Document ID: EPA-HQ-OPP-2010-0311-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-05-05T04:00Z

EPA Registration Division contact: Andrew Ertman (703) 308-9367

Bayer CropScience LLC & Interregional Research Project Number 4 (IR-4)	

Summary of Petitions (PP# 0F7706 & PP# 0E7704)

EPA has received a pesticide petition #0F7706 from Bayer CropScience
LLC, 2 T. W. Alexander Drive, Research Triangle Park, NC 27709
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.594 by
revising the tolerance expression under (a) to read: 

Tolerances are established for residues of thiacloprid, including its
metabolites and degradates.  Compliance with the tolerance levels
specified is to be determined by measuring only thiacloprid
([3-[(6-chloro-3-pyridinyl)methyl]-2-thiazolidinylidene] cyanamide).  

Additionally, this petition proposes to amend 40 CFR part 180.594 by
establishing a tolerance for residues of thiacloprid
([3-[(6-chloro-3-pyridinyl)methyl]-2-thiazolidinylidene] cyanamide) in
or on the raw agricultural commodities pepper (bell and non-bell) at 1.1
parts per million (ppm). 

EPA has also received a pesticide petition #0E7704 from Interregional
Research Project Number 4 (IR-4), 681 US Highway #1 South, North
Brunswick, NJ 08902 proposing, pursuant to section 408(d) of the Federal
Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR
part 180.594 to establish tolerances for residues of thiacloprid
([3-[(6-chloro-3-pyridinyl)methyl]-2-thiazolidinylidene] cyanamide) in
or on the raw agricultural commodities fruit, stone, group 12 at 0.5
ppm. 

EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data supports granting of the petition.
 Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism.  In plants, the metabolism of thiacloprid is
adequately understood for the purposes of establishing these proposed
tolerances.  Unchanged parent thiacloprid accounted for 70% or greater
of the residues in all plant metabolism studies (cotton, tomato, and
apple), with the exception of the material identified in cotton seed. 
In cotton seed, the main component was the 6-chloronicotinic acid
metabolite, accounting for 45.8%.  All residues contained the
6-chloronicotinic acid moiety.  In animals, parent thiacloprid was the
major component in all edible tissues, milk and eggs.  All residues and
metabolites in the animal tissues contained the 6-chloro-pyridinyl
moiety, same as in the plant tissues.  Therefore, the residues of
concern are the combined residues of thiacloprid and its metabolites
containing the 6-chloro-pyridinyl moiety, all calculated as thiacloprid.

	2. Analytical method.    The analytical method for determining residues
in stone fruit and peppers is specific for thiacloprid and metabolites
containing the intact thiazolidine ring and utilizes HPLC with
Electrospray MS/MS-detection.  Thiacloprid and its metabolites are
stable in peppers and stone fruit commodities for at least 10 months
when the commodities are frozen.

	3. Magnitude of residues. Stone Fruits (Sweet cherry/Peach/Plum) -  A
total of 24 field trials (7 sweet cherry, 11 peach and 6 plum) were
conducted in different EPA regions (3 for sweet cherry, 7 for peach and
3 for plum).  Applications were made as ground-based  foliar sprays at
0.25 lb ai/A with 6- to 8-day intervals.  The highest residue at the
14-day PHI was 0.423 ppm, in peaches. The highest residue at a 28-day
PHI was 0.359 ppm, occurring in peaches. Residues in stone fruit RACs
consistently declined in relation to sampling intervals, with lower
residues at the longer PHI (28 days).	

