Adverse Effects
Flurtamone
CAS No.
96525-23-4
 
 

Return to Flurtamone Index Page

Activity: Herbicide (unclassified)
Structure:




Adverse Effects:
Amyloidosis - Systemic
Body Weight Decrease
Bone
Brain
Kidney

Liver
Spleen

According to Rhone-Poulenc, 'Flurtamone is a contact and residual bleaching herbicide. It acts on weeds pre-emergence and early post-emergence, being absorbed by the roots and young stems during the seedlings' growth. Applied post-emergence of young weeds, its action is slower...' Flurtamone is formulated with the herbicidal active substances diflufenican and isoproturon; the product is to be known as 'Roulette.' It will be used on "Field crops, agriculture."
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate. Available online at: http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

Note: Diflufenican is a fluorinated herbicide.


Amyloidosis - Systemic (click on for all fluorinated pesticides)

-- Two-year dietary study in mice. In a carcinogenicity study, groups CD-1 mice (60/sex/dose) were fed diets containing 0, 30, 300, 3500 and 7000 ppm flurtamone (91.9% purity) for at least 78 weeks... The mean intake of flurtamone for males and females was estimated to be 4.5, 45, 525 and 1050 mg/kg bwday at 30, 300, 3500 and 7000 ppm, respectively. After 78 weeks of treatment, the mortality rate for the 7000 ppm female mice was significantly higher than controls and a significant negative survival trend was found in both sexes. The test laboratory pathologist considered systemic amyloidosis to be the major cause of death (Table 5.24) [page 102]. Gross necropsy revealed an increased incidence of enlarged livers and liver masses at dose levels 3500 and of irregular shaped kidneys at 7000 ppm. Significant increases in mean liver weight (absolute and relative) were observed in 3500 and 7000 ppm animals (not statistically significant in 3500 ppm males) at both the interim and terminal sacrifices (Table 5.26). Significant decreases in mean absolute kidney weights were observed in males at 7000 ppm at the interim and terminal sacrifices [page 103]. Microscopic examinations revealed an increased incidence of systemic amyloidosis (most severe in the kidneys) in the 3500 and 7000 ppm animals and the 300 ppm females that died or were sacrificed in extremis. The incidence and severity of renal amyloidosis is given in Table 5.27 [page 104]... Based on the incidence and severity of renal amyloidosis associated with early death in females at 300 ppm, the test laboratory proposed a NOEL for non-neoplastic lesions of 30 ppm (equivalent to approximately 4 mg/kg/day) for this study. The NOEL for neoplastic lesions in mice was determined to be 300 ppm (equivalent to approximately 45 mg/kg/day). In the opinion of the applicant [Rhone-Poulenc Agriculture Ltd], the observed amyloidosis in the above study was not a treatment-related effect of flurtamone administration. The incidences of amyloidosis in this study were re-analysed by an independent pathologist but the histopathological slides were not re-examined. It should be noted that systemic amyloidosis is a common age-related condition in CD-1 mice with a tendency to be more frequent as a cause of death in females than in males and the incidence varies widely within laboratories and between laboratories [page 105]... [page 108].

Flurtamone: Table 5.27 The incidence and severity of renal amyloidosis in unscheduled deaths [page 104]
Dose
Males
Females
(ppm)
Incidence
Mean grade
Incidence
Mean grade
0
1/10 (10%)
0.6
2/7 (29%)
0.9
30
3/5 (60%)
2.4
1/8 (14%)
0.9
300
3/11 (30%)
1.2
7/13 (54%)
2.0
3500
10/13 (77%)
2.9
7/12 (64%)
2.8
7000
10/13 (77%)
2.8
9/19 (47%)
2.1
Flurtamone: Table 5.24 Survival and incidence of amyloidosis as a cause of death [page 103]
Dose
Males
Females
(ppm)
Survival
(%)
Amyloid
(COD*)
Survival
(%)
Amyloid
(COD*)
0
86.8
0/50 (0%)
88.1
1/50 (2%)
30
90.0
3/50 (6%)
87.8
0/50 (0%)
300
78.8
3/50 (6%)
75.5
6/50 (12%)
3500
74.0
8/50 (16%)
77.4
7/50 (14%)
7000
74.5
7/50 (14%)
66.2
9/50 (18%)
COD = cause of death

Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. Available online at:
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

Body Weight Decrease (click on for all fluorinated pesticides)

-- Developmental toxicity. Sprague-Dawley rats (25/dose) were gavaged on days 6 to 15 of pregnancy with doses of 0, 5, 50, 250 or 1000 mg/kg bw/day flurtamone (91.9% pure) in an aqueous suspension of 0.25% CMC containing 1% Tween 80... All rats were terminated on gestation day 20 and received a gross necropsy... Small but statistically significant decreases in mean maternal body weight were observed in the 250 and 1000 mg/kg bw/day groups on gestation days 9-20. When the body weights of the two abnormal dams were excluded from the analysis, mean maternal body weights were significantly lower in the 250 and 1000 mg/kg bw/day groups on gestation days 9-20, and they were also significantly lower in the 5 and 50 mg/kg bw/day groups on gestation days 18-20. Small but statistically significant decreases in mean body weight gain were observed in all treatment groups (including and excluding the abnormal dams) during dosing and between gestation days 6 and 20. During the post-dosing period, mean body weight gain was significantly increased in the 1000 mg/kg/day group only [pages 109-110]... The external, soft tissue and skeletal examinations of the foetuses did not reveal any dose-dependent increases in foetal malformations. Foetuses in the 1000 mg/kg/day group showed evidence of delayed development (i.e. significant decreases in the average number of ossified vertebrae, xiphoid centres, and metatarsals when compared to control). In the top dose group there was also an increase in the average number of thoracic ribs. These skeletal variations are generally considered to be reversible delays in development that resolve with continuted growth and could be expected observations in foetuses with decreased body weights... Because of the reduced body weight gain observed at 5 mg/kg bw/day, a clear NOEl for maternal toxicity could not be determined in this study. Therefore, based on reduced body weight gain at 5 mg/kg bw/day, a LOEL of 5 mg/kg bw/day was determined for maternal toxicity in this study. Based on the developmental effects at the top dose, a NOEL of 250 mg/kg bw/day was determined for foetal toxicity...
-- Developmental toxicity. Rabbit. Artificially-inseminated rabbits (20/dose) were gavaged with doses of 0, 20, 200 or 600 mg/kg bw/day flurtamone (91.9%purity) in an aqueous suspension of 0.25% CMC containing 1% Tween 80 on gestation days 6 to 19... All rabbits were terminated on gestation day 29 and received a gross necropsy... Significant reductions in mean maternal body weight gain were observed during the dosing period at 200 and 600 mg/kg bw/day... The foetal examinations revealed that four foetuses from one top dose litter had interrelated external, soft tissue and skeletal malformations (the dam had 9 implantations with 5 early resorptions). These observations (e.g. open eyelids, cleft palate, syndactylly and irregular shaped skull bones) were considered to be unrelated to treatment because: i) these alterations occurred in 4 litter mates, ii) the litter incidences for these alterations were generally not significantly different from the control group incidences, iii) all other malformations and variations that occurred in high-dose group foetuses, other than those observed in the above 4 litter mates, were single events within the historical control ranges [pages 112-113].
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. Available online at

http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

Bone (click on for all fluorinated pesticides)

