and lethargy. Mice appeared to be moresensitive to the acute toxicity of imidacloprid than rats. Presently, there is no specific antidote,
which acts as an antagonist to the effects imidacloprid. Imidacloprid did not produce skin or eye
irritation in rabbits, or dermal sensitization in guinea pigs. The studies on acute lethality andirritation are summarized in Table 2. NOELs and Lowest-Observed-Effects-Levels (LOELs) for
non-lethal effects are presented in Table 3. NOELs and LOELs were based on clinical findings
and were determined only from studies, which employed sufficient number of animals (i.e., atleast 5 per dose group), included a range of doses and provided experimental details on thetreatment protocol and the observations.
III.B.1 Acute Toxicity in Animals
III.B.1.a. Median lethal dose and toxicity category
Oral-Rat: To assess the acute oral toxicity, technical grade imidacloprid (94.2%) was
administered by gavage as an aqueous suspension to fasted Wistar rats (strain BOR:WISW SPF
Cpb, Bomann, 1989b). There were five animals/sex per each of the eight dose groups, which
received a single dose of imidacloprid. The doses were 50 (males only), 100, 250, 315, 400, 475(females only), 500 and 1800 mg/kg. Clinical signs were evident within 15-40 min after
treatment at doses higher than 50 mg/kg in males and 100 mg/kg in females. The main symptoms
included apathy, labored breathing, tremors, gait incoordination, decreased motility, nasal andurine staining. Mortality was first observed at 400 mg/kg (20% both sexes) and increased
abruptly to 100% at 500 mg/kg. Deaths occurred within 3-7 h following treatment. The medianlethal dose (LD50) for rats was calculated as 424 mg/kg for male rats and 450-475 mg/kg for thefemale rats (Table 2). The NOEL for systemic effects was 50 mg/kg, based on the clinical signs
observed at the LOEL of 100 mg/kg (Table 3).
Oral-Mouse: The acute oral toxicity of imidacloprid was studied in mice (strain Bor:NMRISPF, 5/sex/dose; Bomann 1989a). Imidacloprid (94.2%) was given to the mice via gavage at
doses of 10, 71 (males only), 100, 120, 140, 160 and 250 mg/kg (Table 1). The animals wereobserved for clinical signs and gross pathology. Toxic signs were noted at doses higher than 10
mg/kg. All 5 males treated with 71 mg/kg/day imidacloprid showed apathy and laboredbreathing; decreased motility was noted in 2 males, and one male had tremors. In addition tothese toxic signs, staggering gait and severe trembling were also reported at higher doses (100250 mg/kg). The lowest tested dose, which caused death was 100 mg/kg (20% of the male micedied); 20% of the females died at 120 mg/kg. The toxicity was evident in a relatively brief time(within 5-10 min) following imidacloprid administration. The LD50 was calculated as 131 mg/kg
for male mice and 168 mg/kg for the female mice (Table 2). The NOEL for systemic toxicity
was 10 mg/kg, based on clinical signs in the males observed at the LOEL of 71 mg/kg (Table 3).
21

Table 1. Effects of Imidacloprid in Mice After a Single Gavage Dose (Bomann 1989a).
Acute
Time
Effecta
Doses mg/kg
No. of Mice Tested
10’-1hMortality
5’-4hApathyDecreased 5’-5hmotility
5’-7hLaboredbreathing
1h-2hTremorSpamsodic 5’-1h
state
Staggering 5’-1h
gait

Males

Females

10

71

100

120

140

160

250

10

100

120

140

160

250

5
0
0
0

5
0
5
2

5
1
5
5

5
2
5
5

5
2
5
5

5
5
5
5

5
5
5
5

5
0
0
0

5
0
5
5

5
1
5
5

5
1
5
5

5
2
5
5

5
5
5
5

0

5

5

5

5

5

5

0

5

5

5

5

5

0
0

1
0

2
1

3
2

0
2

5
5

5
4

0
0

5
0

1
1

5
1

5
5

5
5

0

0

2

5

5

5

5

0

5

5

5

5

5

a/ Intensity of clinical signs were as 1 for the males at 71 mg/kg/d and 1-2 for the females at 100 mg/kg. The intensity of clinicalsigns at the higher doses was graded as 2 or 3.

Inhalation-Rat: Imidacloprid was assessed for acute inhalation toxicity in Wistar rats (Pauluhn,
1988a). Five animals/sex/dose were exposed by head/nose only to imidacloprid in the form of
dust (95.3% a.i.) for 4 hours. The concentrations of imidacloprid were 1220, 2577 and 5323
mg/m3 (Table 3). The control groups received air alone. At these concentrations, 89%, 94% and
96% of the dust particles, respectively, had an aerodynamic droplet size (MMAD) larger than 5µm. Particles with MMAD of >5 and up to 10 µm deposit predominantly in the nasopharyngeal
region (head airway region) in rats. Particles with MMAD of < 5 μm deposit in the bronchialregion and the deeper lung airways of rats (Raabe et al., 1988; SOT, 1992; Pauluhn, 2003). Toxic
signs were produced within 4-6 h of the treatment with concentrations higher than 1220 mg/m3,
and included difficult breathing, reduced motility, piloerection and tremors. None of the animals
died as a result of the treatment. The LC50 was >5323 mg/m3. The NOEL for acute inhalation
toxicity was 1220 mg/m3, based on clinical signs at the LOEL of 2577 mg/m3. Using a rat default
breathing rate of 0.96 m3/kg/day, the LOEL 2 and the NOEL2 could be calculated as 412
mg/kg/day and 195 mg/kg/day3, respectively (Table 3). However, it is uncertain whether thelater dose is the NOEL for the acute inhalation toxicity, because of the possible limited
2

Equivalent dosages were calculated by using the rat default breathing rate of 0.96 m3/kg/day inthe following equations:
Dose (mg/kg/day) = Concentration (mg/m3 )x0.96 m 3 4 hours
xkg.day 24 hours

22(1 day exposure)bioavailability of imidacloprid due to the large particle size of the dust. For inhalation toxicantscausing systemic effects, rather than local toxicity, particles that deposit to any region of therespiratory tract (i.e. MMAD of ≤ 10 µm) may be considered as bioavailable (Raabe et al.,1988). However, the study provided data on the percentage of particles with MMAD ≤ 5 µm.
Adjusting the dose of 195 mg/kg/day for 11% of particles with MMAD ≤ 5 µm would result inan acute inhalation NOEL of 20 mg/kg/day.
In a supplemental study using the same experimental protocol, rats were exposed to a liquid
aerosol of imidacloprid (Pauluhn, 1988a). The aerosol was prepared from 2.5% imidacloprid in
Lutrol as a vehicle. A single analytical concentration of 69 mg/m3 was administered to the rats
by head/nose only for 4 h. The equivalent dose2 could be calculated as 11 mg/kg/day. This wasreported as the highest concentration of imidacloprid, which was attainable in the form of aliquid aerosol. Control animals received aerosol alone. Clinical signs or mortalities were notobserved during the 14 day-observation period. This study was considered unacceptable by the
DPR as a fulfillment of the requirement for acute inhalation toxicity data, because themethodology to determine the analytical concentration of imidacloprid was not provided.
In a parallel subacute inhalation toxicity study, 10 Wistar rats/sex/group were exposed byhead/nose only to imidacloprid dust 6 hours/day for 5 days (Pauluhn, 1988a). The concentrationsof imidacloprid were 20, 109 and 505 mg/m3 (Table 3). At these concentrations, 46%, 43% and
82% of the dust particles, respectively, exceeded in size the 5 µm respirable range in rats. The
control groups received air alone. This study included more elaborated toxicity evaluation (e.g.
clinical signs, clinical chemical, hematological and histopathological changes) for a period of 2
weeks after the treatment. The clinical chemistry tests revealed that 5 days of exposure to 109
mg/m3 imidacloprid induced the mixed-function oxidases (MFO) in the liver of about 28%(p<0.01, males) and 142% (p<0.01, females). In addition, 6% (p<0.01) reduction of the bodyweights occurred in the females after 4 days of exposure to 109 mg/m3 imidacloprid. The
activities of the liver MFO in the rats from the 505 mg/m3 were not measured. Mortalities orother cumulative toxic effects were not observed. The author of the study considered theinduction of the MFO and the reduction in body weights at 109 mg/m3 imidacloprid astreatment-related effects and concluded that 20 mg/m3 imidacloprid did not cause toxicity after 5days of inhalation exposure. The equivalent dose 4 could be calculated as 3.2 mg/kg/day.
Adjusting dose of 3.2 mg/kg/day for 54% of particles with MMAD ≤ 5 µm would result in an
NOEL of 1.7 mg/kg/day. This study was considered by the DPR as supplemental information.
Intraperitoneal-Rat: Imidacloprid (94.2%) was studied for acute intraperitoneal (i.p.) toxicity in
Wistar rats (5 animals/sex/dose) (Krotlinger, 1990). The tested doses were: 10, 100, 160, 170,
180, 200, 250 and 500 mg/kg (males) and 10, 100, 150, 180, 200, 224 and 250 mg/kg (females).
Toxic signs were produced within 5 min of treatment with doses higher than 10 mg/kg, andincluded tremors, apathy, reduced motility, phtosis and labored breathing. Mortalities occurredfrom a dose of 170 mg/kg. At this dose, 80% percent of the male rats died within 2.5-5 hours oftreatment; 40% of the female rats died at 180 mg/kg. The LD50 for the i.p. administered
4

Equivalent dosages were calculated by using the rat default breathing rate of 0.96 m3/kg/day inthe following equations:
Dose (mg/kg/day) = Concentration (mg/m3 )x0.96 m 3 6 hours 5 daysx
x
kg.day 24 hours 7 days

23

imidacloprid was estimated as 186 mg/kg/day for female rats and 160-170 mg/kg for male rats
(Table 2). The NOEL was 10 mg/kg, based on toxic effects at the LOEL of 100 mg/kg.
Intraperitoneal-Mouse: In a study published in the open literature, male Swiss-Webster mice
were treated intraperitoneally with imidacloprid and with its metabolite, desnitro-imidacloprid(Chao and Casida, 1997). Both compounds were dissolved in DMSO, however further
experimental details such as the number of animals, doses and the treatment protocol were notprovided. The LD50 for imidacloprid was reported as 39-49 mg/kg, whereas the lethal potency ofthe metabolite desnitro-imidacloprid was significantly higher (7-24 mg/kg, Table 2). Tremors
were observed in mice, which were treated with near-lethal or lethal dose levels, but the exact
doses were not shown.
Dermal-Rat:
In an acute dermal toxicity study, imidacloprid (94.2% in 0.9% NaCl) was applied as a paste to
the shaven area of the back of Wistar rats (5/sex) at a dose of 5000 mg/kg (Krotlinger, 1989).
The treatment site was covered during the 24-hour exposure period. Imidacloprid did not cause
toxic signs and mortalities. The pathological evaluation did not reveal treatment-related changes.
The acute dermal LD50 of imidacloprid in rats was >5000 mg/kg (Table 2).
Primary Dermal Irritation-Rabbits: Imidacloprid (94.2% a.i.) was tested for irritation
potential on the skin of rabbits (Pauluhn, 1988b). Three animals were treated with 500 mg
imidacloprid mixed to a paste in water. The treatment site was covered during the 4-hour
exposure period. The skin was then examined for erythema and edema 14 days post-treatment.
One animal developed erythema 1 h after treatment, which was graded as 1 (slight) in the scaleof 1 to 6; and was cleared within 24 hours. Based on these results, the technical grade
imidacloprid was regarded by the DPR as “not an irritant to skin” (Table 2).
Primary Eye Irritation-Rabbits: Imidacloprid (94.2% a.i.) was tested for irritation potential in
the eyes of rabbits (Pauluhn, 1988c). Three animals received about 60 mg imidacloprid/eye in
0.1 ml physiologic solution. Conjuctival irritation was graded as 2 in a scale of 1 to 3 following 1
h of treatment. The irritation was cleared within 24 h. This study showed that imidacloprid did
not possess a local irritant potential to the eye (Table 2).
Based on the LD50 and LC50, technical imidacloprid (94.2% pure) is a Category II oral toxicant(oral LD50 greater than 50 mg/kg, but lower than 500 mg/kg), Category III dermal toxicant(dermal LD50 between 2000 to 20,000 mg/kg), Category IV inhalation toxicant (greater than 20
mg/liter or 0.02 mg/m3), Category IV eye irritant (no irritation) and a category IV dermal irritant(caused erythema in rabbits that was cleared by 48 hours).
The median lethal doses (LD50) or median lethal concentrations (LC50) for imidacloprid(technical grade and formulations) and its metabolite desnitro-imidacloprid are listed in Table 2.

24

Table 2. Acute LD50 and LC50 Values for Imidacloprid and its Metabolite Desnitro-Imidacloprid.

AnimalSpecies

LD50 (mg/kg) or LC50 (mg/m3)
Route of Exposure

Males

References

Females

Imidacloprid (technical grade 94-98%)
Mouse

Oral

131

168

Bomann 1989a

Mouse

Intraperitoneal

39-

Chao and Casida, 1997

Rat

Oral

424

450-475

Bomann, 1989b

Rat

Intraperitoneal>160 <170

186

Krotlinger, 1990

Rat

Dermal

>5000

>5000

Krotlinger, 1989

Rat

Inhalation 4h dust

>5300a,b,e>5300

Pauluhn, 1988a

Rat

Inhalation 4h aerosol>69c,d,e>69

Pauluhn, 1988a

RabbitDermalNot an irritantPauluhn, 1988b

RabbitEye

Not an irritantPauluhn, 1988c

Desnitro-Imidacloprid
Mouse

Intraperitoneal

7-24

-

Chao and Casida, 1997

Imidacloprid (formulation 23%)
Rat

Oral

>4870

4143

Sheets, 1990a

RabbitDermal

>2000

>2000

Sheets, 1990b

a/ Only 4-11% of the particles had an aerodynamic droplet size <5 µm.
b/ The equivalent dose could be calculated as > 848 mg/kg/day, using a rat default breathing rate of 0.96 m3/kg/day in thefollowing formula:

Dose (mg/kg/day) = Concentration (mg/m 3 )x

0.96 m 3
4 hours.x
kg.day24 hours

c/ 100% of the particles had an aerodynamic droplet size <5 µm; max concentrationd/ The equivalent dose could be calculated as 11 mg/kg/day, using the formula in b.
e/ No effect at this dose.

25

Table 3. Acute No-Observed-Effect Levels (NOELs) and Lowest-Observed-Effect Levels(LOELs) for Imidacloprid.
Acute Study
Species
Exposure

NOEL LOEL
mg/kg/day

Oral (gavage)Rat
5/sex/dose 1 dose50

Oral (gavage)
Mouse
5/sex/dose 1 dose

10

Inhalation
Rat
5/sex/dose 4 h (dust)

192c

Inhalation
Rat
6h/day for 5
10/sex/dosedays (dust)

3.4dStudy Description

Doses (mg/kg/day): 50 (males only), 100, 250, 315,
400, 475 (females only), 500 and 1800 (Bomann,
1989b)
100
Effects at LOEL: Apathy, labored breathing,tremors, gait incoordination, decreased motility, nasal
and urine staining
Doses (mg/kg/day): 10, 71 (males only), 100, 120,
140, 160 and 250 (Bomann, 1989a)
71
Effects at LOEL: labored breathing, decreased
motility, staggering gait and trembling
Concentrations: (mg/m3): 0, 1220, 2577 and 5322
(Pauluhn, 1988a)
412 Dosesa (mg/kg/day): 0, 192, 412 and 848
Effects at LOEL: Difficult breathing, reduced
motility, piloerection and tremors
Concentrations: (mg/m3): 0, 20, 109 and 505(Pauluhn, 1988a)
Dosesb(mg/kg/day): 0, 3, 19 and 87
19d
Effects at LOEL: Induction of MFOf in the liver(28%** males, 142%** females; p<0.01); 6%**
(p<0.01) reduction in body weights of femalesa/ The dosages were calculated using a the following formula in Table 1.
b/ The dosages were calculated a rat default breathing rate of 0.96 m3/kg/day in the following formula:

Dose (mg/kg/day) = Concentration (mg/m 3 )x

0.96 m 3
6 hours 5 days.x
x
kg.day24 hours 7 daysc/ Only 4-11% of the particles had the recommended aerodynamic droplet size <5 µm.
d/ Only 57-18 % of the particles had an aerodynamic droplet size <5 µm.
f/ MFO, Mixed-Function Oxidases;**, Statistically significant difference from controls at p ≤ 0.01 (Fisher’s Exact test)
Note that the toxic signs were evident in a relatively brief time (within 5-40 min) after an oral exposure and in 4-6 h after aninhalation exposure.

III.B.1.b. Additional Acute Toxicity Studies
Other toxicological studies may also be useful for identifying acute NOELs, if toxic effects areobserved after a single dose (e.g., teratological effects) or short-term of exposure (developmental
or neurotoxic effects). Because the nervous system is the main target of imidacloprid, the toxicity
thresholds established from the neurotoxicity studies (Section III.H) are particularly pertinent.
The selection of the critical NOEL for characterizing the risk from acute exposure toimidacloprid is presented in Section IV.A.2. under RISK ASSESSMENT.

26

III.C. SUBCHRONIC TOXICITY
Summary: Seven subchronic toxicity studies were submitted to the DPR to characterize theeffects of imidacloprid in rats, mice, dogs and rabbits. These included 96- and 98-Day dietarystudies in rats, a 107-Day oral study in mice, 28-Day and 13-Week oral studies in dogs, a 3Week dermal treatment in rabbits and a 4-Week inhalation study in rats.
The most common toxic effect observed in the subchronic oral toxicological studies in rats, miceand dogs was a reduction in body weight. The liver was the principal target organ as
demonstrated by the hepatic necrosis or hypertrophy in rats and dogs. The liver toxicity was
further evidenced by the elevated activities of transaminases, alkaline phosphatase and glutamate
dehydrogenase in the serum, and alteration of other clinical chemistry parameters such as
triglycerides, cholesterol and the blood clotting time. Additional morphological effects included
testicular degeneration in rats and dogs; atrophy of thyroid gland and bone marrow, andadvanced involution of the thymus in dogs. Imidacloprid was a potent inducer of the hepatic
mixed-function oxidases. In the oral toxicity studies, dogs appeared to be the most sensitive
species. Subchronic exposure of dogs to imidacloprid resulted in severe tremors, which ischaracteristic for nicotine intoxication.
III.C.1. Oral Studies – Rat
The toxicity of imidacloprid (92.8%) was evaluated in Wistar rats for a period of 98 days (Eiben,
1988a). Ten rats/sex/ were exposed daily to imidacloprid at doses of 0, 120, 600 and 3000 ppm.
Based on the reported food consumption of the animals, the estimated imidacloprid doses were 0,
11, 57 and 409 mg/kg/day (males) and 14, 78 and 513 mg/kg/day (females).
General Toxicity and Clinical Chemistry. Imidacloprid did not cause death at any dietary level.
Body weight reduction (up to 11 % p ≤ 0.05) starting from Week 2 of treatment was evident in
the females at 600 ppm, suggesting that this or higher imidacloprid doses may exceed the
maximum tolerated dose (MTD). Indeed, the average body weight of the animals from both
sexes in the 3000 ppm group was up to 15-24% (p ≤ 0.01) less than the control. This effect wasseen throughout the treatment period. Interestingly, the food consumption was increased by 41%51% by these rats. Therefore, the effect on the body weight was clearly treatment-related andcould not be attributed to food palatability problems. Other effects in the animals at 3000 ppm
included elevated alkaline phosphatase (AP) activity (17-34%, p<0.01) and creatinin levels(22%, p<0.01) in the blood. Decreased levels of glucose (11%, p<0.01) and cholesterol 29%(p<0.01) were measured in the blood of these rats, which is indicative of imidacloprid-inducedchanges in the metabolism of carbohydrates and fats.
Target organs. Cell necrosis was diagnosed in the liver of one male in the 3000 ppm group. The
observed liver change was defined as treatment-related by the authors, because it involved
multifocal cell necroses in central, intermediary and peripheral lobular zones. Further
histological examination revealed degenerative changes of the testicular tubuli in five of the ten
male rats, which were repeatedly exposed to 3000 ppm imidacloprid. This report was considered
supplemental by the DPR, because it was not a FIFRA guideline study, lacked analysis of thediet and presented only limited evaluations of the blood and tissues. The subchronic oral NOEL
was 120 ppm (14 mg/kg/day), based on 11% reduction in body weight of the female rats at the
LOEL of 600 ppm (78 mg/kg/day).

27

In a 13-Week oral toxicity study, imidacloprid (95.3%) was administered through the diet to
Wistar rats (10 rats/sex/group; Eiben, 1989). The dose levels were 0, 150, 600 or 2400 ppm,
which corresponded to average daily doses of 0, 14, 61, or 300 mg/kg/day for males and 0, 20,
83 or 422 mg/kg/day for females. The 13-Week dosing period was followed by a 4-Week
recovery period (no treatment) for the control group and the high-dose animals.
The findings on the subchronic toxicity of imidacloprid were similar to the earlier, range-finding
98-Day study in rats. Mortality and clinical signs were not evident at any dietary level. Body
weights were reduced by about 8% (p ≤ 0.01) in the males from the 600 ppm group. The average
body weight for the males and females at the 2400 ppm group was 14-16% less than control (p ≤0.01), despite their increased food consumption. The body weights of these rats remained
reduced on Day 119 (the end of the recovery period). The liver was the principal target organ.
The authors concluded that the following changes in the serum chemistry of the animals exposed
to 2400 ppm imidacloprid were indicative of hepatotoxicity:(1) Elevated activities in the serum of alkaline phosphatase (AP, 15% p≤ 0.01) and alanine
aminotransferase (ALT, 25% p≤ 0.01).
(2) Decreased levels of protein 8% (p≤ 0.05), albumin (6% p≤ 0.05), triglycerides (52%, p≤ 0.01)
and cholesterol (47% p≤ 0.05).
(3) Lengthening of the blood clotting time (9% females; 10% males, p ≤ 0.01).
The following liver effects were reported for the males in the 2400 ppm dose group: increased
incidence of focal necrosis (4 of 8 males), single cell necrosis (8 of 10 males), swollen nuclei andcytoplasmic transformation (9 of 10 males) and round cell infiltration (all males). Round cell
infiltration, necrosis of hepatocytes and cytoplasmic changes were also observed in 3 males in
the mid-dose (600 ppm). Isolated cell necrosis, necrosis of groups of hepatocytes and round cell
infiltrates are indicative of liver damage. Cytoplasmic changes and swelling of nuclei are oftencaused by an increased liver function (Haschek and Rousseaux, 1998). The subchronic oral
NOEL was 150 ppm (14 mg/kg/day), based on liver toxicity and reduced body weight in themale rats at the LOEL of 600 ppm (61 mg/kg/day).
III.C.2. Inhalation Studies – Rat
Imidacloprid (95.2%) was assessed for subchronic inhalation toxicity in Wistar rats (Pauluhn,
1989). Ten rats/sex/dose were exposed by head/nose only to imidacloprid in the form of dust.
The exposure time was 6 hours/day, 5 days/week over a period of 4 weeks (Table 4). The
concentrations of imidacloprid were 0, 5.5, 30.5 and 191.2 mg/m3/day. The control groups
received air alone. The selection of doses was based on an earlier 5-day subacute study in rats,
which showed a marked induction of MFO in the liver after repeated exposure to 505 mg/m3/day
imidacloprid (Pauluhn, 1988a). The nominal exposure doses 5 could be calculated as 0.9, 5.2 and33 mg/kg/day, when using a rat default breathing rate of 0.96 m3/kg/day. Characterization of theparticles revealed that respirable dust was present in all dose groups (Table 4). More than 95% of
the particles in the lowest dose group (5.5 mg/m3) had MMAD ≤ 5 µm, about 45% - 57% of theparticles in the middle and high dose groups were larger than 5 µm. Particle size of ≤ 10 µm is
5Equivalent dosages were calculated by using the equation in Table 2.

28

generally recommended to assure bioavailability in rats (Raabe et al., 1988; SOT 1992). The
increase in the MMAD with increasing concentrations of imidacloprid was attributed to particle
agglomerations.
Table 4. Effects of Imidacloprid in Wistar Rats After 4-Weeks of Inhalation Head/Nose-Only
Exposure (Pauluhn, 1989).
EffectDose

mg/m3/day
0mg/kg/day0
Body Weight (% of control)
Week 4100

Males
5.5a 30.5b
0.9
5.2

191.3b33

00Females
5.5
30.5
0.9
5.2

191.3
33

100

99

94**

100

100

100

100

Liver Weight (% )Absolute
Relative
ALT (% of control)

100
100
100

97
97
100

93
93
92

93
97
99

100
100
100

101
100
95

107
109
125**

114
112
170**

AP (% of control)

100

109

106

111

100

109

120*

146**

GLDH (% of control)

100

98

147*

330*

100

99

200*

732**

Plasma ChE

100

100

100

100

100

107

74

72

MFO (% of control)
Coagulation Time (sec)

100
34.2

90
34.2

98
35.2

183**
35.5

100
32.6

100
32.5

127*
32.9

TAG (% of control)

100

87

82

50*

100

58

67

177**
35.9*
10%↑
27**

a/ 95% of the particles had MMAD ≤ 5 µm
b/ 45% - 57% of the particles had MMAD ≤ 5 µm.
ALT, Alanine Aminotransferase; AP, Alkaline Phosphatase; MFO, mixed function oxidases; GLDH, glutamate dehydrogenase;
ChE, cholinesterase; *, ** Statistically significant difference from controls at p ≤ 0.05 or p ≤ 0.01, respectively.

The principal toxicological findings were the reduction in body weight gains (6-9%, p ≤ 0.01) of
the male rats from the 191.2 mg/m3/day group and the concentration-dependent increase of 714% in the absolute and relative (to body weight) liver weights of females treated with 30.5 and191.2 mg/m3/day imidacloprid (Table 4). Imidacloprid clearly induced hepatocellular damage
and impairment of the liver function in these females. This was demonstrated by (i) increase in
the activities of the serum ALT, AP and glutamate dehydrogenase (GLDH) by 25%, 70% and732% (p ≤ 0.01), respectively; (ii) elevated bilirubin (25%, p≤ 0.01), (iii) lengthening of
coagulation time (10%, p≤ 0.01) and (iv) elevated urinary pH to a statistically significant extent(from 6.5 in to 7.4). The later effect is generally attributed to a reduced catabolism of hepatic
proteins. Finally, marked induction of the hepatic MFO of 34-83% (p≤ 0.01) was observed in the
animals treated with 30.5 and 191.2 mg/m3/day imidacloprid. Interestingly, the plasma ChE
29

activity was reduced by 26% and 28% in the female rats from the 30.5 and 191.2 mg/m3/day
groups, respectively. The cause of this effect is unknown, because imidacloprid is not a ChE
inhibitor. Since plasma ChE is synthesized in the liver, the decrease in the ChE activity may berelated to the observed changes in the liver function.
This report was not a FIFRA guideline study and thus was considered by the DPR as
supplemental information. Both, the author of the study and the DPR toxicologists establishedthe NOEL for the subchronic inhalation toxicity as 5.5 mg/m3/day (0.9 mg/kg/day), based onchanges in liver weights, alterations in liver function at the LOEL 30.5 mg/m3/day (5.2mg/kg/day).
III.C.3. Oral Studies – Mouse
The toxicity of imidacloprid (92.8%) was evaluated in B6C3F1 mice (10/sex/dose) for a periodof 107 days (Eiben, 1988b). The dietary levels were 120, 600 and 3000 ppm, which reportedly
corresponded to 77, 397 and 2323 mg/kg/day (males) and 91, 453 and 3075 mg/kg/day(females). These imidacloprid doses were based upon daily food consumption, which ranged
from 16-18 g/animal/day for both sexes from the various study groups.
The animals in the 3000 ppm dose group were in poor general condition, had rough coats andmarkedly lower body weights. The average body weight of the males and females in this groupwas 15% and 27% (p ≤ 0.01), respectively, lower than the control. The food consumption at thisdose was distinctly higher (11% males and 51% females) compared to the control, thus
indicating that the reduction in body weight was caused by the treatment. Lower body weight(5%, p≤ 0.05) was also reported for the males at the 600 ppm dose group. Evaluation of clinicalchemistry parameters revealed decreased cholesterol and urea in males (22% and 32%,
respectively, p≤ 0.01) and higher serum AP activity (up to, 47% p≤ 0.01) in males and females
treated with 3000 ppm imidacloprid. A total of 16 mice died at the end of the 13 or 14 week oftreatment, following blood withdrawal. These included one male from the 120 ppm dose-group,
one male from the 600 ppm group, seven males and seven females in the 3000 ppm group. Grosspathological changes were not observed in the mice, which died or were sacrificed at the end of
the study. The imidacloprid-induced drastic weight loss was considered a possible reason for thedeaths of the mice following blood withdrawal in the 3000 ppm dose group. However, mice diedafter repeated treatment with 600 and 120 ppm imidacloprid, which caused less or even no
reduction in the body weights. Similarly, in a chronic study a significant number of males fed
2000 ppm imidacloprid died during manipulations such as blood withdrawals and tattooing(Watta-Gebert, 1991, 1991a; see Section III.D.2. under CHRONIC TOXICITY). In the later
case, the death was reported to be due to hypersensitivity to ether, which was used as anesthesia
during these procedures. This report was not a FIFRA guideline study and thus was considered
supplemental by the DPR. The LOEL was 3000 ppm, based on poor appearance, reduced bodyweights and mortality of the animals.
The results from this study indicated that 600 ppm imidacloprid did not cause apparent toxicity.
However, there was a substantial uncertainty associated with the reported dose of 397 mg/kg/day
as the NOEL for subchronic oral toxicity in mice. This dose was estimated based on unusuallyhigh food consumption. The food intake levels represented about 60%-100% of the mice bodyweight. The report did not indicate whether the calculated quantity of food consumed by themice was corrected for spillage. Therefore, the presented values may reflect errors in theestimation of both, the actual food consumption and the imidacloprid intake. The DPR
30toxicologists adjusted the ingestion of imidacloprid to 1/7 of the mice mean body weight (seeAttachment IV), which is similar to a default food consumption of 15% of the body weight of an
adult mouse (30 g). The revised NOEL would be 86 mg/kg/day, based on the revised LOEL of
427 mg/kg/day.
It is interesting to note that mice appeared to be less sensitive to the subchronic toxicity ofimidacloprid compared to the acute treatment. The subchronic oral NOEL was 9-fold higher than
the threshold for acute toxicity (10 mg/kg/day, based on labored breathing, decreased motility,
staggering gait and trembling at the LOEL of 71 mg/kg/day).
III.C.4. Oral Studies – Dogs
The subchronic toxicity of imidacloprid (92.8%) was examined in Beagle dogs by administrating
it through the diet for a period of 4 or 13 weeks (Tables 5 and 6).
The 4-Week study included four groups of dogs, each containing two males and two females(Block, 1987). The doses were 0, 200 ppm, 1000 ppm and 5000 ppm, which corresponded to 0,
7.3, 31 and 49 mg/kg/day. All animals in the 5000 ppm dose group died or were sacrificed prior
to the completion of the study (Table 5). The first dog died after only 2 days of the treatment; theother three dogs died on Day 18 or Day 24. The clinical signs for the dying animals included
marked reduction in food intake, weight loss (up to 42%), severe tremor, ataxia and vomiting.
One surviving male from the 5000 ppm group had significantly reduced levels of serum
triglycerides and alpha-1 globulin (75% and 82%, p ≤ 0.01, respectively). These changes may be
associated with the observed hepatocellular atrophy in this dog. Treatment-related hepatocellular
atrophy was also diagnosed in the two surviving females from the 5000 ppm group. Additional
toxic effects in the 5000 ppm dose group included atrophy of thyroid gland and bone marrow,advanced involution of the thymus (graded as moderate to severe) and testicular tubule
degeneration. The involution or decrease in size of the thymus represents loss of lymphoid massand degeneration of the epithelial cells, which in turn leads to reduced effectiveness of Tlymphocyte function (Aronson, 1993). The involution of the thymus occurs naturally with aging.
In this context, imidacloprid may be regarded as causing premature aging of the thymus.
The lower tested dose of imidacloprid 1000 ppm caused a decrease in food consumption (17%compared to the pretest level), however, the body weights of these dogs were not affected by thetreatment. Hypertrophy of hepatocytes in one male and follicular atrophy of the thyroid in one
female in this group were reported as morphological alterations produced by imidacloprid. This
report was considered supplemental by the DPR, because it was not a FIFRA guideline study.
Based on the treatment-related morphological changes at the LOEL of 1000 ppm (31mg/kg/day), the subchronic oral NOEL for dogs was 200 ppm (7.3 mg/kg/day).
In the 13 Week dietary study, imidacloprid was administered to Beagle dogs (Bor:Beag strain; 4
dogs/sex/dietary level) as food mash at doses of 0, 200, 600 or 1800 ppm (Ruf, 1990). The 1800ppm produced a drastic reduction in body weight (8-20% less than control) within the first 4
weeks (Table 6). This effect was, at least in part, due to the 30-54% decrease in the food intake.
Because of the low food consumption, the concentration of imidacloprid was thereafter reduced
from 1800 to 1200 ppm until the completion of the study. Nevertheless, the average body weightin the high-dose animals remained lower than the control by 6% (females) and 9% (males) at thecompletion of the study at week 13. Based on the study report on the weekly imidacloprid intake,the average daily doses corresponding to 200, 600 and 1800/1200 ppm could be calculated as 8,
24 and 46 mg/kg/day. There was no mortality or evidence of tissue damage. Vomiting of food or31

mucus occurred at a higher incidence in the females of the 200, 600 and 1800/1200 ppm dosegroups (Table 6). However, the number of vomiting incidents for each of the females neverexceeded 1 over the entire treatment period.
Trembling was evident in all males and females treated with 600 and 1800/1200 ppm
imidacloprid. The trembling occurred within the first 5 weeks of treatment on 1 to 2 occasions in
the animals fed 600 ppm imidacloprid; and as many as 14 times for the dogs of the 1800/1200
ppm group. In addition, severe tremors were reported for all 8 dogs (up to 5 incidents within
Weeks 1-5) in the highest dose group (46 mg/kg/day). The same toxic effects (severe tremors
and vomiting) were observed in the dogs treated with 49 mg/kg/day imidacloprid in the 4-Week
dietary study (Block, 1987; Table 5). The NOEL from this study was 200 (ppm) 8 mg/kg/day,based on clinical symptoms (tremors) at the LOEL of 600 ppm (24 mg/kg/day).
It should be noted that similar doses of imidacloprid produced toxic effects in Beagle dogs,
which differed in severity in the 4-Week and 13-Week studies. For example, imidacloprid at 49
mg/kg/day in the 4-Week study caused a marked toxicity, including 100% mortality. In contrast,
the effects of 46 mg/kg/day imidacloprid fed to the dogs for four weeks in the 13-Week study
were restricted mainly to clinical symptoms, with no deaths and tissue damage. Because thesestudies were conducted in two different laboratories, the inconsistent results may reflect the useof different protocols and different strains or source of animals.
III.C.5. Dermal Studies – Rabbit
In a subchronic dermal toxicity study, imidacloprid (95%) was applied as a paste to the shavenarea of the back and flank of HC:NZW rabbits (5/sex) at a dose of 1000 mg/kg (Flucke, 1990).
The control group included vehicle (2% Cremophor EL in physiological saline solution) treatedanimals. The treatment site was covered with a porous patch 6 hours/day, 5 days/week for 3
weeks. The rabbits were observed for signs of general toxicity, behavioral alterations and skinirritation (evaluated by Draize test). Clinical chemistry examinations were performed prior toand at the end of the treatment period and pathological evaluations were done two or three days
after the last dermal dose. Imidacloprid did not cause toxic signs, mortalities or pathology
changes in the examined organs. The subchronic dermal NOEL for imidacloprid was >1000
mg/kg/day.

32

Table 5. Effects of Imidacloprid in Beagle Dogs After 4 Weeks of Treatment Through the Diets (Block, 1987).
Effects

Dose

Dog 4-Week Dietary Study

5000

b

0

31

49

0

5000a

31

49

0

mg/kg/day

0

Death

0/2

0/2

0/2

2/2

0/2

0/2

0/2

2/2

9.4
9.5
300
300
0/2

8.4
8.7
289
294
0/2

8.4
8.6
250
207 (83%)e
0/2

7.5c
5.5 (73%)d
282d
93 (33%)e
2/2

9.3
9.5
300
300
0/2

7.6
8.0
295
295
0/2

8.1
8.5
283
296
0/2

8.1c
6.0 (74%)d
282d
45 (16%)e2/2

Ataxia

0/2

0/2

0/2

2/2

0/2

0/2

0/2

2/2

Vomiting

0/2

0/2

0/2

1/2f

0/2

0/2

0/2

2/2f

Hepatic Hypertrophy

0/2

0/2

1/2

0/2

0/2

0/2

0/2

0/2

Hepatocellular Atrophy

0/2

0/2

0/2

1/2

0/2

0/2

0/2

2/2

Thyroid Follicular Atrophy

0/2

0/2

0/2

1/2

0/2

0/2

1/2

1/2

Bone Marrow Atrophy

0/2

0/2

0/2

1/2

0/2

0/2

0/2

1/2

Involution of Thymus (moderate-to-severe)

0/2

0/2

0/2

2/2

0/2

0/2

0/2

1/2

Testicular Tubule Degeneration

0/2

0/2

0/2

1/2

-

-

-

-

Triglycerides

0.37

0.43

0.52

0.09d (24%)e

0.34

0.36

0.45

0.34

Alfa-1-Globulin

0.083

0.101

0.122

0.017d (20%)e

0.93

0.111

0.102

0.089

Food Intakec (g/day)Severe Tremors

Week -1
Week 4
Week -1
Week 4

7.3

200

Females
1000

ppm

Body Weightb (kg)

200

Males
1000

7.3

a/ One male died on Day 2 and one female died on Day 18; the other two dogs in this group were euthanased on Day 24.
b/The body weights or the food consumption are expressed as the mean of two animals.
c/ level of the one surviving animal in this group. d/ % of the base-line (pretest at week -1) body weights or food consumption, because the baseline body weights differed
substantially between the dose-groups. e/ percent of the control. f/ The male dog vomited once in the first week; one female vomited twice and the other female vomited once
within the first week.

33

Table 6. Effects of Imidacloprid in Beagle Dogs After 13 Weeks of Treatment Through the Diets (Ruf, 1990)

Dose

Dog 13-Week Dietary Study
Males
ppm

0

200

600

1800/1200

0200

Females600

mg/kg/day

0

8

24

64

0

8

24

Body Weighta (kg)

1200/1800
64

Week -1b 7.3

7.2

7.1

7.0

6.4

6.6

6.4

6.7

Week 13

9.6

9.2

9.6

8.7

9.0

9.5

8.5

8.6

(kg)

(+2.6)(+2)(+2.5)(+1.7)(+2.6)(+2.6)(+2.1)(+1.8)

Food Intakeb (kg/week) Week -1 2.1

2.1

2.1

1.1

2.1

2.1

1.9

2.1

Week 13 2.5

2.5

2.2 (83%)

2.1

2.4

2.4

2.5

2.3

0/4

0/4

4/4

4/4

0/4

0/4

4/4

4/4

0/4

0/4

0/4

4/4

0/4

0/4

0/4

4/4

1/4

1/4

0/4

2/4

0/4

1/4

2/4

3/4

Body Weight Gain

Tremblingd
Severe Tremors
Vomiting

feca/ The body weights or the food consumption are expressed as the mean of four animals.
b/ The measurements were performed 1 week prior to the treatment (pretest level).
c/ The number in parentheses represents percent of the control
d/ Trembling occurred in all males and females in the 600 ppm group within the first week on 1 to 2 occasions; and in all animals in the 1800/1200 ppm group, as many as 14
times within Weeks 1-5.
e/ Severe tremors (up to 5 incidents) were reported for all males and females in the 1800/1200 ppm group within Weeks 1-5.
f/ One control male vomited 4 times within the 1st week. The number of vomiting incidents in each of the males or females in the imidacloprid-treated groups never exceeded 1
over the entire treatment period.

34

III.D. CHRONIC TOXICITY AND ONCOGENICITY
Five chronic toxicity/oncogenicity studies with imidacloprid were submitted to the DPR tocharacterize its long-term toxic effects and potential to cause cancer in rodent and non-rodent
species. These included four 2-year dietary studies in rats and mice and one 1-year oral study in
dogs.
The most common toxic effect in the chronic oral studies was the reduction in body weight. Rats
appeared to be the most sensitive species. The principal morphologic effect was thyroid lesions
in rats. An interesting finding in mice was the development of hypersensitivity to anesthesia after
chronic treatment with imidacloprid. These mice appeared overall healthy, but died shortly after
exposure to ether. It is possible that chronic exposures to imidacloprid may reduce the ability ofmice to respond to an additional challenge with xenobiotics. The evidence for carcinogenicity inthe chronic studies was not sufficient to implicate imidacloprid as a cancer-causing chemical.
III.D.1. Oral Studies – Rat
In a 2-year-chronic toxicity/oncogenicity study, imidacloprid (94.3% a.i.) was administered to
Wistar rats (50/sex/dose) at dietary levels of 0, 100, 300 and 900 ppm (Eiben and Kaliner, 1991).
Ten more rats/sex/dose were used for interim examinations after 1 year of treatment. The
selection of doses was based on results from two earlier subchronic feeding studies in rats, whichshowed necrosis of hepatocytes, changes in the serum chemistry, reduced body weight, anddegenerative testicular alterations at 600 or 3000 ppm. In a supplemental study, 50 rats/sex wereused as controls or fed with imidacloprid at 1800 ppm for 2 years (Eiben, 1991). The aim of thissecond chronic toxicity study was to determine the maximum tolerated dose of imidacloprid(MTD) in rats. The two studies were performed in the same laboratory and the protocols of were
sufficiently similar to permit an evaluation of the overall results. Consequently, the control groupof the combined studies included 100 animals/sex/ and each of the treatment groups had 50
rats/sex/dose. Based on the food consumption, the average daily doses in the chronic studies
corresponded to 5.7, 17, 51or 103 mg/kg/day for males and 7.6, 25, 73 and 144 mg/kg/day forfemales.
Chronic exposure to 1800 ppm imidacloprid resulted in a substantial reduction in body weights
in both sexes at all times. The weight decline reached maximum of 11% -12%, (p ≤ 0.01) at
Week 10. About 5 to 8% (p ≤ 0.01) decrease in body weight was observed in males and females
at the 900 ppm dietary level. The reduction in the body weight was clearly treatment-related,because food intake of the animals from the 900 and 1800 ppm groups was similar to the control.
Although changes in liver morphology were not observed, there were some indications of liver
toxicity for both sexes at 1800 ppm based on alterations in serum chemistry. These included
elevated activities of serum AP (up to 37%, p ≤ 0.01) at 6, 12 and 18 months, creatine kinase (upto 25%, p ≤ 0.01) and aspartate aminotransferase (AST, 43%, p ≤ 0.01), and reduced cholesterollevel (38%, p ≤ 0.01) at 24 months.
The principal treatment-related effect in rats treated for 24 months with imidacloprid was lesions
in the thyroid gland. Parafollicular hyperplasia and fewer colloid aggregation sites in the thyroid
were diagnosed in the rats from the 1800 ppm dose-group (Table 7). There was a marked, dosedependent increase in the incidence and severity of mineralized particles in the thyroid follicles.
This effect became statistically significant in male rats fed 300 ppm of imidacloprid and infemales at 900 ppm (p ≤ 0.001, Table 7). Furthermore, among the 31 males with mineralized
particles in the 300 ppm dose-group, 25 exhibited “Grade 1” severity and 6 showed “Grade 2”
35

severity. The 3 male rats with mineralized colloid from the concurrent control (100 males)
showed only minimal severity (“Grade 1”, Table 7). At all doses, the levels of thyroid hormonesin plasma (T3, T4 and TSH) in these rats were normal. The occurrence of mineralized colloid
indicates involution of follicles and is generally considered as a sign of a biological aging. In thiscontext, imidacloprid may be regarded as causing premature aging of the thyroid follicles.
Historical data on the incidence of mineralized particles were available from the Institute of
Toxicology at BAER AG in Germany. The database was compiled from four, 2-year toxicity
studies (46-48 control rats /sex/per study;) to represent the same period of study (1987-1900,
Kaliner, 1991). In the case of the male rats, 8-63% (average 25%±17%) of the animals could be
affected by mineralized particles; and 2-8% of the females could have mineralized particles in
the colloid. In general, the severity of occurrence in control rats appeared to be minimal (Grade1). In view of the historical data, the 100 ppm dose-group males (28% mineralized particles) wasin the historical range. The NOEL from this study was 100 ppm (5.7 mg/kg/day), based on an
increase in incidence and severity of mineralized particles in thyroid gland in male rats at the
LOEL of 300 ppm (17 mg/kg/day).
Various types of tumors were reported in a total of 20 organ/tissue sites. The incidence ofneoplasms in the liver and the thyroid gland were of particular interest, because hepatic cell
necrosis and thyroid lesions were observed after subchronic or chronic treatment of rats with
1800-3000 ppm imidacloprid. There was no dose-related increase in neoplasms in the thyroid
gland (Table 8). Notably, tumors in the liver were found only in the male rats from the 1800 ppm
treatment group. These included one rat with adenoma, one with carcinoma and two rats withcholangiocellular carcinomas, the later being rarely seen in aging rat (Table 8; Bomhard andRinke, 1994). The authors considered the incidences of hepatic adenomas and carcinomas to bewithin the historical range for these tumors, citing published data by Bomhard et al, (1986). This
paper provided incidences of 827 spontaneous tumors (including liver tumors) in 375 male rats
from the same Wistar strain, but did not mention the rare cholangiocellular carcinomas. In alater report by the same research group, the historical incidence for cholangiocellular carcinomas
was actually zero out of 1270 control male rats (Bomhard and Rinke, 1994). Based on this report
the current incidence for cholangiocellular carcinoma (2/50 males) was outside the historical
range. Nonetheless, the cholangiocellular carcinoma incidence in the males from the 1800 ppm
group was not statistically significant from that for the concurrent controls (0/100 male rats).
Altogether, there was no sufficient evidence to indicate that imidacloprid was oncogenic to rats.