	4. Magnitude of residues. Peppers -  A total of nine field trials (six
trials on bell peppers and three trials on non-bell peppers) were
conducted to measure the magnitude of thiacloprid {YRC 2894;
3-[(6-chloro-3-pyridinyl)methyl]-2-thiazolidinylidene] cyanamide}
residues in/on peppers following three foliar spray applications of YRC
2894 480 SC to pepper plants at a target rate of 0.094 Ib
ai/acre/application (0.091 to 0.097     lb ai/acre/application) for a
total target application rate of 0.282 Ib ai/acre (0.281 to 0.287 lb
ai/acre or 0.315 to 0.322 kg ai/ha). The interval between applications
was 5 to 8 days and the pre-harvest interval was 0, 3 and 7 days. The
highest average field trial (HAFT) total thiacloprid residue was 0.20
ppm in/on bell peppers at commercial maturity at the desired label PHI
of 0 days with a maximum residue of 0.21 ppm. The total thiacloprid
residue decreased with time in the bell pepper study decline trial
samples. The HAFT total thiacloprid residue was 0.34 ppm in/on non-bell
peppers at commercial maturity at the desired label PHI of 0 days with a
maximum residue of 0.35 ppm.

B. Toxicological Profile

	1. Acute toxicity.  The acute oral LD50 values for thiacloprid
technical ranged from 444 (female) to 836 (male) mg/kg in the rat.  The
acute dermal LD50 was greater than 2,000 mg/kg in rats.  The 4-hour rat
inhalation LC50 ranged from 1,223 (female) to >2,535 (male) mg/m3 air
(aerosol).  Thiacloprid was not irritating to rabbit skin or eyes. 
Thiacloprid did not cause skin sensitization in guinea pigs. 

	2. Genotoxicity.  Extensive mutagenicity studies conducted to
investigate point and gene mutations, DNA damage and chromosomal
aberration show thiacloprid to be non-genotoxic.  

	3. Reproductive and developmental toxicity.  In a two-generation
reproduction study, Sprague-Dawley rats were administered dietary levels
of thiacloprid at levels of 0, 50, 300, and 600 ppm.  The no-observed
adverse-effect levels (NOAELs) for reproductive parameters were
established at 3.5 mg/kg/day (50 ppm), based on increased liver and
thyroid weight gains in the parental and F1 generations.  A
developmental toxicity study was conducted with Wistar rats gavaged at
0, 2, 10, and 50 mg/kg.  The following NOAELs were determined: maternal
toxicity; 10 mg/kg/day; and developmental toxicity; 10 mg/kg/day.  A
developmental toxicity study was conducted with rabbits treated orally
by gavage at 0, 2, 10, and 45 mg/kg.  The following NOAELs were
determined: maternal toxicity; 2 mg/kg/bwt/day; and developmental
toxicity; 2 mg/kg/day.  From the developmental toxicity studies in rats
and rabbits, no primary developmental toxic potential could be derived. 
Additionally, a developmental neurotoxicity study was conducted at
dietary doses of 0, 50, 300, or 500 ppm in the female Sprague-Dawley
rat. The targeted concentration of 4.4 mg/kg/day (50 ppm) was considered
a NOAEL for maternal toxicity and the F1 offspring.  No specific
neurobehavioral effects in the offspring were identified up to and
including the highest dose tested of 500 ppm.

	4. Subchronic toxicity.   90-day feeding studies were conducted in
rats, mice, and dogs.  The demonstrated NOAELs for males and females
were 7.3/7.6 mg/kg/day, 27.3 /102.6 mg/kg/day and 8.5/8.9 mg/kg/day for
rats, mice and dogs, respectively. 

	5. Chronic toxicity.   A 2-year rat chronic toxicity/oncogenicity study
demonstrated a NOAEL of 25 ppm.  Liver enzyme induction occurred at
doses > 50 ppm.  A 2-year mice oncogenicity demonstrated a NOAEL at 5.7
mg/kg/day.  A 1-year chronic toxicity study in dogs demonstrated a NOAEL
of 1.2-1.6 mg/kg/day (250 ppm), with slight prostatic weight increases
in some of the 1,000 ppm animals (possibly due to different maturation
in the animals) being the only treatment-related findings.  There is
significant evidence that thiacloprid is not acting through a genetic
mechanism (all genotoxicity studies are negative).  Thiacloprid has been
shown to be significant inducer of liver enzymes, including aromatase. 
Induction of these hepatic enzymes are believed to promote changes in
circulating hormones, leading to elevated estrogen levels and
subsequently indirectly mediated increases in uterine and ovarian tumors
in rats and mice, respectively. Similarly, thyroid tumors seen in the
chronic rat study were also considered consequent to a
hepatically-driven thyroid hormone imbalance and not the results of a
direct action of thiacloprid on the thyroid gland itself.