-- Developmental toxicity. Sprague-Dawley rats (25/dose) were gavaged on days 6 to 15 of pregnancy with doses of 0, 5, 50, 250 or 1000 mg/kg bw/day flurtamone (91.9% pure) in an aqueous suspension of 0.25% CMC containing 1% Tween 80... All rats were terminated on gestation day 20 and received a gross necropsy... The external, soft tissue and skeletal examinations of the foetuses did not reveal any dose-dependent increases in foetal malformations. Foetuses in the 1000 mg/kg/day group showed evidence of delayed development (i.e. significant decreases in the average number of ossified vertebrae, xiphoid centres, and metatarsals when compared to control). In the top dose group there was also an increase in the average number of thoracic ribs. These skeletal variations are generally considered to be reversible delays in development that resolve with continuted growth and could be expected observations in foetuses with decreased body weights... Because of the reduced body weight gain observed at 5 mg/kg bw/day, a clear NOEl for maternal toxicity could not be determined in this study. Therefore, based on reduced body weight gain at 5 mg/kg bw/day, a LOEL of 5 mg/kg bw/day was determined for maternal toxicity in this study. Based on the developmental effects at the top dose, a NOEL of 250 mg/kg bw/day was determined for foetal toxicity...
-- Developmental toxicity. Rabbit. Artificially-inseminated rabbits (20/dose) were gavaged with doses of 0, 20, 200 or 600 mg/kg bw/day flurtamone (91.9%purity) in an aqueous suspension of 0.25% CMC containing 1% Tween 80 on gestation days 6 to 19... All rabbits were terminated on gestation day 29 and received a gross necropsy... The foetal examinations revealed that four foetuses from one top dose litter had interrelated external, soft tissue and skeletal malformations (the dam had 9 implantations with 5 early resorptions). These observations (e.g. open eyelids, cleft palate, syndactylly [see definition below] and irregular shaped skull bones) were considered to be unrelated to treatment because: i) these alterations occurred in 4 litter mates, ii) the litter incidences for these alterations were generally not significantly different from the control group incidences, iii) all other malformations and variations that occurred in high-dose group foetuses, other than those observed in the above 4 litter mates, were single events within the historical control ranges [pages 112-113].
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. Available online at:

http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

FAN Note: "Syndactylly" as spelled in this UK report. The definition for "Syndactyly" in an American dictionary: any degree of webbing or fusion of fingers or toes, involving soft parts only or including bone structure. SYN symphalangism (1), symphalangy, syndactylia, syndactylism. Ref: Stedman's Concise Medical Dictionary for the Health Professions. Illustrated 4th Edition. 2001.

Brain (click on for all fluorinated pesticides)

-- Two-year dietary study in mice. In a carcinogenicity study, groups CD-1 mice (60/sex/dose) were fed diets containing 0, 30, 300, 3500 and 7000 ppm flurtamone (91.9% purity) for at least 78 weeks... The mean intake of flurtamone for males and females was estimated to be 4.5, 45, 525 and 1050 mg/kg bwday at 30, 300, 3500 and 7000 ppm, respectively. After 78 weeks of treatment, the mortality rate for the 7000 ppm female mice was significantly higher than controls and a significant negative survival trend was found in both sexes. The test laboratory pathologist considered systemic amyloidosis to be the major cause of death (Table 5.34) [page 102]... Mean relative brain weights were significantly increased in F0 females at dose-levels 2000 ppm, and in F1 males and females at 5000 ppm. While mean absolute brain weights were significantly reduced in F1 males and females at dose levels 2000 ppm. Other small but statistically significant changes in mean organ weight were considered to be incidental, related to body weight effects or lacked a dose-response relationship. No macroscopic changes were observed which could be related to treatment. The only microscopic finding which could be attributed to compound administration was centrilobular hypertrophy of the liver. Dose-related increases in the incidence of centrilobular hypertrophy were observed in F0 and F1 animals at dose levels 500 ppm (Table 5.31). this centrilobular hypertrophy was considered to be an adaptive biological response [page 108].
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. Available online at:

http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

Kidney (click on for all fluorinated pesticides)

-- Long term toxicity and carcinogenicity. Target / critical effect: Liver: hypertrophy, centrilobular hypertrophy. Kidney: increased amyloidosis in mice. Lowest relevant NOAEL: 2.8 mg/kg bw (2 year rat study) Carcinogenicity: No carcinogenic potential
Ref: July3, 2003. Flurtamone. Sanco/10162/2003-Final. Review report for the active substance flurtamone. Finalised in the [EU] Standing Committee on the Food Chain and Animal Health at its meeting on 4 July 2003 in view of the inclusion of flurtamone in Annex I of Directive 91/414/EEC.
http://www.fluorideaction.org/pesticides/flurtamone.eu.july.2003.pdf

