Page 1 of 12

Addendum to the ToxSAC Report on Fluopyram (Dec. 23, 2009)

(from RAB 3 Risk Assessment Team, 1/13/2010)

On July 16, 2009, ToxSAC met to evaluate the proposed toxicity endpoints and FQPA safety 

factors for fluopyram. The members of ToxSAC evaluated the available data. The toxicity data 

derived from repeated dosing demonstrated that fluopyram predominantly produced liver, 

thyroid, and kidney effects and reduced body weight. Most of the toxicity endpoints and points 

of departure for risk assessment selected for risk assessment were based on the liver and thyroid 

effects. Thyroid effects including thyroid hormonal changes were seen in several studies in rats 

and mice with repeated dosing. However, the available data on thyroid hormonal changes were 

inconsistent and sparse. The ToxSAC raised a concern about the potential influence of thyroid 

hormone on the development of the young animals since the thyroid was not examined in the 

pups. The ToxSAC recommended a comparative thyroid hormone assay on fluopyram and a 10x 

safety factor to account for the uncertainty associated with the lack of this study.

All the data on fluopyram registration are undergoing a global review; the major global partners 

are Germany and Canada. Both Canada and Germany evaluated the toxicology data and 

concluded that the available data demonstrated that the thyroid effect to be secondary to the liver 

effect. The data showed that there were increased liver weight, liver hypertrophy, and increased 

liver enzyme activities. The increased liver enzyme activities enhanced thyroid hormone 

metabolism leading to a decrease in circulating thyroid hormone and perturbation on the 

pituitary-thyroid axis. An increase in TSH level was seen in 14-day mechanistic studies in rats 

and mice. Both Germany and Canada determined that the thyroid effect was secondary to the 

liver toxicity. HED Division director was briefed on this difference and the relevant data were 

presented at the meeting. The attendees at this meeting were Paula Deschamp, Sheila Healy, 

Elizabeth Mendez, Whang Phang, and Tina Levine (Division Director). In this meeting the 

information and data summaries contained in Attachments 1, 2, &3 were presented and 

discussed.

After careful consideration of all data, the RAB3 Risk Assessment Team determines that 

the available data do not support the requirement of a comparative thyroid assay and 

associated 10x FQPA safety factor for the following reasons:

1. The existing data demonstrated slight changes in thyroid hormonal level; the effect 

of hormonal changes was not considered to be a major effect.

2. There was no increase in sensitivity in fetuses which were exposed during pre-natal

duration and pups which were exposed during pre-natal and post-natal periods.

3. The data suggest that the non-neoplastic thyroid effect was associated with the liver 

affect. 
Page 2 of 12

Attachment 1

Fluopyram Discussion

16-December-2009

Objective

To present the current status on endpoints/uncertainty factors proposed for EPA risk assessment 

and the implications for US registrations and global harmonization. 

Background

Fluopyram is a new broad-spectrum systemic fungicide of the carboxamide group. The proposed 

use is to control fungal diseases in practically all crops. It acts by inhibiting succinate 

dehydrogenase in the cell respiration of the fungus (mitochondrial respiration Complex II), thus 

blocking electron transport. Fluopyram is a global review chemical in partnership with Canada 

and Germany. Germany has the work-share lead for review of toxicology data.

Summary of Toxicological Findings

Decreased body weight found in practically all studies; target organ effects are as follows:

- Liver in rats, mice & dogs - increased liver weight, hepatocellular hypertrophy, vacuolation, increased 

liver microsomal enzymes (P-450, BROD,& EROD activities in rats), hepatocellular adenomas and 

carcinomas. 

- Kidneys- increase organ weight associated with hyaline droplet nephropathy in rats

- Thyroid in rats and mice: increased thyroid weight, slight changes in thyroid hormone in the studies 

where thyroid hormones were measure, hypertrophy of the follicular cell, hyperplasia, and thyroid 

follicular cell adenomas. (There are data to suggest that the thyroid effects are due to liver microsomal 

enzyme induction leading to enhanced catabolism of T3 & T4 in the liver and an increase in TSH 

level via feed back mechanism). 

- The data of a recovery group in a 90-day oral toxicity study in rats showed that, after the treated rats 

were maintained on the control diet for 1 month, liver effects seen in the treated rats returned to 

normal; do did the thyroid gland.

Harmonization Issues

1) Carcinogenicity: EPA, PMRA, and Germany agree that the MOA argument for 

carcinogenicity has not been made because dose levels tested for MOA studies were too high 

(greater than the dose which produced tumor in some studies).

