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.: N I A



### 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 Middleton, Co-Chair

## ~ 

# cfn

..**~** Cancer Assessment Review Committee

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


### F i nal Guideline s for Carcinogen Risk Assessment (March, 2005). Attached please find the final

Cancer Assessment Document.Teflubenzuron (PC Code 129048 ) FINAL



### Page 2 of 28 CANCER ASSESSMENT DOCUMENT

EVALUATION OF THE CARCINOGENIC POTENTIAL OF

T eflubenzuron

PC CODE 129048

July 1 , 2015



### C ANCER 

### A SSESSMENT 

### R EVIEW 

### C OMMITTEE

HEALTH EFFECTS DIVISION

OFFICE OF PESTICIDE PROGRAMSTeflubenzuron (PC Code 129048 ) FINAL



### Page 3 of 28 I. EXECUTIVE SUMMARY

................................ ................................ ................................ .. 4

II. INTRODUCTION

................................ ................................ ................................ ................. 6

III. BACKGROUND INFORMATI ON

................................ ................................ .................... 6

IV. EVALUATION OF CARCIN OGENICITY STUDIES

................................ .................... 6

A. C OMBINED 

### C HRONIC 

### T OXICITY 

### /C ARCINOGENICITY 

### S TUDY IN 

### W ISTAR 

### KFM

- H AN 

### R ATS



### ... 6

B. C ARCINOGENICITY 

### S TUDY IN 

### M ICE



### ................................ ................................ ................... 12

V. TOXICOLOGY

................................ ................................ ................................ ................... 16

A. M ETABOLISM



### ................................ ................................ ................................ ..................... 16

B. M UTAGENICITY 

### :

................................ ................................ ................................ ................ 17

C. S TRUCTURE



### - A CTIVITY 

### R ELATIONSHIP



### ................................ ................................ ............. 19

D. S UB



### - CHRONIC AND 

### C HRONIC 

### T OXICITY



### ................................ ................................ ............. 20

E. M ODE OF 

### A CTION 

### S TUDIES



### ................................ ................................ ................................ 24

VI. COMMITTEE’S ASSESSME NT OF THE WEIGHT

- OF

- THE

- EVIDENCE

............ 24

A. M OUSE



### ................................ ................................ ................................ ............................... 24

B. R AT



### ................................ ................................ ................................ ................................ .... 24

VII. CLASSIFICATION OF CA RCINOGENIC POTENTIAL

................................ ........ 25

VIII. QUANTIFICATION OF CA RCINOGENIC POTENTIAL

................................ ...... 26

IX. BIBLIOGRAPHY

................................ ................................ ................................ ............... 26Teflubenzuron (PC Code 129048 ) FINAL



### Page 4 of 28 I. EXECUTIVE SUMMARY

On April 29 , 2015, the Cancer Assessment Review Committee of the Health Effects Division of the Office of Pesticide Programs e valuate d 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 con trol 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%) w ere 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 i n female mice

. The CARC

, based on the observed

non

- neoplastic liver lesions in both sexes, d etermined that the doses tested in both sexes of mice were adequate for assessing the carcinogenic potential of teflubenzuron.

Two separate chronic toxicity/carc inogenicity 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 male s and female s at two higher doses, 0, 2500 or 10,000 ppm for

120 weeks. In males, there was an increase in the incidence of pancreatic carcinom a s and mesenteric lymph node hemangiomas at 500 ppm teflubenzuron . In females, th ere 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) l ack 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

teflubenz uron.

There was no evidence of mutagenicity in vivo or in vitro

.

I n 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 mutagenicit y

.

Quantification of human cancer risk is not required. The CARC recommended using a non

- linearTeflubenzuron (PC Code 129048 ) FINAL



### Page 5 of 28 approach . The chronic Reference Dose (RfD) will adequately account for all chronic toxicity, including carcinogenicity, which could result from exposure to tef lubenzuron.Teflubenzuron (PC Code 129048 ) FINAL



### Page 6 of 28 II. I NTRODUCTION

On April 29 , 2015, the Cancer Assessment Review Committee of the Health Effects Division of the Office of Pesticide Programs evaluate d 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

- di fluoro

phenyl)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 mol t.

