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EPA REGISTRATION DIVISION COMP ANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHE D IN THE FEDERAL REGISTER

EPA Registration Division contact: [Richard Gebken 703-305-6701]

INSTRUCTIONS: Please utilize this outline in prep aring the pesticid e petition. In

cases where the outline element does not apply, please insert “NA-Remove” and

maintain the outline. Please do not chan ge the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green , i.e., “ [insert company name] ,” with the information specific to your action.

TEMPLATE:

[BASF Corporation]

[4E8230]

EPA has received a pesticide petition ([4E8230]) from [BASF Corporation], [26 Davis Drive Research Triangle Park, NC 27709] requesting, 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

1. By establishing a tole rance for residues of

[Teflubenzuron] in or on the raw agricultural commodities [Apple] at [0.5] parts per million (ppm), [Apple, wet pomace] at [0.8] parts per million (ppm), [Broccoli] at [0.2] parts per million (ppm), [Cattle, muscle] at [0.01] parts per million (ppm), [Cattle, meat byproducts] at [0.01] parts per million (ppm), [Cauliflower] at [0.01] parts per million (ppm), [Citrus oil] at [90] parts per million (ppm), [Coffee, bean, green] at [0.6] parts per million (ppm), [Corn, field] at [0.01] parts per million (ppm), [Corn, field, refined oil] at [0.02] parts per million (ppm), [Egg] at [0.01] parts per million (ppm), [Goat, muscle] at [0.01] parts per million (ppm), [Goat, meat byproducts] at [0.01] parts per million (ppm), [Horse, muscle] at [0.01] parts per million (ppm), [Horse, meat byproducts] at [0.01] parts per million (ppm), [Lemon] at [0.9] parts per million (ppm), [Mango] at [1.5] parts per million (ppm), [Melon] at [0.3] parts per million (ppm), [Milk]

at [0.01] parts per million (ppm), [Orange] at [0.6] parts per million (ppm), [Papaya] at [0.4] parts per million (ppm), [Pineapple] at [0.8] parts per million (ppm), [Pork, muscle]

at [0.01] parts per million (ppm), [Pork, meat byproducts] at [0.01] parts per million (ppm), [Poultry, muscle] at [0.01] parts per million (ppm), [Poultry, meat byproducts] at [0.01] parts per million (ppm), [Sheep, muscle] at [0.01] parts per million (ppm), [Sheep, meat byproducts] at [0.01] parts per million (ppm), [Soybean, seed] at [0.05] parts per million (ppm), [Soybean, hulls] at [0.4] parts per million (ppm), [Sugarcane, cane] at [0.01] parts per million (ppm), [Sunflower, seed] at [0.3] parts per million (ppm), [Tomato] at [1.5] parts per million (ppm), and [Tomato, paste] at [5] parts per million2

(ppm). EPA has determined th at the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; 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 n eeded before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. [The registrant has provided plant metabolism studies for apples, spinach and potatoes. Virtually no me tabolism of teflubenzuron was seen in these crops leading to a residues definition of teflubenzuron only for monitoring and risk.

When radiolabelled teflubenzuron formulation is applied to apple tr ees (fruit and leaves) up to 99% of the radioactivity can be extracte d unchanged from the peel and leaf surface up to 72 days after the first application. Therefor e it can be concluded that there are no systemic effects and limited metabolism over this period.

When radiolabelled teflubenzuron formulation is applied to spinach plants, >98% of the radioactivity can be extracted from the leaf surface up to 15 days after the application. After 15 days, 77.1% of the total radioactivit y was present as unchanged teflubenzuron with no single metabolite greater than 10% of the radioactivity present. Therefore, it can

be concluded that there are no systemic effects.

In a second spinach study, unchanged te flubenzuron was the pr edominant residue detected by HPLC analysis of acetone surface rinses and methanol extracts.

Teflubenzuron accounted for 95.6% - 99.9% of the TRR at 15 days after application (DAA) (0.88 - 0.90 mg/kg) and 30 DAA (0.08 - 0.25 mg/kg). Minor unidentified

metabolites were detected at 30 DAA. These did not account for grea ter than 3.2% of the TRR (0.008 mg equiv./kg). This study co nfirms that no significant metabolism of teflubenzuron occurs in spinach and the molecule remains uncleaved.

When radiolabelled teflubenzuron formulation is applied to the leav es of potato plants, more than 98% of the radioactivity can be extracted from leaf surface 63 days after the first application. The total radioactivity was present as unchanged teflubenzuron. No significant residues were detected in potato tubers when radiolabelled formulation was applied to the leaves of potato plants or to the soil. Theref ore it can be concluded that systemic translocation of teflubenzuron is negligible.

In short, the available plant metabolism studi es provide sufficient information regarding

the metabolism of teflubenzur on in all crops and therefore support all of the crops of interest that are subject to this petition

. ]

2. Analytical method. [The proposed enforcement analytical methodology for teflubenzuron has been validated in high oil content, high water content, and high acid content matrices is the Qu EChERS multiresidue method. This method uses high performance liquid chromatography with tandem mass spectrometry detection (HPLCMS/MS).3

The BASF analytical method L0160/01 (analy tical method for determining teflubenzuron and its residues in dry and oily crops by high performance liquid chromatography with tandem mass spectrometry detection) successf ully determines resi dues of teflubenzuron in dry and oily crops. This method has been adequately validated.]

