UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF PREVENTION, PESTICIDES

 AND TOXIC SUBSTANCES

MEMORANDUM

Date: November 25, 2009

SUBJECT: Fluopyram: Report of the Cancer Assessment Review Committee

PC Code: 080302 DP Barcode: N/A

Decision No.: N/A Registration No.: N/A

Petition No.: N/A Regulatory Action: N/A

Risk Assessment Type: Cancer Assessment Case No.: N/A

TXR No.: 0055261 CAS No.: 658066-35-4

MRID No.: N/A 40 CFR: N/A

 

FROM: Jessica Kidwell, Executive Secretary

Cancer Assessment Review Committee 

Health Effects Division (7509P)

THROUGH: Mary Manibusan, Co-chair

Cancer Assessment Review Committee 

Health Effects Division (7509P)

TO: Myron Ottley, Toxicologist

Paula Deschamp, Branch Chief

Registration Action Branch III

Health Effects Division (7509P)

Cynthia Giles-Parker

Fungicide Branch

Registration Division (7505P)

The Cancer Assessment Review Committee met on July 8, 2009 to evaluate the cancer 

classification of Fluopyram in accordance with the EPA’s Final Guidelines for Carcinogen Risk 

Assessment (March, 2005). Attached please find the final Cancer Assessment Document.
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

2

CANCER ASSESSMENT DOCUMENT

EVALUATION OF THE CARCINOGENIC POTENTIAL OF

FLUOPYRAM

PC CODE 080302

November 25, 2009

CANCER ASSESSMENT REVIEW COMMITTEE

HEALTH EFFECTS DIVISION

OFFICE OF PESTICIDE PROGRAMS
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

3

DATA PRESENTATION: ____________________________________

Myron Ottley, Toxicologist

DOCUMENT PREPARATION: ____________________________________

Jessica Kidwell, Executive Secretary

COMMITTEE MEMBERS IN ATTENDANCE: (Signature indicates concurrence with the 

assessment unless otherwise noted.)

Gregory Akerman ____________________________________

Lori Brunsman, Statistician ____________________________________

Marion Copley ____________________________________

Kit Farwell ____________________________________

Ray Kent ____________________________________

Mary Manibusan, Co-Chair ____________________________________

Karlyn Middleton ____________________________________

Rob Mitkus ____________________________________

Esther Rinde ____________________________________

NON-COMMITTEE MEMBERS IN ATTENDANCE: (Signature indicates concurrence with the 

pathology report)

John Pletcher, Consulting Pathologist ____________________________________

OTHER ATTENDEES: Leung Cheng, Barry O’Keefe, Joel Patterson (PMRA observer), 

Meheret Negussie, Steve Funk, Whang Phang, Doug Wolf, Sheila Healy, Paula Deschamp, 

Michael Khan; On conference phone with Global Review Partners- Germany (Philip MarxStölting, David Schumacher) and Canada (Catherine Adcock, Michael Honeyman, Martin 

Gerrits, Carmen Cheung)
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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TABLE OF CONTENTS

EXECUTIVE SUMMARY...................................................................................5

I. Introduction..................................................................................................................................8

II. Background Information.............................................................................................................8

III. Evaluation of Carcinogenicity...................................................................................................9

1. Combined Chronic Toxicity/Carcinogenicity Study in Rats............................................9

2. Carcinogenicity Study in Mice......................................................................................13

IV. Toxicology..............................................................................................................................16

1. Metabolism ....................................................................................................................16

2. Mutagenicity ..................................................................................................................17

3. Structure Activity Relationship......................................................................................18

4. Subchronic and Chronic Toxicity .................................................................................19

5. Mode of Action ...............................................................................27

V. Committee’s Assessment of the Weight-of-the Evidence .......................................................31

VI. Classification of Carcinogenic Potential.................................................................................33

VII. Quantification of Carcinogenicity .........................................................................................33

VIII. Bibliography..........................................................................................................................33
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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EXECUTIVE SUMMARY

On July 8, 2009, the Cancer Assessment Review Committee (CARC) of the Health Effects 

Division of the Office of Pesticide Programs met to evaluate the carcinogenic potential of 

fluopyram. This is the first assessment of fluopyram by the CARC. Fluopyram is a global 

review chemical in partnership with Canada and Germany. Germany has the work share lead for 

review of toxicology data.

Myron Ottley of Risk Assessment Branch III presented the chronic toxicity/carcinogenicity study

in Wistar rats and the carcinogenicity study in C57BL/C6 mice. In a combined chronic toxicity

and carcinogenicity study, groups of 60 male and female Wistar rats were fed a diet containing 0, 

30, 150 and 750 ppm (males) and 0, 30, 150 and 1500 ppm (females) fluopyram for 24 months. 

In males, the top dose level of 750 ppm had to be reduced to 375 ppm from week 85 onwards 

because of the high mortality in this group. Over the whole study period, these dietary

concentrations corresponded to a mean daily intake of 0, 1.20, 6.0 and 29 mg/kg bw in male rats 

or 1.68, 8.6 and 89 mg/kg bw in females. In addition, satellite groups of 10 animals per sex and 

dose were subject to interim sacrifice after 1 year. Groups of 60 male and female C57BL/6J

mice were fed diets containing 0, 30, 150 or 750 ppm of fluopyram (corresponding to a mean 

compound intake of 0, 4.2, 20.9 and 105 mg/kg bw/day in males and 0, 5.3, 26.8 and 129 mg/kg 

bw/day in females, respectively) for up to 78 weeks. After 52 weeks, 10 males and 10 females 

from each group which had been allocated to the chronic phase of the study were killed and 

necropsied. The remaining 50 animals per sex and group (allocated to the carcinogenicity phase) 

continued treatment until scheduled sacrifice after at least 78 weeks of treatment. Information on 

mutagenicity, structure activity relationship and mode of action data for thyroid and liver tumors 

was also presented.

The CARC concluded the following:

Carcinogenicity

Rat

· Administration of fluopyram resulted in the induction of liver tumors in female Wistar rats. 

There were statistically significant trends for liver adenomas (p<0.01), carcinomas (p<0.05) and 

combined liver adenomas and carcinomas (p<0.01). There were significant pair-wise 

comparisons of the 1500 ppm dose group with the controls for liver adenomas at p<0.05 and for 

combined liver adenomas and carcinomas at p<0.01. When compared to historical control data 

(uncensored data) from the testing laboratory, the incidence of hepatocellular adenomas in the 

female high dose group (9/55, 16%) was outside the range of the historical control group (range, 

0 - 5%; average, 1.9%). Similarly, the incidence of hepatocellular carcinomas in the female mid 

(2/56, 4%) and high dose groups (3/55, 5%), while not statistically significant by pair-wise 

comparison, exceeded the range of the historical control group (no carcinomas observed in 10 
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

Page 6 of 35

studies from 2000 - 2006) and was considered to be biologically relevant. There were no 

statistically significant trends or significant pair-wise comparisons of the dosed groups with the 

controls for the male rats. The CARC considered the liver tumors in female Wistar rats to 

be treatment-related.

· Adequacy of Dosing: The doses tested were considered to be adequate and not excessive to 

assess carcinogenic potential in both sexes. In female rats, the highest dose tested of 1500 ppm 

was considered to be adequate. This was based on a 20% decrease in mean body weights and 

increased liver weights (mean: +39%, absolute: +56%), which were dose-related and correlated 

well with findings such as prominent lobulation and hypertrophy. Other effects that occurred at 

the high dose included thyroid follicular cell hypertrophy and colloid alteration, chronic 

progressive nephropathy and kidney tubular dilatation, and retinal atrophy and lenticular 

degeneration of the eye. In male rats, the top dose level of 750 ppm, an excessive dose, had to 

be reduced to 375 ppm from week 85 onwards because of the high mortality in this group. At the 

termination of the study, mortality among high-dose males was 50% of control values. The dose 

of 375 ppm, which is roughly one-half the excessive dose of 750 ppm, however, was considered 

to be adequate. This was based on decreased mean body weight, increased liver weight, liver 

hypertrophy, follicular cell hypertrophy and colloid alteration, chronic progressive nephropathy

and tubular dilatation and tubular hypertrophy (males) all observed at the high dose.

Mouse

· Administration of fluopyram resulted in the induction of thyroid follicular cell tumors in male 

C57BL/6J mice. Male mice had a statistically significant trend at p<0.01 and a significant pairwise comparison of the 750 ppm dose group with the controls at p<0.05 for thyroid follicular cell 

adenomas. There were no statistically significant trends or significant pair-wise comparisons of 

the dosed groups with the controls for the female mice. When compared to historical control 

data (uncensored data) from the testing laboratory, the incidence of thyroid follicular cell 

adenomas in the male high dose group (7/48, 15%) was outside the range of the historical control 

group (range, 0 - 2%; average, 0.4%). The CARC considered the thyroid follicular cell 

adenomas in male C57BL/6J mice to be treatment-related.

· Adequacy of Dosing: The high dose of 750 ppm was considered to be adequate, and not 

excessive, to assess carcinogenic potential in both male and female mice, based on the following: 

1) Increased absolute and relative liver weights in males and females at the high- and mid-dose 

levels. These changes were dose-related, and correlated well with macroscopic findings 

(dark/enlarged livers) and non-neoplastic histopathological lesions (eosinophilic foci [females], 

hepatocellular hypertrophy [both sexes], cholestasis [males], single cell degeneration/necrosis 

[males]); 2) Increased incidence of thyroid follicular cell hyperplasia in both sexes at the high 

dose; and 3) Decreased absolute and relative kidney weights in both sexes at the high dose level, 

along with increased incidence and/or severity of kidney lesions (bilateral cortical basophilic 

tubules, hyaline casts and interstitial mononuclear cell infiltrates, glomerular congestion/ 

hemorrhage, and amyloid deposition) in females.
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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Mutagenicity

There is no concern for mutagenicity.