36

Table 7. Imidacloprid-Induced Mineralization of the Colloid of Thyroid Follicles in Ratsa.
Lesions in Thyroid Gland of Rats
24 months
Dose

b

0
0
100
14

100
7.6
50
6

Females
300
25
50
11

12%

22%

54%*** 76%***5062%*** 88%*** 92%*** 14%
24 months
50
50
50
50

50

50

50

50

5
7
0
-

25
6
0
-

25
16
3
-

5
1
0

9
2
0

19
6
2
-

-

-

-

-

ppm
mg/kg/dayNumber of thyroids
Mineralized particles incolloid
Total (absolute percent)

0
0
100
14

100
5.7
50
12

14%

28%

Number of thyroids
Mineralized particles incolloid
grade 1
grade 2
grade 3
Parafollicular hyperplasia
Total (absolute percent)Colloid aggregation
Total (absolute percent)

50
3
0
0
4
10%
41
82%

Males
300
17
50
31

900
51
50
44

1800
103
50
46

12
24%
20
40%***

10
1
0
5
10%
22
44%

-

-

900
73
50
27

-

1800
144
50
38

8
16%
7
14%***

a/Imidacloprid was administered through the diet to Wister rats for 2 years. The results were based on the incorporation of two 2-year studies with similar protocols (Eiben and
Kaliner, 1991). The first study included dose groups of 0, 100, 300 and 900 ppm the second study had 0 and 1800 ppm dose levels (Eiben, 1991). Data for control rats from the twostudies were pooled together for analysis.
-, Data were not reported in the study.
Statistically significant different from controls at p≤ 0.001 by Fisher exact test. Note that analysis of the data for male rats affected by mineralized particles indicated that atrend test for dose-response would be significant (p ≤ 0.001).
***

37

Table 8. Tumor Incidences from 2-year Dietary Studies with Imidacloprid in Wistar Ratsa.
Incidence of Neoplastic Lesions
24 months
Dose (ppm)(mg/kg/day)Thyroid Gland
Number of thyroids
Parafollicular cell adenoma
Parafollicular carcinoma
Follicular adenoma
Liver
Number of livers
Adenoma
Carcinoma
Cholangioma
Cholangiocellular carcinoma

100
5.7

Males
300
17

900
51

1800
103

100
5
0
4

50
5
0
0

50
6
1
0

50
3
0
0

50
0
0
3

100
0
1
0
0

50
0
1
0
0

50
0
1
0
0

50
0
0
0
0

50
1
1
0
2

0
0

100
7.6

Females
300
900
25
73

1800
144

100
2
1
0

50
4
0
0

50
1
0
0

50
0
1
0

50
4
0
0

100
2
0
1
0

50
0
0
0
0

50
0
0
0
0

50
0
0
0
0

50
0
0
2
0

0
0

a/ The results were based on the incorporation of two 2-year studies with similar protocols. The first study included dose groups of 0, 100, 300 and 900 ppm (Eiben and Kaliner,
1991), the second study employed 0 and 1800 ppm dose levels (Eiben, 1991). Data for control rats from the two studies were pooled together for analysis.

38III.D.2. Oral Studies – Mouse
In two chronic toxicity/oncogenicity studies, imidacloprid (95.3% a.i.) was administered to
B6C3F1 mice (50/sex/dose) for a period of 24 months. The dietary levels were 0, 100, 330 or1000 ppm (Watta-Gebert, 1991) and 0 and 2000 ppm (Watta-Gebert, 1991a). Ten more
mice/sex/dose were used for interim examinations after 12 months of treatment. The two studies
had similar protocols and, therefore, were evaluated together. The reported average daily doses
were 0, 20, 66, 208 or 414 mg/kg/day for males and 0, 30, 104, 274 and 424 mg/kg/day forfemales. The doses were based on the mean daily food consumption ranging from 6.2 to 6.5
g/male/day and from 7.4 to 8.5 g/female day. This food intake represented about 22-28% of the
body weight of an adult mouse. These high levels of food consumption (and imidacloprid intake)may be due to not accounting for food spillage in the calculations for the consumed food.
Unusually high food consumption was also evident in the subchronic study in mice, (Eiben,
1988b; see Section III.C.2. under SUBCHRONIC TOXICITY).
Mice treated with 2000 ppm imidacloprid had substantially lower body weights (up to 29%, p ≤0.01) than controls from the first week of treatment. The reduction in body weights was, at leastin part, due to a decreased food consumption (10-25%). Morphological changes were noted at2000 ppm, including periacinar hypertrophy of hepatocytes in males and mineralization ofthalamus in females. A marked increase in mortality was evident for the males in the 2000 ppm
group that died intercurrently (34 % vs. 12% control, p= 0.002). Interestingly, the number ofmales, which died simultaneously or were sacrificed in moribund conditions, did not differ fromthe control mice (14% vs. 12% control). The significant increase in mortality was due to thelarge number of males, which died during manipulations such as blood withdrawals, tattooing or
as a result of being caught in the automatic feeder. The later was attributed by the authors to thegeneral debilitation and major reduction in body weights caused by imidacloprid. The death of
the animals after blood withdrawal and tattooing was concluded in the report to be indirectly
associated with the treatment. Compared to control mice, males exposed to 2000 ppm
imidacloprid developed hypersensitivity to ether, which was used as anesthesia during theseprocedures. The dying animals exhibited dyspnea, respiratory failure and spasms immediately
after administration of ether. Similarly, in a subchronic 107-Day study, all mice fed 3000 ppm
imidacloprid and males in the 600 and 120 ppm groups died after blood withdrawal (see Section
III.C.2 under Subchronic Toxicity). Overall, these findings suggest that imidacloprid may reduce
the ability of mice to respond to an additional challenge with xenobiotics.
Effects at 1000 ppm consisted of reduced body weight for males (up to 10%, p ≤ 0.01), while thefood consumption was not affected by the treatment. On the basis of these results, 1000 ppm
imidacloprid appeared to be the MTD for male mice. The type and incidence of tumors in all
dose-groups were similar to that for the control animals. Hence, no evidence for oncogenic
potential of imidacloprid was indicated in these studies. The NOEL was 330 ppm based on 10%
reduction in body weight for male mice at the LOEL of 1000 ppm. The DPR toxicologists
adjusted the ingestion of imidacloprid to 1/7 of the mice mean body weight (see Attachment IV),
which is similar to a default food consumption of 15 % of the body weight of an adult mouse.
The revised NOEL would be 47 mg/kg/day, based on the revised LOEL of 143 mg/kg/day.
III.D.3. Oral Studies – Dogs
Imidacloprid was administered through the diet for a period of 52 weeks to Beagle dogs
(4/sex/dietary level) at 200, 500 or 1250 ppm (Allen et al., 1989). The 1250 ppm dose was39

increased to 2500 ppm from week 17 to the end of the treatment. These levels correspond todaily doses of 6, 15 and 41/72 mg/kg/day. Food consumption was decreased by 9-14% in thefemales treated with 1250/2500 ppm imidacloprid. Other effects at 1250/2500 ppm included anincrease in the metabolic activity in the liver, as evidenced by the elevated levels of plasmacholesterol in females (up to 91%, p ≤ 0.01) and liver cytochrome P-450 enzymes for both sexes(51-93%, p ≤ 0.01). The authors considered the later effect to be associated with the increase inliver weight (10-19%, not statistically significant), which was apparent only when expressed as
liver/brain ratio. The more common expression of relative organ weight is the organ weight/bodyweight ratio, which in this case was not statistically significant. The chronic oral NOEL wasestablished by the authors as 500 ppm (15 mg/kg/day), based on liver changes at the LOEL of
1250/2500 ppm (41 mg/kg/day). It should be noted that unlike the mild effects seen in thechronic study, subchronic treatment for 4 or 13 weeks with similar doses (24-64 mg/kg/day)
imidacloprid produced a marked toxicity in dogs, including mortality, severe tremors,morphological changes in liver and thyroid and weight loss.

40

III.E. GENOTOXICITY
Thirteen genotoxicity studies with imidacloprid were submitted to the DPR. The results obtainedin 11 of these tests were negative, including all in vitro point mutation tests, all in vivo
chromosomal aberration tests and all tests for DNA damage and repair capabilities. Imidacloprid
at non-cytotoxic concentration was positive in one of the two in vitro assays for sister chromatid
exchanges (SCE) in Chinese hamster ovary cells (CHO). In addition, it caused in vitro
chromosomal aberrations in human lymphocytes, but at concentrations at which cytotoxicity was
also evident. There were no published reports on the imidacloprid mutagenic potential in the
open literature. The results from the available studies indicated that, under the conditions tested,
imidacloprid did not show a clear genotoxic potential. Studies on genotoxicity of imidacloprid
are summarized in Table 9.
Gene Mutation. Testing of imidacloprid for mutagenicity in vitro in Salmonella typhimurium
provided no evidence that it induced base-pair substitution in strains TA100 and TA1535, orframe shift in S. typhimurium strains TA98 and TA1537 and in Escherichia coli strain WP2uvr(Herbold, 1989a; Watanabe, 1991). Similarly, in an assay for detection of forward mutations,imidacloprid did not increase the resistance of HGPRT-Chinese hamster ovary cells (CHO) to 6thioguanidine when incubated at concentrations up to those causing cytotoxicity (Lehn, 1989).
In Vitro Chromosome Aberrations: In vitro, imidacloprid was clastogenic to human
lymphocytes, causing chromatid gaps and breaks at concentrations at which cell toxicity was also
evident (Herbold, 1989c). These results may not be unequivocal for mutagenic potential or
carcinogenic properties, because the chromosomal aberrations occurred only at cytotoxicity
concentrations. An increased frequency of SCE (44-70%) was reported in vitro in CHO cells in
the absence or presence of metabolic activation system, starting at concentration of 250 µg/ml(Taalman, 1988). Cytotoxicity was observed at concentrations higher than 500 µg/ml, indicatingthat imidacloprid caused reciprocal chromatid interchanges at non-lethal doses. In a separate invitro study in CHO, imidacloprid did not induce SCE up to 1250 µg/ml (Putman and Morris,1989).
Sister chromatid exchanges occur during the S phase. They involve breakage of both DNA
strands, followed by an exchange of whole DNA duplexes (Van Veen and Hawley, 2003). Under
normal circumstances, SCE are thought to be rare at meioses (Kato, 1974). However, they are
efficiently induced by mutagens, which form DNA adducts or interfere with DNA replication. In
this respect, SCE are indicative of recombinational repair, induction of point mutations, gene
amplification and cytotoxicity. Hence, it is a frequent method of testing for potential DNA
damage. On the other hand, it may be argued that the significance of a positive SCE for risk
assessment is less certain than other genotoxicity studies, because of the following reasons: (i) If
SCE occurs, it has no net effects, since technically it is an exchange of identical genetic material
between two chromatids, and (ii) Due of its high sensitivity, the SCE test has a relatively low
predictability of both carcinogens and noncarcinogens in the rodent bioassays (0-45%, Ashby
and Tennant, 1991;Tennant, 1987; Brusick, 2001).
In Vivo Chromosome Aberrations: Tests of mammals treated in vivo with imidacloprid
produced negative results for chromosomal aberrations. No significant increases over control
were observed in the number of micronucleated erythrocytes isolated from mice treated with 80
mg/kg imidacloprid (Herbold, 1988a). There was no evidence for aberrations or SCE in bone41

marrow chromosome preparations from Chinese hamsters, which received 2000-5000 mg/kg
imidacloprid via gavage (Herbold, 1989b; Herbold, 1989d). In a mouse-germ cell assay,
imidacloprid did not increase the number of structural aberrations in chromosomal preparations
from spermatogonial cells up to 80 mg/kg (Volkner, 1990).
DNA Damage and Repair Capabilities. Imidacloprid did not show a DNA-damaging potential
in a rec assays with Bacillus subtilis, as evidenced by the lack of growth inhibition ofrecombination- and repair-deficient mutants (Watanabe, 1990). Imidacloprid was also tested for
induction of mitotic gene recombination in yeast Saccharomyces cervisiae strain D7 (Herbold,
1988b). In this assay, there were no increases in the tryptophan revertants or colonies with red
and/or pink sectors, indicating that imidacloprid did not induce mitotic gene conversion andcrossing-over. Finally, imidacloprid administered by gavage to rats at doses of 5-500 µg/kg did
not increase the nuclear grain counts in the nuclei of primary hepatocytes (Cifone, 1988). This
test demonstrated that there was no apparent DNA damage to stimulate a repair response byunscheduled DNA synthesis (USD).

42

Table 9. Mutagenicity Studies with Imidacloprid.

End Point
Gene Mutation
Reverse mutation

Reverse mutation

Test System

S. typhimurium TA98,
TA100,
TA1535, TA1537

Activation/Dose+/-S9 rat microsomesa
20-12,400 µg/plate

Results

Negative

Forward mutation+/-S9 rat microsomes
Negative
312.5-5000 µg/plate
HPRTb Chinese hamster +/-S9 rat microsomes
Negative
ovary cells
1.25-1225 µg/plate
In Vitro Chromosome Aberration

Structural
Chromosomal
Aberration

Human lymphocytes(cells from 1 male and 1
female)+/-S9 rat microsomes
50-5200 µg /ml; 24 h

Negative up to 50 µg /ml

Sister Chromatid
Exchange

Chinese hamster ovarycells+/-S9 rat microsomes
16.7-5000 µg/ml

Positive (44-70% increased
frequencyc) at ≥ 250 µg/ml withor without S9.

Sister Chromatid
Exchange

Continued

E.coli WP2uvr

Chinese hamster ovary
cells

Positive (14-29%c increased
frequencyc) at cytotoxic
concentrations (500-5200 µg/ml)
without S9.

exposed for 27 h (-S9) and
2h (+S9)
Cytotoxic at 500 µg/ml+/-S9 rat microsomes
Negative up to 1250 µg/ml
25-1250 µg/ml
Cytotoxic at ≥ 25 µg/ml
exposed for 29 h (-S9) and
2h (+S9)43

References*Herbold,
1989a;*Watanabe,
1991*Watanabe,
1991*Lehn, 1989

*Herbold,
1989c;

Taalman, 1988

*Putman andMorris, 1989

Table 6. Mutagenicity Studies with Imidacloprid. (cont).
End Point

Test System

Activation/DoseResults

References

In Vivo Chromosome Aberration
Micronucleus test

Mouse bone marrow
erythrocytes

Sister Chromatid
Exchange

Chinese hamster bonemarrow

Structural
Chromosomal
Aberration

Chinese hamster bonemarrow

Germ cell damage

Mouse spermatozoid

Gavage, 80 mg/kg
5 mice/sex
Bone marrow examined after 24,
48 and 72 h
Gavage, 500-5000 mg/kg; 5
mice/sex
Bone marrow examined after 24 h

Negative

Negative*Herbold,
1989d;

Gavage, 2000 mg/kg
34 animals.
Bone marrow examined after 6,
24 and 48 h
Gavage, 80 mg/kg
5 males/group
Spermatogonia examined after
24, 48 and 72 h

Negative*Herbold,
1989b;

Negative*Volkner,
1990+/-S9 rat microsomes
625-10,000 µg/ml+/-S9 rat microsomes
312.5-5000 µg /disk

Negative*Herbold,
1988b

Negative*Watanabe,
1990

5-500 µg/ml; 19 h

Negative*Cifone, 1988

*Herbold,
1988a;

Other Genotoxicity Tests
Mitotic generecombination

S. Cerevisiae D7

Rec gene mutation

B. subtilis H17(rec+)andM45 (rec-)Primary rat hepatocytes

Unscheduled DNA
synthesis*, Studies acceptable for filing the SB950 data requirements; a/ +/- , with and without S9 fraction from rat liver microsomes;b/ HPRT, Hypoxanthine-Guanine Phosphoribosyl Transferase; c/ Significantly different than control, p ≤ 0.05;
d/ rec-, recombination- and repair-deficient B. subtilis mutants.

44III.F. REPRODUCTIVE TOXICITY
The effects of imidacloprid (95.3%) on reproduction and development were examined in a twogeneration, two-litter study in Wistar rats (30/sex/dose in the parental generation, P1). The
dietary doses were 100, 250 and 700 ppm (Suter et al., 1990). The rats in the P1 generation were
fed imidacloprid during a premating period of 84 days and throughout mating, gestation andlactation for breeding of the offspring (F1A and F1B litters). After weaning on day 21
postpartum, selected F1B animals (26/sex/dose) were fed imidacloprid for 105 days prior tomating, during mating, gestation and lactation for breeding of the F2-generation parental
animals.
Maternal toxicity at 700 ppm included decreased body weight gain and food consumption with amarked reduction during lactation (up to 11% and 17%, respectively, p ≤ 0.05). Liver enzymes
participating in the biotransformation of xenobiotics (cytochrome P-450, O-demethylase and Ndemethylase) were also induced in the maternal animals (up to 37%, p ≤ 0.01). The offspring ofthese dams had a pronounced decrease in body weight gain (up to 13%, p ≤ 0.05) compared tocontrol until weaning at postnatal day 21. Decreased premating body weights (9%, p ≤ 0.05)
were reported for the P1-F1 males. There were no effects on mating indices, fertility, gestation,
litter size, mortality and no evidence of pathology at any dose level. The parental, reproductive
and developmental NOELs were 250 ppm, based on significantly decreased body weights ofadults and pups at 700 ppm.
It should be noted that the mean daily imidacloprid doses varied greatly within a treatment
period (e.g. premating) and between the different treatment periods (premating, mating, gestationand lactation). For example, the report indicated that the parental animals from all dose groups
consumed about 50% less imidacloprid from the middle to the end of the premating period,
compared to the beginning of the treatment. The reason for the dose variability was not provided.
The food consumption was not decreased in the first two dose-groups (100 and 250 ppm) hence;
it is not clear how the dose could be reduced. In addition, the imidacloprid intake by the dams
was markedly increased toward the end of the lactation period, probably due to the growing pups
eating the pesticide-containing pelleted food. The estimated doses corresponding to the NOEL of
250 ppm varied from 13 mg/kg/day to 46 mg/kg/day. The NOEL for adult rats was 13 mg/kg/day
based on decreased premating body weights of P1-F1 males and F1 females at the LOEL of 38
mg/kg/day. The offspring NOEL was 13 mg/kg/day, based on a decreased pup body weight ofboth litters of both generations at the LOEL of 38 mg/kg/day.

45

III.G. DEVELOPMENTAL TOXICITY
The embryo-, fetal and developmental toxicity of imidacloprid were studied in rats and rabbits.
Embryotoxicity was evident only at maternally toxic doses. The main effects on rat fetuses werewavy ribs and disproportionally high number of male fetuses. The developmental effect in the
rabbit was reduced fetal weight. The principal effects and the respective toxicity thresholds in thedevelopmental toxicity studies are summarized in Table 10.
III.G.1. Oral – Rat
In a rat teratology study, imidacloprid (94.2% a.i.) was administered daily by gavage to matedfemale Wistar rats from gestation days (GD) 6 through 15 (Becker et al., 1992). Each dose groupconsisted of 25 rats. The respective doses were 0, 10, 30 and 100 mg/kg/day (Table 10). On GD
21 the fetuses were delivered by a cesarean section and examined for developmental
abnormalities.
The highest tested dose (100 mg/kg/day) produced maternal toxicity and a delay in embryo
development. The maternal toxicity was evidenced by the reduced body weight gain (up to 43%
reduction, p ≤ 0.01) from the third day of treatment to five days after the last dose. The foodconsumption was also decreased (35%, p ≤ 0.01) during the treatment period. The authors
reported that the offspring of these dams had an increased incidence of wavy ribs (fetal incidenceof 4.7% relative to controls (1.2%); this incidence was not statistically significant and was within
the historical range (0 to 5.6%). In addition, exposure of dams to 100 mg/kg/day imidacloprid
resulted in a disproportionally high number of male fetuses (59%). This effect was statisticallysignificant (p ≤ 0.05) relative to control animals, which had approximately 1:1 ratio between
males and females. Furthermore, the sex ratio in the 100 mg/kg/day group was outside thehistorical range (range 45-51.9% male fetuses out of 2194 fetuses; mean 49.5±1.5%). The
historical database was compiled by the authors from 8 developmental toxicity studies torepresent the same period of study (1986-1988).
Presently, it is unclear why the dams at the high-dose group had more male fetuses, since there
was no post-implantation loss, e.g. selective loss of female fetuses, to account for the higher
number of the male fetuses. It was speculated that imidacloprid may possess androgenic
properties, causing virilization of female fetuses, which could explain the profound phenotypic
gender change (See Attachment IV and Study Toxicology Summary). Additional information,such as the genotype of the fetuses, measurements of sex differentiation parameters (e.g.,anogenital distance), or evaluation of the internal sex organs, is needed to support thishypothesis.
Maternal toxicity at doses of 10 and 30 mg/kg/day included reduction in food intake (10 %, p ≤0.01) and a dose-dependent decrease in body weight gain (4% and 11%, respectively). The
decreases in the body weight gain at all doses were noted within the first 5 days of treatment.
The authors reported the reduction in food consumption and body weight gain at 10 mg/kg/day
as adverse effects on the dams and presented this dose as the maternal LOEL; the developmental
NOEL in the study was set at 30 mg/kg/day. The toxicologists at the DPR established thematernal and developmental NOELs at 30 mg/kg/day. The effects at the LOEL of 100 mg/kg/day
included reduction in food consumption and body weight gain (dams), and increased incidenceof wavy ribs and high number of male fetuses. The USEPA considered the 11% decrease (notstatistically significant) in the body weight gain of the dams as the maternal LOEL and used the46

NOEL of 10 mg/kg/day to characterize the risk of the short-term oral, dermal and inhalation
exposures to imidacloprid.
III.G.2. Oral – Rabbit
The developmental toxicity of imidacloprid was examined in the rabbit. Mated Chinchilla rabbits(16/dose level) were treated by gavage from GD 6 through 18 with daily dosage of 8, 24 or 72
mg/kg/day (Becker and Biedermann, 1992). Cesarean section and examination of the dams andfetuses were performed on GD 28. Severe maternal toxicity was observed at the highest tested
dose (72 mg/kg/day). Two dams from this dose-group died on GD 19 and 28, one dam aborted
and two dams had complete resorptions at terminal necropsy. All together, the females in the 72
mg/kg/day dose-group had a higher post-implantation loss (32%, p ≤ 0.01) relative to controls.
Consequently, there was a statistically significant reduction in the number of live fetuses perdam. Food consumption for the surviving females was reduced up to 66% (p ≤ 0.01) compared
to control. In turn, there was an overall weight loss during the entire treatment period. The mean
body weight was decreased by 4% on day 2 of treatment (GD 8). The weight loss became
significantly lower than the controls within 5 days of treatment (8-11%, p ≤ 0.01). The fetuses
from these dams had a reduced body weight (10%, p ≤ 0.01) and delayed ossification. The next
lower dose (24 mg/kg/day) caused a decrease in food consumption (16%, p ≤ 0.01) and areduction in body weight gain of the dams (33%, not statistically significant), compared tocontrol animals. The authors considered the reduction in food consumption and body weight gain
at 24 mg/kg/day as adverse effects on the dams and established the maternal NOEL as 8
mg/kg/day; the developmental NOEL was 24 mg/kg/day (Table 10). The DPR toxicologists andthe USEPA, set both, the maternal and developmental NOELs, at 24 mg/kg/day, based on
mortalities and decreased absolute body weights and body weight gain (dams), increased postimplantation loss and a decreased weight of the offspring at the LOEL of 72 mg/kg/day.
Table 10. Developmental Toxicity of Imidacloprid in the Rat and Rabbit.
SpeciesRata
25 dams/dose

Rabbitb
16 dams/dose

Exposure NOEL LOEL
Oral
(gavage)30

10 doses
GD 6-15
Oral(gavage)
13 doses
GD 6-18

24

Study Description

Doses (mg/kg/day): 0, 10, 30 and 100
Effects at LOEL: Dams: reduction in body weight
100 gain (up to 43%**; within first 3 days of treatment)
and reduction in food consumption (35%**)Fetuses: increased incidence of wavy ribs (5%) andhigh number of male fetuses (59%*)
Doses (mg/kg/day): 0, 8, 24 and 72
Effects at LOEL: Dams: mortalities (3 of 25 dams),
72 weight loss (up to 11%**, start days 2-5), decreasedfood consumption (66%** within first 4 days), postimplantation loss (32%**)Fetuses: decreased body weight (10%**)a/ Becker et al., 1992;b/ Becker and Biedermann, 1992.
**, Statistically significant difference from controls at p ≤ 0.01 (Fisher’s Exact test)47

III.H. NEUROTOXICITY
The acute and subchronic effects of imidacloprid on the nervous system were studied in rats
(Sheets, 1994 a,b,c). Imidacloprid caused neurotoxicity, which was evident from clinical signs,
alterations in the behavior and decreases in the motor activity in rats. The principal effects weretremors, gait abnormalities, reduced response to stimuli, decreased body temperature, decreased
grip strength and rearing, and impaired righting reflex.
III.H. 1. Acute Neurotoxicity
In an acute neurotoxicity study, imidacloprid (98.8%) was administered by gavage in a single
dose to Sprague-Dawley rats (18/sex/dose; Sheets, 1994a). The doses were 0, 42, 151 and 307
mg/kg/day. The control groups included vehicle (0.5% methylcellulose with 0.4% Tween 80)treated animals. The rats in the neurotoxicity group, (12/sex/group) were evaluated forneurobebehavioral signs using the Functional Observational Battery (FOB). Changes in the
motor activity were assessed by the figure-8-maze. Additional 6 rats/sex/group were subjected topathological evaluation. The following tissues were examined for pathology: brain, spinal cord,eyes, peripheral nerves (sciatic, sural and tibial), gasserian ganglion and gastrocnemius muscles.
Based on preliminary findings in rats, the Time to Peak Effect (TOPE) for imidacloprid-induced
behavioral changes was reported to occur between 90 min to 2 h following treatment. In thecurrent study, the clinical observation and the FOB evaluations were performed at pretest, at theTOPE (90 min after dosing), and 7 and 14 days after treatment. The motor activity was assessedat pretest, from 2.5 to 4.5 h following treatment and at Days 7 and 14.
The highest tested dose (307 mg/kg/day) produced severe toxicity, including lethality. Fourmales and ten females in this group died within to 24 hours following treatment (Table 11). All
animals, which were still alive after four hours of dosing had severe tremors and appeared coolto-touch, with their body temperature being reduced by 2°C (males) and 5.5°C (females).
Autonomic signs in these rats included nasal, perianal and urine stains. The CNS effects in thisgroup were evidenced by the markedly decreased activity and reduced response to stimuli.
Additional effects in the rats treated with 307 mg/kg dose included incoordinated gait, decreased
rearing and grip strength, and impaired aerial righting. A higher incidence of animals, whichwere sitting or lying in the cage, tremors and nasal stain was also reported for the 151 mg/kg
dose group. The males and females treated with 151 or 307 mg/kg imidacloprid showed 21-89%(p ≤ 0.05) decrease in the motor and locomotor activity in the figure-8-maze (Table 11). The
females from the lowest tested group (42 mg/kg), exhibited 25-27% decrease in their motor
activity (Table 11). Some of the effects, such as nasal and urine stains, and a decreased activityof the surviving males at the 307 mg/kg group persisted after 7 to 14 days of treatment. Amongthe tested clinical chemistry parameters, the authors considered the decrease in serum
triglycerides as a treatment related effect. At the lowest tested dose (42 mg/kg) the serum
triglycerides were decreased in the males by 23%. This effect became statistically significant inboth sexes treated the 151 and 307 mg/kg imidacloprid (up to 73% decrease, p ≤ 0.05; Table 11).
It should be noted that a decrease in the serum triglycerides was consistently observed after acuteand the subchronic exposure to imidacloprid, which may be related to the liver toxicity noted inthese studies (see next section III.H.2.).
Altogether, the results revealed that imidacloprid caused a range of acute neurotoxic effects
including a decreased activity of the females at the lowest tested dose (42 mg/kg) to severe
toxicity and mortalities for both sexes at the dose of 307 mg/kg. It should be noted that the TOPE48

was determined based on behavioral effects. Limiting the TOPE selection to FOB findings may
not be optimal for observing the motor activity.
The Data Review group at the DPR established a study NOEL of 42 mg/kg/day based on
statistically significant decreases in the motor and locomotor activity of the female rats at the
LOEL of 151 mg/kg/day. For the purpose of risk assessment, a Benchmark Dose (BMD) analysis
was performed and established a BMD05 for acute neurotoxicity of 9 mg/kg/day based on thesame endpoint (see detailed discussion in Sections IV.A.2. and V.B.1. under Risk
Characterization and Risk Appraisal). The USEPA also considered the dose of 42 mg/kg/day as
a LOEL for reduction in motor and locomotor activity.
Table 11. Effects of Imidacloprid in Sprague-Dawley Rats After a Single Gavage Dosea.
Acute Effect

Males

Dose mg/kg
Mortality within 24 h
No. Animals Tested
Tremors

0
0/18

0
0/18

42
0/18

151 307
0/18 10/18

FOB Observations at 90 min TOPEc
12
12
11
12
12
*
0
0
1
10
0

12
0

12
1

12
11*

b

42
0/18

151
0/18

Females307
4/18

Gait incoordination

0

0

0

5*

0

0

0

10*

Decreased activity

0

0

0

7*

0

0

0

7*

Sitting or lying

7

7

0

11

2

6

4

11*

Decreased arousal

1

1

0

8*

0

0

0

10*

Touch – no response

0

1

0

4

0

0

0

7

Uncoordinated right reflex

0

1

0

2

0

0

0

1

Nasal stains

0

0

2

7

0

0

0

3

Perianal stains

0

0

1

1

0

0

0

0

Urine stains

0

0

0

2

1

0

0

0

Rearing (mean)

1.7

1.9

1.9

0.8*

4.4

4.6

3.6

0.9*

Grip strength (kg)

0.43

0.43

0.43 0.28*

0.3

0.31

0.34 0.25*

Motor Function (figure-8-maze) at 2.5-4.5 h
100
95
75
27
100
Motor activity (% of control)

73

52*

19*d

22*

100

75

54

11*d

Clinical Chemistry (within 24 h)
100
77
64*
38*

100

91

44*

27*

Locomotor activity (% of control)
Triglycerides (% of control)

100

91

79*

a/ Data from Sheets, 1994a. The results are expressed as a number of animals, which exhibited a particular effect evaluated by
the FOB; b/ All 14 animals (of 36) in the 307 mg/kg dose-group died within 24 h of treatment. c/ TOPE, Time of Peak Effect;d/ Ten females were tested for motor and locomotor activity due to mortality .
*, Statistically significant difference from controls at p≤ 0.05 (Anova or Dunnet test)49

In a supplemental study, 12 rats/sex were used as controls or treated with imidacloprid via
gavage in a single dose at 20 mg/kg (Sheets, 1994b). The aim of this second study was todetermine the NOEL for the acute neurotoxicity of imidacloprid in rats. The supplemental study
was performed in the same laboratory 6 months after the main study (Sheets, 1994a) and used asimilar protocol. The results indicated that the dose of 20 mg/kg did not cause apparent toxicity,
including a decrease in the motor activity, which was observed in females at the LOEL of 42
mg/kg in the main study. However, there was a substantial uncertainty associated with thereported dose of 20 mg/kg as the NOEL for the acute oral toxicity, because this study did notinclude a high enough dose of imidacloprid to produce toxicity in the rats.
III.H. 2. Subchronic Neurotoxicity
In a subchronic neurotoxicity study, imidacloprid (98.8% a.i.) was administered to Fischer-344
rats (12/sex/dose) at dietary levels of 0, 150, 1000 and 3000 for a period of 13 week (Sheets,
1994c). Based on the food consumption, the average daily doses corresponded to 9.3, 63 and 196
mg/kg/day for males and 10.5, 69, and 213 mg/kg/day for females. The FOB and activity tests on
the figure-8-maze were performed at pretest and at week 4, 8 and 13 of treatment.
During most of the exposure period, imidacloprid caused a reduction in body weights in both
sexes at 1000 (up to 5%, females; 8%, males; p ≤ 0.05) and 3000 ppm (up to 9%, females; 17%,
males; p ≤ 0.05). This effect was due, at least in part, to a decrease in food consumption (up to
13% and 29% for the animals at 1000 ppm and 3000 ppm, respectively. Decreases in the TAG in
the serum (up to 41%, ≤ 0.05) were considered by the authors to be treatment-related for both
sexes exposed to 1000 and 3000 ppm imidacloprid (Table 12). It should be noted that asignificant decrease in the serum triglycerides (55-75%) was consistently observed in most of thesubchronic toxicity studies with imidacloprid (33-409 mg/kg/day). These included: 13-Week oral
treatment in rats (52% TAG decrease; Eiben, 1989); 13-Week neurotoxicity study in rats (41%decrease, Sheets, 1994c), 4-Week inhalation study in rats (73% decrease, Pauluhn, 1989), and 4Week oral study in dogs (75% decrease, Block, 1987). In addition, 73% decrease in the serum
TAG was also reported in the acute neurotoxicity study in rats (Sheets, 1994a). This effect may
reflect imidacloprid-induced changes in the metabolism in liver, as indicated by other studies(Eiben, 1988a and 1989; Pauluhn, 1988a; Eiben 1988b; Block, 1987).
Lower grip strength of the forelimbs was measured in the males exposed to 3000 ppm
imidacloprid, which became statistically significant at the 8 week of treatment (23%, p ≤ 0.05;
Table 12). At the end of the study (13 week), a higher incidence of uncoordinated righting
response was reported for the males exposed to imidacloprid. While only 1 control male (of 12)
showed uncoordinated righting response, there were 2 males from the 150 ppm group, 3 males
form the 1000 ppm group and 7 males from the 3000 ppm group (p ≤ 0.05), which had
uncoordinated landing in the FOB. Females treated with 3000 ppm (213 mg/kg/day)
imidacloprid showed a decrease in the locomotor activity at all test (at weeks 4, 8 and 13; up to21%). Although this effect was not statistically significant, it was consistent with the results fromthe acute neurotoxicity study, where the locomotor activity was reduced by 46% and 89% in thefemales exposed to single doses of 151 and 307 mg/kg imidacloprid, respectively (Sheets,
1994a). In the acute neurotoxicity study, the marked reduction of the locomotor activity was
noted within 2-4 h of treatment. In the subchronic neurotoxicity, the first test on motor activity
was performed after 4 weeks of exposure. Therefore, the 21% reduction in the locomotor activity
may reflect some degree of adaptation to the blockage of the nAChR by imidacloprid.

50

The authors established a NOEL of 9.3 mg/kg/day, based on decreased body weights of the malerats and changes in the clinical chemistry parameters at the LOEL of 63 mg/kg/day. The resultsfrom the subchronic neurotoxicity study with Fischer-344 rats were comparable with the finding
from the subchronic studies in Wistar rats, which established a NOEL of 14 mg/kg/day, based on
reduction in body weight (Eiben 1988a, 1989, see Section III.C.1.).
Table 12. Effects of Imidacloprid in Fischer-344 Rats In a 13-Week Feeding Studya.

Subchronic Effect

Males

Dose ppm
Dose mg/kg/day
Body weight - week 13 (g)% of control

Females

0
0

150
9.3

1000
63

3000
196

0
0

150
10.5

1000
69

3000
213

100

100

92*

84*

100

98

95*

91*

FOB Observationsb
12
No. Animals Tested
1
Uncoordinated right reflex
Grip strength of forelimb % of control
100
Week 4

12
2

11
3

12
7*

12
0

12
0

12
0

12
1

97

100

88*

100

95

95

90

100

93

87

77*

100

100c

100c

100c

100
100
98
91
Motor Function (figure-8-maze)

100

95

94

95

99

91

Week 8
Week 13

Locomotor activity (% of control)
Week 4

100

95

100

100c

100

95

Week 8

100

100

100

100

100

91

Week 13

91
c

79
c

100
95
100
Clinical Chemistry

100

100

100

100

82

100c
100c

64*
74*

100
100

100c
91

68
89

59*
65*

Triglycerides (% of control)
Week 4
Week 13

100
100

100c
100

a/ Data from Sheets, 1994c.
b/ The results are expressed as a number of animals, which exhibited a particular effect evaluated by the FOB
c/ The mean value was higher than the levels measured in the control animals.
*, Statistically significant difference from controls at p≤ 0.05 (Anova or Dunnet’s test)51III.I. DEVELOPMENTAL NEUROTOXICITY
Developmental neurotoxicity (DNT) studies are designed to investigate whether pre- or postnatal exposure to a toxicant affects the neural development. The DNT evaluations ofimidacloprid were focused on the possible adverse neurodevelopment outcomes, including
behavior, learning and memory, and locomotion. Imidacloprid is the first neonicotinoid, forwhich a DNT study has been completed.
Imidacloprid (98.2%) was administered in the diet to mated Sprague-Dawley rats (about 30
rats/dose; Sheets 2001). The females were treated from the gestation day (GD) 0 to GD 20 andthen continued through the lactation day (LD) 21 at doses of 0, 100, 250 and 750 ppm. Based on
the food consumption by the dams during the gestation, the average daily intake of imidacloprid
was reported as 0, 8, 19 and 54.7 mg/kg/day. The pups were indirectly exposed to imidacloprid
for a total of 41 days (20 days in utero and 21 days via lactation). Control groups included
vehicle (corn oil)-treated animals. After weaning on PND 21, the pups from these litters (4 males
and 4 females/litter) were given untreated feed (no pesticide). The dams and the pups wereobserved for signs of general toxicity throughout the treatment period. All dams were sacrificed
on LD 21 following the weaning of the litters. The pups (16 rats/sex/dose) were evaluated fordevelopmental neurotoxicity until about 75 days of age. Six FOB were performed between PND
4 and 60. Motor activity was assessed on the Figure-8-maze on four occasions between PND 1360. Acoustic startle habituation was tested in a Startle system enclosure on PND 22, 38 and 60.
Learning and memory were evaluated using the Passive avoidance test (PND 22 and 29) and theWater maze (PND 60 and 67). Brain tissue from 10 pups/sex/group were analyzed on PND 11
and PND 75.
Dams: The clinical signs in the dams in the 750 ppm group were restricted to a decreased foodconsumption during the gestation and lactation periods (up to 14%, p ≤ 0.05). The body weights
or body weight gains of these dams were not affected.
Offspring: Male and female pups exposed to 750 ppm imidacloprid in utero and via lactation,
had reduced body weights (11-13%, p ≤ 0.05) on PND 4-21; Table 13). Difference in weight at
the high dose persisted after weaning, even when imidacloprid was removed from the diet. At theend of the study the body weight was about 4% less then the control. The motor and locomotor
activity of males and females from the 750 ppm group were decreased by 31-39% at PND 17,
albeit, not statistically significant. The reduction in motion/locomotion persisted in the femaleson the next test occasion (PND 21; 26-37% reduction compared to controls). The authors
ascribed the effects on the motor activity to the treatment, because of the magnitude of theeffects and the occurrence at the high dose in both sexes during the period of exposure.
Changes in motor activity were consistently observed in all of the available neurotoxicity studies
with imidacloprid (Sheets,1994a, 1994c and 2001). In all cases, the females appeared to be more
susceptible. It is interesting to note that similar doses of imidacloprid for different durations
elicited comparable levels of reduction of the motor and locomotor activity in the female rats.
For example, a 27% decrease in the motor activity was reported after 2.5-4 h of exposure to 42
mg/kg/day in the acute neurotoxicity study; in the DNT study the decrease was 39% after 37
days of indirect exposure of the pups to 54.7 mg/kg/day imidacloprid.
Brain measurements of the PND11 pups revealed that the caudate putamen width was decreased
by 6% in the females from the 750 ppm group (2.769 mm in control vs. 2.617 mm in the treated52females, p= 0.037). Furthermore, these females had a substantial reduction (27%) in the
thickness of the corpus callosum (0.602 in control vs. 0.436 in the treated females, p< 0.05).
Despite the significant decreases in these parameters in the female rats at 750 ppm,
morphometric brain measurements were not performed in the intermediate and low dose-groups.
Table 13. Effects of Imidacloprid in Sprague-Dawley Rats in a Developmental Neurotoxicity
Studya.
EffectDose ppm
Dose mg/kg/day
No. Animals Testedb
Body weight – % of control
PND 4
PND 21

Males
0
0
16

100
8
16

Females

250
19
16

750
54.7
16

0
0
16

100
8
16

250
19
16

750
54.7
16

100
100
100
78*
100
100
97
86**
Motor Function (figure-8-maze)

100
100

100
100

100
96

81*
88**

100
100

74
90

99
83

69
63

2.769
0.602

-

-

2.617#
0.436†

Locomotor activity (% of control)
100
100c
88
62
PND 17
c
c
100
100
100
100c
PND 21Brain measurements PND11
Caudate putamen width (mm)Corpus callosum width (mm)

2.67
0.54

-d
-

-

2.71
0.53

a/ Data were from Sheets, 2001.
b/ The rats were exposed to imidacloprid for a total of 41 days (20 days in utero and 21 days via lactation). After weaning on
PND 21, the rats were fed regular diet (no pesticide)c/ The mean value was higher than the levels measured in the control animals.
d/ Dash (“-“) indicated no data.
* **,Statistically significant difference from controls at p≤ 0.05 or p≤ 0.01, respectively (Anova or Dunnett’s test), statistically significant different from controls at p=0.0374 (one-tailed test)#†, statistically significant different from controls p<0.05 (Mann-Whitney test)

Presently, the biological consequence of the imidacloprid-induced decrease in the caudate
putamen width and the thickness of the corpus callosum is not known. However, it is has been
well established that pathological changes in corpus callosum and basal ganglia (including thecaudate nucleus and putamen) affect motor functioning and voluntary motion (Tomimoto et al.,
2004; Ding et al., 2001; Middleton and Strick, 2000). The neuronal nAChRs, which are targets
for imidacloprid in the CNS have been implicated to be involved in some of theseneuropathologies (Cordero-Erausquin et al. 2000; Paterson and Nordberg 2000; Lindstrom
2002). Imidacloprid, its metabolite desnitro-imidacloprid and nicotine, all induced receptor upregulation of the neuronal nAChR in cell cultures. For nicotine, the receptor up-regulation has
been related to the development of tolerance to its effects on the locomotor activity (Marks et al.,53

1992). In this respect, a possible link between the decrease in the caudate putamen and the
corpus callosum widths in the PND 11 females exposed in utero and via lactation to imidacloprid
and the decrease in the motor/locomotor activity in these animals at PND17 should not bedismissed without further investigation.
Decreases in thickness of brain structures of the pups were observed following a total of 32 dosesof imidacloprid to the dams (21 doses in utero and 11 doses during lactation). Therefore, if the
DNT study were to be used to establish a regulatory toxicological level, it would be applicable torepeated (subchronic or chronic) exposures to imidacloprid. However, morphometric brain
measurements of the pups were first performed on PND11, and thus, the timeline of theimidacloprid developmental toxicity could not be determined. Because decreases in brain
structures could theoretically result from a single exposure in utero, a critical NOEL from thisstudy might be pertinent to acute exposures, in particular, to females of childbearing age toprotect fetal exposure.
This study was recently submitted to the DPR and was generally expected to provide a NOEL forthe effects of imidacloprid on the neural development. However, the study was deficient for thelack of morphometric brain measurements in the females at the intermediate and low dosegroups. The LOEL for the marked reduction in the corpus callosum thickness and the decrease incaudate putamen width in the females was 750 ppm (54.7 mg/kg/day). This study could not be
used to determine the developmental NOEL. Applying a default factor of 10 to the LOEL of 54.7
mg/kg/day, the estimated NOEL (ENEL) for developmental neurotoxicity could be as low as 5.5
mg/kg/day. The NOEL for the reduction in body weight and decreased motor activity was 250
ppm (19.4 mg/kg/day).