3. Magnitude of residues. [A range of residue trials were conducted in orange, lemon, apple, tomato, melon, broccoli, caulif lower, sunflower, soybean, corn, coffee, sugar cane, mango, papaya, and pineapple. Following are the results for the crops of interest at the respective application rates a nd pre-harvest intervals (PHI). Tolerances have been calculated using the Orga nization for Economic Co-operation and Development – Maximu m Residue Level (OECD-MRL) calculator.

For oranges, 11 field trials are available that were conducted at the critical Good Agricultural Practices (GAP) ra te of 2 x 0.107 lbs. a.i./A and a PHI of 28 days, giving residues ranging from 0.02 - 0.26 ppm. For tefl ubenzuron in oranges a tolerance of 0.6 ppm has been calculated. Plea se note that 23 total orange trials were conducted, with 11 at the critical GAP, 8 at a lower rate, and 4 at a middle rate. The tolerance of 0.6 ppm is

based on residues from the critical GAP trials on ly. Sixteen orange trials are required by EPA for a domestic US registration, however, ba sed on the countries of interest for this import tolerance, eleven trials were determined to be sufficient

.

For lemons, 5 field trials are available that we re conducted at the crit ical GAP rate of 2 x 0.107 lbs. a.i./A and a PHI of 28 days, gi ving residues ranging from 0.06 - 0.36 ppm. For teflubenzuron in lemons, a tolerance of 0.9 pp m has been calculated. Five lemon trials are required by EPA for a domestic US regist ration and therefore th e available data are

sufficient for the countries of interest.

For apples, 12 field trials are av ailable that were conducted at the critical GAP rate of 4 x

0.04 lbs. a.i./A and a PHI of 7 days, giving residues ra nging from 0.06 - 0.29 ppm. For teflubenzuron in apples a tolerance of 0.5 pp m has been calculated. Sixteen apple trials are required by EPA for a domestic US regist ration, however, based on the countries of interest for this import tolerance, twelve trials were determined to be sufficient.

For tomatoes, 12 field trials ar e available that were conducted at the critical GAP rate of 2 x 0.067 lbs. a.i./A and a PHI of 14 days, giving residues ranging from 0.01 - 0.10 ppm.

For teflubenzuron in tomatoes a tolerance of 0.15 ppm has been calculated. However, since the currently proposed European Union (EU) MRL is higher (i.e., 1.5 ppm) than the calculated USA import tolerance of 0.15 ppm, the EU MRL is proposed here as the

tolerance. Sixteen tomato fiel d trials are required by EPA for a domestic US registration, however, based on the countries of interest for this import tolerance, twelve trials were

determined to be sufficient.4

For melons, 8 field trials are available that we re conducted at the crit ical GAP rate of 3 x

0.67 lbs. a.i./A and a PHI of 7 days, giving residues ra nging from 0.04 - 0.19 ppm. For

teflubenzuron in melons a tolerance of 0. 3 ppm has been calculated. Eight melon field trials are required by EPA for a domestic US registration and theref ore the available data

are sufficient for the countries of interest.

For broccoli, 8 field trials are available that were conducted at the crit ical GAP rate of 2 x 0.033 lbs. a.i./A and a PHI of 14 days, gi ving residues ranging from <0.01 - 0.08 ppm.

For teflubenzuron in broccoli a tolerance of 0.2 ppm has been calculated. Eight broccoli trials are required for a domestic US regist ration and therefore the available data are

sufficient for the countries of interest.

For cauliflower, 8 field trials are available that were conducte d at the critical GAP rate of

3 x 0.02 lbs. a.i./A and a PHI of 21 da ys giving residues of <0.01 ppm. For

teflubenzuron in cauliflower a tolerance of 0.01 ppm has been calculated. Eight cauliflower trials are required for a domestic US registration and therefore the available

data are sufficient for th e countries of interest.

For sunflower seed, 8 field trials are availa ble that were conducted at the critical GAP

rate of 2 x 0.011 lbs. a.i./A and a PHI of 7 days, giving residues ranging from <0.01 - 0.13 ppm. For teflubenzuron in sunflower a to lerance of 0.3 ppm ha s been calculated. Eight sunflower trials are required for a domestic US registration and therefore the

available data are sufficient for the countries of interest.

For soybeans, 10 field trials are available that were conducted at the critical GAP rate of 3 x 0.03 lbs. a.i./A and a PHI of 21 days, giving residues ranging from <0.01 - 0.03 ppm. For teflubenzuron in soybeans a tolerance of 0.05 ppm has been calculated. Twenty soybean field trials are required by EPA for a domestic US regist ration, however, based

on the countries of interest fo r this import tolerance, ten tr ials were determined to be

sufficient.

For corn, 8 field trials are available that were conducted at the critical GAP rate of 4 x

0.02 lbs. a.i./A and a PHI of 30 days giving residues of <0.01 ppm. For teflubenzuron in corn a tolerance of 0.01 ppm has been calculated . Twenty corn field trials are required by EPA for a domestic US registration, however, ba sed on the countries of interest for this import tolerance, eight trials were determined to be sufficient.

For coffee, 8 field trials are av ailable that were conducted at the critical GAP rate of 2 x 0.067 lbs. a.i./A and a PHI of 30 days, gi ving residues ranging from <0.01 - 0.29 ppm.

For teflubenzuron in coffee a tolerance of 0.6 ppm has been calculated. Please note that

16 total coffee trials we re conducted, 8 at the critical GAP and 8 at a lower rate. The tolerance of 0.6 ppm is based on residues from the critical GAP trials only. Five coffee field trials are required for a domestic US registration and ther efore the available data are

more than sufficient for the countries of interest.5

For sugarcane, 5 field trials are available that were conducted at the critical GAP rate of 3 x 0.02 lbs. a.i./A and a PHI of 40 days givi ng residues of <0.01 ppm. For teflubenzuron in sugarcane a tolerance of 0.0 1 ppm has been calculated. Eigh t sugarcane field trials are required by EPA for a domestic US regist ration, however, based on the countries of interest for this import tolerance, five tr ials were determined to be sufficient.