Structure-Activity Relationship (SAR)

The SAR data do not inform the mode of action.

Mode of Action

The CARC concluded that insufficient data were provided to support definitive modes of action 

for the induction of liver tumors in female rats or thyroid follicular cell tumors in male mice. The 

main deficiency included a lack of dose-response concordance with key events and tumors. 

Classification and Quantification of Carcinogenic Potential

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

the CARC classified fluopyram as “Likely to be Carcinogenic to Humans” based on tumors in 

two species and two sexes: a treatment-related increase in thyroid follicular cell adenomas in 

high dose male mice and liver tumors in female rats at the high dose, with incidences exceeding 

that of the laboratory’s historical controls. There is no mutagenic concern for fluopyram. The 

available data do not support the proposed modes of action for the thyroid or liver tumors. 

The CARC recommended the use of a linear low dose extrapolation model applied to the animal 

data (Q1*) for quantitative estimation of human risk. The unit risk, Q1

*

(mg/kg/day)

-1

, of 

Fluopyram based upon female rat liver combined adenoma and carcinoma tumor rates is 

1.55 x 10-2in human equivalents. 
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

Page 8 of 35

I. INTRODUCTION

On July 8, 2009, the Cancer Assessment Review Committee (CARC) of the Health Effects 

Division of the Office of Pesticide Programs met to evaluate the carcinogenic potential of 

Fluopyram. 

II. BACKGROUND INFORMATION

Fluopyram is a global review chemical in partnership with Canada and Germany. Germany has 

the work share lead for review of toxicology data.

Fluopyram is a new broad-spectrum systemic fungicide of the carboxamide group (FRAC Group 

7). It acts on cell respiration in the fungus by inhibiting succinate dehydrogenase (mitochondrial

respiration Complex II), thus blocking electron transport.

The main use of fluopyram is the selective control of a variety of fungal diseases like powdery

mildew species, Botrytis cinerea, and Alternaria solani on grape vines and tomatoes. It is also 

to be used on ornamentals and non-residential turf. Its structure and other pertinent information 

are depicted in the following table.

Chemical 

structure:

13

14

15

16

11

12

10 N

H

9

O

8

7

2

N

1

6

5

4

Cl 3

CF3

CF3

Empirical formula: C16 H11 Cl F6 N2 O

Common name: Fluopyram

Company code: AE C656948

IUPAC name: N-{2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethyl}-2-

(trifluoromethyl)benzamide

CAS name: Benzamide, N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-

(trifluoromethyl)-(9CI)

CAS no.: 658066-35-4

PC Code 080302
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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III. EVALUATION OF CARCINOGENICITY STUDIES

1. Combined Chronic Toxicity/Carcinogenicity Study with Fluopyram in Wistar Rats

Reference: Chronic Toxicity and Carcinogenicity Study of AE C656948 in the Wistar 

Rat by Dietary Administration for 24 months. Bayer Crop Science Project Number: 

SA/04312, M/298339/01/2. Report No. 04312 February 29, 2008. MRID 47372501

A. Experimental Design

In a combined chronic toxicity and carcinogenicity study, groups of 60 male and female Wistar 

rats were fed a diet containing 0, 30, 150 and 750 ppm (males) and 0, 30, 150 and 1500 ppm 

(females) fluopyram for 24 months. In males, the top dose level of 750 ppm had to be reduced to 

375 ppm from week 85 onwards because of the high mortality in this group. Over the whole 

study period, these dietary concentrations corresponded to a mean daily intake of 0, 1.20, 6.0 and 

29 mg/kg bw in male rats or 1.68, 8.6 and 89 mg/kg bw in females. In addition, satellite groups 

of 10 animals per sex and dose were subject to interim sacrifice after 1 year.

B. Discussion of Mortality and Tumor Data

Mortality

Male rats showed a statistically significant trend (p<0.01) for mortality with increasing doses of 

Fluopyram, as well as a significant pair-wise comparison (p<0.05) of the 750 ppm dose group 

with the controls. There was no evidence of significant differences in mortality in female rats 

(Memo, L. Brunsman, June 10, 2009, TXR #0055218).

Tumors

Female rats had statistically significant trends for liver adenomas (p<0.01), carcinomas (p<0.05) 

and combined liver adenomas and carcinomas (p<0.01). There were significant pair-wise 

comparisons of the 1500 ppm dose group with the controls for liver adenomas at p<0.05 and for 

combined liver adenomas and carcinomas at p<0.01 (Table 1). There were no statistically

significant trends or significant pair-wise comparisons of the dosed groups with the controls for 

the male rats. The statistical analyses of the tumors in the female rats were based upon Fisher’s 

Exact Test for pair-wise comparisons and the Exact Test for (Memo, L. Brunsman, June 10,

2009, TXR #0055218).
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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Table 1. Liver Tumor Rates+and Fisher’s Exact Test and Exact Test for Trend Results in 

Female Rats

Dose (ppm)

0 30 150 1500

Adenomas

(%)

p =

2/59

(3)

0.00049**

2/57

(4)

0.67765

0/56

(0)

1.00000

9

a

/55

(16)

0.01978*

Carcinomas

(%)

p =

0/59

(0)

0.02134*

0/57

(0)

1.00000

2/56

(4)

0.23494

3

b

/55

(5)

0.10910

Combined

(%)

p =

2/59

(3)

0.00015**

2/57

(4)

0.67765

2/56

(4)

0.67083

11c/55

(20)

0.00536**

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

week 54.

a

First adenoma observed at week 75, dose 1500 ppm.

b

First carcinoma observed at week 97, dose 1500 ppm.

cOne animal in the 1500 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.

When compared to historical control data (uncensored data) from the testing laboratory, the 

incidence of hepatocellular adenomas in the female high dose group at week 104 (9/55, 16.4%) 

was outside the range of the historical control group (range, 0 - 5%; average, 1.9%). Similarly,

the incidence of hepatocellular carcinomas in the female mid and high dose group at week 104 

(2/56 (4%) mid and 3/55, 5%, high) exceeded the range of the historical control group (no 

carcinomas observed in 10 studies from 2000 - 2006).

C. Non-Neoplastic Lesions in the Liver

Non-neoplastic lesions of the liver are presented in Tables 2a and 2b.
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Table 2a: Incidence and severity of microscopic changes in the liver, all animals of the 

carcinogenicity phase (part 1 of 2)

Sex Males Females

Dose level fluopyram (ppm) 0 30 150 750/375 0 30 150 1500

Dose level fluopyram (mg/kg) 0 1.20 6.0 29.0/15.0 0 1.7 8.6 89

Number of animals examined 60 60 60 58 60 60 60 59

Centrilobular to panlobular hepatocellular hypertrophy: diffuse 

Minimal 1 1 14 15 0 0 0 6

Slight 0 0 0 15 0 0 0 21

Moderate 0 0 0 0 0 0 0 21

Total 1 1 14** 30** 0 0 0 48**

Focus(i) of hepatocellular alteration: clear: focal/multifocal 

Minimal 8 6 6 11 0 3 3 8

Slight 2 2 1 5 1 1 1 3

Total 10 8 7 16 1 4 4 11**

Focus(i) of hepatocellular alteration: eosinophilic: focal/multifocal 

Minimal 12 20 18 15 23 17 14 25

Slight 4 3 10 12 6 7 15 13

Moderate 0 1 2 1 0 2 1 7

Marked 0 0 1 0 0 0 0 3

Total 16 24 31* 28** 29 26 30 48**

Hepatocellular vacuolation: focal/multifocal

Minimal 10 4 13 7 5 10 7 13

Slight 0 2 3 0 1 4 2 9

Moderate 0 1 0 0 0 0 0 0

Total 10 7 16 7 6 14** 9 22**

*: p≤0.05, **: p≤0.01

Table 2b: Incidence and severity of microscopic changes in the liver, all animals of the 

carcinogenicity phase (part 2 of 2)

Sex Males Females

Dose level of fluopyram (ppm) 0 30 150 750/375 0 30 150 1500

Dose level fluopyram (mg/kg) 0 1.20 6.0 29.0/15.0 0 1.7 8.6 89

Number of animals examined 60 60 60 58 60 60 60 59

Increased number of mitoses

Present 0 0 0 0 6 1 5 33

Total 0 0 0 0 6 1 5 33**

Multinucleated hepatocytes with anisocaryosis

Present 1 0 1 0 4 2 6 38

Total 1 0 1 0 4 2 6 38**

Hepatocellular single cell necrosis: focal/multifocal

Minimal 2 0 1 1 0 3 1 25

Slight 0 0 1 0 0 1 0 12

Total 2 0 2 1 0 4 1 37**

Hepatocellular brown pigment(s): focal/multifocal
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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Sex Males Females

Dose level of fluopyram (ppm) 0 30 150 750/375 0 30 150 1500

Dose level fluopyram (mg/kg) 0 1.20 6.0 29.0/15.0 0 1.7 8.6 89

Number of animals examined 60 60 60 58 60 60 60 59

Minimal 0 0 0 0 1 1 2 22

Slight 0 0 0 0 0 0 0 2

Total 0 0 0 0 1 1 2 24**

Accumulation of brown pigments in Kupffer cells: focal/multifocal 

Minimal 6 2 9 5 8 7 9 27

Slight 1 0 1 2 4 3 2 4

Moderate 0 0 0 0 0 0 0 1

Total 7 2 10 7 12 10 11 32**

Hepatocellular macrovacuolation: centrilobular to midzonal: diffuse

Minimal 0 0 0 9 0 0 0 5

Slight 0 0 2 1 0 0 0 4

Moderate 0 0 0 0 0 0 0 2

Total 0 0 2 10** 0 0 0 11**

Extramedullary hematopoiesis: multifocal

Minimal 16 7 10 15 17 24 21 30

Slight 1 3 1 1 2 1 3 3

Moderate 1 0 0 0 0 0 0 0

Total 18 10 11 16 19 25 24 33**

**: p≤0.01

D. Adequacy of the Dosing for Assessment of Carcinogenicity

The doses tested were considered to be adequate and not excessive to assess carcinogenic 

potential in both sexes. 

