UNITED ST ATES ENVIRONMENT AL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

DATE: July 1, 2015 

SUBJECT: Teflubenzuron: Report of the Cancer Assessment Review Committee 

FROM: 

TO: 

PC Code: 129048 

Decision No.: NIA 

Petition No.: NIA 

Risk Assessment Type: NA 

TXR No.: 0057275 

MRID No.: NIA 

DP Barcode: NI A 

Registration No.: NIA 

Regulatory Action: NIA 

Case No.: NIA 

CAS No.: NIA 

40 CFR: NIA 

Jess Rowland, Chair ~C2-,s::s--\..__ Deputy Division Director ~ 

Karlyn 

Cancer 

Middleton, 

Assessment 

Co-Chair 

Review Committee 

~ cfn .. ~ 

Health Effects Division (7509P) 

Anwar Dunbar, Toxicologist 

Risk Assessment Branch I 

Health Effects Division (7509P) 

And 

Carlyn Patrella, Risk Review Manager 

Richard Gebken, Risk Manager 

IVB II 

Pesticide Re-Evaluation Division (7505P) 

On April 29, 2015, the Cancer Assessment Review Committee (CARC) of the Health Effects 

Division, evaluated the carcinogenic potential of Teflubenzuron in accordance with the EPA 's 

Final Guidelines for Carcinogen Risk Assessment (March, 2005). Attached please find the final 

Cancer Assessment Document. 
Teflubenzuron (PC Code 129048) FINAL

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CANCER ASSESSMENT DOCUMENT

EVALUATION OF THE CARCINOGENIC POTENTIAL OF

Teflubenzuron

PC CODE 129048

July 1, 2015 

CANCER ASSESSMENT REVIEW COMMITTEE

HEALTH EFFECTS DIVISION

OFFICE OF PESTICIDE PROGRAMS
Teflubenzuron (PC Code 129048) FINAL

Page 3 of 28

I. EXECUTIVE SUMMARY .................................................................................................. 4

II. INTRODUCTION................................................................................................................. 6

III. BACKGROUND INFORMATION .................................................................................... 6

IV. EVALUATION OF CARCINOGENICITY STUDIES .................................................... 6

A. COMBINED CHRONIC TOXICITY/CARCINOGENICITY STUDY IN WISTAR KFM-HAN RATS ... 6

B. CARCINOGENICITY STUDY IN MICE ................................................................................... 12

V. TOXICOLOGY................................................................................................................... 16

A. METABOLISM..................................................................................................................... 16

B. MUTAGENICITY: ................................................................................................................ 17

C. STRUCTURE-ACTIVITY RELATIONSHIP ............................................................................. 19

D. SUB-CHRONIC AND CHRONIC TOXICITY............................................................................. 20

E. MODE OF ACTION STUDIES ................................................................................................ 24

VI. COMMITTEE’S ASSESSMENT OF THE WEIGHT-OF-THE-EVIDENCE ............ 24

A. MOUSE............................................................................................................................... 24

B. RAT.................................................................................................................................... 24

VII. CLASSIFICATION OF CARCINOGENIC POTENTIAL........................................ 25

VIII. QUANTIFICATION OF CARCINOGENIC POTENTIAL...................................... 26

IX. BIBLIOGRAPHY............................................................................................................... 26
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I. EXECUTIVE SUMMARY

On April 29, 2015, the Cancer Assessment Review Committee of the Health Effects Division of 

the Office of Pesticide Programs evaluated the carcinogenic potential of teflubenzuron. 

In the carcinogenicity study in mice, teflubenzuron was administered in the diet to male and 

female NMRI mice at 0, 15, 75, or 375 ppm for 78 weeks. Male mice had significant trends for 

liver adenomas and combined adenomas and/or carcinomas. The incidences of liver adenomas at 

75 ppm (22%) and 375 ppm (27%) were outside the historical control range of the testing 

laboratory (4.5-16.4%). The combined incidences of liver adenomas and/or carcinomas at 75 

ppm (29%) and 375 ppm (35%) were also outside the laboratory’s historical control value (19%). 

Supporting evidence for these tumors include the presence of pre-neoplastic lesions in the liver

(centrilobular single cell necrosis and phagocytic foci) seen at 75 ppm and above. The CARC 

concluded that the liver tumors in male mice are treatment-related. 

There was no evidence of carcinogenicity in female mice. The CARC, based on the observed 

non-neoplastic liver lesions in both sexes, determined that the doses tested in both sexes of mice 

were adequate for assessing the carcinogenic potential of teflubenzuron. 

Two separate chronic toxicity/carcinogenicity studies in the rat were conducted. In the first 

study, teflubenzuron was administered in the diet to male and female Wistar KFM-Han rats at 0, 

20, 100, or,500 ppm for 120 weeks. In the second study in the same strain of rats, teflubenzuron 

was administered in the diet to males and females at two higher doses, 0, 2500 or 10,000 ppm for 

120 weeks. In males, there was an increase in the incidence of pancreatic carcinomas and 

mesenteric lymph node hemangiomas at 500 ppm teflubenzuron. In females, there was an 

increased incidence of uterine adenocarcinomas at 10,000 ppm. The pancreatic exocrine tumors 

and lymph node tumors in male rats and the uterine tumors in females were not considered to be

treatment related due to: 1) absence of a dose-response; 2) lack of statistical significance in a

pair-wise comparison to the concurrent controls; 3) the incidences were within the historical 

control ranges; and 4) there are no corroborative pre-neoplastic lesions for either tumor type.

The CARC concluded there was no evidence of carcinogenicity in males or female rats.

The CARC, based on the decreases in body weight and liver effects seen in both sexes of rats, 

determined that the doses tested were adequate for assessing the carcinogenic potential of 

teflubenzuron. 

There was no evidence of mutagenicity in vivo or in vitro.

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), 

the CARC classified teflubenzuron as “Suggestive Evidence of Carcinogenic Potential”

based on the presence of liver tumors in male mice. There was no evidence of carcinogenicity in 

female mice or in male or female rats at dose levels that were considered adequate to assess 

carcinogenicity. Additionally, there is no concern for mutagenicity.

Quantification of human cancer risk is not required. The CARC recommended using a non-linear 
Teflubenzuron (PC Code 129048) FINAL

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approach. The chronic Reference Dose (RfD) will adequately account for all chronic toxicity, 

including carcinogenicity, which could result from exposure to teflubenzuron. 
Teflubenzuron (PC Code 129048) FINAL

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II. INTRODUCTION

On April 29, 2015, the Cancer Assessment Review Committee of the Health Effects Division of 

the Office of Pesticide Programs evaluated the carcinogenic potential of teflubenzuron. 

III. BACKGROUND INFORMATION

BASF submitted a petition for establishment of an import tolerance for the active ingredient 

teflubenzuron (N-[[(3,5-dichloro-2,4-difluorophenyl)amino]carbonyl]-2,6-difluorobenzamide; 1-

(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluorobenzoyl)urea; N-[(3,5-dichloro-2,4-difluorophenyl)carbamoyl]-2,6-difluorobenzamide) on in/on the commodities of orange, lemon, apple, 

grape, tomato, melon, broccoli, cauliflower, sunflower, soybean, corn, coffee bean, sugarcane, 

mango, papaya, pineapple, cattle, goat, horse, sheep, hog, and poultry.

Teflubenzuron is reported to act as an insect growth regulator and ovicide in Lepidopterous, 

Coleopterous, Hyrnenopterous and Hemipterous pests. The ovicidal effect of teflubenzuron is 

claimed to be species specific and dependent on the age of the eggs. It acts as an inhibitor of 

chitin formation, interfering with the process of molt. 

IV. EVALUATION OF CARCINOGENICITY STUDIES

The CARC reviewed two separate combined chronic toxicity/carcinogenicity studies in rats. The 

first study conducted in 1987 and the second in 1989.