54

IV. RISK ASSESSMENT
IV.A. HAZARD IDENTIFICATION
IV.A.1. Introduction
Imidacloprid is classified as a Category II toxicant, based on its acute toxicity. In the available
genotoxicity studies and oncogenicity bioassays in rodents, imidacloprid did not show clear
potential to cause chromosome damage or cancer. Therefore, the characterization of the risk ofimidacloprid in this document was based on non-oncogenic effects.
The experimentally determined highest dose at which no effects were observed (NOEL) wasused in delineating the threshold dose for non-oncogenic effects. Therefore, the NOELs were
presented in the context of the LOEL, the lowest dose in the experiment, which produced
toxicologically significant effects. In a toxicity study, the LOEL is the next higher dose above
the NOEL. In some studies, where the lowest tested dose of imidacloprid was the LOEL, a
Benchmark Dose (BMD) approach was used to determine the threshold of the imidacloprid
toxicity (USEPA, 1995). The BMD method involves fitting a mathematical model to the entire
dose-response dataset for a specific endpoint. The BMD is the lower, 95% confidence limit of
the effective dose (LED) required to cause a given response (1%, 5% or 10% effect level) in an
organism.
IV.A.2. Acute Toxicity
IV.A.2.a. Acute Oral Toxicity
Acute toxicity studies with imidacloprid were not available in humans. Therefore, studies inlaboratory animals were considered for determination of the toxicity thresholds. A list of NOELs
and LOELs is shown in Table 14. It includes the thresholds established from all pertinent studies
described in Section III.B, and under any other toxicity categories pertinent to acute exposures,e.g., the threshold for neurotoxicity after a single dose (Section III. H.) and the threshold fordevelopmental effects that can potentially occur after a single exposure in utero (Section III.G.).
The lowest acute oral NOEL was 10 mg/kg/day in mice, based on clinical signs (laboredbreathing, decreased motility, staggering gait and trembling) at the LOEL of 71 mg/kg/day(Bomann, 1989a). This single dosing study was designed for determination of the LD50 andincluded only evaluations of clinical signs (see Section III.B). A wide dose-range was employed(a total of 7 doses ranging from 10 to 250 mg/kg/day); however the study did not include control(untreated) mice. Because of the dose selection, the NOEL in this study was 7-fold lower thanthe LOEL. Therefore, a question could be raised regarding the possibility that the NOEL could
be higher had the dose interval in the study design been reduced within this region. However,modeling of the data on tremors with the quantal BMD Probit model produced an LED05 of 14
mg/kg/day, which is close to the NOEL of 10 mg/kg/day. It is interesting to note that miceappeared to be very sensitive to the acute treatment with imidacloprid (acute NOEL of 10
mg/kg/day), but were less sensitive in the subchronic and chronic studies (NOELs of 86 and 47
mg/kg/day, respectively; see Sections III.C.2. and III.D.2)
The NOEL of 10 mg/kg from the acute study in mice was used by the DPR in the health risk
assessment in 1993, which evaluated imidacloprid for an emergency use on cotton under the55Section 18 of the FIFRA (Lewis et al., 1993). Following the completion of the 1993 health risk
assessment, new acute studies became available to the DPR for defining the critical NOEL.
Table 14. Acute No-Observed-Effect Levels (NOELs) and Lowest-Observed-Effect Levels(LOELs) of Imidacloprid.
Acute StudyNOEL LOEL

Toxic Effects at LOEL

Species

ExposureRat
5/sex/dose

Oral (gavage)
1 dose50100Effects at LOEL: Apathy, labored breathing,tremors, gait incoordination, decreased
motility, nasal and urine staining (Bomann,
1989b#)

Rat
5/sex/dose

Inhalation
4 h (dust; 95%a.i.)192a,b412

Effects at LOEL: Difficult breathing, reduced
motility, piloerection and tremors (Pauluhn,
1988a#)

Rat
10/sex/dose

Inhalation
6h/day for 5 days
(dust; 95% a.i.)

3.4a,c19

Effects at LOEL at day 5: Reduction in bodyweights (6 %**) and induction of MFOd
(142% **) in the liver (Pauluhn, 1988a)

Rat
18/sex/dose
Acute
Neurotox.

Oral (gavage)
1 dose9e42

Effects at LOEL: Decrease in motor andlocomotor activity (25-27%), decreased TAG(23%, Sheets, 1994a)#

Mouse
5/sex/dose

Oral (gavage)
1 dose

10

71

30f

100

24

72

Rat
Oral (gavage)
25 dams/dose
10 doses
Dev. Tox.
(GD 6-15)
Study

RabbitOral (gavage)
16 dams/dose
13 doses
Dev. Tox.
(GD 6-18)
Study

mg/kg

Effects at LOEL: apathy and laboredbreathing), decreased motility, staggering gait
and trembling (Bomann, 1989a#)
Effects at LOEL: Dams: reduction in bodyweight gain (43% ** within first 3 days) andreduction in food consumption (35%**)Fetuses: increased
incidence of wavy ribs (5%) and high numberof male fetuses (59%*; Becker et al., 1992#)
Effects at LOEL: Dams: mortalities (3 of 25dams), weight loss (up to 11%**, start day 2),
decreased food consumption (66%** withinfirst 4 days), post-implantation loss (32%**,
Becker and Biedermann, 1992#)
Fetuses: decreased bodyweight (10%**)a/ For inhalation studies, the dosages were calculated using the formula in Table 1. b/ Only 4-11% of the particles had therecommended MMAD <5 µm. c/ Only 57-18 % of the particles had MMAD <5 µm. e/ LED05 estimated by the BMD model.
f/ 11% reduction in body weight gain of dams at this dose. USEPA established the NOEL at 10 mg/kg/day.
**, Statistically significant difference from controls at p ≤ 0.01 (Fisher’s Exact test).

56

The next higher oral LOEL was from the acute neurotoxicity study in rats (Sheets, 1994a). The
experimental protocol consisted of a single gavage treatment and extensive toxicity evaluations,
including neurobehavior and motor activity. The selected doses produced dose-groups with agradation of the toxic effects, however, they did not include a level of no effect. The principal
finding at the LOEL of 42 mg/kg was the 25-27% decrease in the motor and locomotor activity
in the females (Table 11). This effect became statistically significant for both sexes (up to 89%
decrease) in the next higher doses (151 and 307 mg/kg/day).
In a subsequent study performed in the same laboratory, the dose of 20 mg/kg did not produce
apparent toxicity, including the effects seen at the LOEL of 42 mg/kg in the main study (Sheets,
1994a). However, there was a substantial uncertainty in the NOEL of 20 mg/kg because thestudy did not include a high enough dose of imidacloprid to produce toxicity in the rats. The
USEPA applied an uncertainty factor of 3 to the LOEL of 42 mg/kg/day to estimate an oral acute
NOEL (ENEL) for imidacloprid of 14 mg/kg/day (USEPA, 2003).
As an alternative to the ENEL, the Benchmark Dose (BMD) approach could be considered indetermining the threshold of the imidacloprid acute toxicity. In this approach, the BMD is thelower 95% confidence limit of the effective dose (LED) required to cause a given response in an
organism (USEPA, 1995). Depending on the characteristics and/or the severity of the toxic
responses, a 95% lower bound estimate of the 1%, 5% or 10% effect level may be selected as theLED01, LED05, or LED10, respectively. Unlike the ENEL, which is determined based on one data
point, the LOEL, the BMD method utilizes response levels at all tested doses and hence
minimizes the uncertainty in the determination of the toxicity threshold.
Benchmark Dose Modeling of the Motor Activity Data: The USEPA Benchmark Dose Software
version 1.3.2 (available at http://cfpub.epa.gov/ncea/cfm/bmds.cfm) was used to calculate theLED for imidacloprid. LEDs were derived from the data on motor activity of the female rats
measured in the figure-8-maze (Sheets, 1994a, Section III.H.1. under Acute Neurotoxicity; Table
11). The current DPR default of 5% response level was used to determine the LED for the motor
effects (DPR MT-1, 2004). Of the several available algorithms, the Polynomial model generated
a good curve fit, as indicated by the AIC value (Akaike’s Information Criterion; see Attachment
III). The LED05 was estimated as 9 mg/kg/day (Table 14). The effective dose ED05 corresponding
to the above LED05 was 12 mg/kg/day. Both, the LED05 and the ED05 were close to the USEPANOEL of 14 mg/kg/day, which was estimated by applying an uncertainty factor of 3 to the
LOEL of 42 mg/kg/day (USEPA, 2003).
The DNT study might also be pertinent for establishing a threshold for effects on the developing
nervous system, which can potentially occur after a single exposure in utero. A NOEL of 5.5
mg/kg/day could be estimated from the LOEL of 54.7 mg/kg/day for significant decreases indimensions in brain structures (up to 27%) of the female pups (Sheets, 2001, see Sections III.I.
and IV.A.3.). However, there was a much greater uncertainty associated with the DNT endpoint,
because it was approximated from the LOEL by using a 10-fold default factor.
Conclusions
The two lowest acute oral NOELs for imidacloprid were 9 mg/kg/day and 10 mg/kg/day. The
LED05 of 9 mg/kg/day was estimated from the data on motor activity of the females from theacute neurotoxicity study in rats (Sheets, 1994a; Table 14). The NOEL of 10 mg/kg/day was
based on the LOEL of 71 mg/kg/day for clinical signs, which was established in the acute57

toxicity study in mice (Bomann, 1989a). The acute neurotoxicity study in rats had higher quality
data than the mouse study. It employed more sensitive toxicity evaluation (e.g. clinicalobservations, FOB, motor activity, neuropathology, etc.; Sheets 1994a). The acute neurotoxicity
included a control group and more animals per dose group; and had a clearer dose-response
relationship, which could be described by the continuous BMD model (from USEPA NCEA,
2002). Based on these considerations, the LED05 of 9 mg/kg/day for decreases in motor activity
in rat was selected as equivalence to the NOEL to characterize the acute risk due to oral exposure
to imidacloprid. The ENEL of 5.5 mg/kg/day for decreases in dimensions in brain structures inrats from the DNT study (Sheets, 2001) could be applicable to acute exposures to imidacloprid in
women of childbearing age to protect against fetal exposure.

Figure 4. Estimation of the Threshold of the Imidacloprid Acute Oral Toxicity with the BMD
model.

700

Polynomial Model

Light Beam
I t
ti

600
500
400
300
200
100
0
0
50
LED05 ED05

100

150

200

250

300

Imidacloprid mg/kg/day

Imidacloprid-Induced Decrease in the Motor Activity in Rats. Imidacloprid was administered by gavage in a single dose toSprague-Dawley rats (Sheets, 1994a). The doses were 0, 42, 151 and 307 mg/kg/day. The lowest tested dose produced 27%
decrease in the motor activity of the female rats. The motor activity was assessed using the figure-8-maze by counting light beaminterruptions, The BMD approach was used to calculate the effective dose (ED) and the 95% confidence limit of the effective
dose (LED), which were required to cause a 5% reduction in the motor activity. The Polynomial model generated the best curve
fit among the several available algorithms. The LED05 and ED05 were estimated as 9 and 12 mg/kg/day, respectively.

58

IV.A.2.b. Acute Inhalation Toxicity
Two acute inhalation toxicity studies with imidacloprid in Wistar rats were available for the
NOEL and LOEL determinations (Table 14).
In the study by Pauluhn (1988a), the rats were exposed head/nose only to imidacloprid in theform of dust for 4 hours. The effects at the LOEL of 412 mg/kg/day included difficult breathing,
reduced motility, piloerection and tremors. The same clinical signs were observed at the LOEL
of 100 mg/kg/day in the acute oral study in Wistar rats (Bomann, 1989b, see Table 3 and Table
14). The NOEL was 192 mg/kg/day, which was 21-fold higher than the acute oral NOEL of 9
mg/kg/day from the neurotoxicity study in rats (Sheets, 1994a). This study was designed for
determination of the LC50 and thus more subtle toxic effects might have been missed. In addition,
the data suggested that an adjustment of the NOEL was needed to correct for the bioavailabilityof imidacloprid due to the large particle size of the dust. The study reported that at the NOEL,
only 11% of the dust particles had an aerodynamic particle size less than 5 µm. If only particles
with MMAD ≤ 5 µm were to be considered, the adjusted NOEL would be 21 mg/kg/day.
Nevertheless, the adjusted dose could be higher, since the observed toxicity may be due to larger
particles as well. For toxicants causing systemic effects, a particle size range that deposit
throughout the entire rodent respiratory tract (i.e. MMAD up to 10 μm) is of toxicologic concern(Raabe et al., 1988; SOT, 1992; Pauluhn, 2003). However, data on the percentage of larger
particle size, which could contribute to the systemic toxicity of imidacloprid, were not provided.
In the second inhalation toxicity study, Wistar rats were exposed by head/nose only to
imidacloprid dust for 6 hours/day for 5 days (Pauluhn, 1988a). This study included more
extensive toxicity evaluation (e.g. clinical signs, clinical chemistry, hematological andhistopathological changes). Clinical signs were not observed at any of the tested doses. However,
the highest tested dose in this study (87 mg/kg/day) was 5-fold lower than the dose at whichclinical signs were to be expected (e.g. the LOEL of 412 mg/kg/day from the 4-hour inhalation
study; Pauluhn, 1988a). The reported NOEL was 3.2 mg/kg/day, based on statistically significant
reduction of body weights (6%) and induction of liver MFO in the liver (28%) at the LOEL of 19
mg/kg/day. This NOEL was 56-fold lower than the NOEL from the 4-hour inhalation study (192
mg/kg/day). It was also 3-fold lower than the oral NOEL from the acute neurotoxicity study inrats (9 mg/kg/day; Sheets, 1994a). Adjusting dose of 3.2 mg/kg/day for 54% of particles with
MMAD ≤ 5 µm would result in a NOEL of 1.7 mg/kg/day.
For characterizing the risk of inhalation exposures of contaminants in the air, data frominhalation toxicity studies are preferable. There was, however, a substantial uncertainty
associated with the bioavailability of imidacloprid in both inhalation studies. The 5-Day study
had provided more elaborate evaluations. Nevertheless, there was a greater uncertainty in thereported effects at the LOEL of 19 mg/kg/day (Pauluhn, 1988a), as they may have required
repeated exposures. In this regard, induction of the liver MFO and reduction in body weights
were consistently observed in the subchronic oral and inhalation studies. Thus, the adjusted
NOEL of 1.7 mg/kg/day may not be appropriate for use as an acute inhalation no effect level.
Since the toxicological effects identified in the inhalation studies were systemic rather thanlocalized (i.e., at the site of contact), the oral NOELs and LOELs can reasonably be assumed tobe the thresholds for inhalation exposures. There were no pharmacokinetic studies to determine
the extent of the imidacloprid absorption upon inhalation exposure. In the absence of data, both
DPR and USEPA assumed a default of 100% for the inhalation uptake. Based on the comparable
59

acute toxicity between the oral and inhalation routes, it is possible to extrapolate a threshold fromthe oral route based on the absorbed dose. In conclusion, the oral NOEL of 9 mg/kg/day from theacute neurotoxicity study in rats (Sheets, 1994a) was selected for characterizing the acute risk
due to inhalation exposure to imidacloprid.
IV.A.2.c. Acute Dermal Toxicity
There were no available studies to determine the acute dermal NOEL and LOEL or the extent of
the dermal absorption. The oral NOEL of 9 mg/kg/day from the acute neurotoxicity study in rats
(Sheets, 1994a) was selected for characterizing the risk due to the acute dermal exposure toimidacloprid.
IV.A.3. Subchronic Toxicity
The subchronic NOELs and LOELs for imidacloprid are presented in Table 13. The list included
pertinent studies described in Section III.C., SUBCHRONIC TOXICITY and under any othertoxicity categories pertinent to subchronic exposures, e.g., the threshold for subchronic
neurotoxicity and the threshold for reproductive toxicities.
IV.A.3.a. Subchronic Oral Toxicity
Five oral toxicity studies in rats, one study in mice and two studies in dogs were available for theselection of the critical subchronic NOEL.
The lowest NOEL of 7.3 mg/kg/day was established in Beagle dogs, after 4 weeks of treatment
with imidacloprid (Table 15). This NOEL was based on morphological changes in the liver andthe thyroid gland (hypertrophy of hepatocytes and follicular atrophy) at the LOEL of 31
mg/kg/day (Block, 1987). The toxicity increased abruptly at the next tested dose (49 mg/kg/day)and included mortality, weight loss, severe tremors, ataxia and pathological changes of the liver,thymus, thyroid and testis. The same NOEL in Beagle dogs (8 mg/kg/day) was determinedfollowing 13 weeks of dosing with imidacloprid (Table 15). Tremors were reported at the LOEL
of 24 mg/kg/day.
In a DNT study in rats, statistically significant decreases (up to 27%) in thickness of brain
structures of the PND11 pups were found at the highest tested dose of 54.7 mg/kg/day, following
32 daily oral doses of imidacloprid to the dams (Sheets, 2001). Pups from the intermediate andlow dose-groups were not evaluated for developmental brain effects. Assuming that the LOEL
for DNT is 54.7 mg/kg/day and applying a 10-fold default uncertainty factor, the NOEL could be
estimated as 5.5 mg/kg/day. The ENEL of 5.5 mg/kg/day is close to the NOEL of 7.3 mg/kg/day
established in dogs, but with a greater uncertainty due to the application of a 10-fold default
factor.
The next set of higher NOELs, ranging form 9.3-19.4 mg/kg/day, were identified in studies inrats. Reduction in body weights was consistently observed in all subchronic and reproductive
toxicity studies in rats. The lowest NOEL (9.3 mg/kg/day) was from a subchronic neurotoxicity
study in Fischer-344 rats (Sheets, 1994c). The experimental protocol included 13 weeks ofdosing with imidacloprid and extensive evaluations, such as assessments of the neurobehavioral
and the motor activity. The reported effect at the LOEL of 63 mg/kg/day was a statisticallysignificant reduction (6%) in body weights of the male rats. In a reproductive toxicity study in
Wistar rats, the NOEL was 13 mg/kg/day rats based on significantly decreased body weights60

(13-17%) of the parental animals and the pups from all generations at the LOEL of 38 mg/kg/day(Suter et al., 1990). Statistically significant decreases in body weight (8-11%) were also observedin the 13- or 14-Week subchronic dietary studies in Wistar rats at the LOELs of 57 and61mg/kg/day (Eiben, 1988a; 1989). In the 13-week study, an additional effect at the LOEL wasliver toxicity (necrosis of hepatocytes). Both studies established a NOEL of 14 mg/kg/day. A
NOEL of 19.4 mg/kg/day was determined from the developmental neurotoxicity study inSprague-Dawley rats (Sheets, 2001). It was based on a statistically significant reduction in bodyweights of the pups (13%) and a decreased motor activity LOEL of 54.7 mg/kg/day.
The highest of all subchronic NOELs was determined in B6C3F1 mice treated with imidaclopridfor 107 days (Eiben, 1988b). The effects at the LOEL included mortality, clinical signs and amarked reduction in the body weight (up to 27%). There was a substantial uncertainty associatedwith the reported doses in this study. The imidacloprid doses were estimated based upon
unusually high food consumption, representing about 60%-100% of the mice body weight. The
DPR toxicologists adjusted the ingestion of imidacloprid based on a default food consumption of
15% of the body weight of an adult mouse (30 g). The revised NOEL was 86 mg/kg/day, basedon the revised LOEL of 427.
Conclusions
With the exception of the NOEL from the mouse study, the rest of the subchronic oral NOELs inrats and dogs were in the range of 7.3-19.4 mg/kg/day. The lowest NOEL (7.3 mg/kg/day) wasestablished from two studies in the dog, based on morphological changes of the liver and thethyroid gland, and tremors at the LOEL of 24-31 mg/kg/day. The two dog studies included
extensive toxicity evaluations and the endpoints were relevant, as liver, thyroid effects andtremors were seen in other studies with imidacloprid.
The most common effect in the five studies in rats was decreases in the body weight at the LOEL
of 38-63 mg/kg/day. It should be noted that a reduction in body weights was also observed in thedogs at similar doses (49-63 mg/kg/day). The lowest NOEL in rats was 13 mg/kg/day from thereproductive toxicity study (Suter et al, 1990). Because the rats had higher NOEL than dogs, it
could be argued that the subchronic no effect level is closer to the dose of 13 mg/kg/day than to
the NOEL of 7.3 mg/kg/day in dogs. However the toxicity endpoint defining the NOELs in ratsand dogs were different. In addition, the NOEL of 7.3 mg/kg/day was supported by the ENEL of
5.5 mg/kg/day for developmental neurotoxicity (Sheets, 2001). Thus, the subchronic oral NOELof 7.3 mg/kg/day from the 4- and 13-Week studies in Beagle dogs (Block, 1987; Ruf, 1990) was
selected for characterizing the risk due to subchronic dietary exposures to imidacloprid.
IV.A.3.b. Subchronic Inhalation Toxicity
One subchronic inhalation toxicity study with imidacloprid in Wistar rats was available for the
NOEL and LOEL determinations (Pauluhn, 1989, presented in Section III.C.3. under Subchronic
Toxicity). In this study, the rats were exposed by head/nose only to imidacloprid in the form of
dust over a period of 4 weeks (Tables 4). The NOEL was established as 0.9 mg/kg/day. The
principal effects at the LOEL of 5.2 mg/kg/day were concentration-dependent 7-9% increases in
the absolute and relative liver weights, statistically significant increases in the activities of theserum ALT, AP and GLDH (25%-200%) and induction of the hepatic MFO (27%).
This study included extensive toxicity evaluations. The endpoints were relevant, as changes inliver weights, clinical chemistry parameters and liver function were seen in oral subchronic or61chronic studies. The subchronic inhalation NOEL was 8-fold lower than the subchronic oral
NOEL in dogs (7.3 mg/kg/day). However, the subchronic inhalation NOEL was close to the
NOEL of 1.7 mg/kg/day defined in the 5-Day inhalation study in rats. In the 5-Day inhalation
study, the reported effects were induction of the liver MFO and reduction in body weights(Pauluhn, 1988a; Table 14). Both, the 4-Week and the 5-Day inhalation studies suggested that
inhalation may be a more toxic route. Based on these considerations, the NOEL of 0.9
mg/kg/day from the 4 week-inhalation study in rats was selected for characterizing thesubchronic risk due to inhalation exposure to imidacloprid (Table 15).
The DPR employed the subchronic inhalation LOEL of 5.2 mg/kg/day to calculate the risk of thepesticide workers in the health risk assessment in 1993, which evaluated imidacloprid for an
emergency use on cotton under the Section 18 of the FIFRA (Lewis et al., 1993).
IV.A.3.c. Subchronic Dermal Toxicity
One subchronic dermal toxicity study was available in rabbits, which were treated with the doseof 1000 mg/kg/day imidacloprid (Flucke, 1990). No effects were observed after 3 weeks oftreatment. Since a subchronic dermal NOEL could not be clearly defined from this study, theoral NOEL of 7.3 mg/kg/day, from the 4-Week study in dogs (Block, 1987) was selected forcharacterizing the risk due to subchronic dermal exposures to imidacloprid.

62

Table 15. Subchronic No-Observed-Effect Levels (NOELs) and Lowest-Observed-Effect Levels (LOELs) for Imidacloprid.
Subchronic Study
Species

NOELa LOEL b

Exposure

Toxic Effects at LOEL

mg/kg

Rat
10 sex/doseRat
10 sex/doseRat
12 sex/doseOral
14 weeks
Oral
13 weeks
Oral 13 weeks
Subchr. Neurotox

Rat
30 sex/dose/doseRat
12 sex/dose

Oral
Repro. Toxicity
Oral
41daysa; Dev.Neurot

Rat
10 sex/dose

Inhalation, dust
6 h/5days/4 weeks

0.9

Mouse
10 sex/doseOral
107 days86

Dog
2 sex/dose

Oral 4 Weeks

7.3

Dog
4 sex/doseOral
13 Weeks

8

14

57

14

61

9.3

63

13
19.4

11%* body weight reduction (females, food intake increased, Eiben,
1988a)
Liver toxicity (necrosis of hepatocytes) and reduced body weight(8%*) in male rats, (Eiben, 1989#)
Reduction in body weights (8%**) in male rats (Sheets, 1994b)

Reduction in body weights (13-17 %**) in adults and pups (start: Day
1 of premating and PND 4-throughout lactation; Suter et al., 1990#)
Reduction in body weights (13%**) in pups, decreased motor activity
54.7a
in females (Sheets, 2001)
Increased liver weights (9% absolute and 7% relative) and liver
5.2 toxicity: (↑ ALT 25% **; ↑ AP 20%*; ↑ GLDH 200%**); plasma ChE↓ 26%), induction of hepatic MFO (27%*; Pauluhn, 1989)
Mortality, reduced body weight (15-27%**), poor general condition,427
rough coats, changes in clinical chemistry (↑ ALT 47%**, ↓cholesterol 22%** and ↓ urea 32%**, Eiben, 1988b)
Morphological changes: hepatocyte hypertrophy (one male) and31
thyroid follicular atrophy (one female; Block, 1987)
38

24

Tremors (Ruf, 1990#)

a/ Decreases in thickness of corpus callosum (27%, p< 0.05) and the width of caudate putamen (6%, p< 0.05) were found in the PND11 females. Brain measurements were not
performed in the intermediate and low dose-groups. A NOEL for developmental neurotoxicity could be estimated (ENEL) as low as 5.5 mg/kg/day by applying a default factor of
10 to the LOEL of 54.7 mg/kg/day.
ALT, alanine aminotransferase; AP, alkaline phosphatase; GLDH, glutamate dehydrogenase; ChE, cholinesterase; MFO, mixed function oxidases; *, ** Statistically significant
difference from controls at p ≤ 0.05 or p ≤ 0.01, respectively

63

IV.A.4. Chronic Toxicity
Three chronic oral studies in rats, mice and dogs were available for determination of NOELs andLOELs for imidacloprid (Table 16; also see Section III.D., under CHRONIC TOXICITY).
Chronic inhalation and dermal toxicity studies with imidacloprid were not available. Therefore,
oral studies were used to define the critical NOEL for chronic exposures from all routes.
The lowest oral NOEL of 5.7 mg/kg/day was from a 2-year chronic toxicity/oncogenicity study
in Wistar rats (Eiben and Kaliner, 1991; Eiben, 1991). The principal effect at the LOEL of 17
mg/kg/day was a statistically significant increase (62%) in the incidence and severity ofmineralized particles in thyroid gland in male rats (Tables 7 and 16). In the subchronic studies in
rats, the most common effect was body weight decreases at doses of 38-63 mg/kg/day (Table
15). In the chronic rat study, statistically significant reduction in body weight (12%) was also
seen at a similar dose level (51 mg/kg/day, see Section III.D). The NOEL of 5.7 mg/kg/day was
employed by the DPR to calculate the risk of chronic exposures in the health risk assessment in
1993, which evaluated imidacloprid for an emergency use on cotton under the Section 18 of the
FIFRA (Lewis et al., 1993). The same NOEL was also used by the USEPA to assess the chronicrisk of imidacloprid exposures (USEPA, 2003).
The next higher oral NOEL of 15 mg/kg/day was from a study in Beagle dogs, which weretreated with imidacloprid for a period of 52 weeks (Allen et al., 1989). The reported effects at the
LOEL of 41 mg/kg/day included statistically significant changes in the liver metabolic function(91% increase in the cholesterol level and 200% induction of the liver MFO) and a decrease offood consumption (14%, Table 16). The effects in this study were relatively mild, compared tothe marked toxicity observed in dogs after subchronic treatment (4 and 13-Weeks) with similardoses with imidacloprid, including mortality, severe tremors, morphological changes in liver andthyroid and weight loss (Block, 1987; Ruf, 1990, Tables 5, 6 and 15).
Similar to the subchronic NOELs, the highest chronic NOEL was determined in mice fed withimidacloprid for 24 months (Watta-Gebert, 1991). There was a substantial uncertainty associatedwith the reported doses in this study, because the food intake and, in turn the imidacloprid intake,
was unusually high (about 22-28% of the body weight of an adult mouse). The DPR
toxicologists adjusted the ingestion of imidacloprid to a default food consumption of 15% of the
body weight of an adult mouse. The main effect at the LOEL was statistically significantly
reduced body weights of the males (10%). The revised NOEL was 47 mg/kg/day, based on therevised LOEL of 143 mg/kg/day (Table 16).
Conclusions
The lowest NOEL for imidacloprid of 5.7 mg/kg/day was in rats, based on an increase inincidence and severity of mineralized particles in thyroid gland (Eiben and Kaliner, 1991; Eiben,
1991). The NOEL established in dogs was higher (15 mg/kg/day), but was based upon different
endpoints (i.e. changes in the liver metabolic function). Although thyroid effects were notobserved at any of the doses tested in the chronic dog study (Allen et al., 1989), subchronic
toxicity studies in dogs established a NOEL of 7.3 mg/kg/day based on thyroid follicularatrophy, among other toxic endpoints (Block, 1987; Ruf, 1990). Thus, the subchronic NOEL indogs was in support of the chronic NOEL of 5.7 mg/kg/day for thyroid lesions in rats. In
conclusion, the oral NOEL of 5.7 mg/kg/day in rats was selected for characterizing the risk due
to chronic exposures to imidacloprid. This NOEL is sufficiently close to the ENEL of 5.5 for64

developmental neurotoxicity (Sheets, 2001), and therefore, would be adequate for protection
against the potential effects of imidacloprid on the developing nervous system.
Table 16. Chronic No-Observed Effect Levels (NOELs) and Lowest-Observed-Effect Levels(LOELs) of Imidacloprid.
Chronic Study
Species
Rat
Mouse

Dog

ExposureOral
2 yearOral
2 yearOral
52 Weeks

NOEL

LOEL

Toxic Effects at LOEL

Referencesmg/kg/day
5.7

17

Mineralized particles inthyroid gland (males,
62%** increase)

Eiben and
Kaliner#, 1991;
Eiben, 1991

47a

143a

Reduced body weight(10%*, males)

Watta-Gebert,
1991; 1991a#

41

Liver metabolic changes: ↑liver cytochrome P-450
Allen et al., 1989#
enzymes (200 fold*); ↑cholesterol (91%**)

15

a/ The reported food intake levels represented about 22-28% of the mice body weight. Because of the unusually high foodconsumption (and imidacloprid intake), the doses were revised by the DPR, based on a default food consumption of 15% of the
body weight of an adult mouse (30 g).
* **,Statistically significant difference from controls at p ≤ 0.05 or p ≤ 0.01, respectively.

# The study fulfilled the SB950 data requirement for a specific type testing.

65

IV.A.5. Oncogenicity Weight of Evidence
Two oncogenicity bioassays were available for imidacloprid in rats and mice. In the rat
study, rare liver tumors (cholangiocellular carcinoma) were found in the males (Eiben,
1991). The incidence for cholangiocellular carcinoma was outside the historical range,
albeit, not statistically significant from the concurrent controls. The lack of clear evidenceof oncogenicity at sufficiently high doses, together with the negative genotoxicity underlaboratory conditions, precluded further considerations of the oncogenicity potential of
imidacloprid.
Nevertheless, it should be noted that cholinergic agonists such as ACh and nicotine are
known to stimulate the growth of human cancer cells from lung, colon and gingival
origin (Song et al., 2003a; Ye et al., 2004; Argentin and Ciccheti, 2004). Importantly,
human lung carcinomas have been shown to express nicotinic AChRs and to secrete anddegrade ACh. Both ACh and nicotine stimulated the growth of these cells via activationof the nAChRs, thus suggesting that other nicotinic agonists may have the same effect(Song et al., 2003a,b). The current hypothesis is that ACh may function as an autocrine
growth factor for lung carcinomas (Song et al., 2003b). Recent studies revealed that
nicotine enhanced the proliferation of human lung cancer cells by blocking the
programmed cell death (apoptosis; Jin et al., 2004). Nicotine has also been shown topromote the growth of pre-existing tumors in vivo (Seppa, 2002; Heeschen et al., 2001;
Natori et al, 2003). This effect was attributed to the ability of nicotine to induce growth of
new blood vessels (angiogenesis), which supply oxygen and nourishment to tumors. In
fact, the angiogenic properties of nicotine have been linked to the development of lungand mouth cancers (Seppa, 2002). These data should be considered when assessing theoncogenicity of imidacloprid, because it binds to the ACh binding site on the AChR andis structurally and functionally similar to nicotine. However, the available bioassays were
not designed to test whether imidacloprid promotes the growth of pre-existing tumors. In
conclusion, the current data on imidacloprid may be insufficient to thoroughly evaluate
its tumorogenic properties through a promotion mechanism.

66

IV.B. EXPOSURE ASSESSMENT
Human non-occupational exposure to imidacloprid could result from consuming food andwater containing the pesticide residues (dietary exposure). The general population may bealso exposed to airborne imidacloprid in agricultural regions with extensive applicationof imidacloprid.
This document pertains only to the assessment of the dietary exposure. The lack ofmonitoring data precluded the assessment of the ambient air exposure to imidacloprid at
this time. The occupational exposure and the exposure from residential uses will be
addressed subsequently in an addendum to this document.
IV. B.1. Dietary and Drinking Water Exposure
IV. B.1.a. Introduction
The Department of Pesticide Regulation (DPR) conducts acute and chronic dietary
exposure assessments to evaluate the risk of human exposure to pesticide residues in foodin California (Bronzan and Jones, 1989). Two types of dietary exposure assessments are
conducted: (1) the total dietary exposure is determined based on residue levels on alllabel-approved commodities and (2) exposure to an individual commodity at thetolerance level (DPR MT-3, 2004).
Dietary exposure is a product of the amount of food that is consumed and theconcentration of the pesticide residue in that food. The total exposure in an individual's
diet during a defined period of time (e.g., a day) is the sum of exposure from all foods (invarious forms and as ingredients in food items) consumed within that period:nExposure = ∑ (Residuei x consumptioni of foods),
i =1

where n is the number of foods items in the diet.
Data on the amount of the pesticide residue on food and the food consumption provide
dietary exposures for various population subgroups based on age, gender, ethnicity, andseason and pregnancy/lactation status.
For estimating the acute exposure, the highest residue values at or below the tolerance, orthe distribution of residues are considered. In contrast, for chronic exposure, the mean
residue values are appropriate. Acute exposure is calculated on a per-user basis, i.e.,
including in the distribution of exposures only the days of survey that at least one
commodity with potential pesticide residues is consumed. Chronic exposure to pesticides
is generally calculated using per-capita mean consumption estimates to include the entire
population (DPR MT-3, 2004).
The imidacloprid acute and chronic dietary risk assessments, along with the acute
tolerance assessment, are discussed below. Acute and chronic exposure analyses werecarried out for all combined imidacloprid food uses. USEPA tolerances for residues ofimidacloprid are presently established on a large number (over 270) of fruit and vegetable
crops, and animal commodities (Table 18, CFR 2003 a). As of December 2004, there are
21 active products containing imidacloprid approved for use in California. Bayer Inc. and67

Miles Inc. hold the registration for agricultural food use of these products containing 0.575% imidacloprid as an active ingredient (see Section II.C. TECHNICAL AND
PRODUCT FORMULATIONS).
IV. B.1.b. Consumption Data and Dietary Exposure
The Dietary Exposure Evaluation Model (DEEM™ v. 7.74; Exponent Inc.
http://www.exponent.com/home.html) was used to calculate the dietary risk. The foodconsumption pattern was based on data generated by the United States Department ofAgriculture (USDA) during the 1994-1998 Continuing Survey of Food Intake by
Individuals (CSFII). The CSFII 1994-98 is the most recent and representative
consumption database, which provides information on a 2-day food intake by 20,607
individuals of all ages from 62 geographical areas. The database consists of the 19941996 food consumption survey, along with the 1998 Supplemental Children's Survey(CSFII 1998), which includes an additional 5,559 children from birth to 9 years old.
http://www.barc.usda.gov/bhnrc/foodsurvey/pdf/Csfii98.pdf
Dietary exposure and risk estimates were provided for the average U.S. population and
15 selected population subgroups, including all infants, nursing or non-nursing infants
and children. Subgroups were defined by geographic regions, age, gender or ethnicity.
In addition to calculating the dietary exposure, the DEEM™ Acute Module was used todetermine those foods having the greatest contribution to the total exposure of theindividuals. The Critical Exposure Commodity (CEC) analysis provides consumption
records for individuals at the high end of dietary exposure (in the top 5% or less). The
CEC analysis also identifies the commodities contributing to the high end of the dietary
exposure. The records include the amount of food(s) consumed, body weight, age,residue values and the exposure estimate by food.
For acute exposure estimates, one-day consumption data comprised all the commodities
with imidacloprid tolerances. The consumption of each commodity by each individual ina population subgroup was multiplied by a single residue value (point estimate) for adeterministic risk assessment. For chronic exposure estimates, the average foodconsumption of each population subgroup was multiplied by the mean residue value. The
estimates for both acute and chronic exposure were expressed as a dosage in µg/kg/day.
IV. B.1.c. Exposure to Imidacloprid from Food.
Imidacloprid residues, which are of toxicological significance in plant and animalcommodities, include imidacloprid and its metabolites containing the 6-chloropyridinyl
moiety. This moiety is common for several insecticidal neonicotinoids, which exert
neurotoxicity via blockage of the nAChRs (Tomizawa et al, 2001). The major 6chloropyridinyl metabolites of imidacloprid are desnitro-imidacloprid, olefinicimidacloprid, 4- and 5-hydroxy-imidacloprid, imidacloprid urea and 6-chloronicotinicacid. The published tolerances for imidacloprid are listed in 40 CFR 180.121 and are
expressed for plant and animal commodities as combined residues of imidacloprid parent
compound and its 6-chloropyridinyl metabolites (CFR, 2003a)

68

IV. B.1.d. Residue Data Sources
The residue data for imidacloprid used in the current risk assessment were based on thefollowing sources: USDA Pesticide Data Program (PDP), DPR Market Basket
Surveillance Programs and Field Trial Residue Studies (submitted by the imidacloprid
registrants to support tolerances). Although monitoring data are preferred for risk
assessment, only a few commodities with imidacloprid registrations were screened forresidues under the Federal and State monitoring programs.
1. Pesticide Data Program (PDP)The PDP (www.ams.usda.gov/science/pdp/download.htm) is the most representative
monitoring residue database, because it is designed to obtain pesticide residue data forrisk assessments. The PDP samples are collected in ten states, including California.
In 1999, PDP for the first time monitored raw agricultural (RAC) and processedcommodities for the combined residues of imidacloprid and its 6-chloropyridinyl
metabolites. From 1999 to 2002, PDP examined 5 commodities with tolerances for
imidacloprid (USDA, 1999-2002). Detectable residues were reported in 2000 and 2001
for oranges. In contrast, quantifiable imidacloprid residues were not reported on thefollowing commodities: nectarines (during the 2000-2001 surveillance period); oats
(examined in 1999); sweet peas (analyzed in 2001 and 2002), and tomato paste (canned;
screened in 2001; Table 17). The residue limit of detection (LOD) varied from 0.0250.008 ppm among the national laboratories contracted by USDA to perform the analysis(Table 17).
In 2001 and 2002, PDP analyzed drinking water systems for imidacloprid residues in two
states, New York and California. A total of 329 water samples were screened in 2001 and2002 from wells in the New York state. One sample had quantifiable imidacloprid
residues. The residue LOD varied from 1.5-22.5 ppt. In 2002, the community water
system in California was analyzed at the USDA contract laboratory at Sacramento,
California. A total of 51 samples were screened for imidacloprid and there were no
detectable residues. The residue LOD was 15 ppt (Table 17).
2. DPR Marketplace Surveillance Program.
The DPR monitoring program (http://www.cdpr.ca.gov/docs/pstrsmon/rsmonmnu.htm)
includes commodities, which are not monitored by other programs, and reflects the wide
variety of foods consumed by Californians (DPR, 2002). It is mainly a tool for
enforcement, as it focuses on commodities with known violations of tolerance. Under the
California DPR surveillance program, imidacloprid is analyzed as the parent compound
only (CDFA analytical method No. RES-SM-7). Detectable residues were reported in
2002 for lettuce. There were no detected imidacloprid residues in the following
commodities: cantaloupes, cucumbers, grapes, peppers and chili peppers, strawberries
and tomatillos. The residue limit of detection was 0.4 ppm.
In 2001, preliminary surface water monitoring studies did not detect imidacloprid
residues in the California. The detection limit was 0.05 ppb (see section II.G.4.d. under
Environmental Fate).

69

3. Field Trial Residue Studies.
Bayer Corporation and Miles Inc. (the basic registrant of imidacloprid-containing
products in the US) have submitted field studies evaluating the residues on RAC treatedwith imidacloprid at various label rates, including the maximum. These studies wereconducted for support in the setting of tolerances and measured imidacloprid as combined
residues of the parent compound and its 6-chloropyridinyl metabolites. Field trial data
were available to DPR for selected commodities representing the following crop groups,
as defined in the 40 CFR 180.41: Crop Group 1 (Root and tuber vegetables); Crop Group2 (leaves of root and tuber vegetables); Crop Group 5 (Brassica vegetables); Crop Group6 (Legumes, succulent and dry vegetables); Crop Group 8 (Fruiting vegetables); Crop
Group 9 (Cucurbit Vegetables); Crop Group 10 (Citrus Fruit), Crop Group 11 (PomeFruit); Crop Group 15 (Cereal grain); Subgroup 4-A (Leafy greens) and Subgroup 4-B(Leaf petioles; Tables 17 and 18). Residue data from field trial studies were available to
DPR for an additional 57 RAC and animal commodities (Table 18).