For mangoes, 4 field trials are available that were conducted at the cr itical GAP rate of 3 x 0.268 lbs. a.i./A and a PHI of 15 days, giving residues rangin g from 0.41 - 0.48 ppm. For teflubenzuron in mango a tolerance of 1.5 ppm has b een calculated. Three mango field trials are required for a domestic US registration and ther efore the available data are

more than sufficient for the countries of interest.

For papaya, 4 field trials are available that we re conducted at the crit ical GAP rate of 3 x 0.067 lbs. a.i./A and a PHI of 7 days, givi ng residues ranging from 0.04 - 0.19 ppm. For teflubenzuron in papaya a tolerance of 0.4 ppm has been calculate d. Three papaya field trials are required for a domestic US registra tion and therefore the available data are more

than sufficient for the countries of interest.

For pineapple, 8 field trials ar e available that were conducted at a critical GAP rate of 3 x 0.268 lbs. a.i./A and a PHI of 15 days, givi ng residues ranging from 0.07 - 0.36 ppm. For teflubenzuron in pineapple a tolerance of 0. 8 ppm has been calculated. Eight pineapple field trials are required for a domestic US registration and ther efore the available data are

sufficient for the countries of interest.

A range of processing studies were also carri ed out and all relevant studies are included as part of this submission. The processi ng factors included in the risk assessments presented here are: Soybean oil (0.5), tomato puree (0.45), tomato ju ice (0.17), citrus oil (252), citrus juice (0.04), c itrus peel (4.9), dried apple (8.47), apple juic e (0.06), apple sauce (0.18), field corn meal (0.5), field corn starch (0.5), field corn refined oil (1.5), sunflower seed oil (0.1), wine (0.03), roasted coffee (0.2), in stant coffee (0.2), sugarcane molasses (0.5), sugarcane sugar (0.5) and pineapple pulp (0.078).

Residues of teflubenzuron were shown not to hydrolyze under standard processing

conditions.

Fully validated methods of analysis incl uding independent laboratory validation are

available to monitor residues of teflubenzuron in high water, high acid, high oil and high starch content crops.]

B. Toxicological Profile

1. Acute toxicity. [The acute toxicity studies were completed for teflubenzuron and have been placed in EPA Toxici ty Category III for the dermal LD 50 , and EPA Toxicity Category IV for the oral LD 50 , primary dermal irritation, primary eye irritation,

and the inhalation LC 50 . Teflubenzuron was a non-sensitizer when tested for dermal sensitization.]6

2. Genotoxicty. [Teflubenzuron was negative in th e battery of genotoxicity studies including: Ames Salmonella Assay, in vitro CHO cell chromosome aberration assay, HGPRT Point Mutation Assay, unscheduled DNA synthesis (UDS) in primary rat hepatocytes, and in vivo mouse micronucleus.]

3. Reproductive and developmental toxicity. [The following section summarizes two rat developmental studies, three ra bbit developmental st udies and one rat reproduction study conducted for teflubenzuron.

i. Rat developmental toxicity

. For one rat developmental toxi city study at doses of 0, 10, 50, and 250 mg/kg body weight/day (bw/day), te flubenzuron did not induce any increase

in the incidence of malforma tions. Some maternal toxici ty was observed (abortions) in the high dose group. No devel opment effects were seen at an y dose level. Therefore, for this study, the No-Observed-Effect Level (NOEL) for maternal toxicity is 50 mg/kg/day and the NOEL for developmental toxicity is 250 mg/kg/day, the highest dose tested (HDT).

A second rat developmental study at doses of 0, 100, 300, and 1,000 mg/kg bw/day, had no signs of systemic toxicity observed in any group of the treated females. No effects were detected on the maternal gestation parameters. In the fetuses, a tendency was observed for a higher incidence of 14th rib in the high dose group within the context of a higher tendency for an increased frequency of skeletal variations. However, the biological significance of this finding is mitigated by the f act that out of the 21 instances of 14th rib, 11 were concentrated in two dams (4 in one and 7 in the other) and since the

historical control incidence of this finding is in the range of 6.01 to 15.5 %, and considering that the incidenc e of this finding in the hi gh dose group (11.4%) falls within this range, it is concluded that it is not representing an eff ect of the treatment. The NOEL for teratogenicity is 1,000 mg/kg/day, the HDT.

ii. Rabbit developmental toxicity . The first rabbit developm ent toxicity study was at doses of 0, 10, 50, and 250 mg/kg bw/day. Dose s were based on an oral gavage rangefinding study at 250 mg/kg/day. The slightly reduced survival rate and the slightly

increased incidence of minor “malformations " that were observed in the high dose group (250 mg/kg bw/day) may possibly be interp reted as an indication of a minimal embryotoxic/teratogenic effect but since in a supplementary study (see below) a dose of 500 mg/kg/day did not induce similar effects, it is most likely that th ese effects were just spurious and without any biolog ical significance. Evaluation of the skeletal variations did not give any indication of a fetal growth retardat ion or embryotoxic effect. Consequently, the NOEL for this study for maternal toxicity as well as for embryofetotoxicity can be establishe d at 250 mg/kg/day, the HDT.