IV. EVALUATION OF CARCINOGENICITY STUDIES

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

f irst study conducted in 1987 and the second in 1989

.

A. Combined Chronic Toxicity/Car cinogenicity 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

-Teflubenzuron (PC Code 129048 ) FINAL



### 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 res pective 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 th e 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 hi gher 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 53 i 53

- 78 79

- 104 104 i 105

- 108 108 i 109

- 122 f 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) nTeflubenzuron (PC Code 129048 ) FINAL



### Page 8 of 28 ( ) 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 Fema le Rats

There was an increase in the incidence of u terine adenocarcinomas at the high dose (10, 000 ppm) in the first study but not in the second study. Statistical analyses of th is tumor incidence

w as conducted separately for each study as well as w ith 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 pair

wise comparison (p<0.05) at 10,000 ppm for uterine adenocarcinomas

.

As shown Table 4 , w hen 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 da ta for tumors in Wistar rat s supplied b y 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

T umor: Dose (ppm)

0 20 100 500

Adenocarcinomas# (%)

P = 3 a /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.Teflubenzuron (PC Code 129048 ) FINAL



### Page 9 of 28 Table 2 : Teflubenzuron

– Wistar KFM

- Han Rat Study (MRID 49168812 )

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

T umor: Dose (ppm)

0 2500 10,000

Adenocarcinomas# (%)

P = 0/58 (0)

0.00875** 0/32 (0)

1.00000 5 b /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

T umor: 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 5 a /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

- N eoplastic Lesions in the Uterus : There were no treatment related increase non

neoplastic lesions in the u terus.

.

(ii) Pancreatic Tumor s 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 T able 5). In the second study, 1/ 23 rats had these pancreatic exocrine tumors at the 2,500 ppm concentration but no ne at the 10,000 ppm concentration (see T able 6). These two groups were combined in T able 7 and together showed no dose response up to 10,000 ppm. In a compilation of histori cal 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 n o survival analysis was performed for male rats.Teflubenzuron (PC Code 129048 ) FINAL



### Page 10 of 28 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

T umor: 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

.Teflubenzuron (PC Code 129048 ) FINAL



### Page 11 of 28 (iii) Hemangioma s 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 ( T able 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 a nd 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

statis tically significant ( T able 9) . The incidence s 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 anim als/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.Teflubenzuron (PC Code 129048 ) FINAL



### Page 12 of 28 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, b ody weight, body weight gain, food consumption, ophthalmoscopic examination, hematology, clinical chemistry, organ weights, and gross and histopathologic al 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 on ly. 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 4 9168813 )

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

Dose (ppm) Weeks

1

- 26 27

- 52 52 i 53

- 78 f Total

0 0/60 4/60 10/56 12/45 a 16/49 (33) **n

15 0/60 2/60 10/58 11/47 a 13/49 (27) n

75 0/60 0/59 b 9/59 9/50 9/50 (18) n

375 0/60 0/60 10/60 5/50 5/50 (10) **nTeflubenzuron (PC Code 129048 ) FINAL



### Page 13 of 28 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. Historica l control data for mouse liver

adenomas and carcinomas are presented in T able s 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%) w ere also outside the laboratory’s historical

control valu e (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 = 7 a /58 (12)

0.01576* 5/58 (9)

0.77929 13 a /59 (22)

0.11257 16/60 (27)

0.05090

Carcinomas (%)

p = 4 b /58 (7)

0.54808 6 b /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 c ontrol 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 wa s 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 c ar cinoma 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, t hey 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 c ontrol

. Significance of pair

- wise comparison with control denoted at dose level.