70

Table 17. Anticipated Imidacloprid Residues From Monitoring Databases Used For Acute And Chronic Dietary Exposure
Assessments
Commodity

Source of
Year
Data

Cantaloupe(fresh, juice
DPRand pulp;
honeydew,
Persian)CitrusFruit
PDPe
Group 10d(exceptoranges)g

Cucumbers

DPR

Grapes(juice,juice-conc.,
leaves,raisins,wine,
sherry)DPRfor grapes

Groundcherry

DPR

2002

See

NumberSamples

Acute
Point Est.
Residue(ppm)

Chronic
Average
Residue
(ppm)

1

0.400

0.200

0.120

0.038

Number
Detected
Samples

Detected
Residues(ppm)

Range % Crop
LODab(ppm) Treated

Adj.
Factorc

0No
detectable
residues

0.40

33

Data

for

45

Oranges

0.01

100

2 - 11.4f
juice andjuice conc.

0.4

50

1

0.400

0.200

2002

34

0

No
detectable
residues

2002

71

0

No
detectable
residues

0.450

1.2 x juice
4.3 x raisin

0.400

0.200

0

No
detectable
residues

0.4

100i

1

0.400

0.200

2002

18

71

Continued

Table 17. Anticipated Imidacloprid Residues From Monitoring Databases Used For Acute And Chronic Dietary Exposure
Assessments (continued).

Commodity
Lettuce(head, leaf)
Nectarines

Oats

OrangesPeas(garden dry
and green;
succulent/
blackeye/co
wpea,
snowpeas)

SamplesNumber
Detected
Samples

Detected
Residues
(ppm)

Range
LOD
(ppm)

% CropTreatedb

0.4

85

Number

Source of
Data

Year

DPR

2002

45

3

0.11-0.4

PDP

2000

249

0

2001

259

0

1999

332

0

No
detectable
residues
No
detectable
residues

2000

528

3

2001

531

10

2000

131

PDP
PDP

PDP

0
2001

499

Adj.
Factorc

Acute
Point Est.
Residue
(ppm)

1

0.400

0.01

1

1

0.010

0.08

100

1

0.008
0.120

0.010

0.014-0.12

0.01

1

1.8x juice
6.7x juice
conc.

No
detectable
residues

0.01

1

1

Chronic
Average
Residue
(ppm)
0.200
0.005

0.004
0.038

0.005

Continued

72

Table 17. Anticipated Imidacloprid Residues From Monitoring Databases Used For Acute And Chronic Dietary Exposure
Assessments (continued).

Commodity
Peaches(fresh,dried, juice)Peppers(chilly,
sweet)
Strawberry(fresh,juice)

Source of
Data
PDP fornectarines

Year

NumberSamplesNumber
Detected
Samples

Detected
Residues
(ppm)

Range
LODa
(ppm)

% CropTreatedb

Adj.
Factorc

Acute
Point Est.
Residue(ppm)

Chronic
Average
Residue
(ppm)

See

Data

for

Nectarine

0.01

1

7x driedpeaches

0.010

0.005

0.40

62

1.0

0.400

0.200

0.400

100

1.0

0.400

0.200

No
detectable
residues

0.025

70

-

0.025

0.013

Paste

0.025

70

-

0.025

0.013

No
detectable
residues

15
ppt*

-

-

15 ppt7.5 ppt

DPR

2002

74

0

DPR

2002

28

0

Tomato,paste

PDP data
for tomato
paste
canned

2001

369

0

Tomato,puree andcatsup

PDP

See

Data forTomatoDrinking
Water

PDP in
CA

2002

51

0

No
detectable
residues
No
detectable
residues

a/ LOD, Limit of Detection.
b/ PCT was from the 2003 report by the USDA Biological and Economical Analysis Division (BEAD; USEPA, 2003b); or the highest value from the 1998-2003 Agricultural
Chemical Usage Reports by the USDA National Agricultural Statistical Service.
Continued73

c/ DEEM™ default factors to account for changes in the hydration state of foods.
d/ Citrus Fruit Group 10 as defined in the 40 CFR 180.41: Calamondin*, Citrus citron, Citrus hybrids*, Grapefruit, Kumquat, Lemon, Lime, Mandarin (tangerine), Orange (sweetand sour), Pummelo, Satsuma mandarin* ; * No consumption data in DEEM™
e/ Pesticide Data Program (PDP) implemented by the United States Department of Agriculture (USDA).
f/ Hydration factors were: 2.1 and 8.26 for grapefruit juice and juice-concentrate; 2.0 and 11.4 for lemon juice and juice-concentrate; 2.0 and 6.0 for lime juice and juiceconcentrate; 2.3 and 7.35 for tangerine juice and juice-concentrate.
g/ Residue Distribution File (RDF) containing all detected residues to determine the exposure distribution in Monte Carlo analyses.
h) Department of Pesticide Regulation (DPR) Priority Pesticide and Market Basket Surveillance Programs.
i/ 100% PCT was assumed for all crops, for which information on the percentage of the crops treated with imidacloprid was not available.
*ppt, Part per Trillion

74

Table 18. Imidacloprid Residues from Field Trial Studies Used for Acute and Chronic Dietary
Exposure Assessmentsa.

Commodity
AcerolaAlmonds
Apple (fresh, dried, juice/cider,juice-conc.)
Artichokes, globe
AvocadoBanana (fresh, dried, juice)
Barley (grain)
Beet (sugar roots)
Beet (sugar molasses)
Blueberries

Brassica Vegetables Crop
Group 5 c,dCanola oil (rape seed)
Cattle (dried, fat, kidney, livermeat, meat byproducts)
CorianderCorn grain (bran, endosperm,oil), sweet corn, popcorn)
Cottonseed -meal
Cottonseed -oil
Cranberries(fresh,juice, juice-concentrate)
Currant
Egg (whole, white and yolk)
Elderberry
Fruit, Pome Group 11e(except apples)
Fruit, Stone Group 12f(except nectarines and peaches)
Goat (dried, fat, kidney, livermeat, meat byproducts)

100
100

Acute Residue
Point Estimate
(ppm)
1.00
0.05

Chronic
Average
Residue
(ppm)
0.500
0.025

34

0.50

0.250

100
100
100
100
100
100
100
35 broccoli
56 brussels sprout
20 cabbage
60 cauliflow.
10 collards
30 kale
100

2.50
1.00
0.02
0.05
0.05
0.30
3.50

1.250
0.500
0.010
0.025
0.025
0.150
1.750

3.50

1.750

0.05

0.025

-

0.30

0.150

100

3.50

1.750

100

0.05

0.025

3
3

8.00
6.00

4.000
3.000

100

0.05

0.025

100
100

3.50
0.02
3.50

1.750
0.010
1.750

20 pears

0.60

0.300

100

0.30

0.150

-

0.30

0.150

% Crop Treatedb

Continued
75

Table 18. Imidacloprid Residues from Field Trial Studies Used for Acute and Chronic Dietary
Exposure Assessmentsa (continued).
Chronic
Average
Residue
(ppm)
1.750
0.025
0.500

Commodity% Crop Treatedb

Gooseberries
Grain, Cereal Group 15g
Guava (fruit and juice)
Hog (dried, fat, kidney, livermeat, meat byproducts)
Hops
Horse (horsemeat)
Huckleberries
Juneberry
Leaf Petioles Subgroup 4Bh
Leafy Greens Subgroup 4Ai(except lettuce)
Longan Fruit
Lychee (fresh and dried)
Mango
Milk (water, fat solids, non-fat
solids; milk sugar)
Milk (water, fat solids, non-fat
solids; milk sugar)
Mustard seeds
Okra
Passionfruit (fruit and juice)
Papaya (pulp, juice, dried)
PecansPersimmons
Potatoes (white peeled, peel
only, whole, white dry)
Poultry (fat, liver, meat-lean)
Safflower-oil
Safflower-seed
Sapodilla
Sheep (fat, kidney, liver, leanmeat, meat byproducts; otherorgan meats)
Soybeans(flour defatted, full fat, low fat)

100
100
100

Acute Residue
Point Estimate
(ppm)
3.50
0.05
1.00

-

0.30

0.150

100
100
100
100

6.00
0.30
3.50
3.50
6.00

3.000
0.150
1.750
1.750
3.000

100

3.50

1.750

100
100
100

3.00
3.00
1.00

1.500
1.500
0.500

-

0.10

0.050

-

0.10

0.050

100
100
100
100
100
100

0.05
1.00
1.00
1.00
0.05
3.00

0.025
0.500
0.500
0.500
0.025
1.500

46

0.40

0.200

100
100
100

0.05
0.50
0.05
1.00

0.025
0.25
0.025
0.500

-

0.30

0.150

100

0.50

0.250
Continued

76

Table 18. Imidacloprid Residues from Field Trial Studies Used for Acute and Chronic Dietary
Exposure Assessmentsa (continued).

Acute Residue
Point Estimate(ppm)

Chronic
Average
Residue(ppm)

Commodity% Crop Treatedb

Soybeans (mature seeds dry, oil,sprouted seeds)
Sorghum
Starfruit (carambola)
Vegetables, Cucurbit Group 9j(except cucumbers andcantaloupes)
Vegetable, Fruiting Group 8k(except peppers, groundcherries
and processed tomatoes)
Vegetable, Leaves of root andtuber Group 2l
Vegetable, Legume, Group 6m(except peas and soybeans)
Vegetable, root and tuber,Group 1n (except sugar beet)
WatercressWheat(bran, germ, germ oil, flour;
rough)

100

1.00

0.500

100
100
6 watermelon
7 pumpkin10 squash

0.05
1.00

0.025
0.500

0.50

0.250

36 eggplant

1.00

0.500

4.00

2.000

4.00

2.000

100

0.40

0.200

100

3.50

1.750

100

0.05

0.025

100
6 beansa/ Field trial studies were submitted to the DPR for support in the setting of tolerances. The residue concentrations on thecommodities were at a tolerance level for the acute assessment and ½ of the tolerance for the chronic assessment.
b/ Percent of the crop treated (PCT) adjustments were used only in the chronic analysis for non-blended foods. The average PCT
was from the 2003 report by the USDA Biological and Economical Analysis Division (BEAD; USEPA 2003b) or from the 19982003 Agricultural Chemical Usage Reports by the USDA National Agricultural Statistical Service.
c/ Tolerances for imidacloprid were established for 12 crop groups of related commodities, as defined in the 40 CFR 180.41
d/ Brassica Vegetables Crop Group 5: Broccoli, Broccoli, Chinese (gai lon), Broccoli raab (rapini), Brussels sprouts, Cabbage,
Cabbage, Chinese (bok choy and napa), Cabbage, Chinese mustard (gai choy), Cauliflower, Collards, Kale, Kohlrabi, Mizuna,
Mustard greens, Mustard spinach, Rape greense/ Fruit Pome Group 11: Apple, Crabapple, Loquat, Pear, Quince
f/ Fruit Stone Group 12: Apricot; Cherry, sweet and tart; Nectarine; Peach; Plum (Chickasaw, Damson, Japanese); Plumcot*;Prune
g/ Grain, Cereal, Group 15: Barley; Buckwheat; Corn; Millet, pearl; Millet, proso; Oats; Popcorn; Rice; Rye; Sorghum (milo);
Teosinte; Triticale; Wheat; Wild rice.
h/ Leaf Petioles Subgroup 4-B. Cardoon*; Celery; Celery, Chinese; Celtuce*; Fennel*, Florence*; Rhubarb; Swiss chardi/ Leafy Greens Subgroup 4-A. Amaranth; Arugula; Chervil; Chrysanthemum (edible-leaved and garland); Corn salad; Cress(garden and upland); Dandelion; Dock*; Endive; Lettuce; Orach*; Parsley; Purslane (garden and winter)*; Radicchio (Chicory;
Belgian endive), Spinach; Spinach (New Zealand and vine).
Continued77

j/ Vegetables, Cucurbit Group 9. Chayote*; Chinese waxgourd*; Citron melon*; Cucumber; Gherkin*; Gourd*; Momordica spp.
(balsam apple, balsam pear, bitter melon, chinese cucumber* Muskmelon (true cantaloupe, cantaloupe, casaba, crenshaw melon,
golden pershaw melon, honeydew melon, honey balls, mango melon, Persian melon, pineapple melon, Santa Claus melon, andsnake melon); Pumpkin; Squash, summer; Squash, winter (acorn squash; spaghetti squash); Watermelon.
k/ Vegetable, Fruiting, Group 8. Eggplant; Groundcherry; Pepino; Pepper (bell pepper, chili pepper, cooking pepper, pimento,
sweet pepper); Tomatillo; Tomato.
l/ Vegetables, Leaves of root and tuber, Group 2: Beet, garden; Beet, sugar; Burdock*; Carrot*; Cassava*, bitter and sweet;
Celeriac* (celery root); Chervil*, turnip-rooted; Chicory*; Dasheen (taro); Parsnip*; Radish; Radish, oriental; Rutabaga;
Salsify*; Sweet potato; Tanier*; Turnip; Yam, true
m/ Vegetables, Legumes, succulent and dry, Group 6. Bean (lupin, sweet lupin, white lupin, and white sweet lupin); Bean (field
bean, kidney bean, lima bean, navy bean, pinto bean, runner bean, snap bean, tepary bean, wax bean); Bean (adzuki bean,
asparagus, bean, blackeyed pea, catjang, Chinese longbean, cowpea, Crowder pea, moth bean, mung bean, rice bean, southernpea, urd bean, yardlong bean); Broad bean (fava bean); Chickpea (garbanzo bean); Guar; Jackbean; Lablab bean; Lentil, Pea(dwarf pea, edible-pod pea, English pea, field pea, garden pea, green pea, snowpea, sugar snap pea); Pigeon pea; Soybean;
Soybean (immature seed); Sword bean.
n/Vegetables, Root and Tuber, Group 1. Beet sugar; Beet garden; Burdock; Canna*; Carrot; Cassava, bitter and sweet; Celeriac;
Chayote; Chervil; Chicory; Chufa*; Dasheen (taro); Ginger; Ginseng; Horseradish; Leren*; Parsley; Parsnip; Potato; Radish;Radish, oriental; Rutabaga; Salsify (oyster plant); Salsify, black; Salsify, Spanish; Skirret*; Sweet potato; Tanier; Turmeric;Turnip; Yam bean; Yam, true.
* No consumption data in DEEM™

78

IV. B.2. Acute Exposure
The acute dietary exposure to a pesticide is estimated using the tiered approach in the selectionof the appropriate residue values (DPR MT-3, 2004). The tiered approach begins with the point
estimate (deterministic) steps, which are generally less time-consuming and less labor intensive
than the refining assessment. The Point Estimate Model (Tiers 1-3) employs the tolerance, theupper bound value or the mean residue value. The Monte Carlo probabilistic approach (Tier 4)
can be subsequently used to refine the assessment, taking into account the occurrence anddistribution of residue levels, and provides the probability distribution of exposure.
The DPR uses two thresholds for indicating that the next tier of assessment is needed (DPR MT3, 2004): (1) the MOE at the 99th percentile exposure is within 5-fold of the health protective
level, or (2) the MOE at the 95th percentile exposure is 10-fold of the health protective level. For
imidacloprid, the acceptable MOE is 100. Therefore, the threshold MOE for the next tier ofassessment would be 500 at the 99th or 1000 at the 95th percentiles. These thresholds provide
room for exposures from other potential routes; and the 5-and 10-fold distance from theacceptable MOE ensures the likelihood that dietary exposure would not be a major contributor to
the aggregate risk. In the event that this is not the case, the next tier of exposure may be needed.
IV. B.2.a. Acute Deterministic (Point Estimate) Exposure Assessment
The acute dietary exposure to imidacloprid of the US population and various population
subgroups was assessed using the deterministic approach (Tiers 1 and 2). In this model, a single
value (referred to as a point estimate) was selected to represent the concentration of imidacloprid
on each of the registered commodities.
Tier 1 Point Estimate Assessment: This model assumes that all foods consumed in a given day
contain pesticide residues at the tolerance level. For imidacloprid, this analysis produced
exposures ranging from 73 to 26 µg/kg/day at the 95th; and 115 to 32 µg/kg/day at the 99th
percentiles, respectively (Table 19). These exposures resulted in MOEs below the thresholds of1000 and 500 at the 95th or 99th percentiles, respectively, for all of the population subgroups (seeTable 22 in Section IV. C.2). Therefore, Tier 2 point estimate assessment was used as a next
refining step to calculate the exposure to imidacloprid.
Tier 2 Point Estimate Assessment: The typical assumptions in the Tier 2 are: (i) all consumed
foods contain the highest reported residue at or below the tolerance (ii) pesticide residues below
the LOD are equal to that limit, (iii) All crops are treated with the pesticide and (iv) residue
concentrations do not vary from the time of sampling to the time of consumption (DPR MT-3,
2004).
Consequently, the highest measured residues or the highest LOD within a program were selected
for the commodities nectarines, oats, oranges, peas, processed tomatoes (tomato paste canned)
and drinking water from the PDP databases (Table 17).
In cases where PDP data were not available, DPR monitoring studies on imidacloprid wereconsidered for the residue selection. The highest imidacloprid concentration or the LOD werechosen for the commodities cucumbers, grapes, groundcherries, lettuce, cantaloupe, peppers andstrawberries from the DPR Marketplace Surveillance Program (Table 17).
For several commodities regulatory monitoring data were not available, however, residues
reported for similar foods were used as surrogates. The imidacloprid concentration on the foods
79

from the Citrus Fruit Group 10 (citrus citron, grapefruit, kumquat, lemon, lime, tangerine andpummelo) was assumed to be equal to the highest concentration measured by the PDP onoranges (Table 17). The pesticide residue on peaches was set equal to the LOD for nectarines
reported by the PDP (Table 17). No imidacloprid residues were detected on 508 nectarine
samples analyzed by the PDP in 2000 and 2001. The residues on tomato puree and catsup wereconsidered equal to the LOD reported by the PDP for canned tomato paste. Imidacloprid residues
were not detected on 369 samples of canned tomato paste in 2001. The choice of the mostappropriate surrogate commodity was based on the classification of related raw agriculturalcommodities into crop groups, established in 40 CFR 180.40, and according to the agricultural
practices specified in the product label.
Federal or state multi-year monitoring data were not available for rest of the commodities, forwhich imidacloprid is registered for use. The published tolerances for these foods were chosen to
represent the residues for the Tier 2 acute exposure analysis (Table 18).
Changes in the hydration state of foods can alter the residue concentration compared to the raw
commodities, which were monitored. The following default factors, provided in the DEEM™
Acute Module, were utilized to account for concentration of imidacloprid residues due tochanges in food hydration: 2.1 and 8.26 for grapefruit juice and juice-concentrate; 2 and 11.4 forlemon juice and juice-concentrate; 2 and 6 for lime juice and juice-concentrate; 2.3 and 7.35 fortangerine juice and juice-concentrate; 1.8 and 6.7 for orange juice and juice-concentrate; 1.2 forgrape juice; 4.3 for raisins and 7 for dried peaches. No other adjustment factors were employedin the evaluation of the acute dietary exposure.
The DEEM™ hydration factor was not used (i.e., set to 1) for the commodities with imidacloprid
residues at the tolerance level. Applying the hydration factor to account for residue concentration
could result in a residue level higher than the tolerance, which is illegal.
Based on the paradigms used in this dietary assessment, the 95th percentile of user-day exposures
to imidacloprid ranged from 15 µg/kg/day to 51 µg/kg/day. At the 99th percentile the exposures
ranged from 23 µg/kg/day to 78 µg/kg/day. At both, the 95th and 99th exposure percentiles, thepopulation subgroups “Children 1-2 years” and “All Infants” were identified as the most highly
exposed among the evaluated subgroups (Table 19; see also Attachment I).
The acute Critical Exposure Commodity (CEC) analysis identified several commodities,
including beans, broccoli, apples, tomatoes, spinach and apricots as making substantial
contributions to the overall acute dietary exposure. Beans appeared as the most significant
contributor to the dietary exposure for the majority of the evaluated population subgroups. The
respective food-forms were: Beans-succulent-green-Canned: Cooked or Boiled, Beans-drypinto-Boiled and Beans-dry-kidney-Canned: Boiled. The contribution of beans to the total
dietary exposure to imidacloprid was the highest for the following population subgroups: All
Infants (up to 66% of the total dietary exposure), Children 6-12 yrs. (22%) and Non-Hispanic
Whites (18%). The contribution of Broccoli (in the food-forms of Broccoli-Frozen: Cooked;
Broccoli-Boiled) was the highest for Females 13-49 yrs. (19%), Non-Hispanic Other (14%),
Western Region (13%) and Children 6-12 yrs. (12%). Apples in the food forms of Applesjuice/cider-Uncooked also made a significant contribution to the dietary exposure for the most of
the population subgroups. The contribution was the highest for Non-Hispanic Whites (15%), US
Population, Western Region, Children 1-2 yrs. (13%). It is important to note that spinach(Boiled/Canned and Cooked) and canned apricots were significant contributors to the total80

dietary exposure of the infants (nursing and non-nursing up to 12%). Tomatoes in the food-formsof Tomatoes- Puree; Tomatoes- juice-Canned and Canned: Boiled; and Tomatoes-wholeCanned: Boiled contributed to the high total dietary exposure of Adults 20-49 yrs. (14%),
Females 13-49 yrs (13%), Adults 50+ yrs. (10%) Children 3-15 and 6-12 yrs., Western Regionand Hispanics (up to 7%)
Table 19. Acute Dietary Exposure Estimates for Imidacloprid.
ACUTE DIETARY EXPOSURE a (µg/kg/day)
Population Subgroup
Point Estimate Tier 1
Point Estimate Tier 2
95th Percentile 99th Percentile 95th Percentile 99th Percentile
US Population (all seasons)
30
54
20
38
Western Region
31
54
23
39
Hispanics

33

57

24

43

Non-Hispanic Whites

28

51

20

36

Non-Hispanic Blacks

33

61

24

41

Non-Hispanic Other

35

55

27

43

All infants

66

98

45

70

Infants (nursing, <1yr.)

60

79

36

65

Infants (non-nursing,<1yr.)
Children (1-2 yrs)

65

101

46

71

73

115

51

78

Children (3-5 yrs)

57

87

38

57

Children (6-12 yrs)

36

57

24

42

Youth 13-19

23

35

16

24

Adults 20-49

22

32

15

23

Adults 50+

22

34

26

25

Females (13-49 yrs)

22

32

15

23

a/ DEEM™ program was used for the analysis with the USDA CSFII from 1994-1998.
b/ The acute Point Estimate dietary exposure from all commodities with imidacloprid registrations was calculated at the 95th and99th percentiles of user-days for all population subgroups. The highest exposures are indicated in bold.

IV. B.2.b. Acute Probabilistic (Monte Carlo) Exposure Assessment
Because of lack of monitoring data, the residue level on all of these contributors was represented
by the tolerance. The contribution of these commodities to the high daily exposure of individuals
was a result of: (i) use of imidacloprid tolerances as surrogate for residue concentration and (ii)the consumption of the respective food-forms determined during 1994-1998 CSFII. The current

81tolerances for these contributors are: 4 ppm for beans, 3.5 ppm for broccoli and spinach, 3 ppm
for tomato and apricots and 0.5 ppm for apples.
The Tier 2 analysis produced exposures, which resulted in MOEs below the thresholds of 1000
or 500 at the 95th or 99th percentiles, respectively, for all of the population subgroups (See
Section IV. C.2. under RISK CHARACTERIZATION). As part of the DPR’s tiered approach,the probabilistic analysis can be used as the next refining step of the acute dietary exposure
assessment. The probabilistic evaluation, also known as Monte Carlo analysis, uses the entire
range of pesticide residues available from a data source to calculate the distribution of exposure
for selected population subgroups. The food exposure estimates could be improved byincorporating information on the pesticide use and agricultural or processing practices.
Probabilistically, Monte Carlo exposures at high-end percentiles are often lower than the highend Point Estimate exposures. However, the outcome is largely dependent on the residue
database, especially when residue values could not be treated probabilistically for all foodcommodities.
For imidacloprid, residue distribution data were available only for cucumbers, grapes, nectarines,
oats, oranges, peaches and tomato paste. Distributional data were not available for any of thehigh contributing commodities. Consequently, the resultant high-end exposure distribution from
the Monte Carlo analysis was not significantly different from the pattern of the point estimate,and, thus was not presented in this document.
IV. B.3. Chronic Exposure
For chronic risk assessments, the residue concentration for each food is represented by a single
value. This residue is multiplied by the average consumption of each population subgroup. Total
exposure is the sum of the individual exposures for each selected food and food form. DPR uses
certain assumptions when conducting chronic dietary assessment (DPR MT-3, 2004). Typicalones are: (i) commodities that could contain imidacloprid residues contain the average residue
levels and (ii) the population average daily consumption distribution reflects the longitudinal
consumption patterns of individuals.
Therefore, the arithmetic average of the reported pesticide concentrations was used to estimate
the combined exposure from all commodities with current imidacloprid tolerances. In order toaccount for possible unquantifiable exposures, samples with residues below the limit of detection
were assigned ½ of the LOD. For commodities for which monitoring data were not available, thechronic residue concentration was set equal to ½ of the tolerance. The anticipated chronic
imidacloprid residues are presented in Tables 17 and 18.
This chronic analysis employed percent-crop-treated adjustments to account for the fact that only
a fraction of the total crop acreage was treated. The PCT data were available to refine the residue
values on the following non-blended commodities: apple, broccoli, Brussels sprouts, cabbage,
cauliflower, collards, kale, pears, potatoes, watermelon, pumpkin, squash, eggplant, beans,cantaloupe, cucumber, grapes, lettuce, nectarines, oranges, peaches, peppers, strawberry andtomatoes. The PCT ranged from 1 to 85% (Tables 17 and 18). PCT adjustments were not applied
for blended foods (DPR MT-3, 2004).
Based on the paradigms used in this analysis, the estimated chronic exposures to imidacloprid
ranged from 1.75 µg/kg/day (Females 13-49 yrs.) to 7.41 µg/kg/day (Children 1-2 yrs.; Table
20).

82

Table 20. Chronic Dietary Exposure Estimates for Imidacloprid.
Chronic Exposure(µg/kg/day)a

Population Subgroup
US Population (all seasons)

2.37

Western Region

2.64

Hispanics

2.66

Non-Hispanic Whites

2.28

Non-Hispanic Blacks

2.37

Non-Hispanic Other

3.40

All infants

4.35

Infants (nursing, <1yr.)

1.98

Infants (non-nursing,<1yr.)

5.25

Children (1-2 yrs)

7.41

Children (3-5 yrs)

5.47

Children (6-12 yrs)

3.24

Youth 13-19

1.93

Adults 20-49

1.79

Adults 50+

1.89

Females (13-49 yrs)

1.75

a/ The DEEM™ program was used for the analysis with the USDA CSFII from 1994-1998. The highest exposures are indicatedin bold.
c/ The percent crop treated adjustment factors were used for the commodities: apples; beans, broccoli, Brussels sprouts, cabbage,
cantaloupes, cauliflower, collards, cucumbers, eggplant, grapes, kale, lettuce, nectarines, oranges, peaches, pears, peppers,
potatoes, pumpkin, squash, tomato and watermelon.

83

IV.C. RISK CHARACTERIZATIONIn the case of imidacloprid, the process of risk characterization involved estimating the margin of
exposure (MOE). The MOE for exposure to imidacloprid was calculated as the ratio of thecritical NOEL, established for specific exposure duration and an estimate of a human exposure.
The critical NOELs were determined from oral and inhalation studies (Table 21); NOELs for thedermal route were not available. This document pertains only to the assessment of the dietary
exposure. Therefore, the critical oral NOEL was utilized in the calculation of the MOE for oralroute. The exposures were estimated from the oral (dietary) exposure.
The acute, subchronic and chronic NOELs employed for the characterization of the risk fromexposure to imidacloprid were derived from studies with laboratory animals. Consequently, acalculated MOE of 100 was considered prudent for protection against the imidacloprid toxicity.
The benchmark of 100 includes an uncertainty factor of 10 for interspecies sensitivity and 10 for
intraspecies variability.
Table 21. Critical NOELs and Endpoints for the Risk Characterization of Imidacloprid
Duration/RouteNOEL
mg/kg/day

Acute Oral

9.0b

32-day Oralc

5.5d

Subchronic Oral
Chronic Oral

7.3
5.7

Critical Endpoint
Decreased motor activity in rat;
(Sheets, 1994a)
Decreased widths of corpus callosum
and caudate putamen in PND11 rats
(Sheets, 2001)
Morphologic changes in liver andthyroid and tremors in dog (Block,1987, Ruf, 1990#)
Thyroid lesions in rat; Eiben and
Kaliner, 1991#)

Reference Dosea
mg/kg/day
0.09
0.06
0.07
0.06

a/ Reference Dose (RfD) was estimated as NOEL/uncertainty factor (UF). RfD was based on a UF of 100, 10 each for inter andintra-species extrapolation.
b/ LED05 was used as equivalence to the NOEL. LED05 was calculated with the BMD approachas the 95% confidence limit of the effective dose (ED), which was required to cause a 5% reduction in the motor activity in rats.
c/ This NOEL was estimated from the LOEL of 54.7 mg/kg/day by applying a 10-fold default factor. The ENEL of 5.5
mg/kg/day was used for acute exposures to imidacloprid in women of childbearing age to protect against fetal exposure.
d/ Pups were indirectly exposed to imidacloprid for a total of 41 days (20 days in utero and 21 days via lactation). Decreases inthickness of brain structures of the pups were observed following 32 doses of imidacloprid to the dams (21 doses in utero and 11#
Study was considered acceptable by the DPR according to FIFRA guidelines.
doses during lactation).

IV.C.1. Dietary Exposure
IV.C.1.a. Acute Dietary Exposure
The acute dietary exposure to imidacloprid was estimated using the deterministic (Point
Estimate) model.
Tier 1 Point Estimate Assessment: In this analysis, the imidacloprid residues in all foods were set
equal to the tolerance. The Tier 1 acute dietary exposures were presented in the Table 19. The
corresponding MOEs were calculated using the acute NOEL of 9 mg/kg/day for decrease in84

motor and locomotor activity in rats (Sheets, 1994a). The MOEs ranged from 122 to 417 at the95th percentile and 78 to 281 at the 99th percentile (Table 22). These MOEs were below thethreshold MOE of 1000 at the 95th percentile; or below the threshold MOE of 500 at the 99th
percentiles. Consequently, the Tier 2 was used to refine the dietary exposure (DPR MT-3, 2004).
Tier 2 Point Estimate Assessment: In this analysis all consumed foods were assumed to containthe highest reported residue at or below the tolerance. The Tier 2 acute dietary exposures were
presented in Table 19. The corresponding MOEs ranged from 175 to 614 at the 95th exposure
percentile; and 115 to 394 at the 99th percentile. Children 1-2 yrs were identified as the mosthighly exposed population (Table 22).
Table 22. Acute (Point Estimate) Dietary Risk Estimates for Imidacloprid.
ACUTE MOEa
Population Subgroup
Point Estimate Tier 1
Point Estimate Tier 2th95 Percentile 99th Percentile 95th Percentile 99th Percentile
US Population (all seasons)
302
167
429
237
Western Region
288
167
399
230
Hispanics

274

157

375

206

Non-Hispanic Whites

318

175

462

250

Non-Hispanic Blacks

275

145

383

221

Non-Hispanic Other

257

162

327

210

All infants

139

92

198

128

Infants (nursing, <1yr.)

150

112

250

138

Infants (non-nursing, <1yr .)

137

88

195

127

Children (1-2 yrs)

122

78

175

115

Children (3-5 yrs)

159

103

234

157

Children (6-12 yrs)

249

159

370

186

Youth 13-19

394

254

575

370

Adults 20-49

409

276

595

390

Adults 50+

415

268

554

359

Females (13-49 yrs)

417

281

614

394

a/ DEEM™ program was used for the analysis with the following input parameters: (i) USDA CSFII from 1994-1998, (ii) acute
NOEL of 9 mg/kg (Sheets, 1994a). MOE is defined as NOEL/Acute Dietary Intake. Acute dietary exposure was calculated at the95th and 99th percentiles of user-days for all population subgroups. The lowest MOEs are indicated in bold.

These MOEs were calculated based on the acute NOEL of 9 mg/kg/day for decreases in motor
activity in rats (Sheets, 1994a). Using the ENEL of 5.5 mg/kg/day for developmental
neurotoxicity (Sheets, 2001) to estimate the risk for acute dietary exposure to women inchildbearing age (Females 13-49 yrs.) would result in an MOE of 306 and 239 at the 95th and99th percentiles.
85

The DPR concludes the acute dietary exposure, when the MOE are within 5-fold of the healthprotective level at the 99th percentile, or 10-fold of the health protective level at the 95th
percentile. This was clearly not the case with imidacloprid, where the lowest MOEs (115 and
175 at the 99th and 95th percentiles, respectively) were only marginally above the benchmark of
100. The dietary exposure could be refined further when the single residue concentration for thehigh contributing commodities is replaced with residue distribution in the probabilistic Monte
Carlo modeling. However, distributional data for imidacloprid were not available for any of thehigh contributing commodities to the dietary risk. In conclusion, the lack of sufficient residue
data for imidacloprid precludes a further refinement of the dietary assessment at this time.
IV.C.1.b. Chronic Dietary Exposure
The estimated chronic exposures to imidacloprid are presented in the Table 20. The
corresponding MOEs ranged from 770 for “Children 1-2 yrs” to 3251 for “Females 13-49”,
based on the chronic NOEL of 5.7 mg/kg/day for thyroid lesions in rat (Eiben and Kaliner,
1991). The NOEL of 5.7 mg/kg/day is sufficiently close to the ENEL of 5.5 mg/kg/day fordevelopmental neurotoxicity (Sheets, 2001), and therefore, would be adequate for protection
against the potential effects of imidacloprid on the developing nervous system.
Table 23. Chronic Dietary Risk Estimates for Imidacloprid.
Chronic MOE a (µg/kg/day)a

Population Subgroup

2407
2159
2145
2500
2516
1676
1311
2875
1087
770
1041
1762
2960
3177
3015
3251

US Population (all seasons)Western Region
Hispanics
Non-Hispanic Whites
Non-Hispanic Blacks
Non-Hispanic Other
All infants
Infants (nursing, <1yr.)
Infants (non-nursing,<1yr.)
Children (1-2 yrs)
Children (3-5 yrs)
Children (6-12 yrs)
Youth 13-19
Adults 20-49
Adults 50+
Females (13-49 yrs)

a/ The DEEM™ program was used for the analysis with the following input parameters: (i) USDA CSFII from 1994-1998, and(ii) Chronic NOEL of 5.7 mg/kg/day (based on increased mineralized particles in thyroid gland in two-year feeding study in rats;
Eiben and Kaliner 1991; Eiben 1991). MOE is defined as NOEL/Chronic Dietary Intake. The lowest MOE is indicated in bold.
c/ The percent crop treated adjustment factors were used for the commodities: apples, beans, broccoli, Brussels sprouts, cabbage,
cantaloupes, cauliflower, collards, cottonseed, cucumbers, eggplant, grapes, kale, lettuce, nectarines, oranges, peaches, pears,
peppers, potatoes, pumpkin, squash and watermelon.

86V. RISK APPRAISAL
V.A. INTRODUCTION
This risk assessment for imidacloprid evaluated the risk to 16 population subgroups frompotential residues in food and drinking water. Dietary exposures were estimated under acute andchronic scenarios. Every risk assessment has inherent uncertainties, which reflects limitations in
the knowledge to estimate the potential risk to human health. Assumptions and extrapolations are
made when the available data are insufficient to identify the hazard, to adequately characterize
the dose-response, or to assess the exposure. These, in turn, result in uncertainty in the risk
characterization. Specific areas of uncertainty associated with this risk assessment for
imidacloprid are delineated in the following discussion.
V.B. HAZARD IDENTIFICATION
The most appropriate toxicity data for the hazard identification of imidacloprid would be fromhuman studies. However, toxicity studies with imidacloprid were not available in humans.
Consequently, studies in laboratory animals were used as a source of information at this time.
Critical NOELs derived from oral studies were employed to assess the risk from dietary exposure
to imidacloprid.
V.B.1. Acute Oral Toxicity
The LED05 of 9 mg/kg/day was selected as an equivalence of the NOEL to estimate the risk forthe acute dietary exposure of the US population to imidacloprid. This critical acute oral NOEL
was derived from an acute neurotoxicity study in rats (Sheets, 1994a). The study included
elaborated toxicity evaluation (e.g., neurobehavior, motor activity, neuropathology, clinicalobservations and clinical chemistry). The reported effects were consistent with the toxicity
observed in other toxicity studies with imidacloprid. The range of effects included typicalcholinergic signs, changes in the neurobehavior and motor activity, severe toxicity andmortalities. The most sensitive toxicological endpoint at the LOEL of 42 mg/kg/day was the 2527% decrease in the motor and locomotor activity of the females. This effect became statisticallysignificant (up to 89% decrease, p ≤ 0.05) in both sexes in the next higher doses. Importantly, for
imidacloprid, reduction in motor/locomotor activity was observed in all of the available (acuteand subchronic) neurotoxicity studies. Altogether, the presented findings could be used todetermine acute toxicity endpoints.
In this study, toxicological effects were observed at the lowest tested dose, hence, anexperimental NOEL could not be defined. The general default approach for estimating a NOEL
would be to scale down from the LOEL using an uncertainty factor. USEPA estimated the acute
NOEL for imidacloprid as 14 mg/kg/day, by applying an uncertainty factor of 3 to the LOEL of
42 mg/kg/day (USEPA, 2003). This approach carries greater uncertainties, because it does nottake into account the dose response curve, but rather focuses on only one dose (the LOEL).
These limitations could be overcome with the BMD modeling, which involves fitting amathematical model to the entire dose-response dataset for an endpoint. The model estimates thethreshold dose LED at a defined level of benchmark response (BMR; DPR MT-2, 2004). The
LED is the 95th percent lower bound of the effective dose (ED). The acute neurotoxicity study
had a large sample size (n=18) and a clear dose-response relationship, and thus, was suitable for
BMD modeling. The calculated LED05 of 9 mg/kg/day represented the 5% change in the group87mean relative to the control. The difference between the ED05 and the LED05 and (12 vs. 9
mg/kg/day) was small (i.e., ED/LED ratio <5), which was indicative of good quality
experimental data and a good model fit (DPR MT-2, 2004).
The choice of 5% benchmark response level was based on the current DPR default BMR (DPR
MT-2, 2004). However, the BMR could vary form 1 to 10, depending of the endpoint severity.
Severity considerations could suggest a lower BMR for the imidacloprid-induced reduction in
the motor activity levels. First, decreases in the motor and locomotor activity are known acuteeffects of nicotinic agonists. Second, the Time to Peak Effect (TOPE, 90 min after dosing) was
determined based on FOB findings and thus, may not be optimal for observing the motor activity(Sheets, 1994a). Third, this effect was reported in all of the available neurotoxicity studies.
Similar doses of imidacloprid for different durations induced comparable levels of reduction of
the motor/locomotor activity. In all cases, the female rats were more sensitive. Finally, data fromthe developmental neurotoxicity study suggested that the decrease in the motor/locomotor
activity in the female rats may be related to changes in dimensions of brain areas, which control
motor functioning and voluntary motion (Sheets, 2001); see Section III.I. DEVELOPMENTAL
NEUROTOXICITY). Had a 1% BMR been chosen to model the decrease in the motor activity inthe acute neurotoxicity study, the LED01 and ED01 would have been 1.8 and 2.4 mg/kg/day,
respectively. The LED01 is 5-fold lower than the LED05.
Regardless of these considerations, the choice of the LED05 of 9 mg/kg/day as the acute criticaloral NOEL was supported by the NOEL of 10 mg/kg/day, which was established from the acutetoxicity study in mice (Bomann, 1989a). In addition, the available imidacloprid toxicological
database revealed that the majority of the estimated or established oral NOELs were in the rangeof 5.5-30 mg/kg/day for all endpoints and exposure times.
The estimated NOEL for developmental neurotoxicity was 5.5 mg/kg/day (Sheets, 2001). This
ENEL could be applicable to acute exposures to females of childbearing age. However, there is amuch greater uncertainty associated with the DNT endpoint, because it was approximated fromthe LOEL by using a 10-fold default factor.
V.B.2. Chronic Oral Toxicity
The NOEL of 5.7 mg/kg/day was utilized to estimate the risk of chronic dietary exposure toimidacloprid. This critical oral NOEL was derived from a 2-year chronic toxicity/oncogenicity
study in Wistar rats (Eiben and Kaliner, 1991; Eiben, 1991).
The reported effects were consistent with the toxicity observed in other toxicity studies withimidacloprid. These included reduction in body weight, thyroid toxicity and changes in serum
chemistry. The principal effect at the LOEL of 17 mg/kg/day was a statistically significant
increase (62%) in the incidence and severity of mineralized particles in thyroid gland in malerats. The NOEL of 5.7 mg/kg/day was the lowest from the three available chronic toxicity
studies. While thyroid effects were not observed in the other two chronic studies (in dogs andmice), subchronic toxicity studies in dogs established a NOEL of 7.3 mg/kg/day based on thyroid
toxicity, among other toxic endpoints (Block, 1987; Ruf, 1990). Finally, the NOEL of 5.7
mg/kg/day was sufficiently close to the ENEL of 5.5 mg/kg/day for developmental neurotoxicity(Sheets, 2001), and therefore, would be adequate for protection against the potential effects ofimidacloprid on the developing nervous system.

88

V.C. EXPOSURE ASSESSMENT
V.C.1. Dietary Exposure Assessment
The uncertainty in the exposure assessment is classified in three major categories: (i) parameter
uncertainty, (ii) model uncertainty and (iii) scenario uncertainty (USEPA 1992, Peterson et al,2001).
V.C.1.a. Parameter Uncertainty: Sources of parameter uncertainty in the
dietary exposure assessment include completeness of the food residue database, the use of
surrogate data and measurement, sampling or reporting errors.
The food exposure estimates could be improved if the residue data for the major contributors to
the dietary risk are available. In general, the USDA PDP program is preferred, because it isspecifically designed for generating data for risk assessments. The current food residue databasefor imidacloprid is very limited. In the US, imidacloprid is registered for protection of a large
number of crops (more than 270). Only 14 of them have been tested for imidacloprid residues by
the Federal and State Monitoring programs (USDA and DPR). Residue levels measured by the
PDP and DPR were employed for the following commodities: oranges, nectarines, oats, peas,
canned tomato paste, drinking water, cantaloupes, cucumbers, grapes, lettuce, peppers, chili
peppers, strawberries and tomatillos (Table 17). Attempts were made to decrease the degree of
uncertainty by selecting surrogate commodities from the crop groups of related commodities
established in 40 CFR 180.40. The residues measured by the PDP on oranges and canned tomato
paste were used to model the exposure for the foods from the Citrus Fruit Group 10 and tomato
puree and catsup, respectively (Table 17). The residue on peaches was refined by assigning theLOD of the PDP for nectarines. The use of more refined data for these commodities in the Tier 2analysis resulted in 1.3-1.5-fold lower exposure estimates, compared to the Tier 1-exposures,
which were based on residues at the tolerance level (see Tiers 1 and 2 under Section IV.B.2.5.a).
It should be emphasized, that none of these commodities emerged as a major contributor to thetotal dietary exposure, even when the residue levels were set at the tolerance in Tier 1.
Altogether, replacing the tolerance with the available measured concentrations for foods withsmall impact on the dietary exposure did not significantly refine the 95th-99th acute exposures.
Because of lack of residue data, the rest of the commodities were represented by the tolerance assurrogate for residue concentration. The tolerance is established based on field trial-measured
residues, following maximum application rate and frequency. Typically, these conditions do notreflect the actual use pattern. Therefore, the total acute exposure was a result from consumptionof foods, most of which contained the maximum allowed residue level. Consequently, the highend of exposure was likely reflective of the tolerance for these commodities. Importantly, all of
the foods, which emerged as major contributors (beans, broccoli, apples, tomatoes, spinach andapricots), were represented by the tolerance. With the exception of apples (tolerance of 0.5 ppm),
the tolerances for the rest of the major contributors are high (3-4 ppm). The aforementioned highcontributing commodities should be considered for monitoring of imidacloprid residues.
The dietary exposure assessment may exhibit a level of uncertainty in the consumption datacontained in the 1994-1998 USDA survey. The uncertainty may result from under-representationof actual dietary consumption, reporting errors, response and variation in the culinary habits overthe consumption period.