In female rats, the highest dose tested of 1500 ppm was considered to be adequate. This was 

based on a 20% decrease in mean body weights and increased liver weights (mean: +39%, 

absolute: +56%), which were dose-related and correlated well with findings such as 

prominent lobulation and hypertrophy. Other effects that occurred at the high dose included 

thyroid follicular cell hypertrophy and colloid alteration, chronic progressive nephropathy and

kidney tubular dilatation, and retinal atrophy and lenticular degeneration of the eye.

In males, the top dose level of 750 ppm, an excessive dose, had to be reduced to 375 ppm 

from week 85 onwards because of the high mortality in this group. At the termination of the 

study, mortality among high-dose males was 50% of control values. The dose of 375 ppm, 

which is roughly one-half the excessive dose of 750 ppm, however, was considered to be 

adequate. This was based on decreased mean body weight, increased liver weight, liver 

hypertrophy, follicular cell hypertrophy and colloid alteration, chronic progressive

nephropathy and tubular dilatation and tubular hypertrophy (males) all observed at the high 

dose.
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2. Carcinogenicity Study in C57BL/6J Mice

Reference: Carcinogenicity Study of AE C656948 [fluopyram] in the C57BL/6J Mouse By

Dietary Administration for 18 months. Bayer CropScience.Project Number: SA/05094. Report 

No.05094. December 14, 2007 MRID 47372450

A. Experimental Design

Groups of 60 male and female C57BL/6J mice were fed diets containing 0, 30, 150 or 750 ppm 

of fluopyram (corresponding to a mean compound intake of 0, 4.2, 20.9 and 105 mg/kg bw/day

in males and 0, 5.3, 26.8 and 129 mg/kg bw/day in females, respectively) for up to 78 weeks. 

After 52 weeks, 10 males and 10 females from each group which had been allocated to the 

chronic phase of the study were killed and necropsied. The remaining 50 animals per sex and 

group (allocated to the carcinogenicity phase) continued treatment until scheduled sacrifice after 

at least 78 weeks of treatment.

B. Discussion of Mortality and Tumor Data

Mortality

There was no evidence of significant differences in mortality with increasing doses of Fluopyram in 

male or female mice (Memo, L. Brunsman, June 10, 2009, TXR # 0055218). 

Tumors

Male mice had a statistically significant trend at p<0.01 and a significant pair-wise comparison of 

the 750 ppm dose group with the controls at p<0.05 for thyroid follicular cell adenomas (Table 

3). There were no statistically significant trends or significant pair-wise comparisons of the 

dosed groups with the controls for the female mice. The statistical analyses of the tumors in the 

male and female mice were based upon Fisher’s Exact Test for pair-wise comparisons and the 

Exact Test for trend (Memo, L. Brunsman, June 10, 2009, TXR # 0055218).
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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Table 3. Thyroid Follicular Cell Tumor Rates+and Fisher’s Exact Test and Exact Test for Trend 

Results in Male Mice

Dose (ppm)

0 30 150 750

Adenomas#

(%)

p =

1/49

(2)

0.00357**

1/47

(2)

0.74211

3

a

/48

(6)

0.30076

7/48

(15)

0.02758*

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

week 54.

#No carcinomas were observed.

a

First adenoma observed at week 79, dose 150 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.

When compared to historical control data (uncensored data) from the testing laboratory, the 

incidence of thyroid follicular cell adenomas in the male high dose group at week 78 (7/48, 

14.6%) was outside the range of the historical control group (range, 0 - 2%; average, 0.4%).

C. Non-Neoplastic Lesions

The non-neoplastic lesions observed in liver and thyroid of both sexes of mice are 

presented in Tables 4 and 5.

Table 4: Incidence and severity of microscopic changes in the liver, all animals, 

carcinogenicity phase

Sex Males Females

Dose level of fluopyram (ppm) 0 30 150 750 0 30 150 750

Dose level of fluopyram (mg/kg) 0 4.20 20.9 105 0 5.30 26.8 129

Number of animals 49 49 49 50 48 50 50 50

Eosinophilic focus(i) of altered hepatocytes: focal/multifocal

Minimal 1 0 0 0 0 1 2 0

Slight 0 0 0 2 0 0 0 2

Moderate 0 0 0 0 0 0 0 2

Marked 0 0 0 0 0 0 0 1

Total 1 0 0 2 0 1 2 5*

Centrilobular to panlobular hepatocellular hypertrophy: diffuse

Minimal 0 0 16 3 0 0 18 24

Slight 0 0 22 11 0 0 0 2

Moderate 0 0 0 36 0 0 0 0

Total 0 0 38** 50** 0 0 18** 26**

Number of animals 49 49 49 50 48 50 50 50

Hepatocellular cholestasis: focal/multifocal
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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Sex Males Females

Dose level of fluopyram (ppm) 0 30 150 750 0 30 150 750

Dose level of fluopyram (mg/kg) 0 4.20 20.9 105 0 5.30 26.8 129

Number of animals 49 49 49 50 48 50 50 50

Minimal 0 0 2 29 0 0 0 0

Slight 0 0 0 2 0 0 0 0

Total 0 0 2 31** 0 0 0 0

Hepatocellular single cell degeneration/necrosis: focal/multifocal

Minimal 1 2 7 28 1 1 0 1

Slight 0 0 0 12 0 0 0 0

Moderate 0 0 0 0 0 0 0 1

Total 1 2 7* 40** 1 1 0 2

Interstitial mixed cell infiltrate: focal/multifocal

Minimal 18 15 19 39 8 8 10 8

Slight 0 1 0 1 2 3 2 0

Total 18 16 19 40** 10 11 12 8

Eosinophilic inclusion bodies: focal/multifocal

Minimal 2 3 5 18 0 0 0 0

Slight 0 0 0 1 0 0 0 0

Total 2 3 5 19** 0 0 0 0

Multinucleated hepatocytes: focal/multifocal

Minimal 3 1 3 25 1 0 0 0

Slight 0 0 1 2 0 0 0 0

Total 3 1 4 27** 1 0 0 0

Hepatocellular vacuolation: mainly centrilobular: diffuse

Minimal 21 15 13 0 3 4 1 0

Slight 6 19 11 2 2 5 0 1

Moderate 0 4 3 1 0 1 0 0

Total 27 38* 27 3** 5 10 1 1

*: p≤0.05, **: p≤0.01

Table 5: Incidence and severity of microscopic changes in the thyroid gland, all animals, 

carcinogenicity phase

Sex Males Females

Dose level offluopyram (ppm) 0 30 150 750 0 30 150 750

Dose level of fluopyram (mg/kg) 0 4.20 20.9 105 0 5.30 26.8 129

Number of animals 50 50 50 50 48 50 50 50

Follicular cell hyperplasia: focal/multifocal

Minimal 0 2 10 18 11 4 10 10

Slight 3 2 5 6 5 2 5 12

Moderate 1 2 2 5 1 2 3 6

Marked 0 0 3 3 0 0 1 4

Severe 0 0 1 0 0 0 0 1

Total 4 6 21** 32** 17 8* 19 33**

**: p≤0.01
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D. Adequacy of Dosing for Assessment of Carcinogenicity

The high dose of 750 ppm was considered to be adequate, and not excessive, to assess the 

carcinogenic potential in both male and female mice, based on the following:

 Increased absolute and relative liver weights in males and females at the high- and middose levels. These changes were dose-related, and correlated well with macroscopic

findings (dark/enlarged livers) and non-neoplastic histopathological lesions (eosinophilic 

foci [females], hepatocellular hypertrophy [both sexes], cholestasis [males], single cell 

degeneration/necrosis [males]);

 Increased incidence of thyroid follicular cell hyperplasia in both sexes at the high dose;

 Decreased absolute and relative kidney weights in both sexes at the high dose level, along 

with increased incidence and/or severity of kidney lesions (bilateral cortical basophilic 

tubules, hyaline casts and interstitial mononuclear cell infiltrates, glomerular 

congestion/hemorrhage, and amyloid deposition) in females.

IV. TOXICOLOGY

1. Metabolism

In a two ADME studies, two quantitative whole body autoradiography studies with the two 

different labels and an organ depletion study with [pyridyl-2,6-

14C]fluopyram (MRIDs 47372509, 

47372510, 47372511, 47372512, 47372513), it was shown that fluopyram was quickly absorbed 

(with an absorption half-life of 0.1 – 0.5 h) and excreted (90 - 98% within 72 h). There was 

evidence of significant enterohepatic circulation. In general, toxicokinetics was not different 

between a single dose study and a study with repeated administration, suggesting a low, if any, 

risk for accumulation. In particular, elimination kinetics was not significantly altered. Only

minor sex specific differences in toxicokinetics have been observed, although systemic exposure 

was higher and enterohepatic circulation more pronounced in females. While significant 

differences in the toxicokinetic data existed, depending on the part of the molecule that had been 

radiolabeled, routes of excretion were slightly different depending on the label. When labeled in 

the phenyl ring, excretion via the feces accounted for 47% - 64%, whereas renal excretion ranged 

from 35% - 45% in both sexes. With the pyridyl-label, excretion was 53% fecal and 45% urinary

in male rats but 39% fecal and 60% urinary in females. Exhalation was negligible in all tests. 

Following absorption from the GI tract, fluopyram was widely distributed. Organs with highest 

residues were the liver, the kidneys, Harderian gland and, in some studies and to a lesser extent, 

erythrocytes, adrenals, thyroid, ovaries and carcass.

The analysis of metabolism revealed a number of metabolites including fluopyram-7-hydroxy
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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and -8-hydroxy, fluopyram-pyridyl-acetic acid and fluopyram-benzamid being the most 

abundant. 

