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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 ³3500 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 ³2000 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 ³2000 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
³500 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 ³3500
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 ³ 3500 ppm.
The incidence of hepatic pigment (primarily in the reticuloendothelial
cells) was increased in males at dose levels ³3500 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
³3500 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 ³ 3500 ppm. The incidence
of hepatic pigment (primarily in
the reticuloendothelial cells) was increased in males at dose
levels ³3500 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 ³2000 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 ³500 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
|