- EPA: Carcinogenicity: increased incidence of liver tumors in rats and thyroid tumors in 

mice. The registrant submitted data to demonstrate a mode of action for both liver and 

thyroid tumors. However, these data were insufficient. The CARC classified fluopyram 

as “Likely to be Carcinogenic to Human” and a unit risk, Q1*, of 1.55x10-2 was 

calculated based upon female rat liver tumors (adenomas and carcinomas combined). 

- PMRA has calculated unit risks based on both thyroid adenomas (1.72x10-2) and liver 

tumors (1.21x10-2), whereas Germany is going to classify fluopyram according to its own 

system and conducts the risk using RfD approach.
Page 3 of 12

2) Non-cancer thyroid effects: 

o ToxSAC had evaluated the proposed toxicity endpoints and recommended a 

comparative thyroid assay in rats to be conducted. Due to lack of reliable thyroid 

hormonal measurements in repeated dose studies and uncertainty of the thyroid 

hormonal effects in the pups. This leads to database uncertainty, and a 10x FQPA 

safety factor is recommended to be applied for assessing the risk.

o Currently, PMRA and Germany do not feel that thyroid effect is a concern 

because they believe it is a secondary effect due to increased metabolism of the 

thyroid hormone in the liver.
Page 4 of 12

Attachment 2

Summary Data of Liver and Thyroid Effects Found in Toxicity Studies with Fluopyram

Dose levels 

(mg/kg/day)

Liver Effects Thyroid Effects

28-Day Oral Tox. rats

4.0/4.6 (M/F) None None

31.0/36.1 Liver enzyme increase None

256/263 Liver weight increases, hypertrophy Thyroid weight increases with follicular 

cell hypertrophy

90-Day oral tox. -rats

3.1/3.6 None None

12.5/14.6 None None

60.5/70.1 ↑ liver weight (+25%), hypertrophy, 

& macrovacuolation

↑ thyroid weight (+4%), thyroid follicular 

cell hypertrophy. TSH, T4 and T3 were 

increased. 

204/230 ↑ liver weight (+53%), hypertrophy, 

& macrovacuolation

↑ thyroid weight (+10%), thyroid follicular 

cell hypertrophy. TSH, T4 and T3 were 

increased.

1 month recovery group showed (60.5/70.1 

mg/kg) livers were comparable to those of 

the controls. 

1 month recovery group showed (60.5/70.1 mg/kg) 

thyroid glands were comparable to those of the 

controls. TSH, T3, & T4 returned to the control 

levels.

Carcinogenicity study - mice

4.2/5.3 None None

20.9/26.8 ↑ Liver weight (11-20%), 

hypertrophy, single cell 

degeneration

Thyroid follicular cell hyperplasia

105/129 ↑ Liver weight (11-20%), 

hypertrophy, single cell 

degeneration, vacuolation

Thyroid follicular cell hyperplasia, 

adenomas

Chronic/carcinogenicity study -rats

1.20/1.68 None None
Page 5 of 12

Dose levels 

(mg/kg/day)

Liver Effects Thyroid Effects

6.0/8.6 Hypertocellular hypertrophy, 

marcovacuolation

Thyroid follicular cell hypertrophy

28/89 ↑ Liver weight (17% M, 39% F), 

hypertrophy, single cell 

degeneration, liver tumor in females

↑ thrroid weight (8% M, 23% F),

follicular cell hypertrophy

2-Generation Reproduction Study-rats

2.7/3.2 (M/F) None (parent & offspring) None (parent & offspring)

15.1/17.6 None (parent & offspring) None (parent & offspring)

83.1/96.3 Increase liver weight and heptocentrilobular hypertrophy parent & 

F1 generation.

Thyroid gland was weighed and examined 

no effect was reported for P & F1 

generations..

The numerical details of the above summarized data are presented in the tables following this page.
Page 6 of 12

Attachment 3

Organ weight changes in the 28-day rat study with fluopyram

Dosage level (ppm) 0 50 400 3200 

Males

Liver weight

Absolute (g) 11.13 ± 0.93 11.18 ± 0.93 

(+0.4 %)

12.45 ± 1.15

(+12 %)

17.11 ± 1.76** 

(+54 %)

Bodyweight-relative 2.864 ± 0.210 2.811 ± 0.137 

(-2 %)

3.055 ± 0.176

(+7 %)

4.401 ± 0.239** 

(+54 %)

Brain-relative 567.042 ± 

57.354

565.078 ± 48.426 

(0 %)

607.382 ± 50.971 

(+7 %)