Flurtamone: Table 5.27 The incidence and severity of renal amyloidosis in unscheduled deaths [page 104]
Dose
Males
Females
(ppm)
Incidence
Mean grade
Incidence
Mean grade
0
1/10 (10%)
0.6
2/7 (29%)
0.9
30
3/5 (60%)
2.4
1/8 (14%)
0.9
300
3/11 (30%)
1.2
7/13 (54%)
2.0
3500
10/13 (77%)
2.9
7/12 (64%)
2.8
7000
10/13 (77%)
2.8
9/19 (47%)
2.1

-- Two-year dietary study in mice. In a carcinogenicity study, groups CD-1 mice (60/sex/dose) were fed diets containing 0, 30, 300, 3500 and 7000 ppm flurtamone (91.9% purity) for at least 78 weeks... The mean intake of flurtamone for males and females was estimated to be 4.5, 45, 525 and 1050 mg/kg bwday at 30, 300, 3500 and 7000 ppm, respectively. After 78 weeks of treatment, the mortality rate for the 7000 ppm female mice was significantly higher than controls and a significant negative survival trend was found in both sexes. The test laboratory pathologist considered systemic amyloidosis to be the major cause of death (Table 5.34) [page 102]. Gross necropsy revealed an increased incidence of enlarged livers and liver masses at dose levels 3500 and of irregular shaped kidneys at 7000 ppm. Significant increases in mean liver weight (absolute and relative) were observed in 3500 and 7000 ppm animals (not statistically significant in 3500 ppm males) at both the interim and terminal sacrifices (Table 5.26). Significant decreases in mean absolute kidney weights were observed in males at 7000 ppm at the interim and terminal sacrifices [page 103]. Microscopic examinations revealed an increased incidence of systemic amyloidosis (most severe in the kidneys) in the 3500 and 7000 ppm animals and the 300 ppm females that died or were sacrificed in extremis. The incidence and severity of renal amyloidosis is given in Table 5.27. An increase in the incidence of centrilobular hypertrophy was observed in both sexes at dose levels 3500 ppm. The incidence of hepatic pigment (primarily in the reticuloendothelial cells) was increased in males at dose levels 3500 ppm and in females at 7000 ppm. There was an increase in the incidence of degeneration/inflammation/regeneration in the dorsal nasal turbinates of both sexes at 7000 ppm and in males at 3500 ppm. The severity and incidence of extramedullary haematopoiesis was increased in the spleens of the 7000 ppm males and females [page 104] Based on the incidence and severity of renal amyloidosis associated with early death in females at 300 ppm, the test laboratory proposed a NOEL for non-neoplastic lesions of 30 ppm (equivalent to approximately 4 mg/kg/day) for this study. The NOEL for neoplastic lesions in mice was determined to be 300 ppm (equivalent to approximately 45 mg/kg/day). In the opinion of the applicant [Rhone-Poulenc Agriculture Ltd], the observed amyloidosis in the above study was not a treatment-related effect of flurtamone administration. The incidences of amyloidosis in this study were re-analysed by an independent pathologist but the histopathological slides were not re-examined. It should be noted that systemic amyloidosis is a common age-related condition in CD-1 mice with a tendency to be more frequent as a cause of death in females than in males and the incidence varies widely within laboratories and between laboratories [page 105]... [page 108]
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. Available online at:
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

Liver (click on for all fluorinated pesticides)

Flurtamone: Table 5.31 Incidence of centrilobular hypertrophy of the liver
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. Available only in hard copy. To order a hard copy online go to: http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm 
Dose FO adults F1 adults
ppm Male Female Male Female
0 2/30 0/30 6/30 0/30
75 6/30 1/30 10/30 0/30
500 18/30 5/30 26/30 0/30
2000 28/30 17/30 29/30 22/30
5000 28/30 27/30 28/30 27/30