89

V.C.1.b. Scenario and Model Uncertainty: Three Point Estimate dietary
exposure scenarios were evaluated for imidacloprid under acute and chronic conditions. The
acute dietary exposure estimates for imidacloprid were calculated using the tiered approach inthe selection of the appropriate residue values.
Acute Dietary Exposure. In the initial scenario, the Tier 1 Point Estimate analysis, theconcentration of imidacloprid on all commodities was assumed to be equal to the tolerance. The
MOEs were at or above 100 for all population subgroups at the 95th percentile. However, theMOEs at the 99th percentile were less than 100 for the following population subgroups: Children
1-2 yrs, Non-nursing Infants, All Infants and Children 3-5 yrs. (Table 22). It is highly unlikelythat all the commodities, consumed in a given day, can contain imidacloprid residues at thehighest legally allowed residue level.
Because of the low MOEs, additional refinements of the acute scenario were carried out. In the
Tier 2 acute analysis, the refinement involved the use of imidacloprid concentrations measured
by the PDP and DPR. This analysis produced only a slight increase of the MOE values. The
lowest MOEs were 175 and 115 at the 95th and 99th percentiles, respectively. These MOEs were
only marginally above the health protective level (MOE of 100). The reasons for not achieving asignificant refinement of the Tier 2-exposures were as follows: (i) Imidacloprid is registered for avery large number of foods; (ii) The high-end exposure mostly reflected residues at the tolerance.
The established tolerances for many of the foods, including high consumption commodities, arehigh (3-6 ppm) and (iii) The high contributing commodities were represented by the tolerance,
whereas foods which were assigned measured residues had much less impact on the dietary
exposure.
Additional models could be used to refine the acute dietary exposure. The Monte Carlotechniques employ residue distribution and PCT information to produce more realistic exposure
estimates. However, the lack of sufficient residue data for imidacloprid precluded a further
refinement of the dietary assessment at this time.
Chronic Dietary Exposure. The available data on PCT was used to refine the chronic residue
levels. A major assumption in both scenarios was that chronic residue levels below the LOD
were at ½ of that limit. The chronic dietary MOEs were all greater than 770 (Table 23).
V.D. RISK CHARACTERIZATION
A margin of exposure of 100 is considered sufficiently protective of human health when data arederived from animal studies. The MOE of 100 assumes that humans are 10 times more sensitive
than the laboratory animals and that the sensitivity among human population could vary as muchas 10-fold.
V.D.1. Dietary Exposure
The uncertainties associated with the dietary exposure estimates and the critical NOELs, whichwere used to calculate the dietary MOEs, were discussed in detail in the sections V.B.1-3 andV.C.1.
V.D.1.a. Acute MOE
The acute dietary MOEs for the DPR high-end percentiles are presented in Table 22 (DPR MT-3,
2004). The MOE values ranged from 175 to 614 at the 95th percentile, and from 115-394 at the90

99th percentile. The dietary exposure was assessed by the deterministic (Point Estimate, Tier 2)model. The MOEs were estimated using the acute rat NOEL of 9 mg/kg/day (Sheets, 1994a).
Children 1-2 yrs. and Infants were identified as the most highly exposed population subgroup.
The MOEs for these population subgroups were 175 and 195 at the 95th percentile, and 115 and
128 at the 99th percentile. Using the ENEL of 5.5 mg/kg/day for women in childbearing age toprotect against fetal exposure would result in acute MOEs of 366 at the 95th and 239 at 99th
percentiles, which exceed the benchmark MOE of 100.
It should be noted that in the BMD modeling, the effective dose ED05 corresponding to the above
LED05 was 12 mg/kg/day. This ED05 was in the same range as the USEPA NOEL of 14
mg/kg/day, which was estimated by applying an uncertainty factor of 3 to the LOEL of 42
mg/kg/day (USEPA, 2003). If the ED05 of 12 mg/kg/day was used in the estimation of the acutedietary risk, the MOE values for the highest exposure group (Children 1-2 yrs.) would be 235
and 154 at 95th and 99th percentiles, respectively. For comparison, the USEPA estimated NOELof 14 mg/kg/day would produce MOEs of 275 and 179 at 95th and 99th percentiles, respectively,
for this exposure group.
These MOEs reflect only the risk from the dietary and drinking water exposure. The aggregate(i.e., combined) exposures from ambient air, occupational activities and residential uses ofimidacloprid remain to be assessed.
V.D.1.b. Chronic MOEs
The chronic MOEs for exposure to imidacloprid were over 700. These MOEs were estimatedusing the chronic rat NOEL of 5.7 mg/kg/day (Eiben and Kaliner 1991; Eiben 1991). PCT
assumptions were employed to refine the chronic exposure. The conventional benchmark for the
MOE using a NOEL from an animal study is 100, thus indicating that the chronic dietary
exposure to imidacloprid would not present a potential health risk.
V.D.2. Aggregate Inhalation and Dietary Exposure
The DPR began monitoring for imidacloprid residues in the ambient air in California in 2002.
These studies were preliminary and the information was not sufficient to estimate the acuteinhalation exposure to imidacloprid. The aggregate risk for humans from inhalation and dietary
exposure will be assessed when data become available. Discussion on the choice of theinhalation NOEL will accompany the aggregate assessment.
V.D.3. Aggregate Occupational and Dietary Exposure and Residential and Dietary
Exposure
The aggregate risk for humans from occupational and dietary exposure and from residential anddietary exposure will be subsequently evaluated in an addendum to this RCD.
V.E. ISSUES RELATED TO THE FOOD QUALITY PROTECTION ACT
V.E.1. Pre- and Post- Natal Sensitivity
The FQPA requires considerations of an additional safety factor of up to 10 to account for preand post-natal toxicity and the completeness of the database. The extent of pre- and post-natal
sensitivity can be evaluated based on the completed submission of toxicity studies required under91the Senate Bill 950 (SB950), particularly the studies on developmental and reproductive
toxicities.
One reproductive and two developmental toxicity studies were available for imidacloprid. In rats,
the main fetal effects were wavy ribs and disproportionally high number of male fetuses (Becker
et al., 1992). Both effects occurred at the same doses as the maternal toxicity, which was adecreased weight gain. In a rabbit teratology study, imidacloprid doses caused reduction insurvival, body weight and delayed ossification in fetuses (Becker and Biedermann, 1992). The
same doses were also toxic to the dams (weight loss and death). In a reproductive toxicity study
in rats, decreased body weight gain of pups was observed on PND 4 and 21. The reduction ofmaternal body weight gain and pup survival occurred at the same doses of imidacloprid (Suter etal., 1990). Altogether, a higher pre- and post-natal sensitivity was not indicated in these studies.
Based on these findings, the USEPA in their 2003 risk assessment concluded that an additionalsafety factor is not required to protect infants and children from exposure to imidacloprid(USEPA, 2003).
A developmental neurotoxicity study was recently completed for imidacloprid, whichinvestigated whether pre- or post-natal exposure affected the neural development (Sheets, 2001).
The principal effects were reduction in body weights in pups at PND 4 and up to 75 days of age,decreased motor activity at PND 17 and 21, and decreased width of the caudate putamen andcorpus callosum in females at PND 11 These effects could not be directly compared to thetoxicity in the adult animals. Therefore, conclusions on whether immature rats are more sensitive
to imidacloprid than the adults could not be drawn from this study.
Imidacloprid is structurally and functionally related to nicotine, which pre- and postnatal toxicity
has been well documented. Both nicotine and imidacloprid act via the nAChRs that are present in
the fetal brain, autonomic ganglia and adrenal medulla (Sugiyama et al., 1985; Cairns andWonnacott, 1988).
Nicotine is a known neuroteratogen. In rats, prenatal nicotine exposure causes mitotic arrests,
cell death and a decline in the CNS cell number (Slotkin, 1998). Prenatally, nicotine disrupts theserotonergic systems, which are involved in mood disorders and depression (Xu et al., 2001).
Nicotine inhibits the spontaneous release of catecholoamines from the adrenal medulla duringhypoxia (Slotkin et al., 1995). Massive release of catecholamines is needed to maintain the
cardiac rhythm during oxygen starvation. In fact in humans, prenatal nicotine exposure has beencorrelated with the Sudden Infant Death Syndrome, in which cardiorespiratory failure occurs in a
hypoxic episode, as in sleep apnea. Prenatal and postnatal nicotine exposure in rats has been
linked to growth retardation, learning disabilities, cognitive deficits and hyperactivity (DiFranza
and Lew, 1995). Females appeared to be more affected, thus suggesting that the nicotine effects
could be sex-selective (Xu et al., 2003). Interestingly, the neurotoxicity studies with imidacloprid
revealed changes in the size of brain structure in female rats, which in general were moresensitive to its effect on the motor/locomotor activity (Sheets, 1994a; 1994b and 2001).
These data should be considered when assessing the effects of imidacloprid on the developing
organisms. The available bioassays were not designed to test the more subtle effects ofimidacloprid such as mood disorders, depression and cardiac function during hypoxia. In
conclusion, the current data on imidacloprid may be insufficient to thoroughly evaluate its preand post-natal toxicity.

92V.E.2. Aggregate Exposures
For total non-occupational exposure, the DPR considers contributions to risk from various
exposure sources. These include exposures from food, drinking water, air, and residential
sources. The lack of monitoring data on imidacloprid residues in air precluded an ambient air
exposure assessment at this time and will be assessed when data become available. The exposure
from residential uses will also be addressed subsequently in an addendum to this document.
Therefore, the non-occupational aggregate risk was evaluated from imidacloprid residues in thefood and in the drinking water. The total dietary exposure was calculated with the deterministic(Point Estimate, Tier 2) model. The MOEs ranged from 175 to 614 at the 95th percentile, andfrom 115-394 at the 99th percentile (Table 22). Drinking water did not emerge as a major
contributor to the total dietary exposure.
While the estimated MOEs for exposure from the oral route (food and drinking water) were at or
above the benchmark of 100, they reflect only the risk from the dietary exposure. The aggregate(i.e., combined) exposures from ambient air, occupational activities and residential uses ofimidacloprid remain to be assessed. These additional exposures will lead to reductions in the
MOEs estimated in this assessment.
V.E.3. Cumulative Toxicity
The USEPA recently developed methodology to evaluate the exposure to multiple chemicals
from multiple pathways. The USEPA is required under the FQPA of 1996 to assess the
cumulative risk to human health, which could result from exposure to pesticides with a common
mechanism of toxicity (USEPA, 1999c). The organophosphate (OP) pesticides were the firstgroup with common mechanism of toxicity to undergo a cumulative risk assessment (USEPA,
2002b). Certain members of the carbamate pesticides and triazine-containing pesticides are also
being evaluated for cumulative toxic effects (USEPA, 2002c).
Imidacloprid belongs to the family of the neonicotinoids, which are structurally similar to
nicotine. Both the neonicotinoids and nicotinoids have a common mode of action as agonists of
the nicotinic AChRs (Tomizawa and Casida, 2003). In addition to imidacloprid, four otherneonicotinoids (acetamiprid, thiacloprid, thiamethoxam and nitenpyram) are currently used as
insecticides worldwide (Tomizawa and Casida, 2003). USEPA tolerances are presently
established for the residues of acetamiprid, thiamethoxam and thiacloprid on various crops andanimal commodities (CFR 2003b; CFR 2003c; FR 2003). The same commodities are also
registered for imidacloprid use. In California, the neonicotinoids acetamiprid and thiamethoxam
are registered for food uses. Most of the nicotine-containing pesticide food uses have beencancelled to reduce human risk from dietary exposures. Presently, nicotine-containing pesticides
have tolerances on three commodities: cucumber, lettuce and tomato (CFR 2003d). The same
three crops are also registered for imidacloprid use (CFR 2003a). Therefore, commodities withimidacloprid residues could potentially contain other neonicotinoid and nicotinoid pesticides.
This indicates that a possible multiple chemical exposure could result from the consumption offoods with neonicotinoid and nicotinoid residues.
Quality monitoring residue data would be required for a comprehensive cumulative dietary risk
assessment. Although imidacloprid is one of the most extensively used insecticides, its current
monitoring database is very limited (see section IV. B.2.4. under EXPOSURE ASSESSMENT
and Table 17). The federal and state monitoring programs do not presently screen for residues ofthe other three neonicotionods, which also have a modest agricultural use. In California, the first93

reported use for acetamiprid and thiamethoxam was in 2002 of 6,632 lb and 11,091 lb,
respectively (DPR, 2003). Finally, monitoring residue data are available for the nicotinoidcontaining insecticides, however, their present use on crops is very limited (only on threecommodities with less then 2 lb in 2002; DPR, 2003). In conclusion, the risk of concomitantdietary exposure to multiple neonicotinoid and nicotinoid pesticides would be addressed whenresidue data become available.
V.E.4. Endocrine Effects
Information pertinent for the evaluation of endocrine disruption potential of imidacloprid inanimals is limited. The developmental and reproductive toxicity database in rats and rabbits
showed lower fetal body weight, increased resorption, reduced pup survival, and skeletal
alterations (see: Section III.G. and III.F). Testicular effects in rat and dogs were also reported(Eiben, 1988a, Block, 1987). In a rat DNT study, there were indications of changes in thedimensions of brain structures in female pups (Sheets, 2001). A disproportionally high numberof male fetuses were observed in a rat teratology study (Becker et al., 1992). This effect was
statistically significant, with the sex ratio (59% males) being outside the historical range. The
underlying mechanisms for these effects are not known. In addition, evaluation of endocrine
activities was not part of the protocols in the available studies. More information is needed about
the aforementioned imidacloprid effects and whether they could be occurring via endocrine
disruption.
Imidacloprid is an agonist of the nicotinic AChRs. In the brain, nAChRs regulate the endocrine
system. Other nicotinic agonists, including the structurally related nicotine, are known to haveneuroendocrine effects through interacting with the brain nAChRs (Rhodes, et al., 2001,
Andersson et al., 1988). Nicotine is listed under the California Safe Drinking Water And Toxic
Enforcement Act of 1986 as a chemical known to the State of California cause reproductive
toxicity. These data should be considered when assessing the effects of imidacloprid on theendocrine systems. Testing guidelines and criteria for hazard identification are needed for a clear
evaluation of the endocrine disruption potential.

94VI. TOLERANCE ASSESSMENT
VI.A. BACKGROUND
A tolerance is the legal maximum residue concentration of a pesticide, which may exist in or on
a raw agricultural commodity or processed food. USEPA is responsible under the Federal Food,
Drug, and Cosmetic Act (FFDCA) for setting tolerances for pesticide residues in raw agriculturalcommodities (Section 408 of FFDCA) and processed commodities. The tolerances are
established at levels necessary for the maximum application rate and frequency, and are notexpected to produce deleterious health effects in humans from chronic dietary exposure(USEPA, 1991).
The data requirements for the registration of pesticides and for establishment of tolerances
include: (1) residue chemistry which includes measured residue levels from field studies, (2)environmental fate, (3) toxicology, (4) product performance such as efficacy, and (5) productchemistry (Code of Federal Regulations, 2001). The field studies must reflect the proposed use
with respect to the rate and mode of application, number and timing of applications and the
proposed formulations (USEPA, 1982).
In 1996, the Food Quality Protection Act (FQPA) amended the overall regulation of pesticide
residues under FIFRA and FFDCA (USEPA, 1997a and b). One major change was the removalof the Delaney Clause that prohibited residues of cancer-causing pesticides in processed foods.
FQPA requires scientific evidence to show that tolerances are safe for children. USEPA must
consider applying an additional uncertainty factor of up to 10-fold to take into account potential
pre- and post-natal developmental toxicity and the completeness of the data.
Under FQPA, USEPA is also required to reassess all existing tolerances and exemptions fromtolerances for both active and inert ingredients by 2006 (USEPA, 1997c; 1998). Previously,
USEPA reassessed tolerances as part of its reregistration and Special Review processes. In theevaluation of tolerances, the USEPA uses a tiered approach and the assessment includes alllabel-use commodities.
In California, Assembly Bill 2161 (referred to as the Food Safety Act) requires DPR to “conduct
an assessment of dietary risks associated with the consumption of produce and processed foodtreated with pesticides” (Bronzan and Jones, 1989). In the situation where “any pesticide
represents a dietary risk that is deleterious to health of humans, the DPR shall prohibit or takeaction to modify that use or modify the tolerance.”
VI.B. ACUTE EXPOSURE
The acute tolerance analysis evaluates the health protectiveness of the tolerance for a commodity
in which a pesticide is allowed to be used. It does not include all labeled commodities at theirrespective tolerance levels in the same analysis, because the probability is low for diets tocontain multiple foods at the tolerance levels.
The DPR estimates the acute tolerance exposure as the sum of the 95th percentile exposure forthe commodity of concern at the tolerance and a background exposure (DPR MT 3, 2004). The
background exposure is added to account for residues in other commodities, which may also betreated with the same pesticide. In the first step, the chronic dietary exposure from total dietary95

exposures is used as a surrogate for background exposure. In this step, the exposure contributionof the commodity of interest is “double counted” (e.g. having pesticide residues at the tolerance
and having average “chronic” residues). If the margin of exposure for any population subgroupat this step is above the benchmark for acceptable exposure (i.e., MOE of 100), the acute
tolerance assessment is concluded. If the MOE is below the benchmark, the background dietary
exposure is assessed again but without the commodity for which the tolerance is being evaluated.
In the US, imidacloprid is registered for use on more then 270 individual plant and animalcommodities (CFR 2003a). Because of the large number of registered commodities, tolerance
assessment was carried out only for foods, which had a significant impact on the dietary
exposure. The commodities making substantial contributions to the acute dietary exposure wereselected based on the CEC report from the total (all food) acute dietary analysis (see section IV.
B.2.5.). These included apples, apricots, beans, broccoli and spinach and tomato puree. In
addition, the health protectiveness of the tolerance was assessed for foods with very high USEPA
tolerances (i.e., >5 ppm). These included celery, tomato paste and cotton (tolerance of 6 ppm).
Tolerance assessment was conducted for two more commodities, lettuce and blueberry, althoughthese foods were not identified as high contributors to the acute dietary exposure. Imidacloprid
major use in California is on lettuce; and blueberry is a high consumption food for infants andchildren (FDA, 1991). The imidacloprid tolerance for both commodities is high (3.5 ppm).
Consequently, the residue levels for imidacloprid were set equal to the tolerance to estimate thepotential dietary exposure for each of the 11 commodities described above. The tolerance
exposure was calculated at the 95th percentile for each of the evaluated 16 population subgroups.
The chronic exposure from total dietary exposures was added as a surrogate for backgroundexposure.
The consumption patterns of a given population subgroup is better represented when the survey
sample size is large (i.e. >100 user-days). DPR currently would exclude from the tolerance
assessment population subgroups with less than 25 user days in the 1994-1998 CSFII database,because of the high uncertainty associated with consumption data. Accordingly, the following
population subgroups were not included in the tolerance assessment: All Infants and Non-nursing
Infants (lettuce) and Nursing Infants (broccoli, lettuce, spinach, tomato paste and tomato puree).
Six population subgroups had more than 25, but less than 100 user days for some of theevaluated commodities. Although these subgroups were included in the analysis, the exposureand MOE values should be interpreted with caution, because of the relatively small dietary
sample size. These included: All Infants (broccoli and spinach), Nursing Infants (beans,
blueberry and celery) and Non-nursing Infants (broccoli, spinach and tomato puree), Hispanics,
Children 1-2 yrs. and Youth 13-19 yrs. (spinach).
The range of the exposure and MOE values at the 95th percentile for each of the evaluatedcommodity with imidacloprid at the tolerance level, in the background of the chronic dietary
exposure, is presented in Table 22. The MOEs were calculated using the acute NOEL of 9
mg/kg/day for decrease in motor and locomotor activity in rats (Sheets, 1994a). The MOEs wereat or above the benchmark of 100 for all population subgroups for all of the analyzed foods.
The commodities with the highest amount of dietary exposure at tolerance were tomato paste,spinach, and broccoli. The exposure range was 52.9-15.5, 51.4-12.3, and 46.0-12.7 µg/kg/day,
respectively. These exposures resulted in MOE values ranging from 170-582 (tomato paste),175-730 (spinach), and 196-709 (broccoli). The population subgroups with the lowest MOEs
96

were Children 1-2 yrs (tomato paste and spinach) and All Infants (broccoli). It should be notedthat while the population subgroup All Infants had a relatively small dietary sample size forbroccoli (47 user-days), the consumption patterns of Children 1-2 yrs. for tomato paste andspinach were represented by a large survey sample size (i.e. >100 user-days). In conclusion, theMOE levels (170, 175 and 196) for Children 1-2 yrs and Infants, which consumed tomato paste,spinach and broccoli with tolerance levels of imidacloprid were above the benchmark of 100.
These MOEs were calculated based on the acute NOEL of 9 mg/kg/day for decreases in motor
activity in rats (Sheets, 1994a). Using the ENEL of 5.5 mg/kg/day for developmental brain
effects (Sheets, 2001) to estimate the risk of dietary exposure at tolerance to women inchildbearing age (Females 13-49 yrs.) would result in MOEs ranging from 355 (tomato paste) to2542 (cottonseed oil).
Table 24. Acute Dietary Risk Estimates for Imidacloprid Residues at the Tolerance Level.

Commodity

Range of Exposure Range of Margin Tolerance (ppm)(µg/kg/day) aof Exposure b,cApples29.3- 4.1

307-2200

0.5

Apricot(12)35.2- 2.3

256-3995

3.0

Beans (6)56.6-11.6

159- 774

4.0

Blueberry(5)11.0- 3.8

818-2396

3.5

Broccoli

45.0-12.7

196d- 709

3.5

Celery(4b)16.6- 6.2

543-1454

6.0

Cotton7.5- 2.2

1209-4110

6.0

Lettuce20.5- 8.4

429- 1068

3.5

Spinach(4a)51.4-12.3d175- 730d

3.5

Tomato paste

52.9-15.5

170- 582

6.0

Tomato puree

30.6- 9.1

295- 989

3.0

a/ Acute dietary exposure assessment was conducted for imidacloprid residues on 11 commodities at a level equal to the USEPA
tolerance. DEEM™ program was used for the analysis with the following input parameters: (i) USDA CSFII from 1994-1988 and(ii) acute NOEL of 9 mg/kg (decrease in motor and locomotor activity in rats, Sheets, 1994a). The exposure was calculated as thesum of the 95th percentile exposure for each commodity at the tolerance and the chronic dietary exposure, as a surrogate forbackground exposure.
b/ Margin of Exposure (MOE) is defined as NOEL/Acute Dietary Intake; The number of user-days ranged from 3 to 37173.
c/ Total of 16 consumer groups were considered to be exposed to tolerance levels of imidacloprid residue. These include: US
Population (all seasons), Western Region, Hispanics, Non-Hispanic Whites, Non-Hispanic Blacks, Non-Hispanic Other, Allinfants, Infants (nursing, <1yr.), Infants (non nursing,<1yr.), Children (1-2 yrs), Children (3-5 yrs), Children (6-12 yrs), Youth13-19 yrs, Adults 20-49 yrs, Adults 50+ yrs and Females (13-49 yrs).
The following population subgroups had less than 25 user-days and were not included in the tolerance assessment: Nursing
Infants (broccoli, lettuce, spinach, tomato paste and tomato puree), All Infants (lettuce) and Non-Nursing Infants (lettuce)d/ Exposure estimates were based on ≥ 25 but <100 user-days, therefore the risk estimates may not be representative of the
population.

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VI.C. CHRONIC EXPOSURE
A chronic exposure assessment using residues equal to the established tolerances for individual
or combinations of commodities is not conducted, because it is highly improbable that anindividual would habitually consume single or multiple commodities with pesticide residues attolerance levels. This conclusion is supported by data from both federal and DPR pesticide
monitoring programs, which indicate that less than one percent of all sampled commodities haveresidue levels at or above the established tolerance (PDP 1999-2002; DPR 2002e).

98

VII. CONCLUSIONSThis health risk assessment for imidacloprid evaluated the risk to 16 population subgroups frompotential residues in food and drinking water. Dietary exposures were estimated under acute andchronic scenarios. The exposure estimates were based primarily on the maximum allowed
residue level (tolerance) as surrogate for residue concentration. The critical NOELs were derived
from studies with laboratory animals; therefore, a MOE of 100 was used as the benchmark to
determine the level of human health protection.
The acute point estimate MOEs ranged from 115 to 614 at the DPR high-end percentiles (95thand 99th), and thus, were greater than the benchmark MOE of 100. Children 1-2 yrs. and Infants
were identified as the most highly exposed population subgroups, with MOEs of 175 and 195 at
the 95th percentile, and 115 and 128 at the 99th percentile. The acute MOEs were estimated basedon the acute NOEL of 9 mg/kg/day for decreases in motor activity in rats.
The risk from acute dietary exposure to imidacloprid in women of childbearing age requires
further consideration. Evidence from the developmental neurotoxicity study in rats, suggested
that imidacloprid may affect the neural development. The estimated NOEL for decreases indimensions of brain structures was 5.5 mg/kg/day. This ENEL might be pertinent to acuteexposures of women of childbearing age to protect for fetal exposure. Based on the ENEL of 5.5
mg/kg/day, the acute dietary MOEs for females 13-49 yrs. would be 366 at the 95th and 239 at
99th percentiles, which exceed the general health protective benchmark MOE of 100.
The MOEs for all of the evaluated population subgroups from chronic dietary exposure weregreater than 770, based on the chronic NOEL of 5.7 mg/kg/day for thyroid effects in rats. ThisNOEL is sufficiently similar to the estimated NOEL for developmental neurotoxicity (5.5mg/kg/day), and thus, would be adequate for protection against potential developmental effects
of imidacloprid.
The acute tolerance exposure was calculated as the sum of the 95th percentile exposure for thecommodity of concern at the tolerance and a background exposure. The MOEs for exposure totolerance level imidacloprid were at or above the benchmark of 100. The lowest MOEs were170-196 for Children 1-2 yrs. and Infants, who consumed tomato paste, spinach and broccoli.
The MOEs in this RCD reflect only the risk form the dietary exposure. The potential human
exposures from ambient air, occupational activities and residential uses of imidacloprid will be
subsequently evaluated in an addendum to this RCD. Aggregate exposures to specific population
subgroups from various combined scenarios will also be determined. These additional exposures
will lead to reductions in the MOEs estimated in this assessment. Dietary exposure may have tobe reevaluated using refinements such as measured residue levels from monitoring studies, whendata become available.

99

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Zwart, R., Oortgiesen, M. and Vijverberg, H. P. M. 1994. Nitromethylene heterocycles: Selective
agonists of nicotinic receptors in locust neurons compared to mouse N1E-115 and BC3H1 cells.
Pestic. Biochem. Physiol. 48:202-213.

114

ATTACHMENT I: DEEM Acute Point Estimate Dietary Exposure Assessment
I.1. Tier 1 Residue Data Files
Filename: H:\svetlana\Imidacloprid\DEEM\IMI Acute Tier1 final\Tier 1 Res_Adj F1_1.RS7
Chemical:
RfD(Chronic): 0 mg/kg bw/day NOEL(Chronic): 0 mg/kg bw/day
RfD(Acute): 0 mg/kg bw/day NOEL(Acute): 0 mg/kg bw/day
Date created/last modified: 03-03-2005/15:03:19/14
Program ver. 7.87-------------------------------------------------------------------------------Food Crop
Def Res
Adj.Factors
Comment
Code Grp Food Name
(ppm)
#1
#2
---- ---- ------------------------------- ---------- ------ ------ ------98 O
Acerola1.000000
1.000 1.000 CFR 03
40 14 Almonds
0.050000
1.000 1.000 CFR 03
Full comment: CFR 03; Nov26 03 Sec 18 CA exp June 22 04
498 4A Amaranth3.500000
1.000 1.000 CFR 03
Full comment: CFR 03 subgroup 4a leafy greens
52 11 Apples
0.500000
1.000 1.000 CFR 03
53 11 Apples-dried
0.500000
1.000 1.000 CFR 03
54 11 Apples-juice/cider
0.500000
1.000 1.000 CFR 03
377 11 Apples-juice-concentrate
0.500000
1.000 1.000 CFR 03
410 12 Apricot juice
3.000000
1.000 1.000 CFR 03
Full comment: CFR 03 Group 12 stone fruit
59 12 Apricots
3.000000
1.000 1.000 CFR 03
Full comment: CFR 03 Group 12 stone fruit
60 12 Apricots-dried
3.000000
1.000 1.000 CFR 03
Full comment: CFR 03 Group 12 stone fruit
181 O
Artichokes-globe
2.500000
1.000 1.000 CFR 03
203 1CD Artichokes-jerusalem
0.400000
1.000 1.000 CFR 03
Full comment: CFR 03 Group 1 root & tuber
70 O
Avocados
1.000000
1.000 1.000 CFR 03
497 9B Balsam pear
0.500000
1.000 1.000 CFR 03
Full comment: CFR 03 group 9 cucurbit
72 O
Bananas0.020000
1.000 1.000 CFR 03
Full comment: CFR 03 imported tolearnce
73 O
Bananas-dried
0.020000
1.000 1.000 CFR 03
Full comment: CFR 03 imported tolearnce
378 O
Bananas-juice
0.020000
1.000 1.000 CFR 03
Full comment: CFR 03 imported tolearnce
265 15 Barley0.050000
1.000 1.000 CFR 03
258 6C Beans-dry-blackeye peas/cowpea
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
249 6C Beans-dry-broadbeans
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
259 6C Beans-dry-garbanzo/chick pea
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
227 6C Beans-dry-great northern
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
228 6C Beans-dry-kidney
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
229 6C Beans-dry-lima
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
230 6C Beans-dry-navy (pea)4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
231 6C Beans-dry-other4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
251 6C Beans-dry-pigeon beans
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
232 6C Beans-dry-pinto
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
250 6B Beans-succulent-broadbeans
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
234 6A Beans-succulent-green
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg

115

233
235
236
253
323
324
325
327
326
321
322
197
165
152
7
452
168
451
169
286
382
170
383
301
106
198
143
222
171
199
166
384
61
62
63
447
366
368
367
385

6B

Beans-succulent-lima
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
6A Beans-succulent-other4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
6A Beans-succulent-yellow/wax
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
6
Beans-unspecified
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
M
Beef-dried
0.300000
1.000
M
Beef-fat w/o bones
0.300000
1.000
M
Beef-kidney
0.300000
1.000
M
Beef-lean (fat/free) w/o bones
0.300000
1.000
M
Beef-liver
0.300000
1.000
M
Beef-meat byproducts
0.300000
1.000
M
Beef-other organ meats
0.300000
1.000
1AB Beets-garden-roots
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
2
Beets-garden-tops(greens)
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
9B Bitter melon
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
13B Blueberries
3.500000
1.000
Full comment: FR May 26 04
5B Bok choy
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
5A Broccoli
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
5A Broccoli-chinese
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
5A Brussels sprouts
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
15 Buckwheat
0.050000
1.000
Full comment: CFR 03 regional reg group 15
1AB Burdock
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
5A Cabbage-green and red
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
5B Cabbage-savoy
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
O
Canola oil (rape seed oil)
0.050000
1.000
O
Carambola (starfruit)
1.000000
1.000
1AB Carrots
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
9A Casabas
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
1CD Cassava (yuca blanca)
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
5A Cauliflower
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
1AB Celeriac
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
4B Celery
6.000000
1.000
Full comment: CFR 03 subgroup 4b petioles
4B Celery juice
6.000000
1.000
Full comment: CFR 03 subgroup 4b petioles
12 Cherries
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
12 Cherries-dried
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
12 Cherries-juice
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
4A Chervil
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greensP
Chicken-byproducts
0.050000
1.000
P
Chicken-fat w/o bones
0.050000
1.000
P
Chicken-giblets(liver)0.050000
1.000
0.050000
1.000
P
Chicken-giblets (excl. liver)

116

1.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

FR May1.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000

CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03

369
114
167
386
892
495
20
172
121
267
266
289
268
388
237
238
291
290
55
8
9
389
144
180
191
148
10
177
154
364
363
365
11
178
124
450
330
331
333
332
328
329
12
23
441

P
Chicken-lean/fat free w/o bones
0.050000
1.000
1AB Chicory
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
4A Chicory(french/belgian endive)3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
9B Christophine
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
O
Chrysanthemum
3.500000
1.000
O
Cilantro
3.500000
1.000
10 Citrus citron
0.070000
1.000
Full comment: CFR 03 Group 10
5B Collards
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
19B Coriander
3.500000
1.000
15 Corn grain-bran
0.050000
1.000
15 Corn grain-endosperm
0.050000
1.000
15 Corn grain-oil
0.050000
1.000
15 Corn grain/sugar/hfcs
0.050000
1.000
15 Corn grain/sugar-molasses
0.050000
1.000
15 Corn/pop
0.050000
1.000
15 Corn/sweet
0.050000
1.000
O
Cottonseed-meal
8.000000
1.000
O
Cottonseed-oil
6.000000
1.000
11 Crabapples
0.600000
1.000
Full comment: CFR 03 group 11
O
Cranberries
0.050000
1.000
Full comment: June 13 03
O
Cranberries-juice
0.050000
1.000
Full comment: June 13 03
O
Cranberries-juice-concentrate
0.050000
1.000
Full comment: June 13 03
9A Crenshaws
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
4A Cress-garden/field
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
4A Cress-upland
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
9B Cucumbers
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
13B Currants
3.500000
1.000
Full comment: CFR 03 Group 13B
4A Dandelion-greens
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens8
Eggplant
1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
P
Eggs-white only
0.020000
1.000
P
Eggs-whole
0.020000
1.000
P
Eggs-yolk only
0.020000
1.000
13B Elderberries
3.500000
1.000
Full comment: CFR 03 Group 13B
4A Endive-curley and escarole
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
1CD Ginger
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1AB Ginseng
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
M
Goat-fat w/o bone0.300000
1.000
M
Goat-kidney
0.300000
1.000
M
Goat-lean (fat/free) w/o bone0.300000
1.000
M
Goat-liver
0.300000
1.000
M
Goat-meat byproducts
0.300000
1.000
M
Goat-other organ meats
0.300000
1.000
13B Gooseberries
3.500000
1.000
Full comment: CFR 03 Group 13B
10 Grapefruit-juice
0.023000
1.000
Full comment: CFR 03 Group 10
0.023000
1.000
10 Grapefruit-juice-concentrate

117

1.000
1.000

CFR 03
CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000

CFR 02
CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03

1.000

June 11.000

June 11.000

June 11.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 03

448
22
13
15
392
195
14
315
164
287
393
79
125
334
126
16
18
174
175
24
28
442
27
26
243
182
176
192
32
443
31
30
108
81
96
95
80
141
142
145
146

Full comment: CFR 03 Group 10
Grapefruit peel
0.023000
1.000
Full comment: CFR 03 Group 10
10 Grapefruit-peeled fruit
0.023000
1.000
Full comment: CFR 03 Group 10
O
Grapes1.000000
1.000
O
Grapes-juice
1.500000
1.000
O
Grapes-juice-concentrate
1.500000
1.000
O
Grapes-leaves
1.500000
1.000
O
Grapes-raisins
1.500000
1.000
O
Grapes-wine and sherry
1.500000
1.000
8Groundcherries
1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
6C Guar beans
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
O
Guava-juice
1.000000
1.000
O
Guava
1.000000
1.000
O
Hops
6.000000
1.000
M
Horsemeat
0.300000
1.000
1AB Horseradish
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
13B Huckleberries
3.500000
1.000
Full comment: CFR 03 Group 13B
O
Juneberry
3.500000
1.000
5B Kale3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
5A Kohlrabi
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
10 Kumquats
0.023000
1.000
Full comment: CFR 03 Group 10
10 Lemons-juice
0.023000
1.000
Full comment: CFR 03 Group 10
10 Lemons-juice-concentrate
0.023000
1.000
Full comment: CFR 03 Group 10
10 Lemons-peel
0.023000
1.000
Full comment: CFR 03 Group 10
10 Lemons-peeled fruit
0.023000
1.000
Full comment: CFR 03 Group 10
6C Lentils
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
4A Lettuce-unspecified
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
4A Lettuce-leafy varieties
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
4A Lettuce-head varieties
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
10 Limes-juice
0.023000
1.000
Full comment: CFR 03 Group 10
10 Limes-juice-concentrate
0.023000
1.000
Full comment: CFR 03 Group 10
10 Limes-peel
0.023000
1.000
Full comment: CFR 03 Group 10
10 Limes-peeled fruit
0.023000
1.000
Full comment: CFR 03 Group 10
O
Longan fruit
3.000000
1.000
11 Loquats
0.600000
1.000
Full comment: CFR 03 group 11
O
Lychee-dried
3.000000
1.000
O
Lychees (litchi)/fresh
3.000000
1.000
O
Mangoes
1.000000
1.000
9A Melons-cantaloupes-juice
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
9A Melons-cantaloupes-pulp
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
9A Melons-honeydew
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
9A Melons-persian
0.500000
1.000
10

118

1.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 03

1.000
1.000

CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000

CFR 03
CFR 03

1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

398
319
318
320
280
244
183
130
64
399
269
245
397
36
33
35
34
85
86
84
139
184
225
220
401
92
65
66
402
56
57
404
240
241
405
47
156
157
155

Full comment: CFR 03 group 9 cucurbit
Milk-based water
0.100000
1.000
Milk-fat solids
0.100000
1.000
Milk-nonfat solids
0.100000
1.000
Milk sugar (lactose)
0.100000
1.000
Millet0.050000
1.000
Full comment: CFR 03 regional reg group 15
6C Mung beans (sprouts)
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
5B Mustard greens
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
19B Mustard seed
0.050000
1.000
Full comment: CFR 03
12 Nectarines
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
15 Oats-bran
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Oats
0.050000
1.000
Full comment: CFR 03 regional reg group 15
O
Okra
1.000000
1.000
9B Okra/chinese (luffa)
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
10 Oranges-juice
0.023000
1.000
Full comment: CFR 03 Group 10
10 Oranges-juice-concentrate
0.023000
1.000
Full comment: CFR 03 Group 10
10 Oranges-peel
0.023000
1.000
Full comment: CFR 03 Group 10
10 Oranges-peeled fruit
0.023000
1.000
Full comment: CFR 03 Group 10
O
Papayas-dried
1.000000
1.000
O
Papayas-juice
1.000000
1.000
O
Papayas-pulp
1.000000
1.000
8Paprika
1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
4A Parsley
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
1AB Parsley roots
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1AB Parsnips
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
O
Passion fruit-juice
1.000000
1.000
O
Passion fruit (granadilla)
1.000000
1.000
12 Peaches
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
12 Peaches-dried
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
12 Peaches-juice
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
11 Pears
0.600000
1.000
Full comment: CFR 03 group 11
11 Pears-dried
0.600000
1.000
Full comment: CFR 03 group 11
11 Pears-juice
0.600000
1.000
Full comment: CFR 03 group 11
6C Peas (garden)-dry
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
6AB Peas (garden)-green
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
6B Peas-succulent/blackeye/cowpea
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
14 Pecans
0.050000
1.000
8Peppers-chilli incl jalapeno
1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
8Peppers-other1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
8Peppers-sweet(garden)
1.000000
1.000

D
D
D
D
15

119

1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000

CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000

CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000

CFR 03
CFR 031.000

CFR 031.000

CFR 03

88
158
67
68
69
344
345
347
346
342
343
210
209
211
208
207
362
361
360
149
58
407
212
213
185
408
271
270
409
214
215
274
273
272
295
294
216
473
338

Full comment: CFR 03 Group 8 Fruiting Veg
Persimmons
3.000000
1.000
Pimientos
1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
12 Plums (damsons)3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
12 Plums-prunes (dried)
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
12 Plums/prune-juice
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
M
Pork-fat w/o bone0.300000
1.000
M
Pork-kidney
0.300000
1.000
M
Pork-lean (fat free) w/o bone0.300000
1.000
M
Pork-liver
0.300000
1.000
M
Pork-meat byproducts
0.300000
1.000
M
Pork-other organ meats
0.300000
1.000
1C Potatoes/white-dry
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1C Potatoes/white-peeled
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1C Potatoes/white-peel only
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1C Potatoes/white-unspecified
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1C Potatoes/white-whole
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
P
Poultry-other-fat w/o bones
0.050000
1.000
P
Poultry-other-giblets(liver)0.050000
1.000
P
Poultry-other-lean (fat free) w/
0.050000
1.000
9B Pumpkin
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
11 Quinces
0.600000
1.000
Full comment: CFR 03 group 11
1AB Radishes-japanese (daiken)
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1AB Radishes-roots
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
2
Radishes-tops
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
4B Rhubarb
6.000000
1.000
Full comment: CFR 03 subgroup 4b petioles
15 Rice-bran
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Rice-milled (white)
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Rice-rough (brown)
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Rice-wild
0.050000
1.000
Full comment: CFR 03 regional reg group 15
1AB Rutabagas-roots
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
2
Rutabagas-tops
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
15 Rye-flour
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Rye-germ
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Rye-rough0.050000
1.000
Full comment: CFR 03 regional reg group 15
O
Safflower-oil
0.500000
1.000
Full comment: CFR 03 regional reg
O
Safflower-seed
0.050000
1.000
Full comment: CFR 03 regional reg
1AB Salsify(oyster plant)
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
O
Sapodilla
1.000000
1.000
M
Sheep-fat w/o bone0.300000
1.000
O
8

120

1.000
1.000

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1.000
1.000
1.000
1.000
1.000
1.000

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CFR 03
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CFR 031.000

CFR 031.000

CFR 031.000

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1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
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CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

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1.000
1.000

CFR 03
CFR 03

339
341
340
336
337
413
275
303
307
306
305
304
297
482
255
186
150
415
151
17
416
282
379
218
418
187
37
38
39
420
201
190
163
423
160
162
161
159
355
357
356
358
449
137

M
M
M
M
M
6A

Sheep-kidney
0.300000
1.000
Sheep-lean (fat free) w/o bone0.300000
1.000
Sheep-liver
0.300000
1.000
Sheep-meat byproducts
0.300000
1.000
Sheep-other organ meats
0.300000
1.000
Snowpeas4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
15 Sorghum (including milo)
0.050000
1.000
Full comment: CFR 03
6A Soybean-other1.000000
1.000
Full comment: Emerg. expires 12 31 2006 group 6
6A Soybeans-flour (defatted)
0.500000
1.000
Full comment: Regional; no expir date group 6
6A Soybeans-flour (low fat)0.500000
1.000
Full comment: Regional; no expir date group 6
6A Soybeans-flour (full fat)0.500000
1.000
Full comment: Regional; no expir date group 6
6A Soybeans-mature seeds dry
1.000000
1.000
Full comment: Emerg. expires 12 31 2006 group 6
6A Soybeans-oil
1.000000
1.000
Full comment: Emerg. expires 12 31 2006 group 6
O
Soybeans-protein isolate
0.300000
1.000
6A Soybeans-sprouted seeds
1.000000
1.000
Full comment: Emerg. expires 12 31 2006 group 6
4A Spinach
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
9B Squash-summer
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
9B Squash-spaghetti
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
9B Squash-winter0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
O
Strawberries
0.050000
1.000
O
Strawberries-juice
0.050000
1.000
1A Sugar-beet
0.050000
1.000
1A Sugar-beet-molasses
0.300000
1.000
1CD Sweet potatoes (incl yams)
0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber
2
Sweet potatos-leaves
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
4B Swiss chard
6.000000
1.000
Full comment: CFR 03 subgroup 4b petioles
10 Tangelos
0.023000
1.000
Full comment: CFR 03 Group 10
10 Tangerines
0.023000
1.000
Full comment: CFR 03 Group 10
10 Tangerines-juice
0.023000
1.000
Full comment: CFR 03 Group 10
10 Tangerines-juice-concentrate
0.023000
1.000
Full comment: CFR 03 Group 10
1CD Taro-root
0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber
2
Taro-greens
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
8
Tomatoes-catsup
3.000000
1.000
8Tomatoes-dried
3.000000
1.000
8Tomatoes-juice
3.000000
1.000
8Tomatoes-paste
6.000000
1.000
8Tomatoes-puree
3.000000
1.000
8Tomatoes-whole
1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
P
Turkey-byproducts
0.050000
1.000
P
Turkey--fat w/o bones
0.050000
1.000
P
Turkey-giblets (liver)0.050000
1.000
P
Turkey- lean/fat free w/o bones
0.050000
1.000
P
Turkey-other organ meats
0.050000
1.000
1CD Turmeric0.400000
1.000

121

1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
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1.000

Emerg.