878.091 ± 86.733 

(+55 %)

Kidney weight

Absolute (g) 2.63 ± 0.09 2.49 ± 0.18 (-

5 %)

3.16 ± 0.24** 

(+20 %)

3.13 ± 0.20** 

(+19 %)

Bodyweight-relative 0.676 ± 0.016 0.627 ± 0.053 (-

7 %)

0.777 ± 0.052

(+15 %)

0.801 ± 0.094

(+18 %)

Thyroid weight

Absolute (g) 0.0176 ± 0.0040 0.0197 ± 0.0023

(+12 %)

0.0222 ± 0.0026 

(+26 %)

0.0252 ± 0.0033** 

(+43 %)

Bodyweight-relative 0.00456 ± 

0.00118

0.00499 ± 

0.00085 

(+9 %)

0.00548 ± 0.00086 

(+20 %)

0.00653 ± 

0.00109** (+41 %)

Females

Liver weight

Absolute (g) 5.84 ± 0.36 6.24 ± 0.32

(+7 %)

6.76 ± 0.46

(+16 %)

9.64 ± 1.00** 

(+65 %)

Bodyweight-relative 2.665 ± 0.200 2.773 ± 0.064

(+4 %)

3.072 ± 0.151

(+15 %)

4.599 ± 0.349** 

(+73 %)

*: p≤0.05; **: p≤0.01; Figures in parentheses are % differences from control
Page 7 of 12

Liver weight changes after 90 days of treatment (% change when compared to controls) in rats

Dietary level (ppm) 0 50 200 1000 3200

Males

Mean absolute liver 

Weight (g)

10.94 ± 0.86 10.82 ± 0.63

(-1 %)

12.02 ± 1.19

(+10 %)

13.63 ± 1.13**

(+25 %)

16.77 ± 1.70**

(+53 %)

Mean liver to body 

weight ratio

2.282 ± 0.096 2.277 ± 0.101

(0 %)

2.400 ± 0.151

(+5 %)

2.736 ± 0.188**

(+20 %)

3.669 ± 0.223**

(+61 %)

Females

Mean absolute liver 

Weight (g)

5.74 ± 0.58 5.94 ± 0.32

(+3 %)

6.40 ± 0.43

(+11 %)

7.09 ± 0.58**

(+24 %)

9.09 ± 1.55**

(+58 %)

Mean liver to body 

weight ratio

2.123 ±0.096 2.235 ± 0.105

(+5 %)

2.366 ± 0.071

(+11 %)

2.697 ± 0.172**

(+27 %)

3.699 ± 0.503**

(+74 %)

* = p<0.05. **= p<0.01

Thyroid weight changes after 90 days of treatment(% change when compared to controls) in rats

Dietary level (ppm) 0 50 200 1000 3200

Males

Mean absolute 

thyroid weight (g)

0.0272 ± 0.0052 0.0224 ± 0.0058

(-18 %)

0.0269 ± 0.0048

(-1 %)

0.0282 ± 0.0060

(+4 %)

0.0299±0.0051

(+10 %)

Mean thyroid to 

bodyweight ratio

0.00568 ± 

0.00107

0.00471 ± 

0.00123 (-17 %)

0.00496 ± 

0.00081 (-13 %)

0.00565 ± 

0.00106 (-1 %)

0.00657 ± 

0.00121 (+16 %)

Females

Mean absolute 

thyroid weight (g)

0.0185 ± 0.0021 0.0203 ± 0.0040

(+10 %)

0.0164 ± 0.0042

(-11 %)

0.0184 ± 0.0038

(-1 %)

0.0206 ± 0.0026

(+11 %)

Mean thyroid to 

bodyweight ratio

0.00689 ± 

0.00093

0.00767 ± 

0.00163

(+11 %)

0.00610 ± 

0.00156

(-11 %)

0.00696 ± 

0.00116

(0 %)

0.00841 ± 

0.00097* (+22 %)

* = p<0.05
Page 8 of 12

90-Day Oral Toxicity Study-rats

Thyroid Hormons and TSH Levels in Fluopyram Treated Rats- 3 Week

Dose level

(Mg/kg/day)