A. Combined Chronic Toxicity/Carcinogenicity Study in Wistar KFM-Han Rats 

Citations: Suter, P., Dewert, H., Terrier, CH., et al. (1987). 120-Week chronic toxicity and 

oncogenicity study with CME 134 in the rat. RCC Research & Consulting Company AG, 

CH-4452, Itingen, Switzerland. Study No. RCC No. 027472; BASF Document No. TZ-427-

005. September 2, 1987. MRID 49168811. Unpublished.

Tennekes, H., Stucki, H.P., Luetkemeier, H., et al. (1989). Chronic toxicity and oncogenicity 

(feeding) study with CME 134 in the rat. RCC Research & Consulting Company AG, CH-
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Page 7 of 28

4452, Itingen, Switzerland. Study No. RCC No. 064192; BASF Document No. TZ-427-008. 

December 6, 1989. MRID 49168812. Unpublished. (See Appendix to this DER).

Experimental Design:

In the first study, CME 134 [92.4% a.i., (batch # DW 44/83)] was administered to 70 Wistar 

KFM-Han rats/sex/dose in the diet at concentrations of 0, 20, 100, or 500 ppm. Fifty 

rats/sex/group, designated for the carcinogenicity portion of the study, were fed the test diets 

for 120 weeks (equivalent doses for the respective dietary concentrations were 0, 1.0, 4.8, 

and 24.8 mg/kg bw/day for males, and 0, 1.2, 5.9, and 29.9 mg/kg bw/day for females), and 

20 rats/sex/group, designated for the chronic portion, were fed the test diets for 107 weeks 

(equivalent doses for the respective dietary concentrations were 0, 1.1, 5.4, and 27.6 mg/kg 

bw/day for males, and 0, 1.3, 6.5, and 32.0 mg/kg bw/day for females). 

In the second study, conducted at the same testing laboratory, rats received teflubenzuron in 

their diet at two higher doses; 0, 2500, or 10,000 ppm (equivalent to 0, 122.5, and 487.3 

mg/kg bw/day for males, and 0, 154.0, and 615.2 mg/kg bw/day for females) for 111 weeks. 

Survival Analysis:

There were no statistically significant survival disparities among female rats (Table 1).

+Number of animals that died during the interval/Number of animals alive at the beginning of the interval. i

Interim sacrifices at weeks 53, 104 and 108.

f

Final sacrifice at weeks 112 and 121.

n

Negative pair-wise comparison with the control.

Table 1: Teflubenzuron – Wistar KFM-Han Rat Studies Combined

(MRIDs 49168811 and 49168812)

Female Mortality Rates+ and Cox or Generalized K/W Test Results

Dose 

(ppm)

Weeks

1-26 27-52 53i 53-78 79-104 104i 105-

108

108i 109-

122f

Total

0 0/130 3/130 10/127 9/117 

22/108 

8/86 6/78 6/72 12/66 52/106

(49) 

20 0/70 1/70 10/69 2/59 9/57 0/48 1/48 9/47 13/38 26/51

(51) 

100 0/70 1/70 10/69 0/59 10/59 0/49 4/49 6/45 11/39 26/54

(48)n 

500 0/70 1/70 10/69 4/59 8/55 0/47 4/47 7/43 6/36 23/53

(43)n 

2500 0/60 0/60 0/60 3/60 20/57 7/37 2/30 0/28 0/28 25/53

(47)n 

10,000 0/60 1/60 0/59 6/59 12/53 6/41 2/35 0/33 3/33 24/54

(44)n 
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( ) Percent.

Note: Time intervals were selected for display purposes only.

Significance of trend denoted at control.

Significance of pair-wise comparison with control denoted at dose level

If *, then p < 0.05. If **, then p < 0.01.

Discussion of Tumor Data:

(i) Uterine Tumors in Female Rats

There was an increase in the incidence of uterine adenocarcinomas at the high dose (10, 000 

ppm) in the first study but not in the second study. Statistical analyses of this tumor incidence 

was conducted separately for each study as well as with the data combined from both studies.

The statistical analyses of the tumors in female rats were based upon Fisher’s Exact Test and 

the Exact Test for Trend. Results are shown in Tables 1 through 4.

In the first study (Table 2), there was no statistically significant increase in pair-wise 

comparisons of the dosed groups with the controls for the adenocarcinomas.

In the second study (Table 3), statistical significance was seen for a trend (p<0.01) and pairwise comparison (p<0.05) at 10,000 ppm for uterine adenocarcinomas. 

As shown Table 4, when the results from the two studies were combined, only a trend (no 

pair-wise significance) was seen for the uterine adenocarcinomas. 

In a compilation of historical control data for tumors in Wistar rats supplied by the registrant, 

the range for background incidence of uterine adenocarcinomas was 1-11%. The incidences 

of uterine adenocarcinomas in this present studies were within the historical control range.

Table 1: Teflubenzuron – Wistar KFM-Han Rat Study

(MRID 49168811)

Female Uterine Tumor Rates+ and Fisher’s Exact Test and Exact Trend Test Results

Tumor: Dose (ppm)

0 20 100 500

Adenocarcinomas#

(%)

P = 

3a/56

(5)

0.3185

0/58

(0)

1.00000

1/58

(2)

0.9450

1/59

(2)

0.9469

+Number of tumor bearing animals/Number of animals examined, excluding those that died or were sacrificed before week 54.

#No adenomas were observed.

a

First adenocarcinoma observed at week 108, dose 0 ppm.
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Table 2: Teflubenzuron – Wistar KFM-Han Rat Study

(MRID 49168812)

Female Uterine Tumor Rates+ and Fisher’s Exact Test and Exact Trend Test Results

Tumor: Dose (ppm)

0 2500 10,000

Adenocarcinomas#

(%)

P = 

0/58

(0)

0.00875**

0/32

(0)

1.00000

5b/59

(8)

0.02988*

+Number of tumor bearing animals/Number of animals examined, excluding those that died or were sacrificed before week 54.

#No adenomas were observed.

b

First adenocarcinoma observed at week 89, dose 10,000 ppm.

Note: Significance of trend denoted at control.

Significance of pair-wise comparison with control denoted at dose level.

If *, then p < 0.05. If **, then p < 0.01.

Table 3: Teflubenzuron – Wistar KFM-Han Rat Studies Combined

(MRIDs 49168811 and 49168812)

Female Uterine Tumor Rates+ and Fisher’s Exact Test and Exact Trend Test Results

Tumor: Dose (ppm)

0 20 100 500 2500 10,000

Adenocarcinomas#

(%)

P = 

5/115

(4)

0.02242*

0/58

(0)

1.00000

1/59

(2)

0.92035

1/59

(2)

0.92035

0/32

(0)

1.00000

5a/59

(8)

0.21909

+Number of tumor bearing animals/Number of animals examined, excluding those that died or were sacrificed before week 54.

#No adenomas were observed.

a

First adenocarcinoma observed at week 89, dose 10,000 ppm.

Non-Neoplastic Lesions in the Uterus: There were no treatment related increase nonneoplastic lesions in the uterus. .

(ii) Pancreatic Tumors in Male Rats

In the first study, there appeared to be a potential treatment-related increase in pancreatic

exocrine tumors (2/47) at 500 ppm (see Table 5). In the second study, 1/23 rats had these 

pancreatic exocrine tumors at the 2,500 ppm concentration but none at the 10,000 ppm 

concentration (see Table 6). These two groups were combined in Table 7 and together 

showed no dose response up to 10,000 ppm. In a compilation of historical control data for 

tumors in Wistar rats supplied by the registrant, the background incidence of pancreatic 

acinar cell adenomas, adenocarcinomas, and mixed cell adenomas for male rats >103 weeks 

was 1-4%. The incidences of pancreatic tumors were within the historical control range.