A second (supplemental) rabbit development to xicity study at doses of 0, 250 and 500 mg/kg bw/day, did not induce any remarkable ma ternal or fetal toxicity or teratogenic effects. Additionally, these doses did not reveal any live r enzyme inducin g potential of the test substance. Therefore, for this study, the NOEL for maternal and embryofetotoxicity is 500 mg/kg/day, the HDT.7

A third rabbit development toxicity study at doses of 0 and 1,000 mg/kg b.w./day, did not elicit remarkable maternal nor embryotoxicity . No malformations were recorded. The NOEL for maternal and fetal toxicity is 1,000 mg/kg/day, the HDT.

iii. Rat reproduc tive toxicity . A 2–generation rat reproduction study at doses of 0, 20, 100, and 500 ppm yielded a NOAEL of 500 ppm hi ghest concentration tested (HCT) (25 mg/kg bw/day). No evidence of systemic toxic effects was noted in this study.]

4. Subchronic toxicity. [ i . A 90–day dietary study in rats at doses of 0, 100 (8.0M, 9.1F), 1,000 (81.5M, 94.0F), or 10,000 (809M, 94 2.4F) ppm, resulted in a No-ObservedAdverse-Effect Level (NOAEL) at the mid-dose of 1,000 ppm (equivalent to 81.5 mg/kg/day in males and 94.0 mg/kg/day in fema les) based on the ef fects observed on the liver enzymes at 10,000 ppm. In this study, the liver was identified as the target organ in

both males and females.

ii. A 90–day dietary study in mice at doses of 0, 100 (11.05M mg/kg, 13.7F mg/kg), 1,000 (115.3M mg/kg, 143.1F mg/kg), or 10,000 (1213M mg/kg, 1450F mg/kg) ppm was

based on dose levels establishe d on the basis of the result s of a 4-week range finding study at 100-500, 1,000-5,000 and 10,000 ppm. The re sults of this study have shown that the liver is the target organ in both male and female mice. A NO EL was established at 100 ppm (equivalent to 11.05 and 13.7 mg/kg/day for males and females respectively)

based on the liver effects seen at the mid-dose level of 1,000 ppm.

iii. A 90–day dietary study in dogs at doses of 0, 100 (3.2 mg/kg), 1,000 (30.4 mg/kg), or 10,000 (323 mg/kg) ppm, showed slight to mode rate hepatotoxicity at 10,000 ppm, the HDT. The liver was identified as the target organ. Additionally, teflubenzuron showed that it has irritant properties for the gastri c mucosae. The NOEL ha s been established at 1,000 ppm (equivalent to 30.4 mg/kg for ma les and females), based on mild and

occasional effects seen on the liver at 10,000 ppm (increased liver enzyme activity).

iv. A supplemental 90-day dietary study in dogs was conducted at 0, 30 (1.15 mg/kg), and 100 (4.10 mg/kg) ppm to confirm the results of the previous study. The doses were

selected on the basis of result s of the previous 90-day diet ary study in dogs during which one animal in the 100 ppm group showed some slight changes in the liver resembling those seen in the high dose group (10,000 ppm) whereas thes e changes were not seen in the intermediate group exposed to 1,000 ppm. In this supplemental study, a minor reduction in food consumption at all doses was seen and was not considered as treatment related. In addition, a slight, non-statistically significant reduction in body weight gain

was seen in treated females w ithout any dose effect relationshi p. It would seem that both

of these effects are most li kely not due to the treatmen t, but instead resulted as a consequence of the change in the batch of feed used afte r week five. Diarrhea and vomiting were also seen thr oughout the study. Based upon the results, the NOAEL is above the highest administered dietary c oncentration of 100 ppm (equivalent to 4.1 mg/kg bw/day for males and females).]

5. Chronic toxicity. [ i. A 1–year chronic toxicity study in dogs at doses of 0, 308

(0.98M mg/kg, 1.16F mg/kg), 100 (3.15M mg/kg, 4.02F mg/kg), or 500 ppm (17.3M mg/kg, 17.98F mg/kg) yielded a NOAEL of 50 0 ppm (equivalent to approximately 17.3 mg/kg/day for male dogs and approximately 17.98 mg/kg/day for the female dogs), the HCT. The liver is identified as the target organ.

ii. A 2–year chronic toxicity/carcinogenicity study in rats at doses of 0, 20, 100, 500 ppm provided NOELs for both systemic toxicity a nd oncogenicity. For th e chronic phase of the study, the doses of 20, 100, and 500 ppm correspond to 1.1M mg/kg and 1.3F mg/kg, 5.4M mg/kg and 6.5F mg/kg), and 27.6M mg /kg and 32F mg/kg, respectively. For the oncogencity phase of the stud y the doses correspond to 1.0M mg/kg and 1.2F mg/kg, 4.8M mg/kg and 5.9 mg/kg), and 24.8M mg/kg and 29.9F mg/kg, respectively. For chronic toxicity, the changes observed in so me of the clinical chemistry parameters reflect marginal hepatotoxicity in males of the high dose group. No histopathological

alterations were noted in the liver. The mid-dose level of 100 ppm is equivalent to an average intake of 5.4 and 6.5 mg/kg/day for ma les and females respectively. This dose level is considered as the NOEL for chronic toxicity.