2. Mutagenicity

Fluopyram was tested in a minimum battery of standard genotoxicity and mutagenicity tests in 

vitro and in vivo. The available studies demonstrate that fluopyram has no genotoxic potential. 

There was no indication of gene mutation either in the presence or absence of metabolic 

activation in both the bacterial reverse mutation and mammalian gene mutation tests. The in vitro

chromosome aberration test and the in vivo mouse micronucleus test were both negative and, 

thus, a clastogenic potential may be excluded. 

Study type Metabolic 

activation

Concentrations 

that could be 

assessed

Results Classification

A. In vitro tests

Ames Test with strains TA 1535, TA 

100, TA 1537, TA 98 and TA 102

(Wirnitzer, 2006, ASB2008-5552)

MRID 47372502

+/- 16, 50, 158, 500, 

1581 and 5000 

g/plate

Negative

Acceptable/Guideline

Ames Test with strains TA 1535, TA 

100, TA 1537, TA 98 and TA 102

(Herbold, 2008, ASB2008-5554) 

MRID 47372503

+/- 16, 50, 158, 500, 

and 1581 

g/plate

Negative

Acceptable/Guideline

HPRT Test (V79 cells)

(Herbold, 2006, ASB2008-5556)

MRID 47372504

+/- 1.95 to 256 

g/mL

Negative

Acceptable/Guideline

Chromosome aberrations (V79 cells) 

(Nern, 2005, ASB2008-5555)

MRID 47372505

+/- 30, 60, 120, 180 

and 240 g/mL

Negative

Acceptable/Guideline

B. In vivo tests

Bone marrow micronucleus assay in 

mice – intraperitoneal administration

(Herbold, 2005, ASB2008-5557)

MRID 47372506

Not relevant; 

in vivo test

Dose levels = 

250, 500 & 1000 

mg/kg bw

Negative

Acceptable/Guideline
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3. Structure-Activity Relationship

Fluopicolide, fluazinam and boscalid are considered possible analogs for Fluopyram because 

they have a benzamide sub-structure and/or a pyridine sub-structure, and share a common use as 

fungicides. Among the three analogs, fluopicolide is the closest based on chemical structural 

similarity. The SAR, however, does not inform the mode of action for fluopyram.

Chemical Name Structure

Fluopyram

Benzamide, N-[2-[3-chloro-5-

(trifluoromethyl)-2-pyridinyl]ethyl]-2-

(trifluoromethyl)-(9CI)

CAS Registry No.: 658066-35-4

13

14

15

16

11

12

10 N

H

9

O

8

7

2

N

1

6

5

4

Cl 3

CF3

CF3

Fluopicolide 

(AE C638206 or 2,6-dichloro-N-[[3-chloro5-(trifluoromethyl)-2-

pyridinyl]methyl]benzamide)

CAS Registry No.: 239110-15-7

Cl

Cl

N

H

N

O

F Cl 3C

Fluazinam; IKF-1216

3-Chloro-N-[3-chloro-2,6-dinitro-4-

(trifluoromethyl)phenyl]-5- (trifluoromethyl)-

2-pyridinamine

Caswell#: 959

CAS Registry No.: 79622-59-6

N

N

H

CF3

Cl

Cl

CF3

NO2

O2N

Boscalid

BAS 510; 3-pyridinecarboxamide, 2-chloroN-(4’chloro[1,1’biphenyl]-2-yl)

CAS No. 188425-85-6

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

the CARC classified Fluopicolide as “Not Likely to be Carcinogenic to Humans” based on 
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convincing evidence that a non-genotoxic, mitogenic mode of action for liver tumors was 

established in the mouse and that the carcinogenic effects were not likely at doses that do not 

cause perturbations of the liver.

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

Fluazinam was classified as a “suggestive evidence of carcinogenicity to humans” based on

1) statistically significant increases in hepatocellular adenomas, carcinomas and combined 

adenomas/carcinomas in male CD1 mice (MRID 42208405); 2) statistically increased incidence 

of follicular cell adenocarcinomas and combined follicular cell adenomas/ adenocarcinomas in 

Sprague-Dawley rats (MRID 42248620); equivocal evidence of increased incidence of 

hepatocellular adenomas, carcinomas or combined adenomas/carcinomas for the male mice 

(MRID 44807222) Fluazinam is negative in mutagenicity tests.

In accordance with the EPA’s Draft Guidelines for Carcinogen Risk Assessment (1996), 

Boscalid was classified as “suggestive evidence of carcinogenicity, but not sufficient to assess 

human carcinogenic potential” based on increased incidence of follicular cell adenomas in 

male (MRID 45404827) and female (MRID 45414828) rats. No evidence of carcinogenicity was 

found in mice (MRID 45404901). Boscalid is negative in mutagenicity tests.

4. Subchronic and Chronic Toxicity

a) Subchronic Toxicity

Rat (MRID 47372516)

In a 28-day oral toxicity dose-range finding study in rats (MRID 47372516), groups of Wistar 

rats (5/sex/dose) were administered fluopyram (98.6% purity) in the diet at concentrations of 0, 

50, 400 and 3200 ppm (0, 4.0, 31.0 and 254 mg/kg/day in males and 4.6, 36.1 and 263 mg/kg/day

in females) for 28 days. 

The results showed that at the fluopyram did not produce mortality or clinical signs of toxicity. 

There were no changes in terminal body weights at any dose in either sex. Increases in platelet 

counts and prothrombin times were reported in 3200 ppm males. Total cholesterol and 

triglyceride levels were in increased in 3200 ppm males and females. Liver weights were 

increased in the 400 and 3200 ppm dose groups in both sexes compared with controls, the effect 

being slightly more pronounced in females. At 3200 ppm, the increase was more than 50 % 

compared to controls. This increased weight was associated with enlarged and dark livers at 

macroscopic examination and with minimal to moderate centrilobular hepatocellular hypertrophy

in most animals in both sexes. Similar effects were observed at 400 ppm, however with lower 

magnitude, incidence and severity. In addition to the liver effects, the thyroid gland weights 

(absolute and relative) were higher in males at 3200 ppm and 400 ppm. In association, 

hypertrophy of the follicular cells was observed in 3/5 males. Thyroid gland weight was not 

affected in females although 2/5 animals showed a minimal follicular cell hypertrophy. 
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In addition, a dose-related slight increase in total cytochrome P-450, BROD and PROD activities 

was observed in both sexes at 3200 and 400 ppm. No significant effects were observed at 50 

ppm. 

For establishing the NOAEL and LOAEL for this study, the results of the 90-day oral toxicity

study should be considered along with those of this study. In this study minimal effects were seen 

at 400 ppm. However, in the 90-day oral toxicity study, no effects were seen at 200 ppm. At 1000 

ppm, similar toxic effects were found as those seen in the 3200 ppm of the 28 day dose- range 

finding study. Therefore the NOAEL for the 28-day dose-range finding study lies between 400 

ppm and 200 ppm (equivalent to 31 to 12.5 mg/kg/day), while the LOAEL is 400 ppm (31 

mg/kg/day).

Rat (MRID 47372441)

In a subchronic oral toxicity study (MRID 47372441) fluopyram was administered in the diet for 

at least 90 days to 10 animals/sex/dose group at 0, 50, 200, 1000, and 3200 ppm (equating 

approximately to 0, 3.06, 12.5, 60.5 and 204 mg/kg/day in males and 0, 3.63, 14.6, 70.1, and 230 

mg/kg/day in females). An additional 10 males and 10 females fed either 0 or 3200 ppm of test 

diet for at least 90 days were maintained for a minimum of 28 days to examine the reversibility

of any effects seen. Following exposure at the prescribed dose level, animals were sacrificed and 

subjected to toxicological examination.

There were no treatment-related clinical signs in either sex throughout the study. Food 

consumption rates were essentially similar to controls in all dose groups. At 3200 ppm mean 

overall body weight gain was reduced by 9% in males (p≤0.05) and 17% in females (p≤0.01). 

The effect on mean body weight was still observed after 4 weeks of recovery in both sexes, as the 

magnitude of the decrease was similar to that observed at the end of the treatment phase. At 

1000 ppm, mean body weight parameters were unaffected by the treatment in either sex, with the 

exception of a slight decrease of 15% (not statistically significant) in mean body weight gain per 

day in females during the first week of treatment, compared to controls.

Higher mean prothrombin time was noted at 3200 ppm in males only (+74 %, p≤0.01), when 

compared to the control values. Slightly lower mean hemoglobin concentrations were noted at 

3200 ppm in both sexes and at 1000 ppm in males only. These variations were associated with 

lower mean hematocrit in males and lower mean corpuscular volume and mean corpuscular 

hemoglobin in females at 3200 ppm. Additionally, higher mean platelet (+24 %, p≤0.01) and 

reticulocyte (+50 % for absolute count and +42 % for percentage, p≤0.01) counts were noted at 

3200 ppm in females. There was no evidence of treatment-related changes at 1000 ppm in 

females or at 200 and 50 ppm in either sex. Hematological changes were reversed at the end of 

the recovery period, with the exception of mean hemoglobin concentrations, which remained 

slightly lower than controls.
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Several clinical chemistry variations were statistically significant at 1000 ppm or 3200 ppm, and 

included increased total cholesterol (>45%), decreased total bilirubin (>-30%), increased 

glutamyltransferase (+625%) and triglycerides (+102%). After one month of recovery in the high 

dose group, there was a general tendency towards reversibility. Nevertheless, statistically

significant differences were still noted in mean total cholesterol, globulin concentrations and 

albumin/globulin ratio in females (+19 %, +14 % and -14 % respectively, p≤0.05), compared to 

the control values. The incidence and severity of cellular casts in urine were increased in all 

groups of fluopyram treated males in a dose-related manner, and correlated with hyaline droplet 

nephropathy observed at histopathology examinations. However, these effects were largely

reversible.