There were no reported increases in mortality up to 10,000 ppm teflubenzuron in either study 

for male rats, and no survival analysis was performed for male rats.
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Table 5: Teflubenzuron – Wistar KFM-Han Rat Study

(MRID 49168811)

Male Pancreatic Exocrine Tumor Rates+ and Fisher’s Exact Test and Exact Trend Test Results

Tumor:

Dose (ppm)

0 20 100 500

Carcinomas

(%)

P = 

0/50

(0)

0.0583

0/47

(0)

1.0000

0/49

(0)

1.0000

2/47

(4)

0.2322

+Number of tumor bearing animals/Number of animals examined.

Table 6: Teflubenzuron – Wistar KFM-Han Rat Study

(MRID 49168812)

Male Pancreatic Exocrine Tumor Rates+ and Fisher’s Exact Test and Exact Trend Test Results

Tumor: Dose (ppm)

0 2500 10,000

Carcinomas

(%)

P = 

0/50

(0)

0.5935

1/23

(4)

0.3151

0/50

(0)

1.0000

+Number of tumor bearing animals/Number of animals examined.

Table 7: Teflubenzuron – Wistar KFM-Han Rat Studies Combined

(MRIDs 49168811 and 49168812)

Male Pancreatic Exocrine Tumor Rates+ and Fisher’s Exact Test and Exact Trend Test Results

Tumor: Dose (ppm)

0 20 100 500 2500 10,000

Carcinomas

(%)

P = 

0/100

(0)

0.5833

0/47

(0)

1.0000

0/49

(0)

1.0000

2/47

(4)

0.1007

1/23

(4)

0.1870

0/50

(0)

1.0000

+Number of tumor bearing animals/Number of animals examined.

Note: Significance of trend denoted at control.

Significance of pair-wise comparison with control denoted at dose level.

If *, then p < 0.05. If **, then p < 0.01.

Non-Neoplastic lesions for Pancreatic Tumors: There were no non-neoplastic lesions in the 

pancreas in either sex, in both studies.
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(iii) Hemangiomas in Male Rats:

In the first chronic carcinogenicity study in rats (MRID 49168811), there was a significant 

trend (p<0.01) and a significant pair-wise comparison (P<0.05) at 500 ppm for mesenteric 

lymph node hemangiomas in male rats (Table 8). The incidence of hemangiomas was 1/48, 

3/50, 3/48, and 8/47 at 0, 20, 100, and 500 ppm, respectively. In the second study (MRID 

49168812), hemangiomas were observed in both control and treated groups of male rats at an 

incidence of 6/50, 3/22, and 8/50 at 0, 2500, and 10000 ppm, respectively, and were not 

statistically significant (Table 9). The incidences of hemangiomas observed in both studies

were within the historical control range (2-17%). No corroborating non-neoplastic lesions 

were observed. There were no effects in females.

Table 8: Teflubenzuron – Wistar KFM-Han Rat Study

(MRID 49168811)

Male Mesenteric Lymph Node Hemangioma Rates

Tumor: Dose (ppm)

0 20 100 500

Mesenteric Lymph Node 

Hemangioma (%)

p-value

1/48

(2)

0.00454**

3/50

(6)

0.32420

3/48

(6)

0.30849

8/47

(17)

0.01401*

Table 9: Teflubenzuron – Wistar KFM-Han Rat Study

(MRID 49168812)

Male Mesenteric Lymph Node Hemangioma Rates

Tumor: Dose (ppm)

0 2500 10,000

Mesenteric Lymph Node Hemangioma

(%)

p-value

6/50

(12)

0.3080

3/22

(14)

0.5607

8/50

(16)

0.3871

+Number of tumor bearing animals/Number of animals examined

Adequacy of the Dosing for Assessment of Carcinogenicity:

There was no adverse effect on survival observed for either sex. All dose groups and controls 

had ≥66% survival at study termination. Decreased body weight was observed at the highest 

dose level throughout the study in males only (↓5%) in addition to histopathological 

indicators of liver injury (fatty change and basophilic and mixed cell foci). The highest dose 

tested for each sex (10,000 ppm, for males and females, respectively) is considered to be 

adequate to assess the carcinogenicity of teflubenzuron.
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B. Carcinogenicity Study in Mice

Citation: Suter, P., H. Dewert, C. Terrier, et al. (1987) 18-Month oncogenicity (feeding) 

study with CME 134 in mice. RCC Research & Consulting Company AG (Itingen, 

Switzerland). RCC Project 027810, August 17, 1987. MRID 49168813. Unpublished.

Experimental Design:

In a carcinogenicity study, CME 134 (92.4±0.9% a.i., batch no. DW 44/83) was administered 

to 60 NMRI mice/sex/dose in the diet at dose levels of 0, 15, 75, or 375 ppm (equivalent to 0, 

2.1, 10.5, and 53.6 mg/kg bw/day for males and 0, 3.1, 15.4, and 71.7 mg/kg bw/day for 

females) for 78 weeks. Ten mice/sex/dose were sacrificed at 52 weeks for interim 

evaluations. Evaluated parameters included mortality, clinical signs, body weight, body 

weight gain, food consumption, ophthalmoscopic examination, hematology, clinical 

chemistry, organ weights, and gross and histopathological examination. 

Survival Analysis:

The survival analyses indicated a statistically significant negative trend and a significant 

negative pair-wise comparison of the 375 ppm dose group with the controls in male mice 

(Table 10).

+Number of animals that died during the interval/Number of animals alive at the beginning of the interval.

i

Interim sacrifice at week 52.

f

Final sacrifice at weeks 77-78. n

Negative trend or negative pair-wise comparison with the control.

( ) Percent.

a

Two accidental deaths, both at week 78, one each in the control and 15 ppm dose groups. 

b

One accidental death at week 52, dose 75 ppm

Note: Time intervals were selected for display purposes only.

Significance of trend denoted at control.

Significance of pair-wise comparison with control denoted at dose level.

If *, then p < 0.05. If **, then p < 0.01.

Table 10: Teflubenzuron – SPF NMRI KFM-Han Mouse Study (MRID 49168813)

Male Mortality Rates+ and Cox or Generalized K/W Test Results

Dose (ppm) Weeks

1-26 27-52 52i 53-78f Total

0 0/60 4/60 10/56 12/45a 16/49

(33)**n 

15 0/60 2/60 10/58 11/47a 13/49 

(27)n 

75 0/60 0/59b 9/59 9/50 9/50 

(18)n

375 0/60 0/60 10/60 5/50 5/50 

(10)**n 
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Discussion of Tumor Data:

Male mice had significant trends for hepatocellular adenomas and combined adenomas 

and/or carcinomas, both at p <0.05 (table 11). There were no statistically significant increase 

in pair-wise comparisons of the dosed groups with the controls for tumors in male mice. The 

statistical analyses of the tumors in male mice were based upon Peto’s Prevalence Test due to 

significant survival disparities among the dose groups. Historical control data for mouse liver 

adenomas and carcinomas are presented in Tables 12 and 13. The incidences of liver 

adenomas at 75 ppm (22%) and 375 ppm (27%) were outside the historical control range of 

the testing laboratory (4.5-16.4%). The combined incidences of liver adenomas and/or 

carcinomas at 75 ppm (29%) and 375 ppm (35%) were also outside the laboratory’s historical 

control value (19%). The tumors were supported by non-neoplastic lesions in the liver.