For the evaluation of oncogenicity in this stud y, a statistically significant increase in the incidence of mesenteric ly mph node hemangiomas was obser ved for males of the high dose group when compared to th e controls. The hist orical control data for this type of

tumor show that the incidence rate in the concurrent control gr oup was lower than the

historical control values and that the incidenc e rate in the high dose group was within the historical control range. Usi ng the historical “time to tumor” data for male controls, there was no evidence to suggest that teflubenzur on caused an earlier development of benign mesenteric hemangiomas. Therefore, it is possible to conclude that the difference observed between high dose and control male s in this study is not toxicologically significant. Pancreatic exocrine carcinomas are occasionally observed in untreated aged rats. In this study, this type of tumor wa s observed in one female of the mid dose group and in two males of the high dose group. B ecause of the very low incidence of that tumor, it was considered that they were not tr eatment-related. The results of this study did not show any evidence of a carcinogeni c potential of teflube nzuron. The NOEL for carcinogenicity is 1,000 ppm (equivalent to 24.8 and 29.9 mg /kg bw/day for males and females respectively), the HDT.

iii. A second 2–year chronic toxicity/carcinoge nicity study in rats at doses of 0, 2,500 (122.5M mg/kg, 154.0F mg/kg), and 10,000 (487.3M mg/kg, 615.2F mg/kg) ppm was

conducted with 104 weeks treatment for the chr onic toxicity phase, and 111 weeks for the carcinogenicity phase. The results confirm that the liver is the target organ and that the hepatotoxic effects induced at 2,500 and 10,000 pp m are limited. The changes in plasma concentration levels were actually dose re lated and evidence for a plateau in plasma

levels was not established for the current dose levels of 2,500 and 10,000 ppm. Females appeared to be less susceptible. The occurrence of adenocar cinomas of the uterus in the high dose group at an incidence of 10% compared to no tumors in the concurrent control

females was not considered to be treatment re lated in view of a c ontrol incidence of 8% noted in the previous chronic toxicity/oncogenicity study. The results of the present study confirm that the statistically signific ant increase in the in cidence of mesenteric9

lymph node hemangiomas that was observed in males at 500 ppm in the previous study

was not treatment related as no such tumors we re observed in the treated animals of this study, whereas an incidence of 12 and 16% was noted in male and female controls, respectively.

Similarly, the occurrence of pancreatic exocrine carcinom as in one female at 100 ppm and two males at 500 ppm in the previous study are likely unrelated to the test substance in view of the results of the present study w ith much higher dietar y concentrations, which only reported one pancreatic exocrine carc inoma (in a male) at the mid-dose of 2,500 ppm and none at the 10,000 ppm dose level. Therefore, it can be concluded that teflubenzuron is not carcinogenic in rats under the conditions of this test, including 10,000 ppm (equivalent to 487.3 and 615.2 mg/kg/day for males and females respectively), the HDT.

iv. An 18–month oncogenicity study in mice at doses of 0 , 15 (2.1M mg/kg, 3.1F mg/kg), 75 (10.5M mg/kg, 15.4F mg/kg), or 375 ppm (53.6 mg/kg, 71.7 mg/kg) ,

confirmed that the liver is th e target organ for hepatotoxici ty as well as for oncogenicity. Chronic dietary exposure of mice to teflubenz uron induced a limited increased incidence

of liver adenomas. The NOEL for chr onic toxicity is 15 ppm (equivalent to approximately 2.1 and 3.1 mg/kg/day fo r males and females respectively).

The NOEL for carcinogenicity is 75 ppm (equivalent to 10.5 a nd 15.4 mg/kg/day for males and females respectively).]

6. Animal metabolism: [Three oral metabolism studies in rats were conducted to investigate the metabolism of teflubenzuron in animals. Two of the studies dosed at 25 mg/kg and the third dosed at 25 mg/kg and 750 mg/kg. In addition, a bile duct canulation study was conducted at 25 mg/kg and 750 mg/kg. The relevant results of the studies are

summarized below.

i. Rat: When orally administered to rats, te flubenzuron is rapidly and completely excreted, mostly in the feces, approximately 90% and 93% of the administered dose in males and females, respective ly. An oral dose of 25 mg/kg administered daily over a period of seven days is quickly and complete ly eliminated. Two days after the last treatment, no residues exceeding 0.05 % of the ad ministered radioactivity are detected in the tissues and organs, except in the liver (0.1 to 0.2%). Teflubenzuron is mostly eliminated as the unchanged parent molecule. The excretion pattern is similar in males and females. Only small amount s of radioactivity were detect ed in the urine (< 1 % of the administered dose) and in the carcasses (< 0.01% of the high dose of 750 mg/kg bw). Apart from the parent compound, only sma ll amounts of metabolites are detected, consisting of polar substances. One of th em has been identified as 3,5-dichloro-2,4- difluorophenylurea (CL 902374) in some feces extracts.

In addition, a bile duct canulation study has sh own that the summation of radioactivity in urine, bile, and liver indicated a total ra te of absorption of 18% and 2% of the administered dose at low (25 mg/kg bw) a nd high (750 mg/kg bw) doses, respectively.10

Therefore, teflubenzuron has an overall rate of gastro-intestinal absorption of less than

20% of the administered dose. The metabolic pathway is via meta-hydroxylation of the benzoyl ring and conjugation. Only very sm all amounts of radioactivity correspond to the hydroxylated aniline derivatives. Scission of the benzoyl ureido function represents an additional pathway of degradat ion. Please see Figure 1 belo w (Section D. I. B.) for the proposed metabolic pathway in rats.

ii. Ruminant: Aniline-UL-14C teflubenzuron (ra diochemical purity 97.7 %) was administered orally to two lactating goats, tw ice daily for seven and a half days at a dose rate of 1 mg/kg bw/day (25 ppm diet). Urine and feces were collected every 24 h at which time cages were washed and washings were retained. Milk was coll ected twice daily and blood samples taken at 0, 0.5, 1, 2, 3, 4 and 6 h following the initial dose and prior to each subsequent dose. The goats were sacrific ed 8 h after the final dose. All samples were analyzed by LSC. Feces, liver and bile samples were extracted with methanol and a further bile sample by enzymatic hydrolysis prior to methanol extraction. Extracts were analyzed by HPLC or TLC.

