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/m3air (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

1. Dietary exposure. The Tier 3 acute and chronic dietary exposure assessments 

for thiacloprid use on fruit, pome, group; fruit, stone, group; and peppers were conducted 

using DEEMTM-FCID. DEEMTM-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.