1.000

Region1.000

Region1.000

Region1.000

Emerg.

1.000

Emerg.

1.000
1.000

Emerg.

1.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
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CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03

1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03

219
188
429
424
426
425
427
430
428
189
147
436
278
279
277
437
276
439
221
224

Full comment: CFR 03 Group 1 root&tuber
1AB Turnips-roots
0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber
2
Turnips-tops
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
M
Veal-dried
0.300000
1.000
M
Veal-fat w/o bones
0.300000
1.000
M
Veal-kidney
0.300000
1.000
M
Veal-lean (fat free) w/o bones
0.300000
1.000
M
Veal-liver
0.300000
1.000
M
Veal-meat byproducts
0.300000
1.000
M
Veal-other organ meats
0.300000
1.000
O
Watercress
3.500000
1.000
9A Watermelon
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
9A Watermelon-juice
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
15 Wheat-bran
0.050000
1.000
Full comment: CFR 03
15 Wheat-flour
0.050000
1.000
Full comment: CFR 03
15 Wheat-germ
0.050000
1.000
Full comment: CFR 03
15 Wheat-germ oil
0.050000
1.000
Full comment: CFR 03
15 Wheat-rough0.050000
1.000
Full comment: CFR 03
9B Wintermelon
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
1CD Yambean tuber (jicama)
0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber
1CD Yautia (tannier)0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber

1.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

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CFR 031.000

CFR 031.000

CFR 03

CFR 03I.2. Tier 1 Dietary Exposure and Risk Estimates
California Department of Pesticide Regulation
Ver. 7.87
DEEM ACUTE Analysis for(1994-98 data)
Residue file: Tier 1 Residues+Adj F1.RS7
Adjustment factor #2 NOT used.
Analysis Date: 07-13-2004/17:36:25
Residue file dated: 07-13-2004/17:29:00/14
NOEL (Acute) =9.000000 mg/kg body-wt/day
Daily totals for food and foodform consumption used.
Run Comment: ""U.S. Population---------------

Daily Exposure Analysis /a(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.010629
0.010651
Standard Deviation
0.010908
0.010909
Standard Error of mean
0.000054
0.000054
Margin of Exposure 2/
846
844
Percent of aRfD
11.81
11.83

Percent of Person-Days that are User-Days = 99.80%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00

Exposure----------0.002068
0.003379
0.004676
0.006071
0.007658
0.009534% aRfD
MOE------- ---------2.30
4,352
3.75
2,663
5.20
1,924
6.75
1,482
8.51
1,175
10.59
944

Perc. Exposure----- ----------90.00
0.021808
95.00
0.029714
97.50
0.038805
99.00
0.053729
99.50
0.066137
99.75
0.080544

122% aRfD------24.23
33.02
43.12
59.70
73.49
89.49

MOE
--------412
302
231
167
136
111

70.0080.00

0.011958
0.015461

13.29
17.18

752
582

99.90

0.104662

116.2985

Western region--------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.011326
0.011362
Standard Deviation
0.011044
0.011043
Standard Error of mean
0.000112
0.000112
Margin of Exposure
794
792
Percent of aRfD
12.58
12.62

Percent of Person-Days that are User-Days = 99.68%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.002326
0.003772
0.005133
0.006736
0.008385
0.010323
0.013104
0.016486

Hispanics---------% aRfD
MOE------- ---------2.58
3,868
4.19
2,386
5.70
1,753
7.48
1,336
9.32
1,073
11.47
871
14.56
686
18.32
545

Perc. Exposure----- ----------90.00
0.023407
95.00
0.031188
97.50
0.039028
99.00
0.053863
99.50
0.065352
99.75
0.079283
99.90
0.101485% aRfD------26.01
34.65
43.36
59.85
72.61
88.09
112.76

MOE--------384
288
230
167
137
113
88

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.011430
0.011455
Standard Deviation
0.011711
0.011712
Standard Error of mean
0.000158
0.000159
Margin of Exposure
787
785
Percent of aRfD
12.70
12.73

Percent of Person-Days that are User-Days = 99.78%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.002170
0.003559
0.004939
0.006541
0.008043
0.010179
0.012876
0.016817

Non-hispanic whites-------------------

Mean% aRfD
MOE------- ---------2.41
4,147
3.95
2,528
5.49
1,822
7.27
1,375
8.94
1,118
11.31
884
14.31
698
18.69
535

Perc. Exposure----- ----------90.00
0.023848
95.00
0.032785
97.50
0.043537
99.00
0.057050
99.50
0.069085
99.75
0.083297
99.90
0.105874

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------0.010342
0.010363

123% aRfD------26.50
36.43
48.37
63.39
76.76
92.55
117.64

MOE--------377
274
206
157
130
108
85

Standard Deviation
Standard Error of mean
Margin of Exposure
Percent of aRfD

0.010378
0.000062870
11.49

0.010378
0.000062
868
11.51

Percent of Person-Days that are User-Days = 99.80%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.002139
0.003410
0.004666
0.006006
0.007573
0.009379
0.011659
0.015038% aRfD
MOE------- ---------2.38
4,207
3.79
2,639
5.18
1,928
6.67
1,498
8.41
1,188
10.42
959
12.95
771
16.71
598

Perc. Exposure----- ----------90.00
0.021020
95.00
0.028221
97.50
0.037301
99.00
0.051402
99.50
0.062909
99.75
0.076242
99.90
0.097250% aRfD------23.36
31.36
41.45
57.11
69.90
84.71
108.06

MOE--------428
318
241
175
143
118
92

Non-hispanic blacks-------------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.010732
0.010753
Standard Deviation
0.012593
0.012596
Standard Error of mean
0.0001720.000173
Margin of Exposure
838
836
Percent of aRfD
11.92
11.95

Percent of Person-Days that are User-Days = 99.81%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001378
0.002777
0.004083
0.005608
0.007291
0.009305
0.011716
0.015317% aRfD
MOE------- ---------1.53
6,531
3.09
3,240
4.54
2,204
6.23
1,604
8.10
1,234
10.34
967
13.02
768
17.02
587

Perc. Exposure----- ----------90.00
0.022569
95.00
0.032677
97.50
0.044290
99.00
0.061903
99.50
0.078354
99.75
0.101643
99.90
0.122781% aRfD------25.08
36.31
49.21
68.78
87.06
112.94136.42

MOE--------398
275
203
145
114
88
73

Non-hisp/non-white/non-black----------------------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.013132
0.013164
Standard Deviation
0.011790
0.011786
Standard Error of mean
0.0002650.000267
Margin of Exposure
685
683
Percent of aRfD
14.59
14.63

Percent of Person-Days that are User-Days = 99.76%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD

124

Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.002538
0.004466
0.006357
0.008140
0.009984
0.012624
0.015336
0.019914

All infants-----------% aRfD
MOE------- ---------2.82
3,546
4.96
2,015
7.06
1,415
9.04
1,105
11.09
901
14.03
712
17.04
586
22.13
451

Perc. Exposure----- ----------90.00
0.027670
95.00
0.035015
97.50
0.041831
99.00
0.055349
99.50
0.065040
99.75
0.076904
99.90
0.092380% aRfD------30.74
38.91
46.48
61.50
72.27
85.45
102.65

MOE--------325
257
215
162
138
117
97

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.017456
0.019336
Standard Deviation
0.021325
0.021619
Standard Error of mean
0.000391
0.000416
Margin of Exposure
515
465
Percent of aRfD
19.40
21.48

Percent of Person-Days that are User-Days = 90.28%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.002843
0.004094
0.005468
0.007421
0.010464
0.015101
0.021510
0.033016% aRfD
MOE------- ---------3.16
3,165
4.55
2,198
6.08
1,645
8.25
1,212
11.63
860
16.78
595
23.90
418
36.68
272

Perc. Exposure----- ----------90.00
0.050081
95.00
0.064531
97.50
0.076496
99.00
0.097824
99.50
0.115349
99.75
0.126785
99.90
0.147432% aRfD------55.65
71.70
85.00
108.69128.17140.87163.81

MOE--------179
139
117
92
78
70
61

Nursing infants (<1 yr old)---------------------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.009598
0.014829
Standard Deviation
0.017008
0.019219
Standard Error of mean
0.000586
0.000806
Margin of Exposure
937
606
Percent of aRfD
10.66
16.48

Percent of Person-Days that are User-Days = 64.72%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.000511
0.001369
0.002487
0.003920
0.006291
0.010057
0.017293
0.026714% aRfD
MOE------- ---------0.57
17,595
1.52
6,573
2.76
3,618
4.36
2,295
6.99
1,430
11.17
894
19.21
520
29.68
336

Perc. Exposure----- ----------90.00
0.046113
95.00
0.059802
97.50
0.068860
99.00
0.079920
99.50
0.086785
99.75
0.105368
99.90
0.106167

125% aRfD------51.24
66.45
76.51
88.80
96.43
117.08117.96

MOE--------195
150
130
112
103
85
84

Non-nursing infants (<1 yr old)-------------------------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.020439
0.020444
Standard Deviation
0.022027
0.022028
Standard Error of mean
0.000477
0.000477
Margin of Exposure
440
440Percent of aRfD
22.71
22.72

Percent of Person-Days that are User-Days = 99.98%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.003661
0.004664
0.006063
0.008128
0.011274
0.016105
0.023187
0.034616% aRfD
MOE------- ---------4.07
2,458
5.18
1,929
6.74
1,484
9.03
1,107
12.53
798
17.89
558
25.76
388
38.46
259

Perc. Exposure----- ----------90.00
0.051025
95.00
0.065398
97.50
0.077934
99.00
0.101259
99.50
0.119198
99.75
0.131385
99.90
0.146978% aRfD------56.69
72.66
86.59
112.51132.44145.98163.31

MOE--------176
137
115
88
75
68
61

Children 1-2 yrs----------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.030238
0.030238
Standard Deviation
0.023322
0.023322
Standard Error of mean
0.000360
0.000360
Margin of Exposure
297
297
Percent of aRfD
33.60
33.60

Percent of Person-Days that are User-Days =100.00%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.008407
0.012451
0.015867
0.020049
0.024602
0.029596
0.035429
0.043801% aRfD
MOE------- ---------9.34
1,070
13.83
722
17.63
567
22.28
448
27.34
365
32.88
304
39.37
254
48.67
205

Perc. Exposure----- ----------90.00
0.059278
95.00
0.073497
97.50
0.089668
99.00
0.114523
99.50
0.132060
99.75
0.157755
99.90
0.188044

Children 3-5 yrs----------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.022993
0.022993
Standard Deviation
0.017690
0.017690
Standard Error of mean
0.000189
0.000189
Margin of Exposure
391
391
Percent of aRfD
25.55
25.55

126

% aRfD------65.86
81.66
99.63
127.25146.73175.28208.94

MOE--------151
122
100
78
68
57
47

Percent of Person-Days that are User-Days =100.00%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.006604
0.009457
0.012156
0.015056
0.018212
0.021891
0.026988
0.033762% aRfD
MOE------- ---------7.34
1,362
10.51
951
13.51
740
16.73
597
20.24
494
24.32
411
29.99
333
37.51
266

Perc. Exposure----- ----------90.00
0.045356
95.00
0.056589
97.50
0.068237
99.00
0.086841
99.50
0.105207
99.75
0.117325
99.90
0.136787% aRfD------50.40
62.88
75.82
96.49
116.90130.36151.99MOE--------198
159
131
103
85
76
65

Children 6-12 yrs-----------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.0141390.014139
Standard Deviation
0.011976
0.011976
Standard Error of mean
0.000185
0.000185
Margin of Exposure
636
636
Percent of aRfD
15.71
15.71

Percent of Person-Days that are User-Days =100.00%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.003976
0.005622
0.007153
0.008697
0.010704
0.013334
0.016436
0.020491% aRfD
MOE------- ---------4.42
2,263
6.25
1,600
7.95
1,258
9.66
1,034
11.89
840
14.82
674
18.26
547
22.77
439

Perc. Exposure----- ----------90.00
0.027768
95.00
0.036092
97.50
0.045453
99.00
0.056592
99.50
0.066304
99.75
0.079778
99.90
0.113609% aRfD------30.85
40.10
50.50
62.88
73.67
88.64
126.23

MOE--------324
249
198
159
135
112
79

Youth 13-19 yrs---------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.008614
0.008622
Standard Deviation
0.007877
0.007876
Standard Error of mean
0.000159
0.000159
Margin of Exposure
1,044
1,043
Percent of aRfD
9.57
9.58

Percent of Person-Days that are User-Days = 99.90%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00

Exposure----------0.001954
0.003086
0.004125
0.005283% aRfD
MOE------- ---------2.17
4,605
3.43
2,916
4.58
2,181
5.87
1,703

Perc. Exposure----- ----------90.00
0.017415
95.00
0.022813
97.50
0.029013
99.00
0.035386

127% aRfD------19.35
25.35
32.24
39.32

MOE
--------516
394
310
254

50.00
60.00
70.00
80.00

0.006553
0.008051
0.010035
0.012564

7.28
8.95
11.15
13.96

1,373
1,117
896
716

99.50
99.75
99.90

0.039301
0.045595
0.062646

43.67
50.66
69.61

229
197
143

Adults 20-49 yrs----------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.008479
0.008487
Standard Deviation
0.007056
0.007055
Standard Error of mean
0.000073
0.000073
Margin of Exposure
1,061
1,060
Percent of aRfD
9.42
9.43

Percent of Person-Days that are User-Days = 99.90%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001836
0.002870
0.003967
0.005197
0.006678
0.008268
0.010311
0.013106% aRfD
MOE------- ---------2.04
4,900
3.19
3,135
4.41
2,268
5.77
1,731
7.42
1,347
9.19
1,088
11.46
872
14.56
686

Perc. Exposure----- ----------90.00
0.017494
95.00
0.021992
97.50
0.026701
99.00
0.032499
99.50
0.038319
99.75
0.043799
99.90
0.048849% aRfD------19.44
24.44
29.67
36.11
42.58
48.67
54.28

MOE
--------514
409
337
276
234
205
184

Adults 50+ yrs--------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.008690
0.008693
Standard Deviation
0.006997
0.006997
Standard Error of mean
0.000073
0.000073
Margin of Exposure
1,035
1,035
Percent of aRfD
9.66
9.66

Percent of Person-Days that are User-Days = 99.97%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001830
0.003124
0.004389
0.005644
0.006984
0.008555
0.010454
0.013178

Females 13-49 yrs-----------------% aRfD
MOE------- ---------2.03
4,916
3.47
2,881
4.88
2,050
6.27
1,594
7.76
1,288
9.51
1,052
11.62
860
14.64
682

Perc. Exposure----- ----------90.00
0.017578
95.00
0.021635
97.50
0.026676
99.00
0.033520
99.50
0.038836
99.75
0.043520
99.90
0.053404

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- -----------

128% aRfD------19.53
24.04
29.64
37.24
43.15
48.36
59.34

MOE
--------512
415
337
268
231
206
168

Mean
Standard Deviation
Standard Error of mean
Margin of Exposure
Percent of aRfD

0.008284
0.007107
0.000093
1,086
9.20

0.008295
0.0071050.000093
1,085
9.22

Percent of Person-Days that are User-Days = 99.87%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001696
0.002748
0.003848
0.005033
0.006472
0.0081070.010073
0.012785% aRfD
MOE------- ---------1.88
5,305
3.05
3,274
4.28
2,338
5.59
1,788
7.19
1,390
9.01
1,110
11.19
893
14.21
703

Perc. Exposure----- ----------90.00
0.017135
95.00
0.021566
97.50
0.026140
99.00
0.032025
99.50
0.037233
99.75
0.042561
99.90
0.049975

129% aRfD------19.04
23.96
29.04
35.58
41.37
47.29
55.53

MOE
--------525
417
344
281
241
211
180

I.3. Tier 2 Residue Data Files
Filename: H:\svetlana\Imidacloprid\DEEM\ImI Tier 2a\Tier 2_a_Residues.RS7
Chemical:
RfD(Chronic): 0 mg/kg bw/day NOEL(Chronic): 0 mg/kg bw/day
RfD(Acute): 0 mg/kg bw/day NOEL(Acute): 0 mg/kg bw/day
Date created/last modified: 09-09-2004/10:25:51/14
Program ver. 7.87-------------------------------------------------------------------------------Food Crop
Def Res
Adj.Factors
Comment
Code Grp Food Name
(ppm)
#1
#2
---- ---- ------------------------------- ---------- ------ ------ ------98 O
Acerola1.000000
1.000 1.000 CFR 03
40 14 Almonds
0.050000
1.000 1.000 CFR 03
Full comment: CFR 03; Nov26 03 Sec 18 CA exp June 22 04
498 4A Amaranth3.500000
1.000 1.000 CFR 03
Full comment: CFR 03 subgroup 4a leafy greens
52 11 Apples
0.500000
1.000 1.000 CFR 03
53 11 Apples-dried
0.500000
1.000 1.000 CFR 03
54 11 Apples-juice/cider
0.500000
1.000 1.000 CFR 03
377 11 Apples-juice-concentrate
0.500000
1.000 1.000 CFR 03
410 12 Apricot juice
3.000000
1.000 1.000 CFR 03
Full comment: CFR 03 Group 12 stone fruit
59 12 Apricots
3.000000
1.000 1.000 CFR 03
Full comment: CFR 03 Group 12 stone fruit
60 12 Apricots-dried
3.000000
1.000 1.000 CFR 03
Full comment: CFR 03 Group 12 stone fruit
181 O
Artichokes-globe
2.500000
1.000 1.000 CFR 03
203 1CD Artichokes-jerusalem
0.400000
1.000 1.000 CFR 03
Full comment: CFR 03 Group 1 root & tuber
70 O
Avocados
1.000000
1.000 1.000 CFR 03
497 9B Balsam pear
0.500000
1.000 1.000 CFR 03
Full comment: CFR 03 group 9 cucurbit
72 O
Bananas0.020000
1.000 1.000 CFR 03
Full comment: CFR 03 imported tolearnce
73 O
Bananas-dried
0.020000
1.000 1.000 CFR 03
Full comment: CFR 03 imported tolearnce
378 O
Bananas-juice
0.020000
1.000 1.000 CFR 03
Full comment: CFR 03 imported tolearnce
265 15 Barley0.050000
1.000 1.000 CFR 03
258 6C Beans-dry-blackeye peas/cowpea
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
249 6C Beans-dry-broadbeans
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
259 6C Beans-dry-garbanzo/chick pea
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
227 6C Beans-dry-great northern
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
228 6C Beans-dry-kidney
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
229 6C Beans-dry-lima
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
230 6C Beans-dry-navy (pea)4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
231 6C Beans-dry-other4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
251 6C Beans-dry-pigeon beans
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
232 6C Beans-dry-pinto
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
250 6B Beans-succulent-broadbeans
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
234 6A Beans-succulent-green
4.000000
1.000 1.000 CFR 03
Full comment: CFR 03 group 6 Leg Veg
4.000000
1.000 1.000 CFR 03
233 6B Beans-succulent-lima
Full comment: CFR 03 group 6 Leg Veg

130

235

447

Beans-succulent-other4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
6A Beans-succulent-yellow/wax
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
6
Beans-unspecified
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
M
Beef-dried
0.300000
1.000
M
Beef-fat w/o bones
0.300000
1.000
M
Beef-kidney
0.300000
1.000
M
Beef-lean (fat/free) w/o bones
0.300000
1.000
M
Beef-liver
0.300000
1.000
M
Beef-meat byproducts
0.300000
1.000
M
Beef-other organ meats
0.300000
1.000
1AB Beets-garden-roots
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
2
Beets-garden-tops(greens)
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
9B Bitter melon
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
13B Blueberries
3.500000
1.000
Full comment: FR May 26 04
5B Bok choy
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
5A Broccoli
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
5A Broccoli-chinese
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
5A Brussels sprouts
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
15 Buckwheat
0.050000
1.000
Full comment: CFR 03 regional reg group 15
1AB Burdock
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
5A Cabbage-green and red
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
5B Cabbage-savoy
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
O
Canola oil (rape seed oil)
0.050000
1.000
O
Carambola (starfruit)
1.000000
1.000
1AB Carrots
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
9A Casabas
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
1CD Cassava (yuca blanca)
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
5A Cauliflower
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
1AB Celeriac
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
4B Celery
6.000000
1.000
Full comment: CFR 03 subgroup 4b petioles
4B Celery juice
6.000000
1.000
Full comment: CFR 03 subgroup 4b petioles
12 Cherries
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
12 Cherries-dried
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
12 Cherries-juice
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
4A Chervil
3.500000
1.000

366
368
367
385
369

P
P
P
P
P

236
253
323
324
325
327
326
321
322
197
165
152
7
452
168
451
169
286
382
170
383
301
106
198
143
222
171
199
166
384
61
62
63

6A

Full comment: CFR 03 subgroup 4a leafy greens
Chicken-byproducts
0.050000
1.000
Chicken-fat w/o bones
0.050000
1.000
Chicken-giblets(liver)0.050000
1.000
Chicken-giblets (excl. liver)0.050000
1.000
Chicken-lean/fat free w/o bones
0.050000
1.000

131

1.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

FR May1.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000

CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03

114
167
386
495
20
172
121
267
266
289
268
388
237
238
291
290
55
8
9
389
144
180
191
148
10
177
154
364
363
365
11
178
124
450
330
331
333
332
328
329
12
23
441
448

1AB Chicory
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
4A Chicory(french/belgian endive)3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
9B Christophine
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
O
Cilantro
3.500000
1.000
10 Citrus citron
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
5B Collards
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
19B Coriander
3.500000
1.000
15 Corn grain-bran
0.050000
1.000
15 Corn grain-endosperm
0.050000
1.000
15 Corn grain-oil
0.050000
1.000
15 Corn grain/sugar/hfcs
0.050000
1.000
15 Corn grain/sugar-molasses
0.050000
1.000
15 Corn/pop
0.050000
1.000
15 Corn/sweet
0.050000
1.000
O
Cottonseed-meal
8.000000
1.000
O
Cottonseed-oil
6.000000
1.000
11 Crabapples
0.600000
1.000
Full comment: CFR 03 group 11
O
Cranberries
0.050000
1.000
Full comment: June 13 03
O
Cranberries-juice
0.050000
1.000
Full comment: June 13 03
O
Cranberries-juice-concentrate
0.050000
1.000
Full comment: June 13 03
9A Crenshaws
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
4A Cress-garden/field
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
4A Cress-upland
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
9B Cucumbers
0.400000
1.000
Full comment: DPR 02; 15 samples ND LOD 0.4
13B Currants
3.500000
1.000
Full comment: CFR 03 Group 13B
4A Dandelion-greens
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens8
Eggplant
1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
P
Eggs-white only
0.020000
1.000
P
Eggs-whole
0.020000
1.000
P
Eggs-yolk only
0.020000
1.000
13B Elderberries
3.500000
1.000
Full comment: CFR 03 Group 13B
4A Endive-curley and escarole
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
1CD Ginger
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1AB Ginseng
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
M
Goat-fat w/o bone0.300000
1.000
M
Goat-kidney
0.300000
1.000
M
Goat-lean (fat/free) w/o bone0.300000
1.000
M
Goat-liver
0.300000
1.000
M
Goat-meat byproducts
0.300000
1.000
M
Goat-other organ meats
0.300000
1.000
13B Gooseberries
3.500000
1.000
Full comment: CFR 03 Group 13B
10 Grapefruit-juice
0.120000
2.100
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Grapefruit-juice-concentrate
0.120000
8.260
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Grapefruit peel0.120000
1.000

132

1.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000

CFR 02
PDP 001.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03

1.000

June 11.000

June 11.000

June 11.000

CFR 031.000

CFR 031.000

CFR 031.000

DPR 021.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

PDP 00

1.000

PDP 00

1.000

PDP 00

22
13
15
392
195
14
315
164
287
393
79
125
334
126
16
18
174
175
24
28
442
27
26
243
182
176
192
32
443
31
30
108
81
96
95
80
141
142

Full comment: PDP 00-01 oranges 13 det; LOD 0.01
Grapefruit-peeled fruit
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
O
Grapes0.400000
1.200
Full comment: DPR 02 #34 ND LOD=0.4
O
Grapes-juice
0.400000
1.000
Full comment: DPR 02 #34 ND LOD=0.4
O
Grapes-juice-concentrate
0.400000
3.600
Full comment: DPR 02 #34 ND LOD=0.4
O
Grapes-leaves
0.400000
1.000
Full comment: DPR 02 #34 ND LOD=0.4
O
Grapes-raisins
0.400000
4.300
Full comment: DPR 02 #34 ND LOD=0.4
O
Grapes-wine and sherry
0.400000
1.000
Full comment: DPR 02 #34 ND LOD=0.4
8Groundcherries
1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
6C Guar beans
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
O
Guava-juice
1.000000
1.000
O
Guava
1.000000
1.000
O
Hops
6.000000
1.000
M
Horsemeat
0.300000
1.000
1AB Horseradish
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
13B Huckleberries
3.500000
1.000
Full comment: CFR 03 Group 13B
O
Juneberry
3.500000
1.000
5B Kale3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
5A Kohlrabi
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
10 Kumquats
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Lemons-juice
0.120000
2.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Lemons-juice-concentrate
0.120000 11.400
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Lemons-peel
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Lemons-peeled fruit
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
6C Lentils
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
4A Lettuce-unspecified
0.400000
1.000
Full comment: DPR 02 #14 ND LOD 0.4
4A Lettuce-leafy varieties
0.400000
1.000
Full comment: DPR 02 #14 ND LOD 0.4
4A Lettuce-head varieties
0.400000
1.000
Full comment: DPR 02 #14 ND LOD 0.4
10 Limes-juice
0.120000
2.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Limes-juice-concentrate
0.120000
6.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Limes-peel
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Limes-peeled fruit
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
O
Longan fruit
3.000000
1.000
11 Loquats
0.600000
1.000
Full comment: CFR 03 group 11
O
Lychee-dried
3.000000
1.000
O
Lychees (litchi)/fresh
3.000000
1.000
O
Mangoes
1.000000
1.000
0.400000
1.000
9A Melons-cantaloupes-juice
Full comment: DPR 02; 18 samples ND LOD 0.4
9A Melons-cantaloupes-pulp
0.400000
1.000
10

133

1.000

PDP 00

1.000

DPR 021.000

DPR 021.000

DPR 021.000

DPR 021.000

DPR 021.000

DPR 021.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 03

1.000
1.000

CFR 03
CFR 031.000

CFR 031.000

PDP 00

1.000

PDP 00

1.000

PDP 00

1.000

PDP 00

1.000

PDP 001.000

CFR 031.000

DPR 021.000

DPR 021.000

DPR 021.000

PDP 00

1.000

PDP 00

1.000

PDP 00

1.000

PDP 00

1.000
1.000

CFR 03
CFR 03

1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
DPR 021.000

DPR 02

145
146
398
319
318
320
280
244
183
130
64
399
269
245
397
36
33
35
34
85
86
84
139
184
225
220
401
92
65
66
402
56
57
404
240
241
405
47
156

Full comment: DPR 02; 18 samples ND LOD 0.4
Melons-honeydew
0.400000
1.000
Full comment: DPR 02; 18 samples ND LOD 0.4
9A Melons-persian
0.400000
1.000
Full comment: DPR 02; 18 samples ND LOD 0.4
D
Milk-based water
0.100000
1.000
D
Milk-fat solids
0.100000
1.000
D
Milk-nonfat solids
0.100000
1.000
D
Milk sugar (lactose)
0.100000
1.000
15 Millet
0.050000
1.000
Full comment: CFR 03 regional reg group 15
6C Mung beans (sprouts)
4.000000
1.000
Full comment: CFR 03 group 6 Leg Veg
5B Mustard greens
3.500000
1.000
Full comment: CFR 03 Group 5 Brassica
19B Mustard seed
0.050000
1.000
Full comment: CFR 03
12 Nectarines
0.010000
1.000
Full comment: PDP 00-01 #508 ND LOD 0.01
15 Oats-bran
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Oats
0.008000
1.000
Full comment: PDP 99 #332 ND LOD 0.008
O
Okra
1.000000
1.000
9B Okra/chinese (luffa)
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
10 Oranges-juice
0.120000
1.800
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Oranges-juice-concentrate
0.120000
6.700
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Oranges-peel
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Oranges-peeled fruit
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
O
Papayas-dried
1.000000
1.000
O
Papayas-juice
1.000000
1.000
O
Papayas-pulp
1.000000
1.000
8Paprika
1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
4A Parsley
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
1AB Parsley roots
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1AB Parsnips
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
O
Passion fruit-juice
1.000000
1.000
O
Passion fruit (granadilla)
1.000000
1.000
12 Peaches
0.010000
1.000
Full comment: PDP 00-01 #508 ND LOD 0.01
12 Peaches-dried
0.010000
7.000
Full comment: CFR 03 Group 12 stone fruit
12 Peaches-juice
0.010000
1.000
Full comment: CFR 03 Group 12 stone fruit
11 Pears
0.600000
1.000
Full comment: CFR 03 group 11
11 Pears-dried
0.600000
1.000
Full comment: CFR 03 group 11
11 Pears-juice
0.600000
1.000
Full comment: CFR 03 group 11
6C Peas (garden)-dry
0.010000
1.000
Full comment: PDP 01-02 #630 ND LOD 0.01
6AB Peas (garden)-green
0.010000
1.000
Full comment: PDP 01-02 #630 ND LOD 0.01
6B Peas-succulent/blackeye/cowpea
0.010000
1.000
Full comment: PDP 01-02 #630 ND LOD 0.01
14 Pecans
0.050000
1.000
8Peppers-chilli incl jalapeno
0.400000
1.000
9A

134

1.000

DPR 021.000

DPR 02

1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

PDP 001.000

CFR 031.000

PDP 99

1.000
1.000

CFR 03
CFR 031.000

PDP 00

1.000

PDP 00

1.000

PDP 00

1.000

PDP 00

1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000

CFR 03
CFR 03
PDP 001.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

PDP 011.000

PDP 011.000

PDP 01

1.000
1.000

CFR 03
PDP 02

157
155
88
158
67
68
69
344
345
347
346
342
343
210
209
211
208
207
362
361
360
149
58
407
212
213
185
408
271
270
409
214
215
274
273
272
295
294

Full comment: PDP 02 #24 ND LOD 0.4
Peppers-other
0.400000
1.000
Full comment: PDP 02 #13 ND LOD 0.4
8Peppers-sweet(garden)
0.400000
1.000
Full comment: PDP 02 #13 ND LOD 0.4
O
Persimmons
3.000000
1.000
8
Pimientos
0.400000
1.000
Full comment: PDP 02 #13 ND LOD 0.4
12 Plums (damsons)3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
12 Plums-prunes (dried)
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
12 Plums/prune-juice
3.000000
1.000
Full comment: CFR 03 Group 12 stone fruit
M
Pork-fat w/o bone0.300000
1.000
M
Pork-kidney
0.300000
1.000
M
Pork-lean (fat free) w/o bone0.300000
1.000
M
Pork-liver
0.300000
1.000
M
Pork-meat byproducts
0.300000
1.000
M
Pork-other organ meats
0.300000
1.000
1C Potatoes/white-dry
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1C Potatoes/white-peeled
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1C Potatoes/white-peel only
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1C Potatoes/white-unspecified
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1C Potatoes/white-whole
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
P
Poultry-other-fat w/o bones
0.050000
1.000
P
Poultry-other-giblets(liver)0.050000
1.000
P
Poultry-other-lean (fat free) w/
0.050000
1.000
9B Pumpkin
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
11 Quinces
0.600000
1.000
Full comment: CFR 03 group 11
1AB Radishes-japanese (daiken)
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
1AB Radishes-roots
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
2
Radishes-tops
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
4B Rhubarb
6.000000
1.000
Full comment: CFR 03 subgroup 4b petioles
15 Rice-bran
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Rice-milled (white)
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Rice-rough (brown)
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Rice-wild
0.050000
1.000
Full comment: CFR 03 regional reg group 15
1AB Rutabagas-roots
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
2
Rutabagas-tops
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
15 Rye-flour
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Rye-germ
0.050000
1.000
Full comment: CFR 03 regional reg group 15
15 Rye-rough0.050000
1.000
Full comment: CFR 03 regional reg group 15
O
Safflower-oil
0.500000
1.000
Full comment: CFR 03 regional reg
O
Safflower-seed
0.050000
1.000
Full comment: CFR 03 regional reg
8

135

1.000

PDP 021.000

PDP 02

1.000
1.000

CFR 03
PDP 021.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

216
473
338
339
341
340
336
337
413
275
303
307
306
305
304
297
482
255
186
150
415
151
17
416
282
379
218
418
187
37
38
39
420
201
190
163
423
160
162
161

1AB Salsify(oyster plant)
0.400000
1.000
Full comment: CFR 03 Group 1 root & tuber
O
Sapodilla
1.000000
1.000
M
Sheep-fat w/o bone0.300000
1.000
M
Sheep-kidney
0.300000
1.000
M
Sheep-lean (fat free) w/o bone0.300000
1.000
M
Sheep-liver
0.300000
1.000
M
Sheep-meat byproducts
0.300000
1.000
M
Sheep-other organ meats
0.300000
1.000
6A Snowpeas
0.010000
1.000
Full comment: PDP 01-02 #630 ND LOD 0.01
15 Sorghum (including milo)
0.050000
1.000
Full comment: CFR 03
6A Soybean-other1.000000
1.000
Full comment: Emerg. expires 12 31 2006 group 6
6A Soybeans-flour (defatted)
0.500000
1.000
Full comment: Regional; no expir date group 6
6A Soybeans-flour (low fat)0.500000
1.000
Full comment: Regional; no expir date group 6
6A Soybeans-flour (full fat)0.500000
1.000
Full comment: Regional; no expir date group 6
6A Soybeans-mature seeds dry
1.000000
1.000
Full comment: Emerg. expires 12 31 2006 group 6
6A Soybeans-oil
1.000000
1.000
Full comment: Emerg. expires 12 31 2006 group 6
O
Soybeans-protein isolate
0.300000
1.000
6A Soybeans-sprouted seeds
1.000000
1.000
Full comment: Emerg. expires 12 31 2006 group 6
4A Spinach
3.500000
1.000
Full comment: CFR 03 subgroup 4a leafy greens
9B Squash-summer
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
9B Squash-spaghetti
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
9B Squash-winter0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
O
Strawberries
0.400000
1.000
Full comment: DPR 02 samples 14 ND LOD=0.4
O
Strawberries-juice
0.400000
1.000
Full comment: DPR 02 samples 14 ND LOD=0.4
1A Sugar-beet
0.400000
1.000
1A Sugar-beet-molasses
0.300000
1.000
1CD Sweet potatoes (incl yams)
0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber
2
Sweet potatos-leaves
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
4B Swiss chard
6.000000
1.000
Full comment: CFR 03 subgroup 4b petioles
10 Tangelos
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Tangerines
0.120000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Tangerines-juice
0.120000
2.300
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
10 Tangerines-juice-concentrate
0.120000
7.350
Full comment: PDP 00-01 oranges 13 det; LOD 0.01
1CD Taro-root
0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber
2
Taro-greens
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
8
Tomatoes-catsup
0.025000
2.500
Full comment: PDP 01 #369 paste ND LOD 0.025
8Tomatoes-dried
3.000000
1.000
8Tomatoes-juice
3.000000
1.000
8Tomatoes-paste
0.025000
5.400
Full comment: PDP 01 #369 paste ND LOD 0.025
8Tomatoes-puree
0.025000
3.300

136

1.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
PDP 011.000

CFR 03

1.000

Emerg.

1.000

Region1.000

Region1.000

Region1.000

Emerg.

1.000

Emerg.

1.000
1.000

Emerg.

1.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

DPR 021.000

DPR 02

1.000
1.000
1.000

CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

PDP 00

1.000

PDP 00

1.000

PDP 00

1.000

PDP 001.000

CFR 031.000

CFR 031.000

PDP 01

1.000
1.000
1.000

CFR 03
CFR 03
PDP 011.000

PDP 01

159
355
357
356
358
449
137
219
188
429
424
426
425
427
430
428
189
147
436
278
279
277
437
276
439
221
224

Full comment: PDP 01 #369 paste ND LOD 0.025
Tomatoes-whole
1.000000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg
P
Turkey-byproducts
0.050000
1.000
P
Turkey--fat w/o bones
0.050000
1.000
P
Turkey-giblets (liver)0.050000
1.000
P
Turkey- lean/fat free w/o bones
0.050000
1.000
P
Turkey-other organ meats
0.050000
1.000
1CD Turmeric0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber
1AB Turnips-roots
0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber
2
Turnips-tops
4.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber
M
Veal-dried
0.300000
1.000
M
Veal-fat w/o bones
0.300000
1.000
M
Veal-kidney
0.300000
1.000
M
Veal-lean (fat free) w/o bones
0.300000
1.000
M
Veal-liver
0.300000
1.000
M
Veal-meat byproducts
0.300000
1.000
M
Veal-other organ meats
0.300000
1.000
O
Watercress
3.500000
1.000
9A Watermelon
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
9A Watermelon-juice
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
15 Wheat-bran
0.050000
1.000
Full comment: CFR 03
15 Wheat-flour
0.050000
1.000
Full comment: CFR 03
15 Wheat-germ
0.050000
1.000
Full comment: CFR 03
15 Wheat-germ oil
0.050000
1.000
Full comment: CFR 03
15 Wheat-rough0.050000
1.000
Full comment: CFR 03
9B Wintermelon
0.500000
1.000
Full comment: CFR 03 group 9 cucurbit
1CD Yambean tuber (jicama)
0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber
1CD Yautia (tannier)0.400000
1.000
Full comment: CFR 03 Group 1 root&tuber

8

137

1.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 03

1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000
1.000

CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 03
CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

CFR 03

I.4. Tier 2 Dietary Exposure and Risk Estimates
California Department of Pesticide Regulation
Ver. 7.87
DEEM ACUTE Analysis for(1994-98 data)
Residue file: Tier 2_a_Residues.RS7
Adjustment factor #2 NOT used.
Analysis Date: 09-09-2004/11:08:38
Residue file dated: 09-09-2004/10:25:51/14
NOEL (Acute) =9.000000 mg/kg body-wt/day
Daily totals for food and foodform consumption used.
Run Comment: "Tier 2 Acute - most foods at tolerance (no Adj F 1); a few foods
with PDP and DPR +Adj F1"=========================================================================
U.S. Population---------------

Daily Exposure Analysis /a(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.007417
0.007432
Standard Deviation
0.007623
0.007623
Standard Error of mean
0.000038
0.000038
Margin of Exposure 2/
1,213
1,210
Percent of aRfD
8.24
8.26

Percent of Person-Days that are User-Days = 99.80%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001668
0.002482
0.003274
0.004147
0.005161
0.006459
0.008218
0.010694% aRfD
MOE------- ---------1.85
5,395
2.76
3,626
3.64
2,748
4.61
2,170
5.73
1,743
7.18
1,393
9.13
1,095
11.88
841

Perc. Exposure----- ----------90.00
0.015538
95.00
0.020939
97.50
0.027635
99.00
0.037856
99.50
0.046543
99.75
0.054845
99.90
0.066918% aRfD------17.26
23.27
30.71
42.06
51.71
60.94
74.35

MOE
--------579
429
325
237
193
164
134

Western region--------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.007949
0.007975
Standard Deviation
0.007900
0.007900
Standard Error of mean
0.000080
0.000080
Margin of Exposure
1,132
1,128
Percent of aRfD
8.83
8.86

Percent of Person-Days that are User-Days = 99.68%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001838
0.002730
0.003622
0.004538
0.005615
0.006998
0.008895
0.011582% aRfD
MOE------- ---------2.04
4,895
3.03
3,297
4.02
2,484
5.04
1,983
6.24
1,602
7.78
1,286
9.88
1,011
12.87
777

Perc. Exposure----- ----------90.00
0.016476
95.00
0.022523
97.50
0.029101
99.00
0.039036
99.50
0.047027
99.75
0.056888
99.90
0.065982

138% aRfD------18.31
25.03
32.33
43.37
52.25
63.21
73.31

MOE
--------546
399
309
230
191
158
136

Hispanics---------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.008401
0.008420
Standard Deviation
0.008538
0.008539
Standard Error of mean
0.000115
0.000116
Margin of Exposure
1,071
1,068
Percent of aRfD
9.33
9.36

Percent of Person-Days that are User-Days = 99.78%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001870
0.002815
0.003776
0.004764
0.005837
0.007306
0.009319
0.011981% aRfD
MOE------- ---------2.08
4,811
3.13
3,197
4.20
2,383
5.29
1,889
6.49
1,541
8.12
1,231
10.35
965
13.31
751

Perc. Exposure----- ----------90.00
0.017402
95.00
0.02397897.50
0.032078
99.00
0.043499
99.50
0.051603
99.75
0.061138
99.90
0.073483% aRfD------19.34
26.64
35.64
48.33
57.34
67.93
81.65

MOE
--------517
375
280
206
174
147
122

Non-hispanic whites-------------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.007050
0.007064
Standard Deviation
0.007097
0.007097
Standard Error of mean
0.000042
0.000042
Margin of Exposure
1,276
1,274
Percent of aRfD
7.83
7.85

Percent of Person-Days that are User-Days = 99.80%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001686
0.002452
0.003214
0.004028
0.004966
0.006185
0.007803
0.010132% aRfD
MOE------- ---------1.87
5,337
2.72
3,671
3.57
2,800
4.48
2,234
5.52
1,812
6.87
1,455
8.67
1,153
11.26
888

Perc. Exposure----- ----------90.00
0.014547
95.00
0.019477
97.50
0.025533
99.00
0.035881
99.50
0.043798
99.75
0.052217
99.90
0.063241

Non-hispanic blacks-------------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.007760
0.007775
Standard Deviation
0.008615
0.008617
Standard Error of mean
0.000118
0.000118
Margin of Exposure
1,159
1,157
Percent of aRfD
8.62
8.64

Percent of Person-Days that are User-Days = 99.81%

139% aRfD------16.16
21.64
28.37
39.87
48.66
58.02
70.27

MOE
--------618
462
352
250
205
172
142

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001333
0.002167
0.003005
0.003921
0.005050
0.006615
0.008577
0.011470% aRfD
MOE------- ---------1.48
6,749
2.41
4,153
3.34
2,994
4.36
2,295
5.61
1,782
7.35
1,360
9.53
1,049
12.74
784

Perc. Exposure----- ----------90.00
0.016933
95.00
0.023456
97.50
0.030391
99.00
0.040712
99.50
0.051284
99.75
0.061158
99.90
0.088375% aRfD------18.81
26.06
33.77
45.24
56.98
67.95
98.19

MOE
--------531
383
296
221
175
147
101

Non-hisp/non-white/non-black----------------------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.010113
0.010137
Standard Deviation
0.009573
0.009571
Standard Error of mean
0.000215
0.000217
Margin of Exposure
889
887
Percent of aRfD
11.24
11.26