Overall recovery of radioactivity was >100%; the bulk of the radioactivity was excreted (>99%), with less than 0.04 % in the milk a nd less than 0.3 % in the tissues. Total [14C] residues in the milk (expressed as parent e quivalent) reach a plateau after five days of 0.013 mg a.s./L. The extraction efficiency in whole milk samples wa s reported as 64.2% of the total radioactivity. Total [14C] re sidues in the tissues (expressed as parent equivalent) were 0.486, 0.080, 0.034 and 0.010 mg/kg in liver, fat, kidney, and muscle respectively.

On characterization of the extr actable radioactivity (feces only) the major component was identified as the parent teflubenzuron representing 76.9 and 83.3 % by radio-HPLC and radio-TLC, respectively. A further metabolite was identified by both methods as 1-(3,5- dichloro-2,4-difluorophenyl)-3 -(2,6-difluoro-3-hydroxybenzy l)-urea (Metabolite 3381) at 3.6-3.8 % for HPLC and TLC, respecti vely. A second unknown metabolite was determined by HPLC and accounted for 6%, a nd a further 2.1% of the radioactivity was not resolved from the origin by TLC. The remaining unextractable radioactivity accounted for 4% (0.28 mg/kg) of th e total radioactivity in feces.

A subsequent study was carried out to further characterize the radioactivity occurring in the feces, liver, and milk fro m the initial study. The study confirmed the identity of the major radioactive component in feces as pare nt teflubenzuron. Goat liver extracts were analyzed by TLC but due to the low levels of radioactivity present, identification of the radioactive species was inc onclusive. Analysis by HPLC showed that the major radioactive peak in the liver extract was a polar compound retained at the origin. The enzyme digest sample showed traces of material which chromatographed with 1-(3,5- dichloro-2,4-difluorophenyl)-3-(2,6-difluro-3-h ydroxy benzyl) urea (Metabolite 3381) in one TLC system. Further attempts were ma de to increase extraction efficiency using solvents, proteolytic digestion and acid hy drolysis; however success was limited and indicated that the radioactivity was bound to proteins within the liv er. Overall extraction efficiency in liver was 58.3% of the total radioactivity. Analysis of milk extracts by TLC11

showed the presence of teflubenzuron and a large amount of pola r material. Further attempts to resolve this ma terial into separate compounds following acid hydrolysis produced no interpretable results due to th e low amounts (<0.015 mg/L ) of radioactivity present. As in the previous study no radioact ive components were identified as having the same characteristics as either 3,5-dichloro- 2,4-difluouroalanine (Metabolite El4) or 3,5- dichloro-2,4-difluorophenyl- urea (Metabolite EI5).

iii. Poultry: Aniline-UL-14C-teflubenzuron (rad iochemical purity 97.7 %) was administered orally to eighteen laying hens , twice daily for seven and a half days at a dose rate of 1.25 mg/kg/day (25 ppm diet) (9.375 mg/kg total dose). Excreta were collected every 24 h at which time cages were washed and washings were retained. Eggs were collected twice daily fro m 6 hens throughout the dosing period and for 12 days after the final dose. Blood samples were taken at 0, 0.5, 1, 2, 3, 4, 8, 12 and 24 h following the initial dose and every 24 h thereafter. The hens were sacrificed 8 h after the final dose and selected organs, tissues and body fluids we re retained for analysis. Radioactivity in all samples was analyzed by LSC. Excreta, liver, fat, egg yolk and bile samples were extracted with methanol prior to analysis by HPLC or TLC.

Overall recovery of radioactivity was 95.6 %; the bulk of the radioactivity was excreted (93.9%), with less than 0.01 % in the eggs and less than 0.4 % in the tissues. Total [14C] residues in the egg yolk and white (expressed as parent equivalent) reach a plateau after 9 days of 0.008 mg/kg and 0.0003 mg/kg respective ly. Total [14C] residues in the tissues (expressed as parent equivalent) we re 0.0075, 0.0015, 0.0002 and 0.00004 mg/kg in liver, fat, skin and muscle, respectively.

The major route of elimination of total radioactivity was vi a excreta (including intestine and crop contents at post mort em) accounting for 93.5% of th e total administered dose. The remaining extractable radioactivity accounted for 3% (0.25 mg/kg) of the total radioactivity in feces. On characterization of the extractable radioactivity in the egg yolk, the major component was identified as th e parent teflubenzuron, representing 62.2% of the radioactivity present. Tw o further minor radioactive components were observed, each accounting for 4.8% and 6.6% of the TRR. Neither compone nt had similar retention times to any of the standard substances. The remaining unextractable radioactivity in eggs was 8% (0.00062 mg/kg) of the to tal radioactivity present in eggs. The major radioactive component in liver was parent teflubenzu ron which accounted for 30.2 % of the TRR. Two further radio-peaks were present each a ccounting for 12.7 and 8.5 % of the TRR. In fat, teflubenzuron accounted for 79. 1% TRR and a second radioactive component was observed that accounted for 8.7% TRR. The remaining unextractable radioactivity in liver and fat accounted for 30% and 6% (0.0022 and 0.00009 mg/kg) of the total radioactivity respectively. Radioa ctivity in muscle and egg white was not sufficiently high to enable any characterization.