M/F

TSH T3 T4

Males Females Males Females Males Females

0/0 6.32 ± 2.58 3.51 ± 0.59 1.33 ± 0.19 1.22 ± 0.24 61.9 ± 15.1 34.0 ± 6.5

3.06/3.63 6.58 ± 2.67 3.70 ± 1.31 1.37 ± 0.13 1.41 ± 0.28 57.8 ± 6.7 45.2 ± 10.9

12.5/14.6 5.71 ± 2.00 4.13 ± 0.96 1.31 ± 0.17 1.21 ± 0.27 59.1 ± 9.0 36.7 ± 6.9

60.5/70.1 7.35 ± 1.18 4.14 ± 0.88 1.50 ± 0.24 1.37 ± 0.21 65.8 ± 12.5 44.5 ± 9.8

204/230 10.30 ± 4.95** 5.99 ± 1.13** 1.53 ± 0.23 1.51 ± 0.13* 55.4 ± 10.5 52.3 ± 10.5**

* p<0.05 **p<0.01

90-Day Oral Toxicity Study-rats

Thyroid Hormons and TSH Levels in Fluopyram Treated Rats- 13 Week

Dose level

(Mg/kg/day)

M/F

TSH T3 T4

Males Females Males Females Males Females

0/0 4.44 ± 1.13 4.16 ± 1.45 1.14 ± 0.29 1.46 ± 0.46 48.4 ± 11.0 34.1 ± 11.0

3.06/3.63 6.09 ± 1.93 3.62 ± 0.49 1.27 ± 0.21 1.45 ± 0.31 53.5 ± 14.3 38.3 ± 12.1

12.5/14.6 5.76 ± 1.69 3.73 ± 0.87 1.22 ± 0.34 1.44 ± 0.22 51.7 ± 4.8 44.8 ± 9.2

60.5/70.1 6.82 ± 1.97 3.94 ± 0.69 1.39 ± 0.35 1.60 ± 0.38 69.4 ± 11.4** 47.1 ± 11.6

204/230 8.35 ± 3.12** 5.42 ± 1.90 1.60 ± 0.26** 1.73 ± 0.24 58.2 ± 12.0 38.6 ± 12.2

* p<0.05 **p<0.01

90-Day Oral Toxicity Study-rats

Thyroid Hormons and TSH Levels in Fluopyram Treated Rats- 1-Month Recovery Groups

Dose level

(Mg/kg/day)

M/F

TSH T3 T4

Males Females Males Females Males Females

0/0 7.34 ± 2.08 3.93 ± 1.45 1.26 ± 0.49 1.23 ± 0.17 47.2 ± 8.1 29.0 ± 4.3

204/230 6.34 ± 1.73 3.51 ± 1.03 1.37 ± 0.27 1.36 ± 0.20 43.6 ± 8.0 39.8 ± 11.7

* p<0.05 **p<0.01
Page 9 of 12

Liver weight changes at scheduled sacrifice, chronic phase (% change when compared to 

controls) (Carcinogenicity Study in Mice)

Sex Males Females

Dose level of

fluopyram (ppm)

0 30 150 750 0 30 150 750

Mean absolute liver 

weight (g)

1.26

± 0.10

1.24

± 0.09

(-2 %)

1.40*

± 0.15

(+11 %)

1.47**

± 0.13

(+17 %)

1.09

± 0.13

1.07

± 0.18

(-2 %)

1.31**

± 0.12

(+20 %)

1.40**

± 0.14

(+28 %)

Mean liver to body 

weight ratio (%)

4.53

± 0.366

4.52

± 0.232

(0 %)

5.20**

0.503

(+15 %)

5.68**

0.235

(+25 %)

4.70

± 0.404

4.61

± 0.688

(-2 %)

5.51**

± 0.365

(+17 %)

6.12**

± 0.325

(+30 %)

*: p≤0.05;**: p≤0.01

Incidence and severity of microscopic changes in the thyroid gland, all animals, chronic 

phase (12-Months) (Carcinogenicity study in mice)

Sex Males

Dose level of fluopyram (ppm) 0 30 150 750

Number of animals 9 10 9 10

Follicular cell hyperplasia: focal/multifocal

Minimal 0 0 2 1

Slight 0 0 0 1

Total 0 0 2 2

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

carcinogenicity phase in mice

Sex Males Females

Dose level of

fluopyram (ppm)

0 30 150 750 0 30 150 750

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
Page 10 of 12

Liver weight changes at scheduled sacrifice of the chronic phase (12 month)(% change 

when compared to controls) (Rat Carcinogenicity Study)

Sex Males Females

Dose level of

fluopyram (ppm)

0 30 150 750 0 30 150 1500

Mean absolute liver 

weight (g)

12.21

± 1.33

12.70

± 1.50

(+4 %)

12.43

± 1.05

(+2 %)

14.31 *

± 1.92

(+17 %)