Table 11: Teflubenzuron – SPF NMRI KFM-Han Mouse Study (MRID 49168813)

Male Liver Tumor Rates+ and Peto’s Prevalence Test Results

Tumor: Dose (ppm)

0 15 75 375

Adenomas

(%)

P = 

7a/58

(12)

0.01576*

5/58

(9)

0.77929

13a/59

(22)

0.11257

16/60

(27)

0.05090

Carcinomas

(%)

p =

4b/58

(7)

0.54808

6b/58

(10)

0.21206

4/59

(7)

0.55316

5/60

(8)

0.42637

Combined

(%)

p =

11/58

(19)

0.03246*

11/58

(19)

0.56981

17/59

(29)

0.14580

21/60

(35)

0.06414

+Number of tumor bearing animals/Number of animals examined, excluding those that died or were sacrificed before week 52.

a

First adenomas observed at the interim sacrifice at week 52, simultaneously in the control and 75 ppm dose groups. Typically, interim 

sacrifice animals would not have been included in this analysis, but the first animal that died on study with an adenoma was observed at 

week 56 (in the 75 ppm dose group) and since the interim sacrifice was at week 52, these time points are close enough that the interim 

sacrifice animals should be included in the “at risk” group. 

b

First carcinomas observed at the interim sacrifice at week 52, simultaneously in the control and 15 ppm dose groups. First carcinoma not

in an interim sacrifice animal observed at week 69 in the control group. Typically, interim sacrifice animals would not have been included 

in the analysis of the carcinomas, but since they are included in both the adenoma and combined counts, they have been included in the 

carcinoma counts as well for those less statistically inclined trying to make sense of the combined counts.

c

Two animals in the 5000 ppm dose group had both an adenoma and a carcinoma.

Note: Significance of trend denoted at control.

Significance of pair-wise comparison with control denoted at dose level.

If *, then p < 0.05. If **, then p < 0.01.
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Table 12: Historical Control for liver adenomas in male micea

Reference Sex Adenomas Animals %

Strain: NMRI

Age (Weeks): < 84

Crit Year: N 1983

Source: 000426/82006 HJC

M

F

M+F

22

3

25

185

195

380

11.9

1.5

6.6

Strain: NMRI

Age (Weeks): < 110

Crit Year: N 1984

Source: 08796/84005 HHW

M

F

M+F

16

1

17

157

151

308

10.2

0.7

5.5

Strain: NMRI

Age (Weeks): < 109

Crit Year: N 1985

Source: 005310/83019 JMA

M

F

M+F

36

6

42

220

228

448

16.4

2.6

9.4

Strain: NMRI

Age (Weeks): < 110

Crit Year: N 1985

Source: 005275/85003 JAW

M

F

M+F

9

1

10

200

198

398

4.5

0.5

2.5

Totals:

M

F

M+F

83

11

94

762

772

1534

10.9

1.4

6.1 a Data obtained from page 1032, MRID 49168813 (Carcinoma data listed on page 1033, Hemangioma data listed on page 1034, 

Hemangiosarcoma data listed on page 1035, and Hepatoblastoma data listed on page 1036)

Table 13: Historical Control for liver carcinomas in male micea

Reference Sex Carcinomas Animals %

Strain: NMRI

Age (Weeks): < 84

Crit Year: N 1983

Source: 000426/82006 HJC

M

F

M+F

6

0

6

185

195

380

3.2

0

1.6

Strain: NMRI

Age (Weeks): < 110

Crit Year: N 1984

Source: 08796/84005 HHW

M

F

M+F

0

1

1

157

151

308

0

0.7

0.3

Strain: NMRI

Age (Weeks): < 109

Crit Year: N 1985

Source: 005310/83019 JMA

M

F

M+F

5

1

6

220

228

448

2.3

0.4

1.3

Strain: NMRI

Age (Weeks): < 110

Crit Year: N 1985

Source: 005275/85003 JAW

M

F

M+F

5

0

5

200

198

398

2.5

0

1.3

Totals:

M

F

M+F

16

2

18

762

772

1534

2.1

0.3

1.2 a Data obtained from page 1032, MRID 49168813 (Carcinoma data listed on page 1033, Hemangioma data listed on page 1034, 

Hemangiosarcoma data listed on page 1035, and Hepatoblastoma data listed on page 1036)
Teflubenzuron (PC Code 129048) FINAL

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Non-Neoplastic Lesions

As described in Table 14, at 75 and 375 ppm teflubenzuron, there were significant and dosedependent increases in non-neoplastic liver lesions in male mice (i.e., diffuse hypertrophy, 

centrilobular single cell necrosis, phagocytic foci, and nodular hyperplasia).

Table 14: Incidence and severity of non-neoplastic microscopic findings in male and female miceab

Parameter: Dietary concentration (ppm)

0 15 75 375

Interim Sacrifice: 52 Weeks

Males - # animals (severity) 10 10 10 10

Liver

 Diffuse hypertrophy 1 (2.0) 0 (0.0) 1 (3.0) 6* (3.5)

 Centrilobular hypertrophy 3 (2.0) 6 (2.2) 7 (3.0) 2 (3.5)

 Centrilobular single cell necrosis 0 (0.0) 2 (2.0) 8** (2.9) 8** (3.3)

 Patchy glycogen storage 0 (0.0) 0 (0.0) 0 (0.0) 7** (3.0)

 Kupffer cell proliferation 0 (0.0) 1 (3.0) 5* (2.0) 8** (2.9)

 Phagocytic foci 4 (1.8) 2 (2.5) 8 (2.6) 8 (2.5)

Females - # animals (severity) 10 10 10 10

Liver

Phagocytic foci 4 (2.0) 2 (2.0) 5 (1.6) 8 (2.1)

Patchy fatty change 0 (0.0) 0 (0.0) 2 (1.5) 9** (2.7)

Terminal Sacrifice: 78 Weeks

Males -# animals (severity) 50 50 50 50

Liver

 Nodular hyperplasia 3 (1.7) 1 (2.0) 7 (2.1) 10* (2.4)

Diffuse hypertrophy 0 (0) 5* (2.4) 22** (3.0) 42** (3.8)

Centrilobular hypertrophy 8 (2.1) 18* (2.3) 16 (2.7) 6 (2.8)

Disseminated single cell necrosis 4 (1.8) 8 (1.6) 8 (2.5) 40** (3.7)

Centrilobular single cell necrosis 8 (2.0) 13 (2.1) 26** (3.1) 7 (3.0)

Patchy glycogen storage 1 (2.0) 2 (2.0) 17** (2.9) 38** (2.9)

Kupffer cell proliferation 2 (1.5) 2 (2.5) 25** (2.6) 47** (3.0)

Phagocytic foci 13 (1.5) 19 (2.1) 35** (2.8) 46** (3.1)

Lipofuscin accumulation 8 (2.1) 9 (2.1) 16 (2.3) 25** (2.5)

Centrilobular fatty change 15 (2.1) 14 (2.5) 3** (2.3) 0** (0)

Bile duct proliferation 0 0 3 (2.3) 10** (2.3)

Females - # animals (severity) 49 50 48 49

Liver

 Diffuse hypertrophy 1 (3.0) 2 (3.0) 1 (3.0) 15** (3.1)

Disseminated single cell necrosis 2 (2.0) 9 (1.9) 8 (2.1) 24** (2.5)

Patchy glycogen storage 0 (0) 0 (0) 0 (0) 5* (2.2)

Kupffer cell proliferation 2 (2.0) 2 (2.5) 4 (2.3) 12** (2.8)

Phagocytic foci 16 (1.8) 16 (2.0) 23 (1.7) 32** (2.4)

Lipofuscin accumulation 0 (0) 0 (0) 1 (3.0) 10** (2.3)

Patchy fatty change 1 (2.0) 3 (2.0) 5 (1.4) 21** (2.3) a Data obtained from pages 442-445, MRID 49168813. b Severity scores in parentheses- Grade 1 – Minimal/ Very Few/ Very Small, Grade 2 – Slight/ Few/ Small, Grade 3 = Moderate/ 

Moderate Number/ Moderate Size, Grade 4 = Marked/ Many/ Large, Grade 5 = Massive/ Extensive Number/ Extensive Size, P = 

Finding Present, Severity not scored, key is from page 417 of the study report

*p<0.05, **p<0.01, statistically significant, calculated by the reviewer using the 2 × 2 Chi square test.
Teflubenzuron (PC Code 129048) FINAL

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Adequacy of Dosing for Assessment of Carcinogenicity

Histopathology revealed an increased incidence histopathological findings in the liver

(diffuse hypertrophy, centrilobular single cell necrosis, patchy glycogen storage, Kupffer cell 

proliferation, phagocytic foci, and centrilobular fatty change) associated with increased 

relative liver weight. The highest dose tested for each sex (375 ppm, for males and females) 

is considered to be adequate to assess the carcinogenicity of teflubenzuron.