A subsequent study was carried out to further characterize the radioactivity occurring in the excreta, liver, fat, and egg yolk from th e initial study. The excreta extracts were analyzed by MS and the radioactivity in the other extracts by TLC and HPLC, and quantified by LSC. The study confirmed the identity of the major radioactive component12

in feces, yolk and fat as parent teflubenzu ron. Liver extracts mainly contained parent teflubenzuron and a polar compound which was compared to an enzyme treated sample and shown not to be a conjug ate. No material with chromatographic characteristics comparable to either 3,5-dichloro-2,4-difl uoroalanine or 3,5-dichloro-2,4-difluorophenyl urea were observed by both TLC and HPLC . Kidney extracts contained teflubenzuron and trace amounts (0.02 mg/kg) of a material which co-c hromatographed on TLC and HPLC with 3,5-dichloro-2,4-difluorophenyl-ur ea (Metabolite El5). Overall extraction efficiency in liver was >75% and was >90 % in ki dney, egg yolk, and fat.]

7. Acute neurotoxicity. [An acute neurotoxicity study was conducted with teflubenzuron (98.6% purity). In this st udy Wistar rats (10/sex/dose level) were

administered teflubenzuron via or al gavage at dose levels of 0 (vehicle control), 125, 500, or 2000 mg/kg bw/day. The animals were observed up to two weeks after dosing. The general state of health of the rats was ex amined daily. Body weight determinations, functional observational batteries (FOBs) a nd motor activity measur ements (MA) were carried out seven days prior to and on day of the administration as well as seven and 14 days thereafter. At the end of the study five animals per sex and test group were fixed by in situ perfusion and subjected to neuropathological examin ations. No adverse effects

attributable to the test substance were re ported at any dose level. The NOAEL was identified as 2000 mg/kg/day for both male and female rats, the highest dose tested (HDT).]

8. Subchronic neurotoxicity. [A subchronic neurotoxic ity study was conducted with teflubenzuron (98.6% purity). In this st udy Wistar rats (10/ sex/dose level) were

administered teflubenzuron via the diet at dose levels of 0 (veh icle control), 100, 300, or 1000 mg/kg bw/day for 13 weeks. Food c onsumption was determined once a week. Body weight was measured once a week a nd on days when functional observational batteries (FOBs) and motor activity measurem ents (MA) were carried out. The animals were examined for toxicity or mortality at least once a day. Detailed clinical examinations in an open fiel d were conducted prior to th e start of test substance administration and weekly thereafter. FOBs and MAs were conducte d on one week prior to test substance administration, and on days 1, 22, 50, and 85 of the study. Five animals per sex and test group were fixed by in situ perfusion and subjected to neuropathological

examinations. No adverse ne urobehavioral or neuropatholog ical effects attributable to the test substance were repor ted at any dose level. The NOAEL was identified as 1000 mg/kg/day for both male and female ra ts, the highest dose tested (HDT).]

9. Immunotoxicity. [A 28-day immunotoxicity study was conducted with teflubenzuron (98.6% purity). In this study male C57BL/6 J Rj mice (8/dose level) were

administered teflubenzuron at dose levels of 0 (vehicle control) , 200, 1000, or 5000 ppm (44, 218, or 1059 mg/kg bw/day) via the diet. A positive control group consisting of eight male C57BL/6 J Rj mice received cy clophosphamide monohydrate at a dose level of 10 mg/kg bw/day. Animals were treated for 4 weeks continuously. All animals were immunized six days before blood sampling and necropsy using 0.5 mL sheep red blood cells (4x108 SRBC/mL) administered intr aperitoneally. Food consumption and body weight were determined weekly. The animal s were examined for signs of toxicity or13

mortality at least once a day. Detailed cl inical examinations in an open field were conducted prior to the start of test substance administra tion and weekly thereafter. Measurement of the SRBC IgM antibody titers was performed at the end of the study. Additionally, all animals were assessed by gross pathology and the organ weights of the spleen and thymus were measured and recorded. In the positive control group (cyclophosphamide monohydrate), body weight was significantly decreased from study day 7 to 28, with a body weight loss between study days 0 and 7, SRBC IgM antibody titers were significantly lowered, terminal body weight was significantly reduced, and absolute and relative spleen and thymus weig hts were significantly reduced. No adverse immunotoxicologically relevant or system ic toxicity endpoints attributable to teflubenzuron were reported at any dose le vel. The NOAEL was identified as 5000 ppm (1059 mg/kg bw/day), the highest dose tested (HDT).]

10. Metabolite toxicology. [Acute oral toxicity and mutagenicity studies were

conducted in two teflubenzuron metabolites.

i. Acute oral toxicity. An acute oral toxicity study wa s conducted on the metabolite 3,5- dichloro-2,4-difluoroanili ne (CL 902373) at doses of 1500, 1800 and 2000 mg/kg, and yielded an LD50 of 1986 mg/kg fo r males and 1,552 mg/kg for females.

An acute oral toxicity study was cond ucted on the metabolite 3,5-dichloro-2,4 difluorophenylurea (metabolite 3381) at doses of 300, 390, 507, 659, 857, or 1114 mg/kg bw, and yielded an LD50 of 677 mg/kg bw for males and 703 mg/kg bw for females.

ii. Mutagenicity. An Ames Salmonella Assay was conducted on the metabolite 2,4- difluoro-3,5-dichloroaniline (CL 902373), and under the conditions of this test, it did not induce any chromosome damage.