Percent of Person-Days that are User-Days = 99.76%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.002221
0.003282
0.004351
0.005890
0.007683
0.009258
0.011781
0.015418

All infants-----------% aRfD
MOE------- ---------2.47
4,052
3.65
2,742
4.83
2,068
6.54
1,527
8.54
1,171
10.29
972
13.09
763
17.13
583

Perc. Exposure----- ----------90.00
0.021992
95.00
0.027475
97.50
0.033710
99.00
0.042761
99.50
0.052316
99.75
0.058743
99.90
0.071788% aRfD------24.44
30.53
37.46
47.51
58.13
65.27
79.76

MOE
--------409
327
266
210
172
153
125

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.012695
0.014063
Standard Deviation
0.014599
0.014726
Standard Error of mean
0.000268
0.000284
Margin of Exposure
708
639
Percent of aRfD
14.11
15.63

Percent of Person-Days that are User-Days = 90.28%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00

Exposure----------0.002870
0.004269
0.005367
0.006766% aRfD
MOE------- ---------3.19
3,136
4.74
2,108
5.96
1,676
7.52
1,330

Perc. Exposure----- ----------90.00
0.033299
95.00
0.045329
97.50
0.057581
99.00
0.070046

140% aRfD------37.00
50.37
63.98
77.83

MOE
--------270
198
156
128

50.00
60.00
70.00
80.00

0.008533
0.011288
0.015115
0.021238

9.48
12.54
16.79
23.60

1,054
797
595
423

99.50
99.75
99.90

0.077904
0.086405
0.098301

86.56
96.01
109.22

115
104
91

Nursing infants (<1 yr old)---------------------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.006715
0.010375
Standard Deviation
0.012227
0.013892
Standard Error of mean
0.000421
0.000583
Margin of Exposure
1,340
867
Percent of aRfD
7.46
11.53

Percent of Person-Days that are User-Days = 64.72%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.000502
0.001336
0.002479
0.003757
0.004748
0.007286
0.011083
0.016254% aRfD
MOE------- ---------0.56
17,917
1.48
6,738
2.75
3,629
4.17
2,395
5.28
1,895
8.10
1,235
12.31
812
18.06
553

Perc. Exposure----- ----------90.00
0.028691
95.00
0.035900
97.50
0.052525
99.00
0.06520099.50
0.071247
99.75
0.078182
99.90
0.083682% aRfD------31.88
39.89
58.36
72.44
79.16
86.87
92.98

MOE
--------313
250
171
138
126
115
107

Non-nursing infants (<1 yr old)-------------------------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.014966
0.014969
Standard Deviation
0.014784
0.014784
Standard Error of mean
0.000320
0.000320
Margin of Exposure
601
601
Percent of aRfD
16.63
16.63

Percent of Person-Days that are User-Days = 99.98%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.003830
0.004905
0.005958
0.007408
0.009337
0.012081
0.0161060.022328

Children 1-2 yrs----------------

Mean% aRfD
MOE------- ---------4.26
2,350
5.45
1,834
6.62
1,510
8.23
1,214
10.37
963
13.42
744
17.90
558
24.81
403

Perc. Exposure----- ----------90.00
0.034405
95.00
0.046066
97.50
0.057810
99.00
0.070778
99.50
0.078628
99.75
0.091726
99.90
0.097759

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------0.022297
0.022297

141% aRfD------38.23
51.18
64.23
78.64
87.36
101.92108.62

MOE--------261
195
155
127
114
98
92

Standard Deviation
Standard Error of mean
Margin of Exposure
Percent of aRfD

0.015718
0.000243403
24.77

0.015718
0.000243
403
24.77

Percent of Person-Days that are User-Days =100.00%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.007534
0.010499
0.013074
0.015658
0.018523
0.021854
0.025931
0.031613% aRfD
MOE------- ---------8.37
1,194
11.67
857
14.53
688
17.40
574
20.58
485
24.28
411
28.81
347
35.13
284

Perc. Exposure----- ----------90.00
0.041315
95.00
0.051266
97.50
0.059544
99.00
0.07820099.50
0.093639
99.75
0.099769
99.90
0.125696% aRfD------45.91
56.96
66.16
86.89
104.04110.85
139.66

MOE--------217
175
151
115
96
90
71

Children 3-5 yrs----------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.016667
0.016667
Standard Deviation
0.011654
0.011654
Standard Error of mean
0.000124
0.000124
Margin of Exposure
540
540
Percent of aRfD
18.52
18.52

Percent of Person-Days that are User-Days =100.00%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.005965
0.007882
0.009771
0.011600
0.013597
0.016104
0.019227
0.023568% aRfD
MOE------- ---------6.63
1,508
8.76
1,141
10.86
921
12.89
775
15.11
661
17.89
558
21.36
468
26.19
381

Perc. Exposure----- ----------90.00
0.030882
95.00
0.038461
97.50
0.047179
99.00
0.057123
99.50
0.064933
99.75
0.077067
99.90
0.091022% aRfD------34.31
42.73
52.42
63.47
72.15
85.63
101.14

MOE--------291
234
190
157
138
116
98

Children 6-12 yrs-----------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.009972
0.009972
Standard Deviation
0.008101
0.008101
Standard Error of mean
0.000125
0.000125
Margin of Exposure
902
902
Percent of aRfD
11.08
11.08

Percent of Person-Days that are User-Days =100.00%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
-----

Exposure-----------% aRfD
MOE------- ----------

Perc. Exposure----- -----------

142% aRfD-------

MOE---------

10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

0.003259
0.004484
0.005472
0.006609
0.007760
0.009099
0.011033
0.014168

3.62
4.98
6.08
7.34
8.62
10.11
12.26
15.74

2,761
2,006
1,644
1,361
1,159
989
815
635

90.00
95.00
97.50
99.00
99.50
99.75
99.90

0.019287
0.024302
0.030865
0.041668
0.048275
0.054466
0.060194

21.43
27.00
34.29
46.30
53.64
60.52
66.88

466
370
291
215
186
165
149

Youth 13-19 yrs---------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.005838
0.005843
Standard Deviation
0.005028
0.005027
Standard Error of mean
0.0001020.000102
Margin of Exposure
1,541
1,540
Percent of aRfD
6.49
6.49

Percent of Person-Days that are User-Days = 99.90%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001664
0.002450
0.003103
0.003709
0.004456
0.005325
0.006564
0.008235% aRfD
MOE------- ---------1.85
5,407
2.72
3,674
3.45
2,900
4.12
2,426
4.95
2,019
5.92
1,690
7.29
1,371
9.15
1,092

Perc. Exposure----- ----------90.00
0.011601
95.00
0.015631
97.50
0.018935
99.00
0.024271
99.50
0.029274
99.75
0.033710
99.90
0.043263% aRfD------12.89
17.37
21.04
26.97
32.53
37.46
48.07

MOE
--------775
575
475
370
307
266
208

Adults 20-49 yrs----------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.005662
0.005667
Standard Deviation
0.004843
0.004842
Standard Error of mean
0.000050
0.000050
Margin of Exposure
1,589
1,588
Percent of aRfD
6.29
6.30

Percent of Person-Days that are User-Days = 99.90%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001453
0.002124
0.002734
0.003412
0.004201
0.005215
0.006497
0.008506

Adults 50+ yrs% aRfD
MOE------- ---------1.61
6,193
2.36
4,236
3.04
3,291
3.79
2,637
4.67
2,142
5.79
1,725
7.22
1,385
9.45
1,058

Perc. Exposure----- ----------90.00
0.011756
95.00
0.015022
97.50
0.018290
99.00
0.023067
99.50
0.027620
99.75
0.032385
99.90
0.039230

Daily Exposure Analysis

143% aRfD------13.06
16.69
20.32
25.63
30.69
35.98
43.59

MOE
--------765
599
492
390
325
277
229

--------------(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.006246
0.006248
Standard Deviation
0.005221
0.005220
Standard Error of mean
0.000054
0.000054
Margin of Exposure
1,440
1,440
Percent of aRfD
6.94
6.94

Percent of Person-Days that are User-Days = 99.97%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001554
0.002314
0.003049
0.003841
0.004790
0.005866
0.007293
0.009363% aRfD
MOE------- ---------1.73
5,789
2.57
3,888
3.39
2,951
4.27
2,342
5.32
1,878
6.52
1,534
8.10
1,234
10.40
961

Perc. Exposure----- ----------90.00
0.012676
95.00
0.01622597.50
0.020037
99.00
0.025037
99.50
0.029838
99.75
0.034382
99.90
0.039963% aRfD------14.08
18.03
22.26
27.82
33.15
38.20
44.40

MOE
--------709
554
449
359
301
261
225

Females 13-49 yrs-----------------

Daily Exposure Analysis(mg/kg body-weight/day)
per Capita
per User----------- ----------Mean
0.005530
0.005537
Standard Deviation
0.004771
0.004770
Standard Error of mean
0.000062
0.000062
Margin of Exposure
1,627
1,625
Percent of aRfD
6.14
6.15

Percent of Person-Days that are User-Days = 99.87%

Estimated percentile of user-days falling below calculated exposurein mg/kg body-wt/day with Margin of Exposure (MOE) and Percent of aRfD
Perc.
----10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00

Exposure----------0.001389
0.002043
0.002663
0.003345
0.0041220.005099
0.006395
0.008353% aRfD
MOE------- ---------1.54
6,477
2.27
4,404
2.96
3,379
3.72
2,690
4.58
2,183
5.67
1,765
7.11
1,407
9.28
1,077

Perc. Exposure----- ----------90.00
0.011534
95.00
0.014635
97.50
0.017991
99.00
0.022799
99.50
0.026947
99.75
0.03211999.90
0.039186

144% aRfD------12.82
16.26
19.99
25.33
29.94
35.69
43.54

MOE
--------780
614
500
394
333
280
229

ATTACHMENT II: DEEM Chronic Dietary Exposure Assessment
II.1. Chronic Residue Data Files
Filename: H:\svetlana\Imidacloprid\DEEM\IMI Chronic\Chronic 1.RS7
Chemical:
RfD(Chronic): 0 mg/kg bw/day NOEL(Chronic): 0 mg/kg bw/day
RfD(Acute): 0 mg/kg bw/day NOEL(Acute): 0 mg/kg bw/day
Date created/last modified: 09-07-2004/16:10:40/14
Program ver. 7.87-------------------------------------------------------------------------------Food Crop Food Name
Def Res
Code Grp(ppm)---- ---- ------------------------------- ---------98 O
Acerola0.500000Full comment: CFR 03 chr
40 14
Almonds
0.025000Full comment: CFR 03 112603;Sec18;exp 6'04;chr
498 4A
Amaranth1.750000Full comment: CFR 03 subgroup 4a leafy greens chr
52 11Apples0.250000Full comment: CFR 03 chr
53 11Apples-dried
0.250000Full comment: CFR 03 chr
54 11Apples-juice/cider
0.250000Full comment: CFR 03 chr
377 11
Apples-juice-concentrate
0.250000Full comment: CFR 03 chr
410 12
Apricot juice
1.500000Full comment: CFR 03 Group 12 stone fruit chr
59 12
Apricots
1.500000Full comment: CFR 03 Group 12 stone fruit chr
60 12Apricots-dried
1.500000Full comment: CFR 03 Group 12 stone fruit chr
181 O
Artichokes-globe
1.250000Full comment: CFR 03 chr
203 1CD Artichokes-jerusalem
0.200000Full comment: CFR 03 Group 1 root & tuber chr
70 O
Avocados
0.500000Full comment: CFR 03 chr
497 9B
Balsam pear
0.250000Full comment: CFR 03 group 9 cucurbit chr
72 O
Bananas0.010000Full comment: CFR 03 imported tolearnce chr
73 O
Bananas-dried
0.010000Full comment: CFR 03 imported tolearnce chr
378 O
Bananas-juice
0.010000Full comment: CFR 03 imported tolearnce chr
265 15
Barley0.025000Full comment: CFR 03 chr
258 6C
Beans-dry-blackeye peas/cowpea
2.000000Full comment: CFR 03 group 6 Leg Veg chr
249 6C
Beans-dry-broadbeans
2.000000Full comment: CFR 03 group 6 Leg Veg chr
259 6C
Beans-dry-garbanzo/chick pea
2.000000Full comment: CFR 03 group 6 Leg Veg chr
227 6C
Beans-dry-great northern
2.000000Full comment: CFR 03 group 6 Leg Veg chr
228 6C
Beans-dry-kidney
2.000000Full comment: CFR 03 group 6 Leg Veg chr
229 6C
Beans-dry-lima
2.000000Full comment: CFR 03 group 6 Leg Veg chr
230 6C
Beans-dry-navy (pea)2.000000Full comment: CFR 03 group 6 Leg Veg chr
231 6C
Beans-dry-other2.000000Full comment: CFR 03 group 6 Leg Veg chr
251 6C
Beans-dry-pigeon beans
2.000000Full comment: CFR 03 group 6 Leg Veg chr
232 6C
Beans-dry-pinto
2.000000

145

Adj.Factors RDL Comment
#1
#2
Pntr
------ ------ --- ------1.000 1.000
CFR 03
1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

0.340

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

1.000

CFR 03

1.000

0.060

CFR 03

1.000

0.060

CFR 03

1.000

0.060

CFR 03

1.000

0.060

CFR 03

Full comment: CFR 03 group 6 Leg Veg chr
250 6B
Beans-succulent-broadbeans
2.000000
1.000
Full comment: CFR 03 group 6 Leg Veg chr
234 6A
Beans-succulent-green
2.000000
1.000
Full comment: CFR 03 group 6 Leg Veg chr
233 6B
Beans-succulent-lima
2.000000
1.000
Full comment: CFR 03 group 6 Leg Veg chr
235 6A
Beans-succulent-other2.000000
1.000
Full comment: CFR 03 group 6 Leg Veg chr
236 6A
Beans-succulent-yellow/wax
2.000000
1.000
Full comment: CFR 03 group 6 Leg Veg chr
253 6
Beans-unspecified
2.000000
1.000
Full comment: CFR 03 group 6 Leg Veg chr
323 M
Beef-dried
0.150000
1.000
Full comment: CFR 03 chr
324 M
Beef-fat w/o bones
0.150000
1.000
Full comment: CFR 03 chr
325 M
Beef-kidney
0.150000
1.000
Full comment: CFR 03 chr
327 M
Beef-lean (fat/free) w/o bones
0.150000
1.000
Full comment: CFR 03 chr
326 M
Beef-liver
0.150000
1.000
Full comment: CFR 03 chr
321 M
Beef-meat byproducts
0.150000
1.000
Full comment: CFR 03 chr
322 M
Beef-other organ meats
0.150000
1.000
Full comment: CFR 03 chr
197 1AB Beets-garden-roots
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
165 2
Beets-garden-tops(greens)
2.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber chr
152 9B
Bitter melon
0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
7 13B Blueberries
1.750000
1.000
Full comment: FR May 26 04 chr
452 5B
Bok choy
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
168 5ABroccoli
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
451 5ABroccoli-chinese
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
169 5A
Brussels sprouts
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
286 15
Buckwheat
0.025000
1.000
Full comment: CFR 03 regional reg group 15 chr
382 1AB Burdock
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
170 5A
Cabbage-green and red
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
383 5B
Cabbage-savoy
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
301 O
Canola oil (rape seed oil)
0.025000
1.000
Full comment: CFR 03 chr
106 O
Carambola (starfruit)
0.500000
1.000
Full comment: CFR 03 chr
198 1AB Carrots
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
143 9A
Casabas0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
222 1CD Cassava (yuca blanca)
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
171 5A
Cauliflower
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
199 1AB Celeriac
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
166 4B
Celery3.000000
1.000
Full comment: CFR 03 subgroup 4b petioles chr
384 4B
Celery juice
3.000000
1.000
Full comment: CFR 03 subgroup 4b petioles chr
61 12
Cherries
1.500000
1.000
Full comment: CFR 03 Group 12 stone fruit chr

146

0.060

CFR 030.060

CFR 030.060

CFR 030.060

CFR 030.060

CFR 030.060

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

FR May1.000

CFR 030.350

CFR 030.350

CFR 030.560

CFR 031.000

CFR 031.000

CFR 030.200

CFR 030.200

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 030.600

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

62 12Cherries-dried
1.500000
1.000
Full comment: CFR 03 Group 12 stone fruit chr
63 12
Cherries-juice
1.500000
1.000
Full comment: CFR 03 Group 12 stone fruit chr
447 4A
Chervil
1.750000
1.000
Full comment: CFR 03 subgroup 4a leafy greens chr
366 P
Chicken-byproducts
0.025000
1.000
Full comment: CFR 03 chr
368 P
Chicken-fat w/o bones
0.025000
1.000
Full comment: CFR 03 chr
367 P
Chicken-giblets(liver)0.025000
1.000
Full comment: CFR 03 chr
385 P
Chicken-giblets (excl. liver)0.025000
1.000
Full comment: CFR 03 chr
369 P
Chicken-lean/fat free w/o bones
0.025000
1.000
Full comment: CFR 03 chr
114 1AB Chicory
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
167 4A
Chicory(french/belgian endive)1.750000
1.000
Full comment: CFR 03 subgroup 4a leafy greens chr
386 9B
Christophine
0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
20 10
Citrus citron
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
172 5B
Collards
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
121 19B Coriander
1.750000
1.000
Full comment: CFR 03 chr
267 15
Corn grain-bran
0.025000
1.000
Full comment: CFR 03 chr
266 15
Corn grain-endosperm
0.025000
1.000
Full comment: CFR 03 chr
289 15
Corn grain-oil
0.025000
1.000
Full comment: CFR 03 chr
268 15
Corn grain/sugar/hfcs
0.025000
1.000
Full comment: CFR 03 chr
388 15
Corn grain/sugar-molasses
0.025000
1.000
Full comment: CFR 03 chr
237 15
Corn/pop
0.025000
1.000
Full comment: CFR 03 chr
238 15
Corn/sweet
0.025000
1.000
Full comment: CFR 03 chr
291 O
Cottonseed-meal
4.000000
1.000
Full comment: CFR 03 chr
290 O
Cottonseed-oil
3.000000
1.000
Full comment: CFR 03 chr
55 11Crabapples
0.300000
1.000
Full comment: CFR 03 group 11 chr
8 O
Cranberries
0.025000
1.000
Full comment: June 13 03 chr
9 O
Cranberries-juice
0.050000
1.000
Full comment: June 13 03 chr
389 O
Cranberries-juice-concentrate
0.050000
1.000
Full comment: June 13 03 chr
144 9A
Crenshaws
0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
180 4A
Cress-garden/field
1.750000
1.000
Full comment: CFR 03 subgroup 4a leafy greens chr
191 4A
Cress-upland
1.750000
1.000
Full comment: CFR 03 subgroup 4a leafy greens chr
148 9B
Cucumbers
0.200000
1.000
Full comment: DPR 02; 15 samples ND LOD 0.4 chr
10 13B Currants
1.750000
1.000
Full comment: CFR 03 Group 13B chr
177 4A
Dandelion-greens
1.750000
1.000
Full comment: CFR 03 subgroup 4a leafy greens chr
154 8
Eggplant
0.500000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg chr
364 P
Eggs-white only
0.010000
1.000
Full comment: CFR 03 chr
363 P
Eggs-whole
0.010000
1.000

147

1.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

PDP 000.100

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 030.030

CFR 030.030

CFR 031.000

CFR 03

1.000

June 11.000

June 11.000

June 11.000

CFR 031.000

CFR 031.000

CFR 031.000

1DPR 021.000

CFR 031.000

CFR 030.360

CFR 031.000

CFR 031.000

CFR 03

Full comment: CFR 03 chr
365 P
Eggs-yolk only
0.010000
1.000
Full comment: CFR 03 chr
11 13B Elderberries
1.750000
1.000
Full comment: CFR 03 Group 13B chr
178 4A
Endive-curley and escarole
1.750000
1.000
Full comment: CFR 03 subgroup 4a leafy greens chr
124 1CD Ginger
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
450 1AB Ginseng
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
330 M
Goat-fat w/o bone
0.150000
1.000
Full comment: CFR 03 chr
331 M
Goat-kidney
0.150000
1.000
Full comment: CFR 03 chr
333 M
Goat-lean (fat/free) w/o bone
0.150000
1.000
Full comment: CFR 03 chr
332 M
Goat-liver
0.150000
1.000
Full comment: CFR 03 chr
328 M
Goat-meat byproducts
0.150000
1.000
Full comment: CFR 03 chr
329 M
Goat-other organ meats
0.150000
1.000
Full comment: CFR 03 chr
12 13B Gooseberries
1.750000
1.000
Full comment: CFR 03 Group 13B chr
23 10
Grapefruit-juice
0.038000
2.100
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
441 10
Grapefruit-juice-concentrate
0.038000
8.260
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
448 10
Grapefruit peel
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
22 10
Grapefruit-peeled fruit
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
13 O
Grapes0.200000
1.000
Full comment: DPR 02 #34 ND LOD=0.4 chr
15 O
Grapes-juice
0.200000
1.200
Full comment: DPR 02 #34 ND LOD=0.4 chr
392 O
Grapes-juice-concentrate
0.200000
3.600
Full comment: DPR 02 #34 ND LOD=0.4 chr
195 O
Grapes-leaves
0.200000
1.000
Full comment: DPR 02 #34 ND LOD=0.4 chr
14 O
Grapes-raisins
0.200000
4.300
Full comment: DPR 02 #34 ND LOD=0.4 chr
315 O
Grapes-wine and sherry
0.200000
1.000
Full comment: DPR 02 #34 ND LOD=0.4 chr
164 8Groundcherries
0.200000
1.000
Full comment: DPR 02 #7 ND LOD=0.4 chr
287 6C
Guar beans
2.000000
1.000
Full comment: CFR 03 group 6 Leg Veg chr
393 O
Guava-juice
0.500000
1.000
Full comment: CFR 03 chr
79 O
Guava
0.500000
1.000
Full comment: CFR 03 chr
125 O
Hops
3.000000
1.000
Full comment: CFR 03 chr
334 M
Horsemeat
0.150000
1.000
Full comment: CFR 03 chr
126 1AB Horseradish
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
16 13B Huckleberries
1.750000
1.000
Full comment: CFR 03 Group 13B chr
18 O
Juneberry
1.750000
1.000
Full comment: CFR 03 chr
174 5B
Kale
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
175 5A
Kohlrabi
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
24 10
Kumquats
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
28 10
Lemons-juice
0.038000
2.000

148

1.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

PDP 00

1.000

PDP 00

1.000

PDP 00

1.000

PDP 000.500

2

DPR 020.500

2DPR 020.500

2DPR 020.500

2DPR 020.500

2DPR 020.500

2DPR 021.000

DPR 020.060

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 030.300

CFR 031.000

CFR 031.000

PDP 00

1.000

PDP 00Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
442 10
Lemons-juice-concentrate
0.038000 11.400
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
27 10
Lemons-peel
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
26 10
Lemons-peeled fruit
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
243 6C
Lentils
2.000000
1.000
Full comment: CFR 03 group 6 Leg Veg chr
182 4A
Lettuce-unspecified
0.200000
1.000
Full comment: DPR 02 #14 ND LOD 0.4 chr
176 4A
Lettuce-leafy varieties
0.200000
1.000
Full comment: DPR 02 #14 ND LOD 0.4 chr
192 4A
Lettuce-head varieties
0.200000
1.000
Full comment: DPR 02 #14 ND LOD 0.4 chr
32 10
Limes-juice
0.038000
2.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
443 10Limes-juice-concentrate
0.038000
6.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
31 10
Limes-peel
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
30 10
Limes-peeled fruit
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
108 O
Longan fruit
1.500000
1.000
Full comment: CFR 03 chr
81 11Loquats
0.300000
1.000
Full comment: CFR 03 group 11 chr
96 O
Lychee-dried
1.500000
1.000
Full comment: CFR 03 chr
95 O
Lychees (litchi)/fresh
1.500000
1.000
Full comment: CFR 03 chr
80 O
Mangoes0.500000
1.000
Full comment: CFR 03 chr
141 9A
Melons-cantaloupes-juice
0.200000
1.000
Full comment: DPR 02; 18 samples ND LOD 0.4 chr
142 9A
Melons-cantaloupes-pulp
0.200000
1.000
Full comment: DPR 02; 18 samples ND LOD 0.4 chr
145 9A
Melons-honeydew
0.200000
1.000
Full comment: DPR 02; 18 samples ND LOD 0.4 chr
146 9A
Melons-persian
0.200000
1.000
Full comment: DPR 02; 18 samples ND LOD 0.4 chr
398 D
Milk-based water
0.050000
1.000
Full comment: CFR 03 chr
319 D
Milk-fat solids
0.050000
1.000
Full comment: CFR 03 chr
318 D
Milk-nonfat solids
0.050000
1.000
Full comment: CFR 03 chr
320 D
Milk sugar (lactose)
0.050000
1.000
Full comment: CFR 03 chr
280 15
Millet
0.025000
1.000
Full comment: CFR 03 regional reg group 15 chr
244 6C
Mung beans (sprouts)
2.000000
1.000
Full comment: CFR 03 group 6 Leg Veg chr
183 5B
Mustard greens
1.750000
1.000
Full comment: CFR 03 Group 5 Brassica chr
130 19B Mustard seed
0.025000
1.000
Full comment: CFR 03 chr
64 12
Nectarines
0.005000
1.000
Full comment: PDP 00-01 #508 ND LOD 0.01 chr
399 15Oats-bran
0.025000
1.000
Full comment: CFR 03 regional reg group 15 chr
269 15Oats
0.004000
1.000
Full comment: PDP 99 #332 ND LOD 0.008 chr
245 O
Okra
0.500000
1.000
Full comment: CFR 03 chr
397 9B
Okra/chinese (luffa)
0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
36 10Oranges-juice
0.038000
1.800
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
33 10
Oranges-juice-concentrate
0.038000
6.700
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr

149

1.000

PDP 00

1.000

PDP 00

1.000

PDP 001.000

CFR 030.850

DPR 020.850

DPR 020.850

DPR 021.000

PDP 00

1.000

PDP 00

1.000

PDP 00

1.000

PDP 001.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 030.450

DPR 020.450

DPR 020.450

DPR 020.450

DPR 021.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

0.010

3

1.000
1.000

PDP 00
CFR 03

4

PDP 991.000

CFR 031.000

CFR 030.010

5PDP 000.010

5PDP 00

35 10Oranges-peel
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
34 10
Oranges-peeled fruit
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
85 O
Papayas-dried
0.500000
1.000
Full comment: CFR 03 chr
86 O
Papayas-juice
0.500000
1.000
Full comment: CFR 03 chr
84 O
Papayas-pulp
0.500000
1.000
Full comment: CFR 03 chr
139 8
Paprika
0.500000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg chr
184 4A
Parsley
1.750000
1.000
Full comment: CFR 03 subgroup 4a leafy greens chr
225 1AB Parsley roots
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
220 1AB Parsnips
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
401 O
Passion fruit-juice
0.500000
1.000
Full comment: CFR 03 chr
92 O
Passion fruit (granadilla)
0.500000
1.000
Full comment: CFR 03 chr
65 12Peaches0.005000
1.000
Full comment: PDP 00-01 #508 ND LOD 0.01 chr
66 12Peaches-dried
0.005000
7.000
Full comment: PDP 00-01 #508 ND LOD 0.01 chr
402 12Peaches-juice
0.005000
1.000
Full comment: PDP 00-01 #508 ND LOD 0.01 chr
56 11
Pears
0.300000
1.000
Full comment: CFR 03 group 11 chr
57 11Pears-dried
0.300000
1.000
Full comment: CFR 03 group 11 chr
404 11
Pears-juice
0.300000
1.000
Full comment: CFR 03 group 11 chr
240 6C
Peas (garden)-dry
0.005000
1.000
Full comment: PDP 01-02 #630 ND LOD 0.01 chr
241 6AB Peas (garden)-green
0.005000
1.000
Full comment: PDP 01-02 #630 ND LOD 0.01 chr
405 6B
Peas-succulent/blackeye/cowpea
0.005000
1.000
Full comment: PDP 01-02 #630 ND LOD 0.01 chr
47 14Pecans
0.025000
1.000
Full comment: CFR 03 chr
156 8Peppers-chilli incl jalapeno
0.200000
1.000
Full comment: PDP 02 #24 ND LOD 0.4 chr
157 8Peppers-other
0.200000
1.000
Full comment: PDP 02 #24 ND LOD 0.4 chr
155 8Peppers-sweet(garden)
0.200000
1.000
Full comment: PDP 02 #24 ND LOD 0.4 chr
88 O
Persimmons
1.500000
1.000
Full comment: CFR 03 chr
158 8
Pimientos
0.200000
1.000
Full comment: PDP 02 #24 ND LOD 0.4 chr
67 12Plums (damsons)1.500000
1.000
Full comment: CFR 03 Group 12 stone fruit chr
68 12
Plums-prunes (dried)
1.500000
1.000
Full comment: CFR 03 Group 12 stone fruit chr
69 12
Plums/prune-juice
1.500000
1.000
Full comment: CFR 03 Group 12 stone fruit chr
344 M
Pork-fat w/o bone
0.150000
1.000
Full comment: CFR 03 chr
345 M
Pork-kidney
0.150000
1.000
Full comment: CFR 03 chr
347 M
Pork-lean (fat free) w/o bone
0.150000
1.000
Full comment: CFR 03 chr
346 M
Pork-liver
0.150000
1.000
Full comment: CFR 03 chr
342 M
Pork-meat byproducts
0.150000
1.000
Full comment: CFR 03 chr
343 M
Pork-other organ meats
0.150000
1.000
Full comment: CFR 03 chr
210 1C
Potatoes/white-dry
0.200000
1.000

150

0.010

5

PDP 000.010

5PDP 001.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 030.010

3PDP 000.010

3PDP 000.010

3PDP 000.200

CFR 030.200

CFR 030.200

CFR 030.010

6PDP 010.010

6PDP 010.010

6PDP 011.000

CFR 030.620

7PDP 020.620

7PDP 020.620

7PDP 021.000

CFR 030.620

PDP 021.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 030.460

CFR 03

Full comment: CFR 03 Group 1 root & tuber chr
209 1C
Potatoes/white-peeled
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
211 1C
Potatoes/white-peel only
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
208 1C
Potatoes/white-unspecified
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
207 1C
Potatoes/white-whole
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
362 P
Poultry-other-fat w/o bones
0.002500
1.000
Full comment: CFR 03 chr
361 P
Poultry-other-giblets(liver)0.002500
1.000
Full comment: CFR 03 chr
360 P
Poultry-other-lean (fat free) w/
0.002500
1.000
Full comment: CFR 03 chr
149 9B
Pumpkin
0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
58 11
Quinces0.300000
1.000
Full comment: CFR 03 group 11 chr
407 1AB Radishes-japanese (daiken)
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
212 1AB Radishes-roots
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
213 2
Radishes-tops
2.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber chr
185 4B
Rhubarb
3.000000
1.000
Full comment: CFR 03 subgroup 4b petioles chr
408 15Rice-bran
0.025000
1.000
Full comment: CFR 03 regional reg group 15 chr
271 15Rice-milled (white)
0.025000
1.000
Full comment: CFR 03 regional reg group 15 chr
270 15Rice-rough (brown)
0.025000
1.000
Full comment: CFR 03 regional reg group 15 chr
409 15Rice-wild
0.025000
1.000
Full comment: CFR 03 regional reg group 15 chr
214 1AB Rutabagas-roots
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
215 2
Rutabagas-tops
2.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber chr
274 15Rye-flour
0.025000
1.000
Full comment: CFR 03 regional reg group 15 chr
273 15Rye-germ
0.025000
1.000
Full comment: CFR 03 regional reg group 15 chr
272 15
Rye-rough0.025000
1.000
Full comment: CFR 03 regional reg group 15 chr
295 O
Safflower-oil
0.250000
1.000
Full comment: CFR 03 regional reg chr
294 O
Safflower-seed
0.003000
1.000
Full comment: CFR 03 regional reg chr
216 1AB Salsify(oyster plant)
0.200000
1.000
Full comment: CFR 03 Group 1 root & tuber chr
473 O
Sapodilla
0.500000
1.000
Full comment: CFR 03 chr
338 M
Sheep-fat w/o bone
0.150000
1.000
Full comment: CFR 03 chr
339 M
Sheep-kidney
0.150000
1.000
Full comment: CFR 03 chr
341 M
Sheep-lean (fat free) w/o bone
0.150000
1.000
Full comment: CFR 03 chr
340 M
Sheep-liver
0.150000
1.000
Full comment: CFR 03 chr
336 M
Sheep-meat byproducts
0.150000
1.000
Full comment: CFR 03 chr
337 M
Sheep-other organ meats
0.150000
1.000
Full comment: CFR 03 chr
413 6A
Snowpeas2.000000
1.000
Full comment: CFR 03 group 6 Leg Veg chr
275 15
Sorghum (including milo)
0.025000
1.000
Full comment: CFR 03 chr
303 6A
Soybean-other0.500000
1.000
Full comment: Emerg. expires 12 31 2006 group 6 chr

151

0.460

CFR 030.460

CFR 030.460

CFR 030.460

CFR 031.000

CFR 031.000

CFR 031.000

CFR 030.700

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

1.000

Emerg.

307 6A
Soybeans-flour (defatted)
0.250000
1.000
Full comment: Regional; no expir date group 6 chr
306 6A
Soybeans-flour (low fat)0.250000
1.000
Full comment: Regional; no expir date group 6 chr
305 6A
Soybeans-flour (full fat)0.250000
1.000
Full comment: Regional; no expir date group 6 chr
304 6A
Soybeans-mature seeds dry
0.500000
1.000
Full comment: Emerg. expires 12 31 2006 group 6 chr
297 6A
Soybeans-oil
0.500000
1.000
Full comment: Emerg. expires 12 31 2006 group 6 chr
482 O
Soybeans-protein isolate
0.250000
1.000
Full comment: Regional; no expir date group 6 chr
255 6A
Soybeans-sprouted seeds
0.500000
1.000
Full comment: Emerg. expires 12 31 2006 group 6 chr
186 4A
Spinach1.750000
1.000
Full comment: CFR 03 subgroup 4a leafy greens chr
150 9B
Squash-summer
0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
415 9B
Squash-spaghetti
0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
151 9B
Squash-winter0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
17 O
Strawberries
0.200000
1.000
Full comment: DPR 02 samples 14 ND LOD=0.4 chr
416 O
Strawberries-juice
0.200000
1.000
Full comment: DPR 02 samples 14 ND LOD=0.4 chr
282 1A
Sugar-beet
0.025000
1.000
Full comment: CFR 03 chr
379 1A
Sugar-beet-molasses
0.150000
1.000
Full comment: CFR 03 chr
218 1CD Sweet potatoes (incl yams)
0.200000
1.000
Full comment: CFR 03 Group 1 root&tuber chr
418 2
Sweet potatos-leaves
2.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber chr
187 4B
Swiss chard
3.000000
1.000
Full comment: CFR 03 subgroup 4b petioles chr
37 10
Tangelos
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
38 10
Tangerines
0.038000
1.000
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
39 10
Tangerines-juice
0.038000
2.300
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
420 10
Tangerines-juice-concentrate
0.038000
7.350
Full comment: PDP 00-01 oranges 13 det; LOD 0.01chr
201 1CD Taro-root
0.200000
1.000
Full comment: CFR 03 Group 1 root&tuber chr
190 2
Taro-greens
2.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber chr
163 8Tomatoes-catsup
0.012500
2.500
Full comment: PDP 01 #369 paste ND LOD 0.025 chr
423 8Tomatoes-dried
0.500000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg chr
160 8Tomatoes-juice
0.500000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg chr
162 8Tomatoes-paste
0.012500
5.400
Full comment: PDP 01 #369 paste ND LOD 0.025 chr
161 8Tomatoes-puree
0.012500
3.300
Full comment: PDP 01 #369 paste ND LOD 0.025 chr
159 8Tomatoes-whole
0.500000
1.000
Full comment: CFR 03 Group 8 Fruiting Veg chr
355 P
Turkey-byproducts
0.002500
1.000
Full comment: CFR 03 chr
357 P
Turkey--fat w/o bones
0.002500
1.000
Full comment: CFR 03 chr
356 P
Turkey-giblets (liver)0.002500
1.000
Full comment: CFR 03 chr
358 P
Turkey- lean/fat free w/o bones
0.002500
1.000
Full comment: CFR 03 chr
449 P
Turkey-other organ meats
0.002500
1.000
Full comment: CFR 03 chr
137 1CD Turmeric0.200000
1.000

152

1.000

Region1.000

Region1.000

Region1.000

Emerg.

1.000

Emerg.

1.000

Region1.000

Emerg.

1.000

CFR 030.100

CFR 030.100

CFR 030.100

CFR 031.000

DPR 021.000

DPR 021.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

PDP 00

1.000

PDP 00

1.000

PDP 00

1.000

PDP 001.000

CFR 031.000

CFR 030.700

8PDP 011.000

CFR 031.000

CFR 030.700

8PDP 010.700

8PDP 011.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 03

Full comment: CFR 03 Group 1 root&tuber chr
219 1AB Turnips-roots
0.200000
1.000
Full comment: CFR 03 Group 1 root&tuber chr
188 2
Turnips-tops
2.000000
1.000
Full comment: CFR 03 Group 2 leaves root & tuber chr
429 M
Veal-dried
0.150000
1.000
Full comment: CFR 03 chr
424 M
Veal-fat w/o bones
0.150000
1.000
Full comment: CFR 03 chr
426 M
Veal-kidney
0.150000
1.000
Full comment: CFR 03 chr
425 M
Veal-lean (fat free) w/o bones
0.150000
1.000
Full comment: CFR 03 chr
427 M
Veal-liver
0.150000
1.000
Full comment: CFR 03 chr
430 M
Veal-meat byproducts
0.150000
1.000
Full comment: CFR 03 chr
428 M
Veal-other organ meats
0.150000
1.000
Full comment: CFR 03 chr
189 O
Watercress
1.750000
1.000
Full comment: CFR 03 chr
147 9A
Watermelon
0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
436 9A
Watermelon-juice
0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
278 15Wheat-bran
0.025000
1.000
Full comment: CFR 03 chr
279 15Wheat-flour
0.025000
1.000
Full comment: CFR 03 chr
277 15Wheat-germ
0.025000
1.000
Full comment: CFR 03 chr
437 15Wheat-germ oil
0.025000
1.000
Full comment: CFR 03 chr
276 15Wheat-rough0.025000
1.000
Full comment: CFR 03 chr
439 9B
Wintermelon
0.250000
1.000
Full comment: CFR 03 group 9 cucurbit chr
221 1CD Yambean tuber (jicama)
0.200000
1.000
Full comment: CFR 03 Group 1 root&tuber chr
224 1CD Yautia (tannier)0.200000
1.000
Full comment: CFR 03 Group 1 root&tuber chr

1.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 030.600

CFR 030.600

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 031.000

CFR 030.600

CFR 031.000

CFR 031.000

CFR 03II.2. Chronic Dietary Exposure and Risk Estimates
California Department of Pesticide Regulation
Ver. 7.87
DEEM Chronic analysis for(1994-98 data)
Residue file name: H:\svetlana\Imidacloprid\DEEM\IMI Chronic\Chronic 1.RS7
Adjustment factor #2 used.
Analysis Date 03-22-2005/14:38:44
Residue file dated: 09-07-2004/16:10:40/14
NOEL (Chronic) = 5.7 mg/kg bw/day===============================================================================
Total exposure by population subgroup-------------------------------------------------------------------------------

Population
Subgroup-------------------------------------U.S. Population (total)
Western region
Hispanics
Non-hispanic whites
Non-hispanic blacks
Non-hisp/non-white/non-black
All infants (< 1 year)
Nursing infants
Non-nursing infantsChildren 1-2 yrs

Total Exposure----------------------------------mg/kg
Percent
Margin ofbody wt/dayof NOEL
Exposr 1/------------- --------- --------0.002368
0.04%
2,407
0.002640
0.05%
2,159
0.002657
0.05%
2,145
0.002280
0.04%
2,500
0.002265
0.04%
2,516
0.003401
0.06%
1,676
0.004348
0.08%
1,311
0.001982
0.03%
2,875
0.005246
0.09%
1,087
0.007405
0.13%
770

153

Children 3-5 yrs
Children 6-12 yrs
Youth 13-19 yrs
Adults 20-49 yrs
Adults 50+ yrs
Females 13-49 yrs

0.005474
0.003235
0.001926
0.001794
0.001890
0.001753

154

0.10%
0.06%
0.03%
0.03%
0.03%
0.03%

1,041
1,762
2,960
3,177
3,015
3,251

ATTACHMENT III: Benchmark Dose Modeling. Polynomial Model
Imidacloprid Acute Oral Treatment of Female Rats (Sheets, 1994a)
Decreases In Motor Activity====================================================================Polynomial Model. Revision: 2.2 Date: 9/12/2002
Input Data File: C:\DOCUMENTS AND SETTINGS\SKOSHLUKOVA\DESKTOP\BMD DATA\SVETLANAIMI\BMD_IMI_MOTOR_ACTIVITY.(d)Gnuplot Plotting File: C:\DOCUMENTS AND SETTINGS\SKOSHLUKOVA\DESKTOP\BMD DATA\SVETLANAIMI\BMD_IMI_MOTOR_ACTIVITY.plt
Thu Dec 01 13:47:04 2005====================================================================
BMDS MODEL RUN~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
The form of the response function is:Y[dose] = beta_0 + beta_1*dose + beta_2*dose^2 + ...

Dependent variable = MEAN
Independent variable = COLUMN1
Signs of the polynomial coefficients are not restricted
The variance is to be modeled as Var(i) = alpha*mean(i)^rho
Total number of dose groups = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: 1e-008
Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values
alpha =
1
rho =0
beta_0 =479.728
beta_1 =-1.86631
beta_2 =0.00204728

Parameter Estimates

Variablealpharho
beta_0
beta_1
beta_2Estimate
1.488631.68617489.201-2.11196
0.00278779

Std. Err.
2.79055
0.331116
53.5740.755313
0.00206514

95.0% Wald Confidence Interval
Lower Conf. Limit
Upper Conf. Limit-3.98074
6.95801
1.03722.33515384.198594.204-3.59235-0.631578-0.00125981
0.00683538

Asymptotic Correlation Matrix of Parameter Estimates

alpha
rho
beta_0
beta_1
beta_2

alpha
1
-0.99
0.0043-0.063
0.087

rho
-0.99
1
0.00390.047-0.07

beta_00.00430.0039
1
-0.81
0.69

155

beta_1-0.063
0.047
-0.81
1
-0.98

beta_2
0.087
-0.07
0.69
-0.98
1

Table of Data and Estimated Values of Interest
Dose
Res.
-----0
42
151
307

N

Obs MeanObs Std Dev

Est Mean

Est Std Dev

Chi^2

---

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

504
366
263
96

262
194
93
71

489
405
234
104

226
193
121
61

0.227
-0.7080.833-0.393

12
12
12
10

Model Descriptions for likelihoods calculated

Model A1:

Yij = Mu(i) + e(ij)Var{e(ij)} = Sigma^2

Model A2:

Yij = Mu(i) + e(ij)Var{e(ij)} = Sigma(i)^2

Model A3:

Yij = Mu(i) + e(ij)Var{e(ij)} = alpha*(Mu(i))^rho

Model

Yi = Mu + e(i)Var{e(i)} = Sigma^2

R:

Likelihoods of Interest
Model
A1
A2
A3
fittedR

Log(likelihood)-258.901380-247.959417-249.489767-249.862341-272.173814

DF
5
8
6
5
2

AIC
527.802760
511.918835
510.979534
509.724682
548.347627

Explanation of Tests
Test 1:levels?
Test 2:
Test 3:
Test 4:

Does response and/or variances differ among Dose(A2 vs. R)
Are Variances Homogeneous? (A1 vs A2)
Are variances adequately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
Tests of Interest

Test
Test 1
Test 2
Test 3
Test 4-2*log(Likelihood Ratio)
48.4288
21.88393.06070.745148

Test df

p-value632
1<.0001<.00010.2165
0.388

The p-value for Test 1 is less than .05. There appears
to be adifference between response and/or variances among thedose levels
It seems appropriate to model the data

156

The p-value for Test 2 is less than .05.
non-homogeneous variancemodel appears to be appropriate

A

The p-value for Test 3 is greater than .05.
modeled variance appears
to be appropriate here

TheThe p-value for Test 4 is greater than .05.
chosen seems
to adequately describe the data

The model

Benchmark Dose Computation
Specified effect =0.05
Risk Type=

Relative risk

Confidence level =

0.95

BMD =

11.7644

BMDL =

8.91314BMDL computation failed for one or more point on the BMDL curve.
The BMDL curve will not be plotted

157

ATTACHMENT IV: Summary of Toxicology Data for Imidacloprid
http://www.cdpr.ca.gov/docs/toxsums/pdfs/3849.pdf
CALIFORNIA ENVIRONMENTAL PROTECTION AGENCY
DEPARTMENT OF PESTICIDE REGULATIONMEDICAL TOXICOLOGY BRANCHSUMMARY OF TOXICOLOGY DATAIMIDACLOPRID
Chemical Code # 3849, Document Processing Number (DPN) # 51950
SB 950 # N/A
Original date: 5/24/93
Revised date: 3/30/04
I. DATA GAP STATUS
Chronic toxicity, rat:

No data gap, no adverse effect (other than for oncogenicity, see below)

Chronic toxicity, dog:

No data gap, no adverse effects

Oncogenicity, rat:

No data gap, possible adverse effectOncogenicity, mouse:

No data gap, no adverse effects

Reproduction, rat:

No data gap, no adverse effects

Teratology, rat: No data gap, possible adverse effectTeratology, rabbit:

No data gap, no adverse effects

Gene mutation:

No data gap, no adverse effects

Chromosome effects:

No data gap, possible adverse effect

DNA damage:

No data gap, possible adverse effect

Neurotoxicity:

No data gap, possible adverse effectToxicology one-liners are attached.
All record numbers for the above study types through 209393 (Document No. 51950-0474) were
examined.
In the 1-liners below:** indicates an acceptable study.
Bold face indicates a possible adverse effect.
## indicates a study on file but not yet reviewed.
File name: T033004
Revised by Thomas Moore, 3/30/04
These pages contain summaries only. Individual worksheets may identify additional effects.

