i

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

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

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In 

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

maintain the outline. Please do not change 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 tolerance 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 million
2 

(ppm). EPA has determined that 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 needed 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 metabolism 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 trees (fruit and leaves) 

up to 99% of the radioactivity can be extracted unchanged from the peel and leaf surface 

up to 72 days after the first application. Therefore 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 radioactivity 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 teflubenzuron was the predominant 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 greater than 3.2% of the 

TRR (0.008 mg equiv./kg). This study confirms that no significant metabolism of 

teflubenzuron occurs in spinach and the molecule remains uncleaved.

When radiolabelled teflubenzuron formulation is applied to the leaves 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. Therefore it can be concluded that 

systemic translocation of teflubenzuron is negligible.

In short, the available plant metabolism studies provide sufficient information regarding 

the metabolism of teflubenzuron 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 QuEChERS multiresidue method. This method uses high 

performance liquid chromatography with tandem mass spectrometry detection (HPLCMS/MS).
3 

The BASF analytical method L0160/01 (analytical method for determining teflubenzuron 

and its residues in dry and oily crops by high performance liquid chromatography with 

tandem mass spectrometry detection) successfully determines residues 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, cauliflower, sunflower, soybean, corn, coffee, 

sugar cane, mango, papaya, and pineapple. Following are the results for the crops of 

interest at the respective application rates and pre-harvest intervals (PHI). Tolerances 

have been calculated using the Organization for Economic Co-operation and

Development – Maximum Residue Level (OECD-MRL) calculator.

For oranges, 11 field trials are available that were conducted at the critical Good 

Agricultural Practices (GAP) rate 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 teflubenzuron in oranges a tolerance of 0.6 

ppm has been calculated. Please 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 only. Sixteen orange trials are required by 

EPA for a domestic US registration, however, based on the countries of interest for this 

import tolerance, eleven trials were determined to be sufficient.

For lemons, 5 field trials are available that were conducted at the critical GAP rate of 2 x

0.107 lbs. a.i./A and a PHI of 28 days, giving residues ranging from 0.06 - 0.36 ppm. For 

teflubenzuron in lemons, a tolerance of 0.9 ppm has been calculated. Five lemon trials 

are required by EPA for a domestic US registration and therefore the available data are 

sufficient for the countries of interest.

For apples, 12 field trials are available 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 ranging from 0.06 - 0.29 ppm. For 

teflubenzuron in apples a tolerance of 0.5 ppm has been calculated. Sixteen apple 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.

For tomatoes, 12 field trials are 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 field 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 were conducted at the critical GAP rate of 3 x

0.67 lbs. a.i./A and a PHI of 7 days, giving residues ranging 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 therefore the available data 

are sufficient for the countries of interest.

For broccoli, 8 field trials are available that were conducted at the critical GAP rate of 2 x

0.033 lbs. a.i./A and a PHI of 14 days, giving 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 registration and therefore the available data are 

sufficient for the countries of interest.

For cauliflower, 8 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 21 days 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 the countries of interest.

For sunflower seed, 8 field trials are available 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 tolerance of 0.3 ppm has 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 registration, however, based 

on the countries of interest for this import tolerance, ten trials 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, based on the countries of interest for this 

import tolerance, eight trials were determined to be sufficient.

For coffee, 8 field trials are available that were conducted at the critical GAP rate of 2 x

0.067 lbs. a.i./A and a PHI of 30 days, giving 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 were 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 therefore 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 giving residues of <0.01 ppm. For teflubenzuron

in sugarcane a tolerance of 0.01 ppm has been calculated. Eight sugarcane field trials are 

required by EPA for a domestic US registration, however, based on the countries of 

interest for this import tolerance, five trials were determined to be sufficient.

For mangoes, 4 field trials are available that were conducted at the critical GAP rate of 3 

x 0.268 lbs. a.i./A and a PHI of 15 days, giving residues ranging from 0.41 - 0.48 ppm. 

For teflubenzuron in mango a tolerance of 1.5 ppm has been calculated. Three mango 

field trials are required for a domestic US registration and therefore the available data are 

more than sufficient for the countries of interest.

For papaya, 4 field trials are available that were conducted at the critical GAP rate of 3 x

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

teflubenzuron in papaya a tolerance of 0.4 ppm has been calculated. Three papaya field 

trials are required for a domestic US registration and therefore the available data are more 

than sufficient for the countries of interest.

For pineapple, 8 field trials are available that were conducted at a critical GAP rate of 3 x

0.268 lbs. a.i./A and a PHI of 15 days, giving 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 therefore the available data are 

sufficient for the countries of interest.