V. TOXICOLOGY

A. Metabolism

The ADME for teflubenzuron was well characterized in a series of oral gavage studies using 

low- and high-doses (25 and 750 mg/kg bw). Animals were tested using single and repeated 

dosing regimens. Biliary excretion and tissue accumulation experiments are also carried out. 

Regarding absorption, following a single oral dose of 25 mg/kg bw, the Cmax was 0.46 

μg/ml and the Tmax was 8 hours for males. For females, the Cmax was 0.25 μg/ml and the 

Tmax ranged from 2 to 8 hours. From the 1 to the 8 hours post dosing, nearly constant 

plasma levels were found and started to decline at twenty four hours. Plasma concentrations 

declined to less than 0.01 μg equivalents/mL in both sexes at the end of the experimental 

period (7 days). 

Following single oral dosing at 750 mg/kg bw, the Cmax was 3.27 μg/ml and the Tmax was 

24 hours. For females, the Cmax was 1.43 μg/ml and the Tmax was 0.67 hours. The second 

day after treatment, the plasma levels declined to 1.05 in males whiles levels were consistent 

in females. By the end of the 7 day testing period, plasma levels decreased to 0.06 and 0.08 

μg equivalents/mL in male and female rats, respectively. 

Tissue accumulation and distribution was negligible for both sexes treated with radiolabeled 

test material for 7 consecutive days; being less than 1% of the administered dose at all 

intervals. The highest detectable levels of the radiolabel were in the liver (~0. 23-0.33% for 

both sexes) which peaked from 1 to 6 hours and then gradually decreased. All other tissues 

were less than 0.1%.

The majority of the radiolabel was recovered in the feces (>90%), and was identified as the 

parent compound. Three metabolites were isolated. Two products were structural isomers 

formed by hydroxylation of the benzoyl ring at positions 3 and 4, while the remaining 

metabolite was formed by substitution of one fluorine atom by hydroxide, likely on the 

aniline ring. Biliary extracts showed meta-hydroxylation of the benzoyl ring followed by 

conjugation was the predominant pathway. Only very small amounts of radioactivity coeluted with the hydroxylated-aniline derivatives of CME 134 while hydrolytic treatments of 
Teflubenzuron (PC Code 129048) FINAL

Page 17 of 28

bile indicated that phenyl urea may also be present as a sulfate conjugate.

Regarding excretion, following single low-dosing, radiolabel detected in the 0 - 48 hour 

interval yielded 45.43-46.60% of the administered dose in the feces, 15.28-17.04% in the 

bile, and 1.26-1.54% in the urine in both sexes. For this interval and dose, the amount of 

radiolabel remaining in the tissues and carcass accounted for an average of 23% of the 

administered dose. Following single high-dosing, radiolabel detected in the 0 - 48 hour 

interval, yielded 57.91-71.77% of the administered dose in the feces, 1.64-2.12% in the bile, 

and 0.29-0.40% in the urine in both sexes. For this interval and dose, the amount of 

radiolabel remaining in the tissues and carcass accounted for an average of 19% of the 

administered dose. (MRID #s: 49168823, 49168824, 49168825, 49168826)

B. Mutagenicity:

Teflubenzuron was evaluated for genetic toxicity in the following assays: bacterial mutation 

assays in Salmonella typhimurium and Escherichia coli, in vitro mammalian cell gene 

mutation tests in Chinese hamster V79 cells, in vivo (mouse bone marrow) and in vitro

cytogenetics, and unscheduled DNA synthesis (UDS) tests in primary rat hepatocytes. 

Results from these studies are presented in Table 15. As shown, teflubenzuron was not

mutagenic in bacteria or mammalian cells and not clastogenic in mammalian cells in vitro. 

Teflubenzuron was also not clastogenic or aneugenic in a rat micronucleus assay. All of these 

studies were classified as acceptable/guideline and they satisfy the specific requirement for 

mutagenicity data. Similarly, teflubenzuron was not genotoxic up to cytotoxic concentrations 

in the UDS assay.

Table 15: Summary of the Genotoxicity Studies for teflubenzuron

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5100 Bacterial Mutation 

Assay In S. 

typhimurium And 

E .coli

49168814 (1982)

Acceptable /guideline

Non-activated conditions: 

0, 125, 250, 500, 1250, 

2500 and 5000 μg/plate

Activated conditions: 

0, 125, 250, 500, 1250, 

2500 and 5000 μg/plate

There was no evidence of induced mutant 

colonies over background.
Teflubenzuron (PC Code 129048) FINAL

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Table 15: Summary of the Genotoxicity Studies for teflubenzuron

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5100 Bacterial Mutation 

Assay In S. 

typhimurium And 

E .coli

49168815 (1982)

Acceptable /guideline

Non-activated conditions: 

0, 25, 50, 125, 250, 500 

and 1000 μg/plate

Activated conditions: 

0, 25, 50, 125, 250, 500

Third test: 0, 25, 50, 75, 

100, 125, 150, 200, 250, 

300, 350, 400, 450 and 

500 μg/plate

There was no evidence of induced mutant 

colonies over background.

870.5100 In vitro Bacterial 

Gene Mutation 

(Bacterial system, 

Salmonella 

typhimurium; and 

Escherichia coli)/ 

mammalian 

activation gene 

mutation assay

49168817 (2003)

Acceptable /guideline

0, 5, 17, 50, 167, 500 and 

1667 μg/plate ± S9

There was no evidence of induced mutant 

colonies over background.

870.5300 In Vitro

Mammalian Cell 

Gene Mutation 

Test

49168816 (1986)

Acceptable /guideline

0, 5, 10, 25 and 50 μg/mL 

± S9 

Either without or with activation, the test article 

did not induce a mutagenic response in Chinese 

hamster V79 cells at any concentration level. 

There was no evidence of induced mutant 

colonies over background.

870.5735 In Vitro

Cytogenetics

49168817 (1985)

Acceptable /guideline

0 and 50 μg/mL (7-hour 

preparation time) 

0, 4, 25 and 50 μg/mL 

(18-hour preparation time) 

0 and 50 μg/mL (28-hour 

preparation time)

Without or with S9 activation, there was no 

increase in the percent of aberrant cells, 

including or excluding gaps, or in the percent 

of cells with exchanges, among the cells that 

were treated with the test article using a 7, 18 

or 28 preparation interval. All of the positive 

controls gave appropriate responses. There was

no evidence of chromosome aberrations 

induced over background.

870.5395 In vivo

Mammalian 

Cytogenetics -

Erythrocyte 

Micronucleus 

assay

49168818 (1983)

Acceptable /guideline

5000 mg/kg bw (M/F)

There was not a significant increase in the 

frequency of micronucleated polychromatic 

erythrocytes in bone marrow after any 

treatment condition in either sex.
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Table 15: Summary of the Genotoxicity Studies for teflubenzuron

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5550 Unscheduled 

DNA Synthesis in 

Primary Rat 

Hepatocytes/Mam

malian Cell 

Culture

49168818 (1986)

Acceptable /guideline

0, 0.4, 1.0, 4.0, 10.0, 40.0

and 100.0 μg/mL for 3 h 

(preliminary cytotoxicity 

assay)

0, 1.0, 3.3, 10.0, 33.0 and 

100.0 μg/mL, for 3 hours 

(main assay)

There was no evidence that unscheduled DNA 

synthesis, as determined by unscheduled 

incorporation of (3

H)-Tdr into hepatocyte DNA 

[(3

H)-Tdr dpm/μg DNA], was induced.

C. Structure-Activity Relationship 

Teflubenzuron is structurally related to Diflubenzuron as can be seen from the chemical 

structures below. The only difference is the aniline moiety.