	6. Animal metabolism.  In animals, parent thiacloprid was the major
component in all edible tissues, milk and eggs.  All residues and
metabolites in the animal tissues contained the 6-chloro-pyridinyl
moiety, same as in the plant tissues.  Therefore, the residues of
concern are the combined residues of thiacloprid and its metabolites
containing the 6-chloro-pyridinyl moiety, all calculated as thiacloprid.

	7. Metabolite toxicology. Two specific metabolites, KKO 2254 and WAK
6999, were examined toxicologically.  In addition to negative Ames
tests, the acute toxicological potential for both sexes, as measured by
LD50, was determined to be >2,000 mg/kg for both metabolites.  In light
of these findings no special toxicological concerns, exceeding that of
thiacloprid, would be expected from the metabolites of the parent
compound.	

	8. Endocrine disruption.  The toxicology database for thiacloprid is
current and complete.  Studies in this database include evaluation of
the potential effects on reproduction and development and an evaluation
of the pathology of the endocrine organs following short- or long-term
exposure.

C. Aggregate Exposure

were conducted using DEEM™-FCID.  DEEM™-FCID dietary exposure
assessments rely upon the U.S. EPA Office of Pesticide Program’s (OPP)
Food Consumption Intake Database (FCID). Data used in the dietary
exposure model were (1) residue data from residue field trials, (2)
processing factors from laboratory studies, (3) estimated percent crop
treated information for the currently registered and proposed uses of
thiacloprid, (4) consumption data from the 1994-1996 and 1998 USDA
Continuing Survey of Food Intake by Individuals (CSFII) and (5)
translation data to raw agricultural commodities from the Food Commodity
Intake Database (FCID).

The drinking water estimated concentrations used in this analysis are
taken directly from the Agency’s risk assessment of 2003. The acute
reference dose (aRfD = 0.01 mg/kg bwt/day) was based upon an acute NOEL
of 3.1 mg/kg bwt/day from the acute oral neurotoxicity study in rats and
an uncertainty factor of 300. The chronic reference dose (cRfD = 0.004
mg/kg bwt/day) was based upon a chronic NOEL of 1.2 mg/kg bwt/day and an
uncertainty factor of 300. The chronic cancer assessment was based upon
a Q* of 0.0406 (mg/kg bwt/day)-1.

	i. Food.    The acute dietary exposure estimates at the 99.9th
percentile for the US Population was calculated to be approximately
27.8% of the acute RfD.  The population subgroup with the highest
exposure was infants at 67.5% of the acute RfD. Chronic dietary exposure
estimates from residues of thiacloprid for the US Population was 1.9% of
the chronic RfD.   The population subgroup with the highest exposure was
infants with 7.6% of the chronic RfD utilized. The chronic cancer
dietary exposure estimate for the general population is 2.4 x 10 -6. All
of these exposures included both food and water. 

	ii. Drinking water. The drinking water estimated concentrations used in
this analysis are taken directly from the Agency’s risk assessment of
20038.  The drinking water estimated concentrations (DWEC) were
determined by EFED/EPA for the use on apples.   EFED determined surface
water estimated concentrations to be 10.2 ppb for acute scenarios, 2.36
ppb for chronic scenarios, and 1.52 ppb for cancer scenarios. 
Groundwater estimated concentrations are 0.06 ppb for acute and chronic
scenarios.  The highest value is chosen from surface and groundwater
estimates for the acute and chronic scenarios. Therefore the surface
water estimates were incorporated directly into the DEEM-FCID analyses
for acute, chronic, and cancer assessments as point estimates.  The food
forms used in the analyses were “water, direct, all sources” and
“water, indirect, all sources”.