A range of processing studies were also carried out and all relevant studies are included 

as part of this submission. The processing factors included in the risk assessments 

presented here are: Soybean oil (0.5), tomato puree (0.45), tomato juice (0.17), citrus oil 

(252), citrus juice (0.04), citrus peel (4.9), dried apple (8.47), apple 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), instant 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 including 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 Toxicity Category III for the dermal LD50, and EPA 

Toxicity Category IV for the oral LD50, primary dermal irritation, primary eye irritation, 

and the inhalation LC50. Teflubenzuron was a non-sensitizer when tested for dermal 

sensitization.]
6 

2. Genotoxicty. [Teflubenzuron was negative in the 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 rabbit developmental studies and one rat 

reproduction study conducted for teflubenzuron.

i. Rat developmental toxicity. For one rat developmental toxicity study at doses of 0, 10,

50, and 250 mg/kg body weight/day (bw/day), teflubenzuron did not induce any increase 

in the incidence of malformations. Some maternal toxicity was observed (abortions) in 

the high dose group. No development effects were seen at any 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 fact 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 incidence of this finding in the high dose group (11.4%) falls within

this range, it is concluded that it is not representing an effect of the treatment. The NOEL

for teratogenicity is 1,000 mg/kg/day, the HDT.

ii. Rabbit developmental toxicity. The first rabbit development toxicity study was at 

doses of 0, 10, 50, and 250 mg/kg bw/day. Doses 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 interpreted 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 these effects were just 

spurious and without any biological significance. Evaluation of the skeletal variations 

did not give any indication of a fetal growth retardation or embryotoxic effect. 

Consequently, the NOEL for this study for maternal toxicity as well as for embryofetotoxicity can be established at 250 mg/kg/day, the HDT.

A second (supplemental) rabbit development toxicity study at doses of 0, 250 and 500 

mg/kg bw/day, did not induce any remarkable maternal or fetal toxicity or teratogenic 

effects. Additionally, these doses did not reveal any liver enzyme inducing 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 reproductive toxicity. A 2–generation rat reproduction study at doses of 0, 20,

100, and 500 ppm yielded a NOAEL of 500 ppm highest 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, 942.4F) 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 females) based on the effects 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 established on the basis of the results of a 4-week range finding

study at 100-500, 1,000-5,000 and 10,000 ppm. The results of this study have shown that 

the liver is the target organ in both male and female mice. A NOEL 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 moderate 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 gastric mucosae. The NOEL has been established at

1,000 ppm (equivalent to 30.4 mg/kg for males 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 results of the previous 90-day dietary 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 these 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 without any dose effect relationship. It would seem that both 

of these effects are most likely not due to the treatment, but instead resulted as a 

consequence of the change in the batch of feed used after week five. Diarrhea and 

vomiting were also seen throughout the study. Based upon the results, the NOAEL is 

above the highest administered dietary concentration 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, 30
8 

(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 500 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 and oncogenicity. For the 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 study 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 some 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 males and females respectively. This dose 

level is considered as the NOEL for chronic toxicity.

For the evaluation of oncogenicity in this study, a statistically significant increase in the 

incidence of mesenteric lymph node hemangiomas was observed for males of the high 

dose group when compared to the controls. The historical control data for this type of 

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

historical control values and that the incidence rate in the high dose group was within the 

historical control range. Using the historical “time to tumor” data for male controls, there 

was no evidence to suggest that teflubenzuron caused an earlier development of benign 

mesenteric hemangiomas. Therefore, it is possible to conclude that the difference 

observed between high dose and control males in this study is not toxicologically 

significant. Pancreatic exocrine carcinomas are occasionally observed in untreated aged 

rats. In this study, this type of tumor was observed in one female of the mid dose group 

and in two males of the high dose group. Because of the very low incidence of that

tumor, it was considered that they were not treatment-related. The results of this study 

did not show any evidence of a carcinogenic potential of teflubenzuron. 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/carcinogenicity 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 chronic 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 ppm are limited. The changes in plasma 

concentration levels were actually dose related 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 adenocarcinomas 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 related in view of a control incidence of 8% 

noted in the previous chronic toxicity/oncogenicity study. The results of the present 

study confirm that the statistically significant increase in the incidence of mesenteric
9 

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

was not treatment related as no such tumors were 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 carcinomas 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 with much higher dietary concentrations, which 

only reported one pancreatic exocrine carcinoma (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 the target organ for hepatotoxicity as well as for oncogenicity. 