In the 1997 Registration Eligibility Decision (RED) document (EPA 738-R-97-008), EPA 

determined that there was sufficient evidence of non-carcinogenicity in humans for 

Diflubenzuron (Group E). There was no evidence of Diflubenzuron-related induction of 

neoplastic lesions in rats fed up to 500 mg/kg/day for two years and mice fed up to 1500 

mg/kg/day for 91 weeks. The main toxic signs observed were hemolytic anemia, erythrocyte 

destruction, and methemoglobinemia. It is interesting to note that, p-chloroaniline (PCA), a

metabolite or degradation product of Diflubenzuron, has been clearly shown to be 

carcinogenic in rodents by NTP (NTP Technical Report No. 351, 1989) and considered to be 

a probable human carcinogen (Group B2). As far as Diflubenzuron itself is concerned, the 

small amounts (<2%) of carcinogenic metabolites released were apparently inadequate to 

cause cancer in rodent studies.

Based on comparison to Diflubenzuron, there is no SAR support for Teflubenzuron itself as a 

potential carcinogen. 

Cl

N

H

F

N

H

O

F

Cl

F

F

O

Teflubenzuron

N

H

F

N

H

O

Cl

F

O

Diflubenzuron
Teflubenzuron (PC Code 129048) FINAL

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D. Sub-chronic and Chronic Toxicity

Sub-chronic Toxicity

Repeated Dose 90-day Oral Toxicity Study in Rats

In a 13-week oral feeding toxicity study (MRID 49168794), CME 134 (Teflubenzuron, 

96.5% a.i., Lot No. 36/83/1) was administered to groups of 10 Wistar rats/sex/dose in the diet 

at dose levels of 0, 100, 1000, or 10,000 ppm (equivalent to 0, 8, 82, and 809 mg/kg bw/day 

for males and 0, 9, 94, and 942 mg/kg bw/day for females). An additional concurrent 5 

rats/sex/dose were treated with the control or high-dose diet for 13 weeks and sacrificed after 

a 4-week recovery period. 

Treatment of male and female rats for 13 weeks with dietary concentrations of CME 134 up 

to 10,000 ppm did not induce clinical signs of toxicity or mortality, and did not induce effects 

on body weight, body weight gain, food consumption, ophthalmoscopic parameters, or 

examined hematological or urinalysis parameters. Treatment did, however, slightly to 

moderately increase the liver-associated activities of aspartate aminotransferase, alanine 

aminotransferase, alkaline phosphatase, and ornithine carbamyl transferase, particularly in 

high-dose male rats, after 6 and 13 weeks of treatment. The activities of these enzymes 

returned to baseline activities following the 4-week recovery period in both high-dose male 

and female rats. No increase in absolute or relative to body liver weights were found in midor high-dose male rats, and no microscopic correlates were observed after 13 weeks of 

treatment or the 4-week recovery period. The absolute and relative to body liver weights of 

high-dose female rats were statistically increased 17% - 19% after 13-weeks of treatment, but 

again, no microscopic correlates were observed. No effect on absolute or relative to body 

weights was found in female rats following the 4-week recovery period. 

Repeated Dose 90-day Oral Toxicity Study in Mice

In a subchronic oral toxicity study (MRID 49168795), Teflubenzuron (91.4% a.i., Lot No. 

DW44/83) was administered to four groups of 12 ICR (Crj:CD-1) mice/sex/dose at dietary 

levels of 0, 100, 1000, or 10,000 ppm (equivalent to 0, 11.85, 115.3, and 1,213 mg/kg bw/day 

for males or 0, 13.7, 143.1, and 1,450 mg/kg bw/day for females, respectively) for 13 weeks. 

Body weights and food consumption were measured and recorded at pre-determined weekly 

intervals. Hematological parameters were measured, and all animals were subjected to a 

detailed necropsy examination after the completion of treatment. Tissues from all animals in 

the control and high dose groups were subjected to comprehensive histological evaluation.

At 100 ppm, there were no toxicologically relevant treatment-related clinical signs, or effects 

on survival, food consumption, hematology, and urinalyses in all three dose groups for both 

sexes, and no changes were noted in clinical chemistry, organ weight or gross and 

microscopic organ analysis. 
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At 1,000 ppm, serum Alanine aminotransferase (ALT/also SGPT) and cholesterol were 

elevated in females (↑55 and ↑29% respectively). There were increased absolute and 

relative liver weights in males (↑24 and ↑21%) and females (↑29 and 20%). 

Macroscopically there were enlarged livers for males (66% of animals) and females (33% of 

animals) compared to the controls (8% for males and 0% for females). In males there was 

centrilobular hepatocyte swelling (92% of animals) and fatty changes (83%).

At 10,000 ppm, one male died due to urinary insufficiency. Serum Alkaline Phosphatase 

(AP) was elevated in females (↑32%). Alanine aminotransferase (ALT/SGPT) was elevated 

in males and females (↑94 and ↑136% respectively) and cholesterol was elevated in females 

(↑51% respectively). There were increased absolute and relative liver weights in males (↑31 

and ↑37%) and females (↑52 and ↑51%). Macroscopically there were enlarged livers for 

males (75% of animals) and females (83% of animals) compared to the controls (8% for 

males and 0% for females). In males there was an increased incidence of darkened livers 

(54%) compared to the control (0%). In males there was an increased incidence of 

centrilobular hepatocyte swelling (92% of animals) compared to the control (8%). There 

was a lower non-statistically significant incidence of fatty changes in the livers of males 

(45%) compared to the control (8%).

Chronic Toxicity

Repeated Dose 1-Year Oral Toxicity Study in Rats

In a combined chronic toxicity/carcinogenicity study (MRID 49168811), CME 134 [92.4%

a.i., (batch # DW 44/83)] was administered to 70 Wistar KFM-Han rats/sex/dose in the diet 

at concentrations of 0, 20, 100, or 500 ppm. Fifty rats/sex/group, designated for the 

carcinogenicity portion of the study, were fed the test diets for 120 weeks (equivalent doses 

for the respective dietary concentrations were 0, 1.0, 4.8, and 24.8 mg/kg bw/day for males, 

and 0, 1.2, 5.9, and 29.9 mg/kg bw/day for females), and 20 rats/sex/group, designated for 

the chronic portion, were fed the test diets for 107 weeks (equivalent doses for the respective 

dietary concentrations were 0, 1.1, 5.4, and 27.6 mg/kg bw/day for males, and 0, 1.3, 6.5, and 

32.0 mg/kg bw/day for females). A subsequent combined chronic toxicity/carcinogenicity 

study (MRID 49168812), conducted to complement the findings in MRID 49168811, was 

initiated about 2 years after initiation of the first study using similar methods at the same test 

facility, but the rats were administered 0, 2500, or 10,000 ppm in the diet (equivalent to 0, 

122.5, and 487.3 mg/kg bw/day for males, and 0, 154.0, and 615.2 mg/kg bw/day for 

females) for 111 weeks. The findings are summarized in an Appendix to this DER. The 

results in the second study, which are important to the overall interpretation of 

carcinogenicity and toxicity findings in the first study, are discussed in this Executive 

Summary. 

There were no treatment-related effects on survival rates, clinical signs, body weight, body 

weight gain, food consumption, ophthalmology examinations, hematology parameters, or 

urinalysis data. There were no treatment related effects at 20 and 100 ppm. The respective 
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mean plasma concentrations of CME 134 from samples collected during week 107 were 

0.02, 0.06, 0.27 μg/L for males, and 0.02, 0.04, and 0.15 μg/L for females. The values did not 

reflect the five-fold step increases in CME 134 concentration in the diet, and the plasma 

concentrations in females were equal to or lower than in the male counterparts, even though 

compound intake on a mg/kg bw/day basis was higher in females. 