At Week 3, TSH levels were elevated in both sexes at 3200 ppm (+63 %, p≤0.05 and +71 %,

p≤0.01, respectively), together with an increase in mean T3 and T4 levels in females (+24 %, 

p≤0.05 and +54 %, p≤0.01, respectively), whereas at Week 13, only an increase in mean TSH 

and T3 levels was noted in males (+88 and +40 %, respectively, p≤0.01). At 1000 ppm, mean 

TSH level was increased by 54 % (not statistically significant) and T4 level was significantly

increased by 43 % in males on Week 13. A dose dependent increase of T3, T4 and TSH was 

observed in both sexes at most time points and for most parameters at all dose levels when 

compared to controls, however, without being significant or of relevant magnitude at the lower 

two dose levels of 200 and 50 ppm. These changes were reversed in the recovery phase.

Mean body weights were not statistically changed by fluopyram administration. Mean absolute 

and relative liver weights were statistically increased in males and females at 1000 ppm and 3200 

ppm (+ 20 to +25%, and +53% to +74%, respectively). Mean absolute and relative kidney

weights were statistically increased predominantly in males (+25% - +34%) at 1000 ppm and 

3200 ppm. Thyroid weights were also statistically higher (+10% to +22%) in males and females 

at 3200 ppm. These various increases were only partially reversed after the one-month recovery

period.

Microscopic effects of treatment with fluopyram were seen in the liver, kidney, thyroid gland and 

lung. In the liver, minimal to moderate centrilobular hepatocellular hypertrophy was observed 

with a dose-related increase in incidence and severity at 3200 and 1000 ppm in both sexes and 

minimal centrilobular hepatocellular hypertrophy was observed at 200 ppm in males. In addition, 

minimal to moderate periportal to midzonal hepatocellular macrovacuolation was observed in 

females at 3200 and 1000 ppm. In the kidney, hyaline droplet nephropathy (characterized by

basophilic tubules, hyaline droplets in proximal tubules and granular casts in the medulla) and 

hyaline casts were higher at 3200 and 1000 ppm in males, in comparison with controls. Hyaline 

droplet nephropathy was also slightly higher at 200 ppm in males. In the thyroid gland, a higher 

incidence of minimal to slight diffuse hypertrophy of follicular cells was seen at 3200 and 

1000 ppm in both sexes compared to controls and internal historical control data. After the 

recovery period, liver and thyroid gland were comparable between the high dose and control 

groups, indicating that the changes noted after 90 days of treatment were reversible in these 

organs. In the kidney in the high dose groups, basophilic tubules, hyaline droplets in proximal 
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tubules, granular casts in the medulla and hyaline casts were persistent in the kidney of some 

males.

In this study in rats the lowest dose level of 50 ppm represented the No Observed Effect Level 

(NOEL) in males and females (equating to 3.06 / 3.63 mg/kg body weight/day). At the next 

higher dose level of 200 ppm (12.5 / 14.6 mg/kg bw/d), however, treatment-related effects were 

confined to a rather adaptive liver weight increase due to hepatocellular hypertrophy that was 

associated with non-significant changes in clinical chemistry parameters. Because these findings 

were not considered adverse, the NOAEL for both sexes was set at 200 ppm (12.5 / 14.6 mg/kg 

bw/day), and the LOAEL is 1000 ppm (60.5 / 70.1 mg/kg bw/day) based on organ weight

changes, and clinical chemistry and histopathological findings in liver, thyroid and kidneys.

Mouse (MRID 47372517)

In a 28-day oral toxicity dose-range finding study in mice (MRID 47372517), groups of 

C57BL/6J mice (5/sex/dose) were administered fluopyram (98.4% purity) in the diet at 

concentrations of 0, 150, 1000 and 5000 ppm (0, 24.7, 162, and 747mgkg/day in males and 0, 

31.1, 197, 954 mg/kg/day in females) for 28 days. The mg/kg dose equivalent for the high dose 

males (747 mg/kg/day) was calculated for weeks 1-3 only due to mortality or early sacrifice in 

this group.

At 5000 ppm, all males and 3/5 females were sacrificed prior to scheduled sacrifice. All 

unscheduled sacrificed animals presented the following clinical signs: reduced body weights, 

decreased motor activity, hunched posture, piloerection, wasted appearance and/or coldness to 

touch in both sexes together with labored respiration, and distended abdomen. The two surviving 

females at 5000 ppm, had elevated total cholesterol (+118 %) and total protein (+16 %) 

concentrations, and alanine aminotransferase activities (+384 %). Mean absolute and relative 

liver weights were higher at 5000 ppm in females and at 1000 and 150 ppm in both sexes. These 

changes were found to be dose-related. Gross pathology showed enlarged and dark livers males 

and females, the Thymus size was reduced in 4/5 males and 1/3 females, and distended abdomen 

was noted in 3/5 males. Red liquid was observed in the thoracic cavity in all males. 

Histopathology indicated. Histopathology demonstrated hypertrophy of the hepatocytes in males 

and females and hepatocellular focal necrosis was also noted in surviving females.

At 1000 ppm, there was a slight decrease in the daily mean body weight gain during study

Week 2 in males. No treatment-related effect on mean body weight and mean body weight 

change parameters was noted at 1000 ppm in females or 150 ppm in either sex. No effect on 

mean food consumption was noted in animals surviving to terminal sacrifice. Enlarged liver was 

seen in all males and in 4/5 females. Hepatocellular hypertrophy was seen in all 1000 ppm males 

and 2/5 females, and focal necrosis was found in 2/5 females.

At 150 ppm, there was a slight increase in liver weights, and liver hypertrophy was seen in all 

males and 3/6 females. 
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In consideration of NOAEL and LOAEL, the results show that hepatocellular hypertrophy at 150 

ppm (24.7 mg/kg/day) (LDT), but currently liver hypertrophy is considered to be an adaptive 

effect. However, more pronounced liver effects (hypertrophy and focal necrosis) are seen at 1000 

ppm and above. NOAEL for this study can be established at 150 ppm (24.7 mg/kg/day). LOAEL 

is 1000 ppm (162 mg/kg/day) based on increased incidence of liver hypertrophy and focal 

necrosis in the liver.

Mouse (MRID 47372442)

In a sub-chronic oral toxicity study (MRID 47372442), fluopyram was administered in the diet 

for at least 90 days to C57BL/6J mice at the following doses – 0, 30, 150 and 1000 ppm 

(equating approximately to 0, 5.4, 26.6 and 188 mg/kg/day in males and 0, 6.8, 32.0 and 

216 mg/kg/day in females). A negative control group received plain diet. Animals were then 

sacrifice and subjected to toxicological examination.

There were no treatment-related clinical signs of toxicity observed in animals at any dose level.

No treatment-related mortality occurred in the test animals at any dose level. Body weight and 

food consumption were not affected by treatment.

Blood analysis: At 1000 ppm, mean alanine aminotransferase activity was higher in males and 

females (+205 and +109 % after removal of an outlier in the female control values, respectively, 

p≤0.01), compared to the control groups. In addition in males, mean alkaline phosphatase activity

was higher (+21 %, p≤0.01), mean albumin and mean total cholesterol concentrations were lower 

(-12 and -40 %, respectively, p≤0.01) and a tendency towards higher values was noted in 

aspartate aminotransferase activity (+46 %, p≤0.05). In females, a tendency towards lower mean 

albumin concentration was also noted (-9 %, p≤0.01). At 150 treatment-related changes consisted 

in a lower mean total cholesterol concentration in both sexes (-41 and -30 %, 

respectively, p≤0.01) and lower total protein and albumin concentrations in males (-6 % and –

7 %, p≤0.01), associated with lower total bilirubin in males and females (- 43 %, significant only

in males) compared to the control group. At 30 ppm the only observed finding was a significant 

decrease in total cholesterol in males (-30 %, p≤0.01).

There was no relevant change in terminal body weight in either sex. Mean absolute and/or 

relative liver weights were statistically significantly higher at 1000 ppm (+36% to +45%) and 

150 ppm (+14% to +28%) in both sexes, with a dose-related effect. At 30 ppm, mean absolute 

liver weight and relative liver to body weight ratio were statistically significantly higher (+11% 

to +13%) in females only, but this change was considered not to be toxicologically relevant since 

it was not associated with any histological change. Mean absolute and relative adrenal gland 

weights were increased by between 87 % and 92 % at 1000 ppm in males compared to controls, 

the difference being statistically significant for mean adrenal gland to body weight ratio only

(p≤0.05). At 1000 ppm, enlarged livers were observed in 8/10 males and 9/10 females, and dark 

livers were observed in 5/10 males and 10/10 females.
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Effects of treatment with fluopyram were seen in the liver and adrenal gland in both sexes. In the 

liver, there was a minimal to moderate hypertrophy of centrilobular hepatocytes in both sexes at 

1000 and 150 ppm. This finding correlated with the enlarged livers observed at necropsy in 

animals given 1000 ppm and the statistically significant increase in liver weight seen in animals 

given 1000 or 150 ppm. Also observed was a greater incidence of minimal or slight focal 

necrosis in both sexes at 1000 ppm, when compared to controls. Minimal or slight focal necrosis 

was present in 3/10 males and 6/10 females given 1000 ppm, compared to one female in the 

control group. In the adrenal glands at 1000 ppm, there was a lower incidence of cortical steroid 

pigment in males and a greater incidence of minimal to slight cortical vacuolation in females, 

compared to controls. The change noted in males at 1000 ppm was considered to be slight 

compared to the magnitude of increase in adrenal gland weights seen in this sex. No treatmentrelated changes were observed in the adrenal glands at 150 or 30 ppm in either sex. In the forestomach of males given 1000 ppm, there was a slightly greater incidence of focal epithelial 

hyperplasia than in controls. However, as these changes in males were only focal and isolated, 

they were considered not to be treatment-related. In females, the incidence and severity of this 

finding were comparable between controls and treated animals.