7.51

± 0.99

7.37

± 1.01

(-2 %)

7.67

± 1.43

(+2 %)

10.44 **

± 1.61

(+39 %)

Mean liver to body 

weight ratio

1.86

± 0.12

1.93

± 0.18

(+4 %)

1.88

± 0.15

(+1 %)

2.19 **

± 0.18

(+17 %)

2.17

± 0.19

2.19

± 0.22

(+1 %)

2.26

± 0.20

(+4 %)

3.35 **

± 0.33

(+54 %)

*: p≤0.05; **: p≤0.01

Rat liver weight changes at scheduled sacrifice of the carcinogenicity phase (% change 

when compared to controls)

Sex Males Females

Dose level of

fluopyram

(ppm)

0 30 150 750/375 0 30 150 1500

Mean absolute 

liver weight (g)

12.56

± 1.71

11.09 *

± 1.12

(-12 %)

14.02 *

± 2.06

(+12 %)

13.24

± 2.25

(+5 %)

9.46

± 2.19

9.69

± 2.12

(+2 %)

9.89

± 2.12

(+5 %)

13.16 **

± 2.87

(+39 %)

Mean liver to 

body weight ratio

2.06

± 0.33

1.94

± 0.26

(-6 %)

2.22

± 0.39

(+8 %)

2.32

± 0.43

(+12 %)

2.37

± 0.37

2.31

± 0.30

(-3 %)

2.52

± 0.35

(+6 %)

3.70 **

± 0.59

(+56 %)

*: p≤0.05; **: p≤0.01

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

carcinogenicity phase 

Sex Males Females

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

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
Page 11 of 12

Sex Males Females

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

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

Rat thyroid gland weight changes at scheduled sacrifice of the chronic phase (% change 

when compared to controls) (Carcinogenicity Study)

Sex Males Females

Dose level of

fluopyram

(ppm)

0 30 150 750 0 30 150 1500

Mean absolute 

thyroid gland 

weight (g)

0.0272

± 0.0059

0.0280

± 0.0036

(+3 %)

0.0244

± 0.0066

(-10 %)

0.0295

± 0.0059

(+8 %)

0.0201

± 0.0052

0.0196

± 0.0063

(-2 %)

0.0213

± 0.0048

(+6 %)

0.0248

± 0.0058

(+23 %)

Mean thyroid 

gland to body 

weight ratio

0. 0042

± 0.0009

0.0043

± 0.0006

(+3 %)

0.0038

± 0.0012

(-10 %)

0.0045

± 0.0008

(+9 %)

0.0058

± 0.0013

0.0057

± 0.0015

(-1 %)

0.0063

± 0.0013

(+9 %)

0.0080 **

± 0.0019

(+38 %)

**: p≤0.01

Incidence and severity of microscopic changes in the rat thyroid gland, all animals of the 

chronic phase (12 months)

Sex Males Females

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

Number of animals examined 10 10 10 10 10 10 10 10

Follicular cell hypertrophy: diffuse

Minimal 0 0 2 2 0 0 0 4

Slight 0 0 0 2 0 0 0 1

Total 0 0 2 4 0 0 0 5

Colloid alteration

Minimal 4 4 3 2 1 0 0 3

Slight 0 1 1 2 0 0 0 1

Moderate 0 0 0 3 0 0 0 0

Total 4 5 4 7 1 0 0 4
Page 12 of 12

Incidence and severity of microscopic changes in the rat thyroid gland, all animals of the 

carcinogenicity phase

Sex Males Females

Dose level of fluopyram

(ppm) 0 30 150 750/375 0 30 150 1500

Number of animals examined 58 59 57 54 60 60 60 58

Follicular cell hyperplasia: focal/multifocal

Minimal 0 0 0 2 1 1 0 2

Slight 0 0 0 1 1 1 1 2

Moderate 1 0 0 0 0 0 0 0

Marked 0 0 1 0 0 0 0 0

Total 1 0 1 3 2 2 1 4

Follicular cell hypertrophy: diffuse

Minimal 1 0 3 5 0 0 1 7

Slight 0 0 1 2 0 0 0 4

Moderate 0 0 0 0 0 0 0 1

Total 1 0 4 7** 0 0 1 12**

Colloid alteration

Minimal 18 5 12 10 5 6 10 17

Slight 8 9 16 20 2 1 5 15

Moderate 2 1 4 9 0 0 1 3

Marked 0 0 0 0 0 0 0 1

Total 28 15 32 39** 7 7 16* 36**

*: p≤0.05, **: p≤0.01