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 Bay er CropScienc e 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 re ad: Tolerances are established for residues of thiacloprid, including its metabolites and degradates. Compliance with the tolerance levels specified i s to be determined by measuring only

thiacloprid ([3 - [(6 - chloro - 3 - py ridinyl)meth yl ] - 2 - thiazolidinyliden e] cy anamide) . Additionally , this petition proposes to amend 40 CFR part 180. 594 by establishing a tolerance for residues of thiacloprid ([3 - [(6 - chloro - 3 - py ridinyl)meth yl ] - 2 - thiazolidinylidene] cy anamide) 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 F ederal 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 - py ridinyl)methyl] - 2 - thiazolidinylidene] cy anamide) in or on the raw agricultural commodities f ruit, 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 full y evaluated the sufficiency

of the submitted data at this tim e 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 adequatel y understood for the purposes of es tablishing 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 meta bolites in the animal tissues contained the 6 - chloro - py ridinyl moiety , same as in the plant tissues. Therefore, the residues of concern are the combined residues ofthiacloprid and its metabolites containing the 6 - chloro - py ridinyl moiet y, all calculated a s thiacloprid. 2. Analytical method . The anal yt ical method for determining residues in stone fruit and peppers is specific for thiacloprid and metabolites containing the intact thiazolidine ring and utilizes HPL C with Electrospray MS/MS - detection. T hiacloprid 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 pe ach 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 spray s at 0.25 lb ai/A with 6 - to 8 - day intervals. The highest residue at the 14 - day

PHI was 0.423 pp m, in peaches. The highest residue at a 28 - day PHIwas 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 . Pepp ers - 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 - py ridinyl)methyl] - 2 - thiazolidinylidene] cy anamide} 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 o r 0.315 to 0.322 kg ai/ha). The interval between applications was 5 to 8 day s and the pre - harvest interval was 0, 3 and 7 day s. The highest average field trial (HAFT) total thiacloprid residue was 0.20 ppm in/on bell peppers at commercial maturity at the d esired 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 PHIof 0 day s with a maximum residue of 0.35 ppm. B. Toxicological Profile 1. Acute toxicity . The acute oral LD50 values for thiacloprid tec hnical 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 L C50 ranged from 1,223 (female) to >2,535 (male) mg/m 3 air (aerosol). Thiacloprid was not irritating to rabbit skin or ey es. Thiacloprid did not cause skin sensitization in guinea pigs. 2. G enotoxic i ty . Extensive mutagenicit y 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 stu dy , 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) forreproductive parameters were established at 3.5 mg/kg/day (50 ppm), based on increased liver and thy

roid 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 b y 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 dev elopmental 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 - ye ar rat chronic toxicity /oncogenicit y study demonstrated a NOAEL of 25 ppm. L iver enzy me induction occurred at doses > 50 ppm. A 2 - year mice oncogenicity demonstrated a NOAEL at 5.7 mg/kg/day . A 1 - ye ar chronic toxicity study in dogs demonstrated a N OAEL 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 onl y 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 enzy

mes, including aromatase. Induction of these hepatic enzy mes 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 , thy roid tumors seen in the chronic rat study were also considered consequent to a hepatic ally - driven thy roid hormone imbalance and not the results of a direct action of thiacloprid on the th yr oid 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 - py ridinyl 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 - py ridinyl 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 L D 50, was determined to b e >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 thiacl oprid 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 analy sis are taken directly from the Agenc y’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 uncertaint y factor of 300. The chronic reference dose (cRfD = 0.004 mg/kg bwt/day) was based upon a chronic NOE L of 1.2 mg/kg bwt/day and an uncertaint y 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 99.9 th percentile for the US Population was calculate d to be approximately 27.8 % of the a cute RfD. The population subgroup wi th the highest exposure was infants at 67 .5% of the a cute RfD. Chronic dietary exposure estimates from residues of thiacloprid for the US Population was 1.9 % of the c hronic RfD. The population subgroup wi th the highest exposure was infants with 7.6 % of the c hronic RfD utilized. The chronic cancer dietary exposure estimate for the general po pulation is 2.4 x 10 - 6

. All of these exposures included both food and water. ii. Drinking w ater . The drinking water estimated concentrations used in this anal ys is are taken directly from the Agency ’s risk assessment of 2003 8

. The drinking water estimated concentrations (DWEC) were determined b y 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 f

rom surface and groundwater estimates for the acute and chronic scenarios. Therefore the surface water estimates were incorporated directly into the DEEM - FCID anal ys es for acute, chronic, and cancer assessments as point estimates. The food forms used in the analy ses 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 cl ass of chemistry called the chloro - nicotinyls. For this class of chemistry

and it s registered compounds EPA has not y et conducted a detailed review of common mechanisms to determine whether it is appropriate, or how to include these chemicals in a cumulat ive 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 b y other substances. For the purposes of these t olerance 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 complet eness 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 generall y 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 accep table 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 h ighly exposed subpopulation ( infants). In assessing the potential for additional sensitivity of infants and ch ildren 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 ani mal 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 an y observed s ys t emic toxicity . FFDCA Section 408 provides that EPA may apply an additional safet y 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 - ye ar chronic toxicity

/carcinogenicit y stud y, 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 - ye ar reproductive toxicity study in rats (50 mg/kg bwt/day). Since a 300 - folduncertaint y 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, Bay er CropScience has concluded that the total aggregate exposure to thiacloprid from all existing and propo sed uses will utilize at most 68% of the acute RfD and 8 % of the chronic RfD even for the most highly

ex posed population subgroups ( infants) . In addition, the cancer assessment for the U.S. Population shows that the cancer dietary exposure (food and water) for the genera l U.S. Population is less than 3 x 10 - 6

. Therefore, there is a reasonable certaint y that no harm will result to infants an d children from the currentl y proposed uses of thiacloprid. F. International Tolerances A CODEX Max imum Residue Levels (MRL’s) has been established for residues of thiacloprid in/ on pome fruit at 0.7 mg/kg .