Chronic dietary exposure of mice to teflubenzuron induced a limited increased incidence 

of liver adenomas. The NOEL for chronic toxicity is 15 ppm (equivalent to 

approximately 2.1 and 3.1 mg/kg/day for males and females respectively).

The NOEL for carcinogenicity is 75 ppm (equivalent to 10.5 and 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, teflubenzuron is rapidly and completely 

excreted, mostly in the feces, approximately 90% and 93% of the administered dose in 

males and females, respectively. An oral dose of 25 mg/kg administered daily over a 

period of seven days is quickly and completely eliminated. Two days after the last 

treatment, no residues exceeding 0.05 % of the administered 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 amounts of radioactivity were detected 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 small amounts of metabolites are detected, 

consisting of polar substances. One of them has been identified as 3,5-dichloro-2,4- 

difluorophenylurea (CL 902374) in some feces extracts.

In addition, a bile duct canulation study has shown that the summation of radioactivity in 

urine, bile, and liver indicated a total rate of absorption of 18% and 2% of the 

administered dose at low (25 mg/kg bw) and 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 small amounts of radioactivity correspond to the 

hydroxylated aniline derivatives. Scission of the benzoyl ureido function represents an 

additional pathway of degradation. Please see Figure 1 below (Section D. I. B.) for the 

proposed metabolic pathway in rats.

ii. Ruminant: Aniline-UL-14C teflubenzuron (radiochemical purity 97.7 %) was 

administered orally to two lactating goats, twice 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 collected 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 sacrificed 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 and less than 0.3 % in the tissues. Total [14C] 

residues in the milk (expressed as parent equivalent) reach a plateau after five days of

0.013 mg a.s./L. The extraction efficiency in whole milk samples was reported as 64.2% 

of the total radioactivity. Total [14C] residues 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 extractable 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-hydroxybenzyl)-urea (Metabolite 3381) at

3.6-3.8 % for HPLC and TLC, respectively. A second unknown metabolite was 

determined by HPLC and accounted for 6%, and 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 the total radioactivity in feces.

A subsequent study was carried out to further characterize the radioactivity occurring in 

the feces, liver, and milk from the initial study. The study confirmed the identity of the 

major radioactive component in feces as parent teflubenzuron. Goat liver extracts were 

analyzed by TLC but due to the low levels of radioactivity present, identification of the 

radioactive species was inconclusive. 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-hydroxy benzyl) urea (Metabolite 3381) in 

one TLC system. Further attempts were made to increase extraction efficiency using 

solvents, proteolytic digestion and acid hydrolysis; however success was limited and 

indicated that the radioactivity was bound to proteins within the liver. Overall extraction 

efficiency in liver was 58.3% of the total radioactivity. Analysis of milk extracts by TLC
11

showed the presence of teflubenzuron and a large amount of polar material. Further 

attempts to resolve this material into separate compounds following acid hydrolysis 

produced no interpretable results due to the low amounts (<0.015 mg/L) of radioactivity 

present. As in the previous study no radioactive 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 (radiochemical 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 from 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 were 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 respectively. Total [14C] residues in the tissues 

(expressed as parent equivalent) were 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 via excreta (including intestine 

and crop contents at post mortem) accounting for 93.5% of the 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 the parent teflubenzuron, representing 62.2% of 

the radioactivity present. Two further minor radioactive components were observed, each 

accounting for 4.8% and 6.6% of the TRR. Neither component had similar retention

times to any of the standard substances. The remaining unextractable radioactivity in eggs 

was 8% (0.00062 mg/kg) of the total radioactivity present in eggs. The major radioactive 

component in liver was parent teflubenzuron which accounted for 30.2 % of the TRR. 

Two further radio-peaks were present each accounting 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. Radioactivity 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 the 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 component
12

in feces, yolk and fat as parent teflubenzuron. Liver extracts mainly contained parent 

teflubenzuron and a polar compound which was compared to an enzyme treated sample 

and shown not to be a conjugate. No material with chromatographic characteristics 

comparable to either 3,5-dichloro-2,4-difluoroalanine 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-chromatographed on TLC and 

HPLC with 3,5-dichloro-2,4-difluorophenyl-urea (Metabolite El5). Overall extraction 

efficiency in liver was >75% and was >90 % in kidney, egg yolk, and fat.]