	2. Non-dietary exposure.  There are no current thiacloprid uses on turf
or ornamental plants, including homeowner uses.

D. Cumulative Effects

	Thiacloprid is part of a class of chemistry called the
chloro-nicotinyls.  For this class of chemistry and its registered
compounds EPA has not yet conducted a detailed review of common
mechanisms to determine whether it is appropriate, or how to include
these chemicals in a cumulative risk assessment. Unlike other pesticides
for which EPA has followed a cumulative risk approach based  on a common
mechanism of toxicity, thiacloprid does not appear to produce a toxic
metabolite produced by other substances. For the purposes of these
tolerance actions; therefore, EPA has not assumed that thiacloprid has a
common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population.  Using the conservative exposure assumptions
described above and based on the completeness of the toxicity data, it
can be concluded that dietary exposure (including water) to residues of
thiacloprid from all existing and proposed uses will utilize less than
28% of the acute RfD and less than 2% of the chronic RfD for the U.S.
population.   EPA generally has no concerns for exposures below 100% of
the RfD because the RfD represents the level at or below which exposure
will not pose any appreciable risk to human health. The cancer lifetime
risk assessment for the US Population gives an acceptable risk estimate
of 2.4 X 10(-6) for food and water. 

	2. Infants and children.  Using the conservative exposure assumptions
described above and based on the completeness of the toxicity data, it
can be concluded that dietary exposure (including water) to residues of
thiacloprid from all proposed uses will utilize less than 68% of the
acute RfD and less than 8% of the chronic RfD for the most highly
exposed subpopulation (infants).   In assessing the potential for
additional sensitivity of infants and children to residues of
thiacloprid, the data from developmental studies in both rat and rabbit
and a two-generation reproduction study in rats have been considered. 
The developmental toxicity studies evaluate potential adverse effects on
the developing animal resulting from pesticide exposure of the mother
during prenatal development.  The reproduction study evaluates effects
from exposure to the pesticide on the reproductive capability of mating
animals through two generations, as well as any observed systemic
toxicity.  

FFDCA Section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal effects and the completeness of the
toxicity database.  Based on current toxicological data requirements,
the toxicology database for thiacloprid relative to pre- and post-natal
effects is complete.  Further for thiacloprid, the NOAEL of 1.2 mg/kg
bwt/day from the 2-year chronic toxicity/carcinogenicity study, which
was used to calculate the cRfD (discussed above), is already lower than
the NOELs from the developmental studies in rats (10 mg/kg bwt/day) and
rabbits (2 mg/kg bwt/day) and lower than the NOEL from the 2-year
reproductive toxicity study in rats (50 mg/kg bwt/day).  Since a
300-fold uncertainty factor is already used to calculate the RfD, an
additional safety factor for infants and children is not warranted. This
conclusion was also the conclusion of the Agency.

Using the conservative exposure assumptions described above, Bayer
CropScience has concluded that the total aggregate exposure to
thiacloprid from all existing and proposed uses will utilize at most 68%
of the acute RfD and 8% of the chronic RfD even for the most highly
exposed population subgroups (infants).  In addition, the cancer
assessment for the U.S. Population shows that the cancer dietary
exposure (food and water) for the general U.S. Population is less than 3
x 10-6.   Therefore, there is a reasonable certainty that no harm will
result to infants and children from the currently proposed uses of
thiacloprid.   

F. International Tolerances

	A CODEX Maximum Residue Levels (MRL’s) has been established for
residues of thiacloprid in/on pome fruit at 0.7 mg/kg.