158II. TOXICOLOGY ONE-LINERS AND CONCLUSIONSCOMBINED, RAT** 009,-010,-011; 119472, 119473, 119475; Chronic Toxicity and Cancerogenicity Studies on Wistar
Rats (Administration in Food over 24 Months), (Authors: R. Eiben, G. Kaliner; 831; Rat; Bayer AG,
Dept. of Toxicology, D-56 Wuppertal 1, West Germany; Report Nos. 100652, 101931, 102658; 9/6/91;
NTN 33893 Technical (94.3% purity); 60 animals/sex/group; Doses: (Study #1)-0, 100, 300, 900 ppm,
(Study #2)-0, 1800 ppm; Mortality: (104 wks)-O (M:16/100, F:26/100), 100 (M/F:6/50), 300 (M:6/50,
F:10/50), 900 (M:6/50, F:13/50), 1800 (M:5/50, F:10/50); Clinical Observations: no treatment-related
signs; weight gain reduced in 1800 ppm group (M: 5%), (F: 11%); Hematology: no treatment effect;
Serum Chemistry: increased alkaline phosphatase activity (F, 1800 ppm) at 6, 12, 18 months; Gross
Pathology: no treatment-related lesions; Histopathology: (non-neoplastic lesions) increased incidence ofmineralized particles in colloid of thyroid gland, (neoplastic) cholangiocellular carcinoma in livers of 2
males (1800 ppm); possible adverse effect: cholangiocellular carcinoma; NOEL: 100 ppm, based on theincidence of mineralized particles in the thyroid glands of males in the 300 ppm group; Study acceptable.
(Moore, 4/7/93)
CHRONIC TOXICITY, DOG** 013; 119478; "52-Week Oral Toxicity (Feeding) Study with NTN 33893 Technical in the Dog"
(Author: Allen, T.R., et al, Research and Consulting Co., Itingen, Switzerland, Lab Project ID 100015,
10/19/89); NTN 33893 Tech. (Batch No. 180587, 94.9% purity); 0, 200, 500 and 1250/2500 ppm in feed
(pellet-form) to 4 dogs/sex/dose for 52 weeks; the 1250 ppm dose was increased to 2500 ppm at week 17
due to the lack of apparent toxicity; no animals died during the study; there were no treatment-related
effects on clinical signs, body weights, ophthalmoscopy, hearing, hematology or urinalysis; there was aslight but nonsignificant increase of liver weights in both sexes of the high dose group; there was also aslight increase in plasma cholesterol in females and an increase in liver cytochrome P450 in both sexes at
the high dose; NOEL (M/F) = 500 ppm (based on increased liver cytochrome P450); Acceptable(Patterson, 4/9/93).
ONCOGENICITY, MOUSE** 014,-015; 119479; 119480; Carcinogenicity Study on B6C3F1 Mice (Administration in the Food for
24 Months), (Author: B. Watta-Gebert); 832; Mouse; Bayer AG, Department of Toxicology, D-56
Wuppertal 1, West Germany; Study Nos. 100693, 101929; 1/28/91, 10/24/91; NTN 33893 Technical(purity: 95.3%); 60 animals/sex/group; Doses: (Study #1) 0, 100, 330, 1000 ppm, (Study #2) 0, 2000
ppm; Mortality: 0 (M:9/100, F:26/100), 100 (M:6/50, F:7/50), 330 (M:3/50, F:9/50), 1000 (M:8/50,
F:9/50), 2000 (M:17/50, F:14/50); Clinical Observations: no treatment-related effects; weight gain
reduced (2000 ppm) (M: 29%, F: 26%); Hematology: reduced wbc count (2000 ppm) (1000 ppm, F only);
Serum Chemistry: alk. phosphatase activity increased (2000 ppm), cholesterol level decreased (2000ppm), urea level decreased (2000 ppm, M only); Gross Pathology: no treatment-related lesions; absolute
liver, brain, lung, spleen, kidney, and adrenal gland (F only) weights decreased (2000 ppm), liver (F only,
1000 ppm); relative liver, spleen weights decreased (F only, 2000 ppm); Histopathology: slight periacinar
hepatocytic hypertrophy (M only, 2000 ppm); mineralization in the thalamus (F only, 2000 ppm); notreatment-related incidence of neoplasms; no adverse effect identified; NOEL: 1000 ppm, (estimatedcompound intake: 143.1 mg/kg/day), based on reduced weight gain and increased mortality of animals in2000 ppm group; Study acceptable. (Moore, 4/9/93)

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016; 119481; Pilot Range-Finding Study for a Cancerogenesis Study on B6C3F1 Mice, (Author: R.
Eiben); 821; Mouse; Bayer AG, Department of Toxicology, D-56 Wuppertal 1, West Germany; Report
No. 99808; 10/24/88; NTN 33983 Technical (purity: 92.8%); 10 animals/sex/group; Doses: 0, 120, 600,
3000 ppm; Mortality: 0 (M/F:0/10), 120 (M:1/10, F:0/10), 600 (M:1/10, F:0/10), 3000 (M/F:7/10);
Clinical Observations: poor appearance (3000 ppm), significant reduction of body weight gain (3000ppm); Hematology: no treatment-related effects; Serum Chemistry: elevation of alkaline phosphatase(3000 ppm); Gross pathology: no treatment-related lesions, reduced absolute brain, heart, liver, kidneys,
spleen (F only), and adrenals (F only) weights (3000 ppm), reduced relative liver (F only), heart, andspleen (F only) weights (3000 ppm); Histopathology: no treatment-related lesions; target organ not
identified; no possible adverse effect identified; NOEL: 600 ppm, (estimated daily intake: 85.7
mg/kg/day), based on poor appearance, reduced weight gain and increased mortality in the 3000 ppm
group; Study supplemental. (Moore, 4/8/93)
REPRODUCTION, RAT** 019; 119496; Multiple Generation Reproduction Study in Rats, (Authors: P. Suter ~7et. al.~1); RCC,
Research and Consulting Company AG, Itingen, Switzerland; Study No. 100647; 6/21/90; NTN 33893
Technical (purity: 95.3%); P generation: 30 animals/sex/group, F1B generation: 26 animals/sex/group; 2litters/generation; Dose: 0, 100, 250, 700 ppm; Mortality: (P) 0 (M:0/30, F:2/30), 100 (M:0/30, F:1/30),
250 (M/F:0/30), 700 (M/F:0/30), (F1B) 0 (M/F:0/30), 100 (M/F:0/30), 250 (M:1/30, F:0/30), 700(M/F:0/30); Clinical observations: decreased body weight gain (F0-700 ppm M, F1B F); Hematology: notreatment-related effects; Clinical Biochemistry: increased O-demethylase activity (F1B-250 ppm F, 700
ppm M,F), N-demethylase activity (F1B-700 ppm M), and cyt. P450 activity (F1B-700 ppm, M);
Necropsy: no treatment-related lesions, no effect on organ weights; Histopathology: no treatment-related
lesions; Reproductive factors: no treatment-related effects on fertility index, litter size; Developmental
factors: no treatment-related abnormalities, decreased weight gain (F1A, F1B, F2A, F2B-M,F, 700 ppm),
no treatment-related effect on gestation index, viability index, or lactation index; no adverse effects
identified; NOEL: (parental) 700 ppm, (reproductive) 700 ppm, (developmental) 250 ppm (based on
decreased weight gain for pups, 700 ppm); Study acceptable. (Moore, 4/14/93)
TERATOLOGY, RAT** 017; 119482; Embryotoxicity Study (including Teratogenicity) with NTN 33893 Technical in the Rat(Authors: H. Becker, ~7et. al.~1); 833; Rat; RCC, Research & Consulting Company AG, Itingen,
Switzerland; Study No. 98571; 1/8/92; NTN 33893 Technical (purity: 94.2%); 25 females/group; Doses0, 8.9, 25.9, 94.1 mg/kg/day (analytical), test material administered by gavage from day 6 post coitum
through day 15; No mortality; Clinical observations: no treatment-related signs, mean food consumption
and body weight gain decreased during treatment period (94.1 mg/kg/day); Necropsy: notreatment-related lesions; Developmental: high percentage of male fetuses, increased incidence of wavy
ribs (94.1 mg/kg/day); possible adverse effect: increased percentage of male fetuses; Maternal NOEL =25.9 mg/kg/day (based on decreased body weight gain and reduced food consumption of the 94.1
mg/kg/day treatment group; Developmental NOEL = 25.9 mg/kg/day (based on increased incidence ofwavy ribs in the fetuses of the 94.1 mg/kg/day treatment group); Study acceptable. (Moore, 4/19/93)
TERATOLOGY, RABBIT** 018; 119484; Embryotoxicity Study (including Teratogenicity) with NTN 33893 Technical in the
Rabbit, (Authors: H. Becker, K. Biederman); 833; Rabbit; RCC, Research and Consulting Company AG,
CH 4452 Itingen, Switzerland; Study No. 98572; 1/8/92; 16 females/group; Doses: 0, 7.0, 20.5, 64.3

160

mg/kg/day (analytical), doses administered by gavage from day 6 post coitum through day 18; Mortality:
0 (0/16), 7.0 (0/16), 20.5 (0/16), 64.3 (2/16); Clinical observations: reduced food consumption, bodyweight loss day 6 to 19, one abortion (64.3 mg/kg/day), reduced body weight gain day 6 to 19 (20.5mg/kg/day); Necropsy: no treatment-related lesions; Developmental: one abortion, two total resorptions,increased post-implantation loss, reduced mean fetal weight (64.3 mg/kg/day); no adverse effects;
Maternal NOEL = 20.5 mg/kg/day (based on mortality of dams, decreased body weight gain for 64.3
mg/kg/day treatment group); Developmental NOEL = 20.5 mg/kg/day (based on increased
post-implantation loss, decreased fetal weight of the offspring in the 64.3 mg/kg/day treatment group);
Study acceptable. (Moore, 4/16/93).
GENE MUTATION**51950-020; 119497; mutagenicity; 842; "NTN 33893; Reverse Mutation Assay (~7Salmonella
typhimurium and Escherichia coli~1)"; author, M. Watanabe; Nihon Tokushu Noyaku Seizo K.K., Basic
Research Division, Hino Institute, Toxicological Research Laboratory, Japan; 1/17/91; report #101276;
Imidacloprid Technical (NTN 33893; 93.7% purity); doses (+/- S9 microsomes): 312.5, 625, 1250, 2500,& 5000 mg/plate, triplicate cultures, 2 independent trials; ~7S. typhimurium~1 tester strains TA98, 100,
1535, & 1537 and ~7E. coli~1 strain WP2/uvrA; positive controls +/- S9 were successful in all instances;
48 hr exposure; no adverse effects: there was no evidence for mutagenicity (~7i.e.~1 an increase inrevertants arising in low-histidine or low typtophan medium) in any tester strain, regardless of thepresence or absence S9 activating microsomes; Acceptable. (Rubin, 4/8/93)**51950-020; 119498; mutagenicity; 842; "NTN 33893; Mutagenicity Study for the Detection ofInduced Forward Mutations in the CHO-HGPRT Assay" author, H. Lehn; Bayer AG, Institute of
Toxicology, FRG; 1/6/89; report #98584; Imidacloprid Technical (NTN 33893; 95.2% purity); doses
ranged between 0-125 mg/ml in the absence of S9 activating microsomes and between 0-1222 mg/ml in
the presence of S9; 5 hr exposure; cytotoxicity was evident directly after treatment with 70 and 80 mg/ml
test article, +/- S9, respectively; no adverse effects: no increase in 6-thioguanine resistance wasmeasured under any condition, thus NTN 33893 is not considered mutagenic in this system; Acceptable.
(Rubin, 4/8/93)** 51950-020; 119499; mutagenicity; 842; "NTN 33893; Salmonella/Microsome Test to Evaluate
for Point Mutagenic Effects"; Bayer AG, Institute of Toxicology, FRG; author, B.A. Herbold; 1/6/89;
report #98570; Imidacloprid Technical (NTN 33893; 95.0% purity); ~7S. typhimurium~1 strains TA 98,
TA 100, TA 1535, & TA 1537; doses, Test #1 (+/- 30% S9): 0, 20, 100, 500, 2500, & 12,500 mg/plate;
Test #2 (-S9, +10% S9, & +30% S9): 0, 775, 1550, 3100, 6200, & 12,400 mg/plate; slight cytotoxicity athigh dose based on titer determinations in high-histidine agar; no adverse effects: no evidence formutagenicity (~7i.e.~1 an increase in revertants arising in low-histidine agar) in any tester strain,
regardless of the presence or absence S9 microsomes and despite the success of the positive control
compounds; Acceptable. (Rubin, 4/14/93)
CHROMOSOME EFFECTS** 51950-020; 119500; structural chromosome aberration; 843; Chinese hamsters; "NTN 33893;
In Vivo Cytogenetic Study of the Bone Marrow in Chinese Hamster to Evaluate for Induced Clastogenic
Effects"; Bayer AG, Institute of Toxicology, FRG; author, B.A. Herbold; 11/24/89; report #100021;
Imidacloprid Technical (NTN 33893; 94.6% purity); dose: 2000 mg/kg body wt., administered by gavage
as a suspension in 0.5% aqueous Cremophor (10 ml/kg); positive control: 30 mg/kg cyclophosphamide;161

animals sacrificed at 6, 24, & 48 hr post dose (positive & negative controls were sacrificed at 24 hr only);
5/sex/sacrifice group; deaths: 4/34 animals treated with test article from acute toxicity; no variations of
biological significance were seen in chromosomal integrity among all treatment groups and negative
controls; positive controls exhibited large increases in % metaphases with aberrations; no adverse
effects: NTN 33893 is not clastogenic in this assay under the conditions tested; Acceptable. (Rubin,
4/15/93)** 51950-020; 119501; structural chromosome aberration; 843; "NTN 33893; In Vitro
Cytogenetic Study with Human Lymphocytes for the Detection of Induced Clastogenic Effects"; Bayer
AG, Institute of Toxicology, FRG; author, B.A. Herbold; 6/16/89; report #99262; Imidacloprid Technical(NTN 33893; 95.2% and 99.8% purity, 1st & 2nd expts., respectively); cells freshly isolated from 1 male
& 1 female volunteer; doses (-/+ S9 microsomes), Expt. #1: 0, 50, 500, & 5000 mg/ml; Expt. #2: 0, 1300,
2600, & 5200 mg/ml; cytotoxicity, indicated by a decline in mitotic index, was most prominent w/o S9(declines to 64% of control @ 500 mg/ml in Expt. #1 and 41.4% of control @ 1300 mg/ml in Expt. #2)
and was only weakly apparent w/S9; clastogenesis, indicated mainly by the appearance of chromosomal
gaps & breaks, was also most prominent w/o S9 (metaphases w/aberrations excluding gaps increased
from 3.0% in controls to 14% @ 5000 mg/ml w/no effect @ 50 & 500 mg/ml in Expt. #1 and from 2.0%
to 10.0 and 28.0% @ 1300 & 2600 mg/ml in Expt. #2); only weak clastogenic effects seen in the presenceof S9; possible adverse effects: NTN 33893 is clastogenic in this assay under the conditions tested;
Acceptable. (Rubin, 4/16/93)** 51950-020; 119503; structural chromosome aberration; 843; Mouse; "NTN 33893;
Micronucleus Test on the Mouse to Evaluate for Clastogenic Effects"; author, B.A. Herbold; Bayer AG,
Institute of Toxicology, FRG; 6/27/88; report #102652; Imidacloprid Technical (NTN 33893; 95.3%
purity); dose: 80 mg/kg body wt., administered by gavage as a suspension in 0.5% aqueous Cremophor(10 ml/kg); positive control: 20 mg/kg cyclophosphamide; animals sacrificed 24, 48, & 72 hr post dose;
5/sex/sacrifice group; no adverse effects: no test article-induced statistically significant increase overnegative controls was observed in the number of micronucleated polychromatic or normochromatic cells
despite the success of the positive controls; no statistically significant alterations occurred in the ratio ofpolychromatic to normochromatic cells; Acceptable. (Rubin, 4/19/93)** 51950-020; 119504; structural chromosome aberration; 843; Mouse; "Mouse Germ-Cell
Cytogenetic Assay with NTN 33893"; author, W. Volkner; Cytotest Cell Research GmbH & Co. KG, In
den Leppsteinswiesen 19, Robdorf, FRG; 5/22/90; report #102654; Imidacloprid Technical (NTN 33893;
94.1% purity); dose: 80 mg/kg body wt., administered by gavage as a suspension in 0.5% aqueous
Cremophor (10 ml/kg); positive control: 10 mg/kg doxorubicin sulfate HCl dosed in saline; animals
sacrificed 6, 24, & 48 hr post dose; 6/males/sacrifice group (only 5 were evaluated); spermatogonia wereisolated from both testes and prepared on slides; despite a successful positive control, the test article
failed to induce any biologically relevant increase in spermatogonial chromosome aberrations; neither the
positive control nor the test article had an effect on mitotic index; no adverse effects: under theconditions tested, NTN 33893 is neither clastogenic nor cytotoxic to mouse spermatogonia; Acceptable.
(Rubin 4/20/93)
DNA DAMAGE
51950-020/158; 119502/128284; other genetic effects; 844; Chinese hamsters; "NTN 33893; Sister
Chromatid Exchange in Bone Marrow of Chinese Hamsters In Vivo"; author, B.A. Herbold; 6/16/89

162

(original), 11/11/93 (supplement); Report #99257-1; Imidacloprid Technical (NTN 33893; 95.0% purity);
doses: 0, 500, 1000, & 2000 mg/kg body wt., administered by gavage as a suspension in 0.5% aqueous
Cremophor (10 ml/kg b.w.); positive control: 10 mg/kg cyclophosphamide (CP); animals sacrificed 24 hr
post dose, 2 hr after colcemid treatment to arrest cells in metaphase; 5/sex/dose (50 metaphases/animal
analyzed for SCE); marrow preparations made from the femur; no deaths; no toxic clinical signs;
cytotoxicity was present at 1000 and 2000 mg/kg (mitotic index declined at both doses to 83.3% of
controls); no change in proportion of cells in 1st, 2nd, & 3rd metaphases indicating no effect on cell
cycling; sister chromatid exchange rate was also unaffected (SCE mean rate per metaphase was 2.01,
2.17, 2.28, & 2.41 for 0, 500, 1000, & 2000 mg/kg, respectively) despite successful positive control (SCErate was 15.27 for 10 mg/kg CP, p<.01); Acceptable. (Rubin, 4/19/93; revised from unacceptable withsubmission of individual animal data by Rubin, 3/8/94)** 51950-020; 119505; other genetic effects; 844; "Clastogenic Evaluation of NTN 33893 in an
In Vitro Cytogenetic Assay Measuring Sister Chromatid Exchange in Chinese Hamster Ovary (CHO)
Cells"; author, R.D.F.M. Taalman; Hazleton Biotechnologies, Landjuweel, Veenendaal, The Netherlands;
4/21/88; report #102655; Imidacloprid Technical (NTN 33893); 95.2% purity; doses, -S9, Trial I: 16.7,
50, 166.7, & 500 mg/ml; Trial II: 100, 250, 500, & 1000 mg/ml; +S9, Trial I: 166.7 & 500 mg/ml and 1.7& 5.0 mg/ml; Trial III: 500 mg/ml and 1, 2, & 3 mg/ml; Trial II/-S9 and Trial III/+S9 gave results
indicating a dose-dependent rise in SCE/diploid cell (4, 44, 56, & 96% over solvent control for Trial
II/-S9 and 0, 8, 28, & 70% over solvent control for Trial III/+S9); cytotoxicity was present atconcentrations above (and including) 500 mg/ml -S9 and at 3 mg/ml +S9; possible adverse effects: NTN
33893 induces SCE in CHO cells in the absence and presence of S9 under the conditions tested;
Acceptable. (Rubin 4/21/93)** 51950-020; 119506; other genetic effects; 844; "Sister Chromatid Exchange Assay in Chinese
Hamster Ovary Cells"; author, D.L. Putnam & M.J. Morris; Microbiological Associates, Inc., Rockville,
MD; 9/12/89; report #99676; Imidacloprid Technical (NTN 33893); 95.2% purity; doses, -S9: 25, 50,
100, 200, & 400 mg/ml; +S9: 157, 313, 625, & 1250 mg/ml; no adverse effects: no evidence forinduction of SCE in the presence or absence S9 in this system despite cytotoxicity present at each dosetested; Acceptable. (Rubin 4/21/93)** 51950-020; 119507; other genetic effects; 844; ~7Bacillus subtilis~1; "NTN 33893; Rec-assay
with Spores in the Bacterial System"; author, M. Watanabe; Nihon Tokushu Noyaku Seizo K.K., Basic
Research Division, Hino Institute, Toxicological Research Laboratory, Japan; 6/18/90; report #101275;
Imidacloprid Technical (NTN 33893; 94.7% purity; doses (-/+ S9): 312.5, 625, 1250, 2500, 5000
mg/disk; positive controls, mitomycin C (-S9) and 2-aminoanthracene (+S9) successfully generated large
differences in growth inhibition zone between the Rec+ and Rec- ~7B. subtilis~1 strains H17 and M45,
respectively, indicating a positive gene damaging effect; no adverse effects: no test article-induced
differences were observed in growth inhibition zones between the 2 strains, thus no damage occurred
which a Rec+ DNA repair system might have remedied; Acceptable. (Rubin 4/22/93)** 51950-020; 119508; other genetic effects; 844; "Mutagenicity test on NTN 33893 in the Rat
Primary Hepatocyte Unscheduled DNA Synthesis [UDS] Assay"; (author, M.A. Cifone; Hazleton
Laboratories America, Inc., Kensington, MD, report #98573, 12/21/88); Imidacloprid Technical (NTN
33893); 95.2% purity; 5 trials, cells isolated from each of 2 rats/trial; Trials 1, 2, & 4 were non-functional;
doses, Trial 3: 5 (Rat #2 only), 10, 25, 50, 100, 250, & 500 mg/ml; doses, Trial 5: 50, 100, 250, 375, 500,
750 mg/ml; higher concentrations not analyzed because of excessive toxicity; UDS assessed by163

autoradiographic determination of 3H-thymidine incorporation; criteria for positive UDS response (netnuclear grain count more than 6 above negative controls, % nuclei w/> 6 grains was at least 10% of the
population more than controls, % nuclei w> 20 grains exceeds 2% of the population) not fulfilled at any
dose (the positive control, 2-acetyl aminofluorene, was successful); however; there was evidence for aweakly positive response at high doses; no adverse effects; Acceptable. (Rubin 4/23/93)** 51950-020; 119509; other genetic effects; 844; "NTN 33893; Test on ~7S. cerevisiae D7~1 to
Evaluate for Induction of Mitotic Recombination"; author, B.A. Herbold; Bayer AG, Institute of
Toxicology, FRG; 6/27/88; report #102653; Imidacloprid Technical (NTN 33893); 95.3% purity; 2 trials;
single test tube/dose replated onto 10 plates in complete agar medium to detect mitotic crossing over bycolony color or in tryptophan-deficient agar to detect mitotic gene conversion; doses: 0, 625, 1250, 2500,
5000, 10000 mg/ml; positive controls: -S9, methyl methane sulfonate; +S9, cyclophosphamide; noadverse effects: since there were no changes in the numbers of red or pink colonies or in the ability togrow in tryptophan-deficient medium as compared to negative controls, there was no evidence of theoccurrence of recombination events, either in the form of crossing over or gene conversion; positive
controls stimulated both types of recombination; Acceptable. (Rubin 4/26/93)
ACUTE NEUROTOXICITY
51950-0472, -0473; 209391, 209392; “An Acute Oral Neurotoxicity Screening Study with Technical
Grade Imidacloprid (NTN 33983) in Rats”; (L.P. Sheets; Miles Inc., Agriculture Division, Toxicology,
Stilwell, KS; Study Nos. 106348, 106348-1; 2/16/94 and 6/7/94); Two acute neurotoxicity studies were
performed. In the 1st study, eighteen Sprague-Dawley rats/sex/group were dosed orally by gavage with 0,
42, 151 or 307 mg/kg of Imidacloprid Technical (NTN 33893 technical, batch no. 2030030, purity: 98.8%(8/92)). Six animals/sex/group were identified as the satellite animals and used for clinical pathology
testing. In the 2nd study, 12 females/group were likewise dosed orally with 0 or 20 mg/kg of the test
material (same batch no., purity: 98.6% (4/94)). In the 1st study, 4 males and 10 females in the 307 mg/kg
group died within two days of dosing. In the functional observational battery (FOB) performed 90
minutes after dosing, some of the 307 mg/kg group animals displayed tremors and incoordination in their
gait in the home cage and open field tests. In the home cage, some of these animals exhibited greater orless than normal activity levels. In the open field test, the animals were generally more sluggish in their
movements. The mean frequency of rearing was also reduced for both sexes of this group (M: NS, F:<0.05). In the reflex/physiologic testing, some of the animals in the high dose had no reaction to touch,auditory or pinch stimuli. For the 151 mg/kg group females, one of the 12 animals exhibited tremors in
the FOB on Day 0. Mean hindlimb strength was lower for the 307 mg/kg males on Day 0. Mean motor
and locomotor activities for both sexes in the 151 and 307 mg/kg groups were lower than those of thecontrol on Day 0. Although some of the values for the hematological and clinical chemical parameters in
the 307 mg/kg group were significantly different from those of the control, these differences were notconsidered to be toxicologically relevant. In the necropsy examination, the mean absolute brain weight
for the 307 mg/kg males was less than that of the control (p<0.05), the relative weights were notsignificantly different. No treatment-related effects were noted in the 2nd study. Possible adverse effect:
tremors and other signs of neurotoxicity; NOEL (M/F): 42 mg/kg (based upon the decreased motor andlocomotor activity levels and presence of tremors in the 151 mg/kg treatment group); Study acceptable.
(Moore, 3/3/04)
SUBCHRONIC NEUROTOXICITY
51950-0471; 209390; “A Subchronic Dietary Neurotoxicity Screening Study with Technical Grade
Imidacloprid (NTN 33983) in Fischer 344 Rats”; (L.P. Sheets; Miles Inc., Agriculture Division,

164

Toxicology, Stilwell, KS; Study No. 106356; 6/13/94); Eighteen Fischer 344 rats/sex/group received 0,140, 963 or 3027 ppm of Imidacloprid Technical (NTN 33893 technical, batch no. 2030030, purity:
97.6% (3/93)) in the diet for 13 weeks ((M) 0, 9.3, 63.3, 196 mg/kg/day, (F) 0, 10.5, 69.3, 213
mg/kg/day). Six animals/sex/group were used as satellite animals of use in the hematology and clinicalchemistry evaluations. No deaths occurred during the study. The mean body weights and foodconsumption of both sexes in the 963 and 3027 ppm groups were lower than those of the control group(p<0.05). In the Functional Observational Battery (FOB), although the mean hindlimb grip strength of
the 3027 ppm males was lower after 8 weeks of treatment (p<0.05) and a greater number of these males
had a slightly uncoordinated righting reflex at 13 weeks (p<0.05), these results did not indicate aconsistent effect and were considered to be incidental. Otherwise, no other effects were evident in the
FOB. In the clinical chemistry evaluation, serum triglyceride concentrations were lower for both sexes inthe 3027 ppm group at both 4 and 13 weeks (p<0.05). Mean phosphate levels were reduced for both
sexes in the 3027 ppm group at 4 weeks and for the males in that group at 13 weeks (p<0.05). The mean
albumin concentrations for the 3027 ppm females were lower than those of the controls at both 4 and 13
weeks (p<0.05). Although the mean values of other parameters for the 3027 ppm group demonstrated anincrease or decrease over the values for the controls, the observed effects were not consistent over thecourse of the study or were doubtful toxicological significance. There were no treatment-related effects
evident in the hematology results, the necropsy or the histopathology examinations. No signs ofneurotoxicity were noted. No adverse effect indicated. Subchronic NOEL (M/F): 140 ppm ((M) 9.3
mg/kg/day, (F) 10.6 mg/kg/day) (based upon lower mean body and food consumption of the 963 ppm
group). Study acceptable. (Moore, 3/5/04)

DEVELOPMENTAL NEUROTOXICITY
51950-0474 209393 Sheets, L. P., “A developmental neurotoxicity screening study with technical grade
Imidacloprid in Wistar Rats,” Bayer Corp., Stilwell, KS, 9/14/01. Study # 99-D72-DV: Bayer Report No.
110245. Thirty Crl:W(HAN)BR mated females/group were dosed in diet with 0, 100, 250, or 750 ppm
imidacloprid (98.2% purity) throughout gestation and lactation (ending lactation day 21). Estimatedmean gestation exposures were 8.2, 19, and 57 mg/kg/day. Estimated mean exposures during lactation
days 0-14 were 0, 15, 36, and 104 mg/kg/day. At least 21 litters per group were of sufficient size tomaintain offspring until sacrifice at about postnatal day (PND) 75. Maternal NOEL = 250 ppm, based ontransient reduction in food consumption during lactation days 0-7. Developmental toxicity NOEL cannot
be determined because intermediate groups were not evaluated in the presence of a conspicuous change in
750 ppm in morphometric measurements (see below). Most endpoints other than the morphometricmeasurements were evaluated in intermediate dose levels, and none of these found treatment effects at
250 ppm. Findings at 750 ppm in offspring were reduced mean pup weight (5 g) at PND 21 weaning,
reduced motor activity in PND 17 males and females and in PND 21 females, modest reductions in motor
and locomotor activities during the first recording interval in PND 60 males (suggesting a slight reduction
in exploratory activity in a novel environment), and a substantial reduction in the thickness of the corpus
callosum in PND 11 females only (not reflected in PND 75 rats of either sex). Study is not acceptable,
and appears not to be upgradeable. The apparent corpus callosum change in 750 ppm females at PND 11
indicates a need to analyze intermediate groups. The statistic procedures for PND 11 morphometricmeasurements need to examined. Morphometric measurements should be performed in intermediategroups wherever an effect is statistically significant at 750 ppm. Cited positive control method validation
studies contemporary with this study are requested. See discussion of DPR review for details on concerns

165about study conduct and report presentation. Other than these issues, this study addressed the full scopeof evaluations that pertain to developmental neurotoxicity studies. Aldous, 3/24/04.
STUDIES ON METABOLITES
1950-025; 119521; 842; mutagenicity; "WAK 3839; Reverse Mutation Assay (~7Salmonella
typhimurium~1 and ~7Escherichia coli~1)"; author: M. Watanabe; Nihon Tokushu Noyaku Seizo K.K.,
Basic Research Division, Hino Institute, Tox. Research Lab., Japan; 11/26/90; report #100668; WAK
3839, a metabolite of NTN 33893; 98.3% purity; ~7S. typhimurium~1 strains TA98, TA100, TA1535, &TA1537, and ~7E. coli~1 strain WP2/uvrA; doses (-/+ S9): 312.5, 625, 1250, 2500, & 5000 mg/plate;positive controls were successful; either no effect or very weak effects of test article on revertant
frequency were observed; WAK 3839 is not mutagenic in these systems under the conditions tested;
Acceptable. (Rubin, 4/26/93)
51950-025; 119522; 842; mutagenicity; "WAK 3839; Mutagenicity Study for the Detection ofInduced Forward Mutations in the V79-HGPRT Assay In Vitro"; author: H. Lehn; Bayer AG, Departmentof Toxicology, Wuppertal, FRG; 8/15/89; report #100662; WAK 3839, a metabolite of NTN 33893;
98.9% purity; doses (based on solubility limit and cytotoxicity test): 500, 1000, 1500, 1750, & 2000
mg/ml for both -S9 trials and 1 of 2 +S9 trials; for the other +S9 trial the doses were 500, 750, 1000,
1250, 1500, & 1750 mg/ml; after plating 4 x 106 cells/250 ml flask, the cells were exposed to test article(-/+ S9 microsomes) for 5 hr followed by an "expression period" of exponential growth and subsequent
replating under selective conditions (10 mg/ml 6-thioguanine) at 3 x 105 cells/100 mm dish; after 7 days
the colonies were fixed and counted; duplicate exposure dishes were run, each dish generating 8 replicate
dishes in the selection condition; test article did not induce 6-thioguanine resistance at any dose despite
success of positive controls (-S9, ethyl methane sulfonate; +S9, DMBA); it is not mutagenic in thissystem under these conditions; Acceptable. (Rubin, 4/26/93)
51950-025; 119523; 842; mutagenicity; "WAK 3839; Mutagenicity Study for the Detection ofInduced Forward Mutations in the CHO-HGPRT Assay In Vitro"; author: H. Lehn; Bayer AG,
Department of Toxicology, Wuppertal, FRG; 2/22/89; report #100661; WAK 3839, a metabolite of NTN
33893; 94.3% purity; doses (based on solubility limit and cytotoxicity test), -S9: 62.5, 125, 250, 500,
1000, & 2000 mg/ml; +S9: 500, 750, 1000, 1250, 1500, & 2000; after plating 4 x 106 cells/250 ml flask,
the cells were exposed to test article (-/+ S9 microsomes) for 5 hr followed by an "expression period" ofexponential growth and subsequent replating under selective conditions (10 mg/ml 6-thioguanine) at 3 x
105 cells/100 mm dish; after 7 days the colonies were fixed and counted; duplicate exposure dishes wererun, each dish generating 8 replicate dishes in the selection condition; test article did not consistently
induce 6-thioguanine resistance at any dose despite success of positive controls (-S9, ethyl methane
sulfonate; +S9, DMBA); it is not mutagenic in this system under these conditions; Acceptable. (Rubin,
4/27/93)51950-025; 119524; 843; structural chromosome aberration; "WAK 3839 or NTN37571;
Micronucleus Test on the Mouse After Intraperitoneal Injection"; author: B.A. Herbold; Bayer AG,
Department of Toxicology, Wuppertal, FRG; 10/3/89; report #100664; WAK 3839 (aka NTN 37571), a
metabolite of NTN 33893; 98.9% purity; dose (based on pilot toxicity test): 0 & 50 mg/kg body wt.,
administered intraperitoneally as a suspension in 0.5% aqueous Cremophor (10 ml/kg); positive control:
20 mg/kg cyclophosphamide (sacrificed @ 24 hr only); animals sacrificed 24, 48, & 72 hr post dose, bonemarrow erythroblasts isolated from femur; 5/sex per sacrifice group; no test article-induced increase over166

negative controls was observed in the # of micronucleated polychromatic or normochromatic cells despite
the success of the positive controls; Acceptable. (Rubin, 4/27/93)
51950-025; 119525; 843; structural chromosome aberration; "NTN 37571: Micronucleus Test on
the [sic] Mice After I.P. Treatment; Pilot Study"; author: M. Usami; Nihon Tokushu Noyaku Seizo K.K.,
Basic Research Division, Agricultural Chemicals Institute, Japan; 11/29/88; report #100679; NTN 37571(aka WAK 3839), a metabolite of NTN 33893; 96.4% purity; doses: 0, 20, 40, & 80 mg/kg body wt.,
administered intraperitoneally as a suspension in DMSO:olive oil (1:10, 10 ml/kg); positive control: 4
mg/kg mitomycin C; animals sacrificed 30 hr post dose, bone marrow erythroblasts isolated from femur;
5 males/dose; no test article-induced increase over negative controls was observed in the # of
micronucleated polychromatic or normochromatic cells despite the success of the positive controls; nochange in the polychromatic/normochromatic cell ratio; Unacceptable (no females were tested, only asingle sampling time was tested, and no individual data were presented). (Rubin, 4/27/93)
51950-025; 119527; 843; structural chromosome aberration; "WAK 3839; Micronucleus Test on
the Mouse After Oral Application"; author: B.A. Herbold; Bayer AG, Department of Toxicology,
Wuppertal, FRG; 10/3/89; report #100663; WAK 3839, a metabolite of NTN 33893; 98.9% purity; dose(based on pilot toxicity test): 100 mg/kg body wt., administered by gavage as a suspension in 0.5%
aqueous Cremophor (10 ml/kg); positive control: 20 mg/kg cyclophosphamide; animals sacrificed 24, 48,& 72 hr post dose, bone marrow erythroblasts isolated from femur; 5/sex per sacrifice group; the 48-hr
sacrifice group showed a statistically significant increase over controls in micronucleated polychromatics(2.0/1000 % 0.8 ~7vs~1 0.7/1000 % 0.9 in controls sacrificed at 24 hr, p<0.01) which may be partiallyaccounted for by the abnormally low value of the controls compared to historical controls; slightnon-statistically significant increases over negative controls were also observed in the # of
micronucleated polychromatic cells in the 24- and 72-hr sacrifice groups; positive controls sacrificed at
24 hr raised the # of micronucleated cells to 16.1 % 7.9 per 1000 polychromatics; there may be a weakeffect of the test article on micronucleus formation under these conditions; Acceptable. (Rubin, 4/27/93)
51950-025; 119528; 843; structural chromosome aberration; "NTN 37571: Micronucleus Test on
the [sic] Mice After Oral Treatment; Pilot Study"; author: M. Usami; Nihon Tokushu Noyaku Seizo K.K.,
Basic Research Division, Agricultural Chemicals Institute, Japan; 11/29/88; report #100680; NTN 37571(aka WAK 3839), a metabolite of NTN 33893; 96.4% purity; doses (based on a preliminary toxicity
determination): 0, 40, 80, & 160 mg/kg body wt., administered by gavage as a suspension in
DMSO:polyethylene glycol 400 (1:5, 10 ml/kg); positive control: 4 mg/kg mitomycin C, injected
intraperitoneally; animals sacrificed 30 hr post dose, bone marrow erythroblasts isolated from femur; 5males/dose; no test article-induced increase over negative controls was observed in the # of
micronucleated polychromatics or change in the polychromatic/normochromatic cell ratio despite thesuccess of the positive controls in raising the # of micronucleated polychromatics and lowering thepolychromatic/normochromatic ratio; Unacceptable (no females were tested, positive controls were notadministered by the same route as the test article, only a single sampling time was used, and no individual
data were provided). (Rubin, 4/28/93)
51950-025; 119529; 843; structural chromosome aberration; "Chromosome Aberration Assay in
Chinese Hamster V79 Cells In Vitro with WAK 3839"; author: A. Heidemann; Cytotest Cell ResearchGmbH & Co., Robdorf, FRG; 9/27/89; report #100666; 98.8% purity; doses (based on a preliminary
cytotoxicity determination and test article solubility), -/+ S9: 0.1, 0.3, & 1.0 mg/ml; cultures harvested 7(high dose only), 18, & 28 (high dose only) hr after start of the 4 hr exposure; positive controls ethyl

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methane sulfonate (-S9) and cyclophosphamide (+S9) showed distinct increases in aberrations; despite
cytotoxicity of the test article at the mid and high dose indicated by a decline in mitotic index and at thehigh dose by a decline in plating efficiency (-S9 only), there was no increase in chromosome aberrations;
WAK 3839 is not clastogenic in this system under these conditions; Acceptable. (Rubin, 4/28/93)
51950-025; 119530; 843; structural chromosome aberration; "NTN 37571: In Vitro Cytogenetic
Assay Measuring Chromosome Aberrations in CHO-K1 Cells"; author: M. Usami; Nihon Tokushu
Noyaku Seizo K.K., Basic Research Division, Agricultural Chemicals Institute, Japan; 11/5/88; report#100678; NTN 37571 (aka WAK 3839), a metabolite of NTN 33893; purity not reported; doses, -/+ S9(based on preliminary toxicity tests): 0, 0.25, 0.5 & 1 mg/ml; positive controls: -S9, 1 mg/ml
N-methyl-N'-nitro-N-nitrosoguanidine; +S9, 0.5 mg/ml dimethylnitrosamine; exposure time: -S9, 24 & 48
hr; +S9, 4 hr; 4 x 103 cells/flask seeded (flask size not given), duplicate cultures exposed/condition, test
article exposure began 48 hr later; colchicine added 2 hr prior to harvest to arrest cells in metaphase; 50
metaphases examined/flask (100/condition total); possible slight increase in % cells with chromosome
aberrations under -S9 condition (control cells @ 48 hr w/aberrations excluding gaps = 1%, exposed cells= 2, 5, & 4%, respectively), but beneath the 10% limit considered by the investigators to be biologically
relevant; no increase in +S9 cells; positive controls were successful; Unacceptable, but may be
upgradeable upon submission of test article purity and size of flask used in assay. (Rubin, 4/29/93)
51950-025; 119531; 844; other genotoxic effects; "Unscheduled DNA Synthesis [UDS] inPrimary Hepatocytes of Male Rats In Vitro with WAK 3839"; author: R. Fautz; 4/24/89; report #100665;
98.9% purity; hepatocytes (derived freshly from male animals because female-derived cells purportedlylack certain activating enzymes) seeded at 105/ml in 35 mm culture dishes containing 1-25 mm coverslip; doses (based on a preliminary cytotoxicity determination and test article solubility), Expt. I & II: .04,
.13, .44, 1.33, 4.44, 13.33, 44.44, 133.33, 444.44, & 1333.33 mg/ml (last 2 doses Expt. II only); Expt. III:13.33, 44.44, 133.33, 444.44, & 1333.33 mg/ml; 18 hr exposure; triplicate dishes run at eachconcentration; positive control: 11.16 mg/ml 2-acetyl aminofluorene; UDS measured by autoradiographic
determination of 3H-thymidine incorporation into DNA; severe cytotoxicity observed only in Expt. I
above 133.33 mg/ml (other expts. were negative); no reproducible test article dependent increase inincorporation was observed under any condition despite the consistent success of the positive control; test
article does not induce UDS in this system under the conditions tested; Unacceptable, but possibly
upgradeable with submission of cytotoxicity data. (Rubin, 4/29/93)

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