An Ames Salmonella Assay was conduct ed on the metabolite 3,5-dichloro-2,4 difluorophenylurea (metabolite 3381) and under th e conditions of this test, it did not induce any chromosome damage.]

11. Endocrine disruption

. [ No special studies investig ating potential endocrine

effects of teflubenzuron have been conduc ted. However, no evidence of endocrine disruption-like effects have been reported in the battery of toxicity studies which have been conducted with teflubenzuron. Therefore, there is no reason to expect that any such effects would be likely.]

C. Aggregate Exposure

1. Dietary exposure. [Import tolerances are proposed for residues of teflubenzuron on the following raw agricultural commodities and processed fractions: orange; lemon; citrus oil; apple; apple, wet pomace; tomato; tomato, paste; melon; broccoli; cauliflower; sunflower seed; soybean; soybean, hulls; corn, field; corn, field, refined oil; coffee, bean, green; sugarcane, cane; mango; papaya; and pineapple. Secondary tolerances are proposed for residu es in cattle, muscle; cattle, meat byproducts;14

goat, muscle; goat, meat byproducts; hor se, muscle; horse, meat byproducts; pork, muscle; pork, meat byproducts ; sheep, muscle; sheep, meat byproducts; milk; poultry, muscle; poultry, meat byproducts; and egg.

For the purposes of assessing the potential dietary exposure, an exposure assessment including all of the above cr ops, meat, milk, and eggs was conducted using the Dietary Exposure Evaluation Model-Food Consumption Intake Database (DEEM-FCID) software, consumption data derived from the 2003-2008 National He alth and Nutrition Examination Survey (NHANES), and average an ticipated residues as calculated from residue field trial data. Estimated potential concentrations in drinking water were not incorporated into the dietary exposure assessm ent because there are no domestic uses of teflubenzuron and therefore no residues in water.]

i. Food. [ Acute Dietary Exposure: There is no acute population adjusted dose (aPAD) for teflubenzuron, so an acute diet ary exposure assessment was not conducted.

Chronic Dietary Exposure. The chronic population ad justed dose (cPAD) of 0.01 mg/kg bw/day was used to characterize risk associated with chronic dietary exposures. BASF has conducte d a chronic dietary exposure analysis with DEEM-FCID using the average residues from field trials for all commodities that are the subject of this petition. Additional assumptions include 100% crop treated and default processing factors, except where empirical processing fact ors were available. Empirical processing factors are available for soybean oil (0.5), toma to puree (0.45), tomato juice (0.17), citrus oil (252), citrus juice (0.04), citrus peel (4.9 ), dried apple (8.47), a pple juice (0.06), apple sauce (0.18), field corn meal (0.5), field corn starch (0.5), field corn refined oil (1.5), sunflower seed oil (0.1), wine (0.03), roasted coffee (0.2), in stant coffee (0.2), sugarcane molasses (0.5), sugarcane sugar (0.5) and pine apple pulp (0.078). Antic ipated residues in

livestock commodities were assumed to be 0.01 ppm based on the proposed EU

tolerances for these commodities . Potential residues in wa ter were not included because there are no proposed or registered domestic uses. The chronic dietary assessment was conducted for the overall US population and se lect subpopulations (i .e., all infants <1 year old, children aged 1-2 years old, chil dren aged 3-5 years old, children aged 6-12 years old, youths aged 13-19 years old, adults aged 20-49 years old, adults 50+ years old, and females aged 13-49 years old) . The results of this chronic analysis indicate that the most highly exposed population is children aged 1-2 years ol d, with an estimated chronic dietary exposure of 0.002442 mg/kg bw/day, which corresponds to 24.4% of the cPAD. For the overall US population, the chr onic exposure is calculated to be 0.000626 mg/kg bw/day, which corres ponds to 6.3% of the cPAD.]

ii. Drinking water. [Since this will be an import to lerance use only, drinking water exposures are not relevant.]

2. Non-dietary exposure. [Teflubenzuron is currently not registered for use on any residential non-food site. Therefore, reside ntial exposure to teflubenzuron residues will be through dietary exposure only.]15

D. Cumulative Effects

[Teflubenzuron is a member of the benz oylurea class of insecticides. Other members of this class are registered for us e in the United States. Although teflubenzuron and other benzoylureas may have similar insecticidal modes of action, there are no

available data to determine whether te flubenzuron has a common mechanism of mammalian toxicity with other benzoylureas or information on how to include this pesticide in a cumulative risk assessment. Th erefore, for the purposes of this tolerance petition no assumption has been made with regard to cumulative exposure with other compounds having a comm on mode of action.]

E. Safety Determination

1. U.S. population . [Using the conservative ex posure assumptions described

above and based on the completeness of the toxicity data base, it can be concluded that dietary exposure to teflubenzuron from all proposed import crop uses will be 6.3% of the cPAD for the overall US popula tion. EPA generally has no concern for exposures below

100% of the PAD because the PAD represents the level at or below which daily aggregate exposures wi ll not pose appreciabl e risks to human health. Thus, it can be

concluded that there is a re asonable certainty that no harm will result from aggregate exposure to residues arising from the proposed tolerances that are the subject of this petition.]

2. Infants and children. [Using the conservative expos ure assumptions described

above and based on the completeness of the toxicity data base, it can be concluded that dietary exposure to teflubenzuron from all proposed import crop uses will be ≤ 24.4% of

the cPAD for infants and childr en. Since no reproductive or developmental issues have been identified in any of the studies, an a dditional FQPA safety factor is not necessary.]

F. International Tolerances

[There are established Code x and European Union MRLs.]