The NOAEL for this study is 150 ppm (equating to 26.6 and 32.0 mg/kg bw/day in males and 

females respectively). The LOAEL is 1000 ppm (approximately 118 or 216 mg/kg bw/day for 

males and females, respectively) based on liver effects (hypertrophy, necrosis, changes in related 

clinical chemistry parameters).

b) Chronic Toxicity

Rat (MRID 47372501)

In a combined chronic toxicity and carcinogenicity study (MRID 47372501), groups of 60 

male and female Wistar rats were fed a diet containing 0, 30, 150 and 750 ppm (male animals) 

and 0, 30, 150 and 1500 ppm (females) fluopyram for 24 months. In males, the top dose level of 

750 ppm had to be reduced to 375 ppm from week 85 onwards because of the high mortality in 

this group. Over the whole study period, these dietary concentrations corresponded to a mean 

daily intake of 0, 1.20, 6.0 and 29 mg/kg bw in male rats or 1.68, 8.6 and 89 mg/kg bw in 

females. In addition, satellite groups of 10 animals per sex and dose were subject to interim 

sacrifice after 1 year. 

Overall, there was a statistically significant increase in mortality in males at 750/375 ppm during 

the study and after 24 months although no clear cause for these premature deaths could be 

established. At the highest dose levels of 750/375 in males or 1500 ppm in females, respectively, 

mean body weights were significantly reduced in both sexes at various times throughout the 

study. The main target organs were the liver, kidneys and the thyroid gland, and also the eyes. 

Liver toxicity became apparent by an increase in organ weight at the two upper dose levels in 
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male rats and in the highest dose group in females. This was sometimes accompanied by gross 

pathological findings such as nodules/masses which correlated histologically with neoplastic 

changes. 

Clinical chemistry findings suggesting hepatotoxicity were minor in nature and confined to the 

respective top dose level in both sexes. They comprised occasionally higher mean triglyceride 

concentrations and slightly lower mean glucose concentrations in the females. Activity of 

alkaline phosphatase was reduced in both sexes throughout the study but achieved statistical 

significance only occasionally. Histological changes included a higher incidence of altered 

hepatocytes (eosinophilic foci) and hepatocellular brown pigments, focal or multifocal 

hepatocellular vacuolation, increased number of mitoses, centrilobular to panlobular hypertrophy

and hepatocellular single cell necrosis with females being much more affected. Again, this might 

be due to the higher dose that the female rats were fed. At the mid dose level of 150 ppm, 

however, histopathological lesions (hypertrophy) were confined to male rats and, thus, were in 

line with the increase in organ weight that was noted in the same sex only. 

In the kidneys, marked degenerative changes such as chronic progressive nephropathy or 

focal/multifocal (medullar or cortical) tubular dilatation, together with an increased incidence of 

tubular golden/brown pigments (mainly in females) and collecting ducts hyperplasia, were 

observed at the high dose level. In addition, a higher incidence of hyaline droplets and of renal 

cysts was noted in male rats. At the mid dose level of 150 ppm, male rats still displayed a higher 

frequency of tubular hypertrophy or dilatation. During the first year of treatment, but not 

thereafter, urinalysis revealed higher incidences of abnormal color of urine (orange to red) in 

females and a higher incidence and severity of cellular casts in males. This latter finding was also 

confirmed in male rats receiving the intermediate dose.

Effects of fluopyram on the thyroid gland were demonstrated by an increased organ weight at the 

highest dose level in both sexes. This finding was associated with histopathological changes 

(follicular cell hyperplasia and/or hypertrophy, colloid alteration/depletion) that were of less 

severity or frequency but yet to be noted at the mid dose level, too.

In addition, the eyes were affected by long-term treatment. Ophthalmologic examination revealed 

abnormal color of the retinal fundus in females after 12 months. At the 24-month examination, 

this condition was observed in females and males, together with small retinal vessels. In addition, 

hyperreflectivity in the retina was noted in females and corneal opacity, edema of the cornea and 

nuclear opacity in males. These effects were more severe at the top dose level and less 

pronounced but still present after 2 years in the male and female groups receiving the 

intermediate dose. Histologically, bilateral retinal atrophy was noted at the highest dose level, 

together with a higher incidence of lens degeneration. 

A tendency towards lower erythrocyte parameters (hemoglobin concentration, mean corpuscular 

volume, hematocrit and/or mean corpuscular hemoglobin) was observed in the female high dose 

group throughout the study confirming evidence from short-term studies that the red blood cells 
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might be an additional target. The same tendency was observed in high dose males at most time 

points, however, statistical significance was not achieved. The assumption of an effect on the 

blood was further substantiated by a more frequent occurrence of extramedullary hematopoiesis 

in the livers of high dose females. In contrast to the subchronic study, prothrombin time was this 

time shorter in the female high dose group with the difference being significant at months 6 and 

12. 

Therefore, the NOAEL was 30 ppm (1.2 and 1.7 mg/kg bw/day in males and females, 

respectively). The LOAEL of 150 ppm (6.0 and 8.6 mg/kg/day, males and females), is based on 

nephropathy in the kidney, follicular cell hypertrophy in the thyroid, and increased liver weight 

with gross pathological and histopathological findings. 

Mouse (MRID 47372450)

In a mouse carcinogenicity study (MRID 47372450), groups of 60 male and female 

C57BL/6J mice were fed a diet containing 0, 30, 150 or 750 ppm of fluopyram (corresponding to 

a mean compound intake of 0, 4.2, 20.9 and 105 mg/kg bw/day in males and 0, 5.3, 26.8 and 

129 mg/kg bw/day in females, respectively) for up to 78 weeks. After 52 weeks, 10 males and 10 

females from each group which had been allocated to the chronic phase of the study were killed 

and necropsied. The remaining 50 animals per sex and group (allocated to the carcinogenicity

phase) continued treatment until scheduled sacrifice after at least 78 weeks of treatment. 

There were no unscheduled deaths or clinical signs occurring during the study that could be 

attributed to treatment. The survival rate was not different among the control and dose groups. 

Body weight gain was decreased only in high and mid dose males and only during the second 

trimester of the study (weeks 26 to 54). Afterwards, some compensatory growth was observed 

resulting in a mean final body weight that was similar to the control group value.

A slightly higher mean platelet count was determined in top dose males but no other changes in 

hematological parameters were seen.

Pathological examination revealed that the liver, the thyroid gland and the kidneys were the main 

target organs in mice. 

Mean absolute and relative liver weights were markedly increased in high and mid dose males 

and females at interim sacrifice as well as at study termination. The increment exhibited a clear 

dose response. At these two upper dose levels, gross necropsy findings such as dark and enlarged 

livers were corroborated by an increase in non-neoplastic histopathological lesions such as 

centrilobular to panlobular hypertrophy, hepatocellular cholestasis, single cell 

degeneration/necrosis or eosinophilic foci. A few of these non-neoplastic effects on the liver 

were observed only in males pointing to a higher vulnerability of this sex with regard to 

hepatotoxicity.
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Toxic effects on the thyroid were noted at the top dose level in both males and females and in the 

mid dose male group. The main non-neoplastic finding, i.e., follicular cell hyperplasia became 

apparent in male mice at interim sacrifice already. In line with that, the only neoplastic change in 

this study consisted of a higher incidence of follicular cell adenoma in high dose males (7/50) as 

compared to the control group (1/50). This difference was statistically significant (p≤0.05).

Mean absolute and relative kidney weights were decreased at the 750 ppm dose level in both 

sexes. In addition, a higher incidence and/or severity of bilateral cortical basophilic tubules, 

hyaline casts(s) and interstitial mononuclear cell infiltrates, glomerular congestion/

hemorrhage(s), and more pronounced amyloid deposition (mainly in the glomerular interstitium) 

was noted at this dose but only in females.

Thus, the No Observed Adverse Effect Level (NOAEL) in this study was 30 ppm in males 

(equivalent to 4.2 mg/kg/day) and females (equivalent to 5.3 mg/kg/day). The LOAEL was 150 

ppm (equivalent to 20.9 mg/kg bw/day in males and 26.8 mg/kg bw/day in females) based on 

hepatocellular hypertrophy in the liver in both sexes and follicular cell hyperplasia in the thyroid 

gland in males.

5. Mode of Action 

1. Mode of Action for Thyroid Follicular Cell Tumors in Male Mice

The registrant, Bayer CropScience, submitted a proposed mode of action for the thyroid follicular 

cell tumors seen in male mice using the International Programme on Chemical Safety (IPCS)

framework (MRID 47753406). Their postulated MOA for fluopyram-induced thyroid follicular 

cell tumors in mice involved the perturbation of homeostasis of the pituitary–thyroid axis by an 

extra thyroidal mechanism that is not the result of genotoxicity. The key events proposed 

included: 1) increases in liver enzyme activity, similar in pattern to the phenobarbital-induced 

enzyme activity pattern, 2) alterations in thyroid and pituitary hormone levels, 3) increase in 

thyroid growth, and 4) lesion progression in the thyroid from hyperplasia to neoplasia. Thyroid 

follicular cell adenomas in male mice were associated with chronic exposure to 105 mg/kg/day

fluopyram. In addition to the subchronic and chronic studies, the registrant submitted MOA 

studies to further elucidate the MOA for fluopyram exposing mice for short durations (3, 4 and 

14 days) to doses of 300 mg/kg/day (MRID No. 47567128, 47372519, 47690101). A summary of 

the results of this MOA analysis is provided in the table below. 

Mode of Action--

Thyroid Tumors in Mice

Key Events Animal Evidence Dose Concordance Temporal 

Association
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

Page 28 of 35

Mode of Action--

Thyroid Tumors in Mice

Key Events Animal Evidence Dose Concordance Temporal 

Association

Induction of Liver 

Enzymes

3-day day mechanistic study at 2000 ppm, 

308 mg/kg/day [MRID 47567128]

14-day mechanistic study at 2000 ppm or 

314 mg/kg/day [MRID 47372519]

Increased Total CYT P450, PROD, 

EROD and BROD at 2000 ppm

No. Studies were performed 

at dose levels higher than the 

tumorigenic dose of 105 

mg/kg/day.