If * , then p < 0.05. If ** , then p < 0.01.Teflubenzuron (PC Code 129048 ) FINAL



### Page 14 of 28 Table 12 : Historical Control for liver adenomas in male mice a

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

Total s: 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 mice a

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

Total s: 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



### Page 15 of 28 Non

- Neoplastic Lesions

As described in Table 14, at 75 and 375 ppm teflubenzuron, there were significant and dose

dependent increase s 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 mice ab

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 Pres ent, 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



### Page 16 of 28 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 l iver 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 a lso 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 do sing, 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 equiva lents/mL in male and female rats, respectively.

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

test material for 7 consecu tive 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 les s 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 conju gation was the predominant pathway. Only very small amounts of radioactivity co

eluted with the hydroxylated

- aniline derivatives of CME 134 while hydro lytic treatments ofTeflubenzuron (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, radiolab el 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 carca ss 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 b oth 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 , i n 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 vi tro

. 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 u p 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



### Page 18 of 28 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, 12 5, 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 perc ent 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.Teflubenzuron (PC Code 129048 ) FINAL



### Page 19 of 28 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/ μ g 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 les ions 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

DiflubenzuronTeflubenzuron (PC Code 129048 ) FINAL



### Page 20 of 28 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.

Treat ment 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 weig ht, 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

aminotran sferase, 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

- dos e male and female rats. No increase in absolute or relative to body liver weights were found in mid

or 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

- determi ned 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 clini cal chemistry, organ weight or gross and microscopic organ analysis.Teflubenzuron (PC Code 129048 ) FINAL



### Page 21 of 28 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 hep atocyte 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

centrilob ular 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 Tox icity 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/g roup, 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 f emales), 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

facili ty, 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

re sults 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 respectiveTeflubenzuron (PC Code 129048 ) FINAL



### Page 22 of 28 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), s tatistically 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 activ ity 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 week s. 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 incre ased

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

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

At 10,000 ppm (MRID #49168812), statistically increased AST activit y (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 A LT 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 w eeks 26

- 104, but not week 111. No histologic correlate for the

incre ased calcium levels was noted. AST activity was statistically elevated by 68% in females at the high diet ary concentration at week 111. Non

- neoplastic liver lesions observed only in m ales 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 ob served 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, andTeflubenzuron (PC Code 129048 ) FINAL



### Page 23 of 28 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 a nd 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 signifi cantly 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, alan ine aminotransferase activity was significantly increased 124

- 196% at 52 and 78 weeks and lactate dehydrogenase activity was significan tly increased 66% at 78

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

li ver 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 liv er 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 inc idence 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 inc idences 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 theTeflubenzuron (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), K upffer 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 Act ion 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

- neopl a stic lesions in the liver.

Adequacy of Dosing: The doses tested in both sexes w ere considered to be adequate and not excessive, for assessing carcinogenicity in both sexes. This was based upon increased

incide nces of microscopic lesions in the liver (diffuse hypertrophy, centrilobular single cell necrosis, patchy glycogen storage, Kupffer cell proliferation, phagocytic foci, and centrilobular fatty change s ) 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 t eflubenzuron based on decreased body weight that was observed at the highest dose level throughout the study in males only an d an increased incidence of histopathological lesions in the liver ( fatty changes and basophilic and mixed cell foci ) in both sexes at the highest doses testedTeflubenzuron (PC Code 129048 ) FINAL



### Page 25 of 28 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 d iflubenzuron, a similar benzoylurea insecticide, there is no SAR support for t eflubenzuron 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, in cluding 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., Luetkem eier, 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. Unpublishe d.

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, D

6507 Ingelheim, Germany. Study No. 134AA

- 651

- 001. August 31, 1984. Unpublished.

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

14 

### C

- 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 Registrat ion

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 14 

### C

- 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. (19 82) 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, D

6100 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 WP2 uvr A. 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, 1 987.)

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 Regist ration Document Number:

TZ

- 425

- 004. January 27, 1987. [Translated from Japanese for American Cyanamid Company, October 30, 1997 ]. MRID 49168795. Unpublished.