-- Short term toxicity. Target / critical effect: Liver: Hepatomegaly, centrilobular hypertrophy. Lowest relevant oral NOAEL / NOEL: 5 mg/kg bw (1 year dog study). Lowest relevant dermal NOAEL / NOEL: 1000 mg/kg bw (21 day study in rat)
-- Long term toxicity and carcinogenicity. Target / critical effect: Liver: hypertrophy, centrilobular hypertrophy. Kidney: increased amyloidosis in mice. Lowest relevant NOAEL: 2.8 mg/kg bw (2 year rat study) Carcinogenicity: No carcinogenic potential

Ref: July3, 2003. Flurtamone. Sanco/10162/2003-Final. Review report for the active substance flurtamone. Finalised in the [EU] Standing Committee on the Food Chain and Animal Health at its meeting on 4 July 2003 in view of the inclusion of flurtamone in Annex I of Directive 91/414/EEC.
http://www.fluorideaction.org/pesticides/flurtamone.eu.july.2003.pdf

-- Two-year dietary study in mice. In a carcinogenicity study, groups CD-1 mice (60/sex/dose) were fed diets containing 0, 30, 300, 3500 and 7000 ppm flurtamone (91.9% purity) for at least 78 weeks... The mean intake of flurtamone for males and females was estimated to be 4.5, 45, 525 and 1050 mg/kg bwday at 30, 300, 3500 and 7000 ppm, respectively. After 78 weeks of treatment, the mortality rate for the 7000 ppm female mice was significantly higher than controls and a significant negative survival trend was found in both sexes. The test laboratory pathologist considered systemic amyloidosis to be the major cause of death (Table 5.34) [page 102]. Gross necropsy revealed an increased incidence of enlarged livers and liver masses at dose levels 3500 and of irregular shaped kidneys at 7000 ppm. Significant increases in mean liver weight (absolute and relative) were observed in 3500 and 7000 ppm animals (not statistically significant in 3500 ppm males) at both the interim and terminal sacrifices (Table 5.26). Significant decreases in mean absolute kidney weights were observed in males at 7000 ppm at the interim and terminal sacrifices [page 103]. Microscopic examinations revealed an increased incidence of systemic amyloidosis (most severe in the kidneys) in the 3500 and 7000 ppm animals and the 300 ppm females that died or were sacrificed in extremis. The incidence and severity of renal amyloidosis is given in Table 5.27. An increase in the incidence of centrilobular hypertrophy was observed in both sexes at dose levels 3500 ppm. The incidence of hepatic pigment (primarily in the reticuloendothelial cells) was increased in males at dose levels 3500 ppm and in females at 7000 ppm... [page 105]. Significant increases in mean relative liver weight were observed in males and females in both generations at dose-levels 2000 ppm. Mean absolute liver weights were significantly increased in F0 males, F0 females and F1 mates at 5000 ppm, and in F0 males and F1 females at 2000 ppm... The only microscopic finding which could be attributed to compound administration was centrilobular hypertrophy of the liver. Dose-related increases in the incidence of centrilobular hypertrophy were observed in F0 and F1 animals at dose levels 500 ppm (Table 5.31). This centrilobular hypertrophy was considered to be an adaptive biological response [page 108]
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. Available online at:

http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

Spleen (click on for all fluorinated pesticides)

-- Two-year dietary study in mice. In a carcinogenicity study, groups CD-1 mice (60/sex/dose) were fed diets containing 0, 30, 300, 3500 and 7000 ppm flurtamone (91.9% purity) for at least 78 weeks... The mean intake of flurtamone for males and females was estimated to be 4.5, 45, 525 and 1050 mg/kg bwday at 30, 300, 3500 and 7000 ppm, respectively. After 78 weeks of treatment, the mortality rate for the 7000 ppm female mice was significantly higher than controls and a significant negative survival trend was found in both sexes. The test laboratory pathologist considered systemic amyloidosis to be the major cause of death (Table 5.34) [page 102]... The severity and incidence of extramedullary haematopoiesis was increased in the spleens of the 7000 ppm males and females [page 104]..
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. Available online at
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

 
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