Yes

Hormone Changes

(Decreased T3, T4, 

Increased TSH)

3-day day mechanistic study at 2000 ppm, 

308 mg/kg/day [MRID 47567128]

4-day mechanistic study at 200 ppm 

[MRID 47690101]

14-day mechanistic study at 2000 ppm or 

314 mg/kg/day [MRID 47372519]

No decreases in T3 observed.

Some decreases in T4 observed.

Increase in T4 clearance over 24 hrs.

Increase in TSH.

No. Studies were performed 

at dose levels higher than the 

tumorigenic dose.

Yes

Increases in cell growth

(Increased thyroid 

weight, Increased 

thyroid hypertrophy 

and hyperplasia)

Mouse carcinogenicity Study

0, 30, 150, 750 ppm

(0, 4.2/5.3, 20.9/26.8, 105/129 

mg/kg/day, Males/Females)

Thyroid hyperplasia observed at 20.9 and 

105 mg/kg/day at 1 year and 18 months. 

Not seen at 90 days [MRID: 47372450]

No increase in thyroid weight and no 

thyroid hypertrophy observed in 

subchronic or chronic mouse studies.

Yes, some evidence of 

thyroid hyperplasia observed 

at and below the tumorigenic 

dose of 750 ppm (105 

mg/kg/day)

Yes

Thyroid follicular cell 

tumors

Mouse carcinogenicity Study

[MRID: 47372450]

Tumors observed at 750 

ppm (105 mg/kg/day)

--

The CARC evaluated the submitted MOA and concluded that there is insufficient data to 

support the proposed MOA for fluopyram induced thyroid follicular cell tumors. The 

major deficiency in the analysis was the lack of dose-response concordance with key events 

and tumors. The MOA studies were performed at doses that were above the tumorigenic 

dose. There is no data for several key events at or below the tumorigenic dose, which is 

required as experimental support for the MOA. While temporal association was 

established, the missing dose concordance data precludes an acceptable MOA. In addition, 

while a comparison to Phenobarbital MOA is informative, the MOA for fluopyram must 

stand on its own.
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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2. Mode of Action for Liver Tumors in Female Rats

The registrant, Bayer CropScience, submitted a proposed mode of action for the liver tumors in 

female rats using the IPCS framework (MRID 47753406). They postulated a mitogenic MOA for 

fluopyram-induced liver tumors. It involved the induction of liver enzymes, including 

cytochrome P450s (CYP450) isozymes, consequent liver cell proliferation and hypertrophy, and 

altered hepatic foci, ultimately progressing to neoplasia. The specific MOA for fluopyram was 

considered by the registrant to be similar to the phenobarbital MOA for liver tumors in rats. Liver 

tumors in female rats were associated with chronic exposure to 89 mg/kg/day (1500 ppm)

fluopyram. In addition to the subchronic and chronic studies, the registrant submitted a MOA 

study to further elucidate the MOA for fluopyram exposing rats for short durations (7 days) to a 

dose of 190 mg/kg/day (3000 ppm) (MRID 47372520). A summary of the results of the MOA 

analysis is provided in the table below. 

Mode of Action—Mitogenesis

Liver Tumors in Rats

Key Events Animal Evidence Dose Concordance Temporal 

Association

Nuclear Receptor 

Activation

No -- --

Increased Induction of 

CYP Phase I Enzymes

7-day mechanistic study at 3000 ppm, 193 

mg/kg/day [MRID 47372520]

28-day subchronic study with liver 

enzyme induction at 50, 400 and 3200 

ppm, 4.6, 36.1 and 263 mg/kg/day 

[MRID 47372516]

No. Study was performed at 

dose levels higher than the 

tumorigenic dose of 1500 

ppm, 89 mg/kg/day.

Yes. BROD and PROD 

elevated at 400 ppm, below

tumorigenic dose

Yes

Measured at 7 

days and 28 

days

Increased Liver Weight 7-day mechanistic study at 3200 ppm, 

193 mg/kg/day [MRID 47372520]

28-day subchronic study at 50, 400 and 

3200 ppm, 4.6, 36.1 and 263 

mg/kg/day [MRID 47372516]

90-day subchronic. at 50, 200,1000, 3200 

ppm, 3.63,14.6, 70.1, 230 mg/kg/day 

[MRID 47372441]

No. Studies were performed 

at dose levels higher than the 

tumorigenic dose of 1500 

ppm, 89 mg/kg/day.

No. Liver weight increase 

seen only at 3200 ppm, 

higher than tumorigenic dose.

Yes. Liver weight changes 

seen at 1000 and 3200 ppm

Yes

Measured at 7 

days, 28 days, 

90 days and 2 

years
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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Mode of Action—Mitogenesis

Liver Tumors in Rats

Key Events Animal Evidence Dose Concordance Temporal 

Association

Increased Liver 

Hypertrophy and 

Hyperplasia

28 day subchronic study at 3200 ppm 

[MRID 47372516]

90 subchronic study at 3200 ppm [MRID 

47372441]

Chronic/Oncogenicity study at 1500 ppm

[MRID 47372501]

No. Hypertrophy seen only 

at 3200 ppm, higher than 

tumorigenic dose.

Yes. Hypertrophy seen at 

1000 and 3200 ppm

Yes. Hypertrophy seen at 

1500 ppm, the tumorigenic 

dose.

Yes

Hypertrophy 

observed at 7 

days, 28 days, 

90 days and 2 

years

Increased Cell 

Proliferation

7-day mechanistic study

[MRID 47372520]

No. Studies were performed 

at dose levels higher than the 

tumorigenic dose.

No time-course 

data on cell 

proliferation. 

Tested only at 7 

days

Inhibition of Apoptosis

No -- --

Liver Tumors Chronic/Oncogenicity study

[MRID 47372501]

Tumors observed at 1500 

ppm (89 mg/kg/day)

The CARC evaluated the submitted MOA and concluded that there was insufficient data to 

support the proposed MOA for fluopyram induced liver tumors. The major deficiency in 

the analysis was the lack of dose-response concordance with key events and tumors. The 

MOA studies were performed at doses above the tumorigenic dose. There is no MOA data 

at or below the tumorigenic dose, which is required as experimental support for the MOA. 

In addition, there is no time course data on cell proliferation. Ideally, a study of several 

weeks duration is needed with early time points (minimum of 2 time points of 90 days or 

less) to demonstrate that cell proliferation is not sustained. The data submitted was not 

sufficient and tested only 1 dose and 1 time point. While temporal association was 

established for several key events, the missing dose concordance data and adequate cell 

proliferation data preclude an acceptable MOA. In addition, while a comparison to 

Phenobarbital MOA is informative, the MOA for fluopyram must stand on its own.
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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

The Committee considered the following for a weight-of-evidence determination of the 

carcinogenic potential of fluopyram:

1. Carcinogenicity

Rat

● Administration of fluopyram resulted in the induction of liver tumors in female Wistar rats.

There were statistically significant trends for liver adenomas (p<0.01), carcinomas (p<0.05) and 

combined liver adenomas and carcinomas (p<0.01). There were significant pair-wise 

comparisons of the 1500 ppm dose group with the controls for liver adenomas at p<0.05 and for 

combined liver adenomas and carcinomas at p<0.01. When compared to historical control data 

(uncensored data) from the testing laboratory, the incidence of hepatocellular adenomas in the 

female high dose group (9/55, 16%) was outside the range of the historical control group (range, 

0 - 5%; average, 1.9%). Similarly, the incidence of hepatocellular carcinomas in the female mid 

(2/56, 4%) and high dose groups (3/55, 5%), while not statistically significant by pair-wise 

comparison, exceeded the range of the historical control group (no carcinomas observed in 10 

studies from 2000 - 2006) and was considered to be biologically relevant. There were no 

statistically significant trends or significant pair-wise comparisons of the dosed groups with the 

controls for the male rats. The CARC considered the liver tumors in female Wistar rats to 

be treatment-related.

● Adequacy of Dosing: The doses tested were considered to be adequate and not excessive to 

assess carcinogenic potential in both sexes. In female rats, the highest dose tested of 1500 ppm 

was considered to be adequate. This was based on a 20% decrease in mean body weights and 

increased liver weights (mean: +39%, absolute: +56%), which were dose-related and correlated 

well with findings such as prominent lobulation and hypertrophy. Other effects that occurred at 

the high dose included thyroid follicular cell hypertrophy and colloid alteration, chronic 

progressive nephropathy and kidney tubular dilatation, and retinal atrophy and lenticular 

degeneration of the eye. In male rats, the top dose level of 750 ppm, an excessive dose, had to 

be reduced to 375 ppm from week 85 onwards because of the high mortality in this group. At the 

termination of the study, mortality among high-dose males was 50% of control values. The dose 

of 375 ppm, which is roughly one-half the excessive dose of 750 ppm, however, was considered 

to be adequate. This was based on decreased mean body weight, increased liver weight, liver 

hypertrophy, follicular cell hypertrophy and colloid alteration, chronic progressive nephropathy

and tubular dilatation and tubular hypertrophy (males) all observed at the high dose.

Mouse
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

Page 32 of 35

● Administration of fluopyram resulted in the induction of thyroid follicular cell tumors in male 

C57BL/6J mice. Male mice had a statistically significant trend at p<0.01 and a significant pairwise comparison of the 750 ppm dose group with the controls at p<0.05 for thyroid follicular cell 

adenomas. There were no statistically significant trends or significant pair-wise comparisons of 

the dosed groups with the controls for the female mice. When compared to historical control 

data (uncensored data) from the testing laboratory, the incidence of thyroid follicular cell 

adenomas in the male high dose group (7/48, 15%) was outside the range of the historical control 

group (range, 0 - 2%; average, 0.4%). The CARC considered the thyroid follicular cell 

adenomas in male C57BL/6J mice to be treatment-related.