At 500 ppm (MRID #49168811), statistically significant increased (p≤0.05) AST and ALT 

activities were observed in males for weeks 14 through 78, and for ALT a significant 

increase was also observed for week 120. The activity increase was about 30% to 50% for 

AST and 2.5- to 3-fold higher for ALT, except for week 120 in which the ALT activity 

increase was about 40%. A 2- to 3-fold increase of OCT activity was observed in males for 

the 53- and 78-week sampling points. 

At 2,500 ppm (MRID #49168812), statistically increased AST activity (68-165%) and ALT 

activity (167-445%) were observed in males for all measurement times (26-111 weeks) 

except at 78 weeks. Statistically increased calcium concentrations (2.8-6.9%) were observed 

in females for weeks 26-104, but not week 111. No histologic correlate for the increased 

calcium levels was noted. Non-neoplastic liver lesions observed only in males were increased

incidences of mixed cell foci. Increased incidence of fatty change in the liver was observed in 

both males and females. Increased incidence of basophilic cell foci was observed in males.

At 10,000 ppm (MRID #49168812), statistically increased AST activity (68-165%) and ALT 

activity (167-445%) were observed in males for all measurement times (26-111 weeks) 

except at 78 weeks. Statistically increased calcium concentrations (2.8-6.9%) were observed 

in females for weeks 26-104, but not week 111. No histologic correlate for the increased 

calcium levels was noted. AST activity was statistically elevated by 68% at week 111. Males 

had statistically increased liver weights and liver-to-body weight ratios (+20%). Statistically 

increased AST activity (↑68-165%) and ALT activity (↑167-445%) were observed in males 

at both dietary concentrations for all measurement times (26-111 weeks) except at 78 weeks. 

Statistically increased calcium concentrations (↑2.8-6.9%) were observed in females at both 

dietary concentrations for weeks 26-104, but not week 111. No histologic correlate for the 

increased calcium levels was noted. AST activity was statistically elevated by 68% in 

females at the high dietary concentration at week 111. Non-neoplastic liver lesions observed 

only in males were increased incidences of mixed cell foci, focal hepatocellular hyperplasia; 

and spongiosis hepatitis. Increased incidence of fatty change in the liver was observed in 

both males and females. Increased incidence of basophilic cell foci was observed in males 

and in females. Centrilobular hypertrophy is an adaptive response (non-adverse) and was 

observed in both males and females at 2500 and 10,000 ppm.

Carcinogenicity Mouse (78 Weeks)

In a carcinogenicity study (MRID 49168813), CME 134 (92.4±0.9% a.i., batch no. DW 

44/83) was administered to 60 NMRI mice/sex/dose in the diet at dose levels of 0, 15, 75, or 

375 ppm (equivalent to 0, 2.1, 10.5, and 53.6 mg/kg bw/day for males and 0, 3.1, 15.4, and 
Teflubenzuron (PC Code 129048) FINAL

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71.7 mg/kg bw/day for females) for 78 weeks. Ten mice/sex/dose were sacrificed at 52 

weeks for interim evaluations. Evaluated parameters included mortality, clinical signs, body 

weight, body weight gain, food consumption, ophthalmoscopic examination, hematology, 

clinical chemistry, organ weights, and gross and histopathological examination. 

In all three dose groups, no treatment-related effects were observed on the following 

parameters: mortality, clinical signs, body weight, body weight gain, food consumption, 

ophthalmoscopic examination, and hematology parameters. 

At 75 ppm, the incidences of centrilobular cell necrosis and Kupffer cell proliferation were 

significantly increased (80% and 50% vs. 0% in the controls) at 52 weeks. At the terminal 

sacrifice, the incidences of diffuse hypertrophy (44% vs. 0% in the control), centrilobular 

single cell necrosis (52% vs. 16% in the control), patchy glycogen storage (34% vs. 2% in 

the control), Kupffer cell proliferation (50% vs. 4% in the control) and phagocytic foci (70% 

vs. 26% in the control) were significantly increased in the males. A trend for increasing 

incidence of phagocytic foci was also observed in females (50 vs. 40% in the control). 

At 375 ppm, statistically significant increases were observed in the activities of aspartate 

aminotransferase (↑130-168%), alanine aminotransferase (329-583%), and ornithine 

carbamyl transferase (↑398-549%) in males at 52 and 78 weeks. Alkaline phosphatase 

activity was increased 100% and lactate dehydrogenase was increased 125% in males at 52 

weeks. In females, alanine aminotransferase activity was significantly increased 124-196% at 

52 and 78 weeks and lactate dehydrogenase activity was significantly increased 66% at 78 

weeks. At the interim sacrifice at 52 weeks, absolute and relative (to body and brain weights) 

liver weights were increased 30-40% in both sexes, compared to controls. By the terminal 

sacrifice at 78 weeks, absolute and relative (to body and brain weights) liver weights in males 

were increased 65-70% and 27-28% in females. 

At 52 weeks, several liver lesions were found including diffuse hypertrophy (60% vs. 10% in 

the control), single cell necrosis (80% vs. 0% in the control), patchy glycogen storage (70% 

vs. 0% in the control), Kupffer cell necrosis (80% vs. 0% in the control), and phagocytic foci.

There was a trend for increasing incidence of phagocytic foci (80% vs. 40% in the control). 

In females sacrificed at 52 weeks, a significantly increased incidence of patchy fatty changed 

was observed (90% vs. 0% in the control). A trend for increasing incidence of phagocytic 

foci was also observed for females in the mid- and/or high-dose groups (80% vs. 40% in the 

control). 

At the terminal sacrifice, the incidences of diffuse hypertrophy (84% vs. 0% in the control), 

centrilobular single cell necrosis (80% vs. 16% in the control), patchy glycogen storage (76% 

vs. 2% in the control), Kupffer cell proliferation (70% vs. 4% in the control) and phagocytic 

foci (92% vs. 26% in the control) were significantly increased in the males. Furthermore in 

males, the incidences of nodular hyperplasia (20% vs. 6% in the control), disseminated single 

cell necrosis (40% vs. 8% in the control), lipofuscin accumulation (50% vs. 16% in the 
Teflubenzuron (PC Code 129048) FINAL

Page 24 of 28

control) and bile duct proliferation (20% vs. 0% in the control) were also significantly 

increased. In females, there was a significant increase in the incidences and severity of 

diffuse hypertrophy (30% vs. 2% in the control), disseminated single cell necrosis (48% vs. 

4% in the control), patchy glycogen storage (10% vs. 0% in the control), Kupffer cell 

proliferation (24% vs. 4% in the control), phagocytic foci (64% vs. 32% in the control), 

lipofuscin accumulation (20% vs. 0% in the control), and patchy fatty change (42% vs. 2% in 

the control). 

E. Mode of Action Studies

No Mode of Action data were submitted for teflubenzuron.

VI. COMMITTEE’S ASSESSMENT OF THE WEIGHT-OF-THE-EVIDENCE 

A. Mouse

Liver Tumors: In the CME 134 male mice, there was a dose-dependent increase in liver 

tumors which were considered to be treatment related. This was supported the presence of 

pre-neoplastic lesions in the liver.

Adequacy of Dosing: The doses tested in both sexes were considered to be adequate and not 

excessive, for assessing carcinogenicity in both sexes. This was based upon increased 

incidences of microscopic lesions in the liver (diffuse hypertrophy, centrilobular single cell 

necrosis, patchy glycogen storage, Kupffer cell proliferation, phagocytic foci, and 

centrilobular fatty changes) associated with increased relative liver weight.

B. Rat

Pancreatic, Mesenteric Lymph Node and Uterine Tumors: In Wistar rats, the observed 

pancreatic and lymph node tumors in males and the observed uterine tumors in females were 

considered to be not treatment related due to; 1) absence of a dose-response; 2) lack of 

statistical significance in a pair-wise comparison to the concurrent controls; 3) the incidences 

were within the historical control ranges; and 4) there are no corroborative pre-neoplastic 

lesions for either tumor type. 