7. Acute neurotoxicity. [An acute neurotoxicity study was conducted with 

teflubenzuron (98.6% purity). In this study Wistar rats (10/sex/dose level) were 

administered teflubenzuron via oral 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 examined daily. Body weight determinations, 

functional observational batteries (FOBs) and motor activity measurements (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 examinations. No adverse effects 

attributable to the test substance were reported 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 neurotoxicity study was conducted 

with teflubenzuron (98.6% purity). In this study Wistar rats (10/sex/dose level) were 

administered teflubenzuron via the diet at dose levels of 0 (vehicle control), 100, 300, or

1000 mg/kg bw/day for 13 weeks. Food consumption was determined once a week. 

Body weight was measured once a week and on days when functional observational 

batteries (FOBs) and motor activity measurements (MA) were carried out. The animals 

were examined for toxicity or mortality at least once a day. Detailed clinical 

examinations in an open field were conducted prior to the start of test substance 

administration and weekly thereafter. FOBs and MAs were conducted 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 neurobehavioral or neuropathological effects attributable to

the test substance were reported at any dose level. The NOAEL was identified as 1000 

mg/kg/day for both male and female rats, 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 cyclophosphamide 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 intraperitoneally. Food consumption and body 

weight were determined weekly. The animals were examined for signs of toxicity or
13

mortality at least once a day. Detailed clinical examinations in an open field were 

conducted prior to the start of test substance administration 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 weights were significantly reduced. No adverse 

immunotoxicologically relevant or systemic toxicity endpoints attributable to 

teflubenzuron were reported at any dose level. 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 was conducted on the metabolite 3,5- 

dichloro-2,4-difluoroaniline (CL 902373) at doses of 1500, 1800 and 2000 mg/kg, and 

yielded an LD50 of 1986 mg/kg for males and 1,552 mg/kg for females.

An acute oral toxicity study was conducted 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 (CL902373), and under the conditions of this test, it did not 

induce any chromosome damage.

An Ames Salmonella Assay was conducted on the metabolite 3,5-dichloro-2,4 

difluorophenylurea (metabolite 3381) and under the conditions of this test, it did not 

induce any chromosome damage.]

11. Endocrine disruption. [No special studies investigating potential endocrine 

effects of teflubenzuron have been conducted. 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 residues in cattle, muscle; cattle, meat byproducts;
14

goat, muscle; goat, meat byproducts; horse, 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 crops, 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 Health and Nutrition 

Examination Survey (NHANES), and average anticipated residues as calculated from 

residue field trial data. Estimated potential concentrations in drinking water were not 

incorporated into the dietary exposure assessment 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 dietary exposure assessment was not conducted.

Chronic Dietary Exposure. The chronic population adjusted dose (cPAD) of

0.01 mg/kg bw/day was used to characterize risk associated with chronic dietary 

exposures. BASF has conducted 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 factors were available. Empirical processing 

factors are available for soybean oil (0.5), tomato puree (0.45), tomato juice (0.17), citrus 

oil (252), citrus juice (0.04), citrus peel (4.9), dried apple (8.47), apple 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), instant coffee (0.2), sugarcane 

molasses (0.5), sugarcane sugar (0.5) and pineapple pulp (0.078). Anticipated residues in 

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

tolerances for these commodities. Potential residues in water were not included because 

there are no proposed or registered domestic uses. The chronic dietary assessment was 

conducted for the overall US population and select subpopulations (i.e., all infants <1 

year old, children aged 1-2 years old, children 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 old, 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 chronic exposure is calculated to be

0.000626 mg/kg bw/day, which corresponds to 6.3% of the cPAD.]

ii. Drinking water. [Since this will be an import tolerance 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, residential exposure to teflubenzuron residues will 

be through dietary exposure only.]
15

D. Cumulative Effects

[Teflubenzuron is a member of the benzoylurea class of insecticides. Other 

members of this class are registered for use in the United States. Although teflubenzuron 

and other benzoylureas may have similar insecticidal modes of action, there are no 

available data to determine whether teflubenzuron has a common mechanism of 

mammalian toxicity with other benzoylureas or information on how to include this 

pesticide in a cumulative risk assessment. Therefore, for the purposes of this tolerance 

petition no assumption has been made with regard to cumulative exposure with other 

compounds having a common mode of action.]

E. Safety Determination

1. U.S. population. [Using the conservative exposure assumptions described 

above and based on the completeness of the toxicity database, 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 population. 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 will not pose appreciable risks to human health. Thus, it can be 

concluded that there is a reasonable 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 exposure assumptions described 

above and based on the completeness of the toxicity database, 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 children. Since no reproductive or developmental issues have 

been identified in any of the studies, an additional FQPA safety factor is not necessary.]

F. International Tolerances

[There are established Codex and European Union MRLs.]