● Adequacy of Dosing: The high dose of 750 ppm was considered to be adequate, and not 

excessive, to assess carcinogenic potential in both male and female mice, based on the following: 

1) Increased absolute and relative liver weights in males and females at the high- and mid-dose 

levels. These changes were dose-related, and correlated well with macroscopic findings 

(dark/enlarged livers) and non-neoplastic histopathological lesions (eosinophilic foci [females], 

hepatocellular hypertrophy [both sexes], cholestasis [males], single cell degeneration/necrosis 

[males]); 2) Increased incidence of thyroid follicular cell hyperplasia in both sexes at the high 

dose; and 3) Decreased absolute and relative kidney weights in both sexes at the high dose level, 

along with increased incidence and/or severity of kidney lesions (bilateral cortical basophilic 

tubules, hyaline casts and interstitial mononuclear cell infiltrates, glomerular congestion/ 

hemorrhage, and amyloid deposition) in females.

2. Mutagenicity

There is no concern for mutagenicity.

3. Structure-Activity Relationship

The SAR data do not inform the mode of action.

4. Mode of Action

The CARC concluded that insufficient data were provided to support definitive modes of action 

for the induction of liver tumors in female rats or thyroid follicular cell tumors in male mice. 

Deficiencies included a lack of dose-response concordance with key events and tumors. 

VI. CLASSIFICATION OF CARCINOGENIC POTENTIAL
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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

the CARC classified fluopyram as “Likely to be Carcinogenic to Humans” based on tumors in 

two species and two sexes: a treatment-related increase in thyroid follicular cell adenomas in 

high dose male mice and liver tumors in female rats at the high dose, with incidences exceeding 

that of the laboratory’s historical controls. There is no mutagenic concern for fluopyram. The 

available data do not support the proposed modes of action for the thyroid or liver tumors. 

VII. QUANTIFICATION OF CARCINOGENIC POTENTIAL

The CARC recommended the use of a linear low dose extrapolation model applied to the animal 

data (Q1*) for quantitative estimation of human risk.

1

The unit risk, Q1

*

(mg/kg/day)

-1

, of 

Fluopyram based upon female rat liver combined adenoma and carcinoma tumor rates is 

1.55 x 10-2in human equivalents (Memo. L. Brunsman, 11/17/09, TXR No. 0055280).

VIII BIBLIOGRAPHY

47372441 Kennel, P.; AE C656948 – 90-day toxicity study in the rat by dietary administration; 

Bayer CropScience S.A., Sophia Antipolis, France; Report No.: SA 04048; 

Document No.: M-250946-01-2; December 07, 2007; Pages: 709

47372442 Kennel, P.; AE C656948 – 90-day toxicity study in the mouse by dietary

administration; Bayer CropScience S.A., Sophia Antipolis, France; Report No.: SA 

04052; Document No.: M-251136-01-2; February 20, 2008; Pages: 324

47372450 Wason, S. M.; Carcinogenicity study of AE C656948 in the C57BL/6J mouse by

dietary administration; Bayer CropScience S.A., Sophia Antipolis, France; Report 

No.: SA 05094; Document No.: M-295688-01-2; January 15, 2008; Pages: 2477

47372501 Kennel, P.; Chronic toxicity and carcinogenicity study of AE C656948 in the Wistar 

rat by dietary administration; Bayer CropScience S.A., Sophia Antipolis, France; 

Report No.: SA 04312; Document No.: M-298339-01-2; March 14, 2008; Pages: 

4088

47372502 Wirnitzer, U.; AE C656948 - Salmonella/microsome test plate incorporation and 

preincubation method; Bayer HealthCare AG, Wuppertal, Germany; Report No.: 

AT02911; Document No.: M-269978-01-2; December 03, 2007; Pages: 56

47372503 Herbold, B.; AE C656948 (project: AE C656948) - Salmonella/microsome test -

Plate incorporation and preincubation method; Bayer HealthCare AG, Wuppertal, 

 

1 At the July 8, 2009 meeting, the CARC recommended a classification of “Likely” with no quantification. 

Following this meeting, as per the recommendation of the CARC chair, a revote was requested to be consistent with 

the cancer guidelines. Subsequently, the CARC recommended a “Likely” classification with quantification.
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

Page 34 of 35

Germany; Report No.: AT04419; Document No.: M-298529-01-2; April 14, 2008; 

Pages: 65

47372504 Herbold, B.; AE C656948 - V79/HPRT-test in vitro the detection of induced forward 

mutations; Bayer HealthCare AG, Wuppertal, Germany; Report No.: AT02875; 

Document No.: M-268775-01-2; December 03, 2007; Pages: 40

47372505 Nern, M.; AE C656948 (project: AE C656948) - In vitro chromosome aberration test 

with chinese hamster V79 cells; Bayer HealthCare AG, Wuppertal, Germany; Report 

No.: AT02798; Document No.: M-266066-01-2; December 03, 2007; Pages: 51

47372506 Herbold, B.; AE C656948 - Micronucleus-test on the male mouse; Bayer HealthCare 

AG, Wuppertal, Germany; Report No.: AT02753; Document No.: M-263710-01-2; 

December 03, 2007; Pages: 51

47372509 Klempner, A. (2008) [Phenyl-UL-(Carbon 14)]AE C656948: Absorption, 

Distribution, Excretion and Metabolism in the Rat. Project Number: MEF/07/508, 

M11819165, M/298614/01/2. Unpublished study prepared by Bayer CropScience 

AG. 366 p.

47372510 Koester, J.; Klempner, A. (2008) [Pyridyl-2,6-(Carbon 14)]AE C656948 -

Metabolism in Organs and Tissues of Male and Female Rats (3 Timepoints). Project 

Number: MEF/08/115, M1824540/4, M/298834/01/2. Unpublished study prepared 

by Bayer CropScience AG. 268 p.

47372511 Klempner, A. (2008) [Pyridyl-2,6-(Carbon 14)]AE C656948: Absorption, 

Distribution, Excretion and Metabolism in the Rat. Project Number: MEF/07/486, 

M31819167, M/298924/01/2. Unpublished study prepared by Bayer CropScience 

AG. 266 p.

47372512 Koester, J.; Kelmpner, A. (2008) [Pyridyl-2,6-(Carbon 14)]AE C656948: 

Distribution of the Total Radioactivity in Male and Female Rats Determined by

Quantitative Whole Body Autoradiography (QWBA), Determination of the Exhaled 

[(Carbon 14) Dioxide]. Project Number: MEF/07/457, M/1819149/3, 

M/296485/01/2. Unpublished study prepared by Bayer CropScience. 125 p.

47372513 Koester, J.; Klempner, A. (2008) [Phenyl-UL (Carbon 14)]AE C656948: 

Distribution of the Total Radioactivity in Male and Female Rats Determined by

Quantitative Whole Body Autoradiography (QWBA), Determination of the Exhaled 

[(Carbon 14) Dioxide] and Metabolic Profiling in E. Project Number: MEF/07/456, 

M/1811509/5, M/296623/01/2. Unpublished study prepared by Bayer CropScience. 

201 p.
FLUOPYRAM CANCER ASSESSMENT DOCUMENT FINAL

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47372516 Kennel, P.; AE C656948 - Exploratory 28-day toxicity study in the rat by dietary

administration; Bayer CropScience S.A., Sophia Antipolis, France; Report No.: SA 

03332; Document No.: M-085510-01-3; January 14, 2008; Pages: 224

47372517 Kennel, P.; AE C656948 - Preliminary 28-day toxicity study in the mouse by dietary

administration; Bayer CropScience S.A., Sophia Antipolis, France; Report No.: SA 

04013; Document No.: M-088486-01-3; January 14, 2008; Pages: 171

47372519 Rouquie, D.; AE C656948 - Mechanistic 14-day toxicity study in the mouse by

dietary administration (hepatotoxicity and thyroid hormone investigations); Bayer 

CropScience S.A., Sophia Antipolis, France; Report No.: SA 07215; Document No.: 

M-299522-01-2; April 14, 2008; Pages: 262

47372520 Blanck, M.; AE C656948 (AE C656948) - 7-day mechanistic study in the female 

Wistar rat by dietary administration; Bayer CropScience S.A., Sophia Antipolis, 

France; Report No.: SA 07323; Document No.: M-299274-01-2; April 03, 2008; 

Pages: 160

47567128 Rouquie, D.; AE C656948 - Mechanistic 3-day toxicity study in the male mouse 

(pharmacokinetic investigations of the clearance of intravenously administered 125Ithyroxine); Bayer CropScience, Sophia Antipolis, France; Report No.: SA 08159; 

Document No.: M-308369-01-2; October 07, 2008; Pages: 78

47690101 Rouquie, D.; AE C656948 - Definitive mechanistic 4-day toxicity study in the male 

mouse (pharmacokinetic investigations of the clearance of intravenously

administered 125I-thyroxine); Bayer CropScience, Sophia Antipolis, France; Report 

No.: SA 08288; Document No.: M-328662-01-2; February 16, 2006; Pages: 82

47753406 Van Goethem, D.; Wason, S.; Mileson, B. (2009) Fluopyram: Weight of Evidence 

Evaluation of Thyroid Carcinogenesis in Mice and Liver Carcinogenesis in Rats 

Using the IPCS Mode of Action Framework. Project Number: 051809, 

M/347600/01/1. Unpublished study prepared by Bayer CropScience LP. 49 p.

Memo L. Brunsman. 2009. Fluopyram Qualitative Risk Assessment Based on Wistar Rj:WI

(IOPS HAN) Rat and C57BL/6J Mouse Dietary Studies. June 10, 2009. 

TXR # 0055218.

Memo L. Brunsman. 2009. Fluopyram Quantitative Risk Assessment Based on Wistar 

Rj:WI (IOPS HAN) Rat Dietary Study. November 17, 2009. TXR # 0055280.