Adequacy of Dosing: 

It was concluded that the dose levels tested were adequate in both sexes to assess the 

carcinogenicity of teflubenzuron based on decreased body weight that was observed at the 

highest dose level throughout the study in males only and an increased incidence of

histopathological lesions in the liver (fatty changes and basophilic and mixed cell foci) in

both sexes at the highest doses tested 
Teflubenzuron (PC Code 129048) FINAL

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Mutagenicity:

Based on the results from the battery of guideline genetic toxicity studies, there is no concern 

for mutagenicity for teflubenzuron.

Structure Activity Relationship (SAR):

Based on comparison to diflubenzuron, a similar benzoylurea insecticide, there is no SAR 

support for teflubenzuron itself as a potential carcinogen.

VII. CLASSIFICATION OF CARCINOGENIC POTENTIAL

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), 

the CARC classified teflubenzuron as “Suggestive Evidence of Carcinogenic Potential” based on 

the presence of rare liver tumors in male mice only. There was no evidence of carcinogenicity 

in female mice or in male or female rats. There is also no concern for mutagenicity. 
Teflubenzuron (PC Code 129048) FINAL

Page 26 of 28

VIII. QUANTIFICATION OF CARCINOGENIC POTENTIAL

Not required. The CARC recommended using a non-linear approach (i.e., reference dose 

(RfD)) that will adequately account for all chronic toxicity, including carcinogenicity, that could 

result from exposure to teflubenzuron. 

IX. BIBLIOGRAPHY

MRID No. CITATION

49168811 Suter, P., Dewert, H., Terrier, CH., et al. (1987). 120-Week 

chronic toxicity and oncogenicity study with CME 134 in the rat. RCC Research & Consulting 

Company AG, CH-4452, Itingen, Switzerland. Study No. RCC No. 027472; BASF Document 

No. TZ-427-005. September 2, 1987. Unpublished.

49168812 Tennekes, H., Stucki, H.P., Luetkemeier, H., et al. (1989). 

Chronic toxicity and oncogenicity (feeding) study with CME 134 in the rat. RCC Research & 

Consulting Company AG, CH-4452, Itingen, Switzerland. Study No. RCC No. 064192; BASF 

Document No. TZ-427-008. December 6, 1989. Unpublished.

None Historical Control Data on Neoplastic Findings In 

HsdRccHan: WIST, Wistar Hannover Rats (Planned Sacrifice after 103 Weeks). Compiled 

From 2-Year Bioassays Performed at RCC LTD. Itingen/Switzerland.

49168813 Suter, P., H. Dewert, C. Terrier, et al. (1987) 18-Month 

oncogenicity (feeding) study with CME 134 in mice. RCC Research & Consulting Company AG 

(Itingen, Switzerland). RCC Project 027810, August 17, 1987. Unpublished.

49168823 Schlüter, H. (1984). Initial investigations on the 

biokinetics of CME 134 in the rat. Celamerck GmbH u. Co. KG, Biochemical Laboratory, D6507 Ingelheim, Germany. Study No. 134AA-651-001. August 31, 1984. Unpublished.

49168824 Schlüter, H. (1986). The biokinetics and metabolism of 

14C-CME 134 in the rat. Celamerck GmbH u. Co. KG, Biochemical Laboratory, D-6507 

Ingelheim, Germany. Study No. CUB 6/85, CM Doc. No. 134AX-651-007, BASF Registration 

Document No. TZ-440-003. December 4, 1986. Unpublished. 

49168825 Schlüter, H. (1985). Investigations on the metabolism of 

CME 134 in the rat. Celamerck GmbH u. Co. KG, Biochemical Laboratory, D-6507 Ingelheim, 

Germany. CM Doc. No. 134AA-651-003, BASF Registration Document No. TZ-440-002. 

August 15, 1985. Unpublished.

 
Teflubenzuron (PC Code 129048) FINAL

Page 27 of 28

49168826 Hawkins, D.R. and Mayo, B.C. (1987). The biliary 

excretion and metabolism of 14C-CME 134. Department of Chemical Metabolism and 

Radiosynthesis, Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, PE18, 6 ES, 

England. HRC Report No. CMK 7/871263, CM Doc. No. 134AX-651-010. October 15, 1987. 

Unpublished

49168814 Kramer, P.J. (1982) In Vitro Assessment for Mutagenic 

Potentia1 in Bacteria With and Without Addition of a Metabolizing System. Institute of 

Toxicology, E. Merck, Darmstadt, Germany. Study Identification No. 4/71/82 134AA-457-001, 

BASF Registration Document Number TZ-435-001, October 11, 1982. Unpublished.

49168815 Kramer, P.J. (1982) In Vitro Assessment for Mutagenic 

Potentia1 in Bacteria With and Without Addition of a Metabolizing System. Institute of 

Toxicology, E. Merck, Darmstadt, Germany. Study Identification Number: Experiment T 12 

500, CM Doc. No. 134FZ-463-004, BASF Registration Document Number TZ-470-007, October 

11, 1982. MRID 49168815. Unpublished.

49168816 Heidmann, A. (1986) Detection of Gene Mutations in

Somatic Mammalian Cells in Culture: HGPRT-Test with V79 Cells. Laboratory for 

Mutagenicity Testing, 3, D-6100 Darmstadt, Germany. Study Identification No. LMP 135 B, CM 

Doc. No. 134AC-457-005, BASF Registration Document Number TZ-435-005, January 13, 

1986. Unpublished.

49168817 Heidmann, A. (1985) Chromosome Aberrations in Cells of 

Chinese Hamster Cell Line V79. Laboratory for Mutagenicity Testing, Schnittspahnstr., 3, D6100 Darmstadt, Germany. Study Identification No. LMP 135 C, CM Doc. No. 134AB-457-003, 

BASF Registration Document Number TZ-435-003, November 4, 1985. Unpublished.

49168818 Guenard, J. (1983) Mouse Micronucleus Assay with CME 

134. RCC, Research & Consulting Company AG, P.O. Box 4452, Itingen, Switzerland. Study 

Identification No. RCC Project 025672, BASF Registration Document Number TZ-435-002, 

December 29, 1983. MRID 49168818. Unpublished.

49168819 Muller, E. (1986) Unscheduled DNA Synthesis in 

Hepatocytes of Male Rats In Vitro (UDS Test). LMP, Schnittspahnstr. 3, D-6100 Darmstadt, 

Germany. Study Identification No. LMP 135 A, CM Doc. No. 134AC-457-006, BASF 

Registration Document Number TZ-435-006, January 22, 1986. Unpublished.

49168827 Stevenson, F.M. (2003) 3,5-dichloro-2,4-

difluorophenylurea. Testing for Mutagenic Activity with Salmonella typhimurium TA 1535, TA 

1537, TA 98 and TA 100 and Escherichia coli WP2uvrA. Inveresk Research, Tranent, EH33 

2NE, Scotland; BASF Registration Document Number 2003/1018602, November 3, 2003. 

Unpublished.
Teflubenzuron (PC Code 129048) FINAL

Page 28 of 28

49168793 Suter, P., Horst, K., Luetkemeier, H., et al. (1983) 13-

Week subchronic toxicity (feeding) study with CME 134 in the rat. Research & Consulting 

Company (RCC) AG, P.O. Box CH-4452, Itingen, Switzerland. RCC Project No. 018843 

(Shell Agrar Doc. No. 134AB-435-006, BASF Registration Document No. TZ-425-002). 

November 1, 1983. MRID 49168794. Unpublished. (Note: the Study Report was issued on 

December 1, 1987.)

49168795 Takahashi K. (1987) 13 Week subacute toxicity study with 

Teflubenzuron in mice. (Final Report). The Institute of Environmental Toxicology, No.772, 2-

chome, Suzuki-cho, Kodaira-shi, Tokyo, 187 Japan. BASF Registration Document Number: 

TZ-425-004. January 27, 1987. [Translated from Japanese for American Cyanamid Company, 

October 30, 1997]. MRID 49168795. Unpublished.