Return to Dichlofluanid
Index Page
Activity: Fungicide,
Acaricide, Wood Preservative
Structure:
Adverse Effects:
Blood
Bone
- Cranial osteosclerosis
Brain
Carginogenic
Endocrine: Ovary; Vitellogenesis
Endocrine: Pituitary
Endocrine: Suspected Disruptor
Endocrine: Testicular
Endocrine: Thyroid
Genotoxic - Potent Cytoxicant
Kidney
Liver
Contamination
Environmental
Dichlofluanid
is widely used on food crops in Japan. Also widely used
on food crops in the European Union up to July 25, 2003
- after which date it is not allowed to be used.
Dichlofluanide
has been reported as a hormonally active substance in the
environment in a review of the German Umweltbundesambt (Schramm
et al., 1996). However, a concentration range for which this
"hormonal activity" was found, was not reported
(page 44).
[Schramm K.-w., thumm W. * Kettrup A. (1996).
Hormonal active substances in the environment: exposition,
impact and detection. Expert Round. Endocrinically active
chemicals in the environment. UBA Texte 3/96. Umweltbundesamt,
Germay.]
Ref: RIVM report 601506005.
BIOCIDES (II). Refined aquatic environmental risk assessment
of 28 priority biocides. B.J.W.G. Mensink. November 2000.
RIVM = Rijksinstituut voor Volksgezondheid en Milieu. National
Institute of Public Health and the Environment.
http://www.rivm.nl/bibliotheek/rapporten/601506005.pdf
|
Blood
(click on for all fluorinated pesticides)
-- One-year Study.
A repeat-exposure study using Beagles (4/dose/sex) is available;
it was GLP and OECD Annex V compliant. Animals were administered
either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid
(90 % purity) in capsule form for one year. The top dose was reduced
at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity.
As a NOEL could not be established with the initial dosing regime,
a subsequent study was carried out in which 0 or 1.25 mg kg -1
d -1 dichlofluanid was used. Interim blood samples were taken
at 13, 26, 39 and 52 week (terminal bleed); in addition samples
were taken from some animals in the top-dose group at 14, 15 and
19 weeks... The haematology findings in males receiving 37.5 mg
kg -1 d -1 from 6 months onwards were decreased
numbers of erythrocytes (4 %), haemoglobin concentration (7.5
%) and haematocrit (7.4 %). Mild to moderate hepatic haemosiderin
deposition was reported and was particularly extensive in two
animals. None of these effects achieved statistical significance.
However, as they were outside the range of supplied historical
control data they were considered to be
treatment related. The following data, in animals at the
top dose, outside the range of supplied historical control data
(еееее2SD), except BUN, creatinine, and triglyceride levels in
females. This clinical chemistry data refers to the first study
and unless otherwise stated the data were collected at study termination.
Increases in ALP (215 % and 18 % males and
females respectively), AST (81 % males only*), ALT (595 % and
293 % males and females respectively) and gammaGT (360 % males
only) levels were reported in animals 37.5 mg kg -1 d -1 . An
increase in ALT levels (350 % males only) at 12.5 mg kg -1 d -1
was also reported. Serum concentrations of cholesterol were elevated
in animals receiving 12.5 mg kg -1 d -1 (20 % and 23 % males and
females respectively) and 37.5 mg kg -1 d -1 (132 %* and 89 %
males and females respectively). The serum concentration of triglycerides
were elevated in females only (63 % and 59 % at 12.5 mg kg -1
d -1 and 37.5 mg kg -1 d -1 respectively). Elevated BUN (males
only 114 %) and creatanine levels were reported (77 %* and 22
%* males and females respectively) at 37.5 mg kg -1 d -1 . One
male receiving 12.5 mg kg -1 d -1 was also reported to have elevated
BUN and creatanine levels (*statistically significant)...
Ref: January
2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The Health and Safety Executive Biocides
& Pesticides Assessment Unit, Magdalen House, Stanley Precinct
Bootle Merseyside L20 3QZ Available from: Department for Environment,
Food and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Bone
(click
on for all fluorinated pesticides)
--
In the chronic
studies, the most consistent findings were cranial
osteosclerosis in the rat, and findings consistent with
fluorosis in a 2-year mouse study.
Clinical chemistry findings with supportive histopathology were
observed in a 1-year study in the dog which were indicative of
renal and liver damage. A detailed assessment of cranial
osteosclerosis was performed in a 2-year study in the rat;
a LOEL was established at 10-14 mg kg -1 d -1 . There was a clear
increase in the incidence of cranial osteosclerosis
in the low- and middle-dose groups, with almost all animals affected
at the top dose. These findings are likely to be secondary
to fluorosis in these animals. In terms of interspecies comparisons,
in a mouse 2-year study, thickening of both
the appositional bone of the cranial vault and nasal turbinates,
and tooth alveolitis were observed at the top dose of 1,731-1,873
mg kg -1 d -1 . These findings are also considered to be a secondary
consequence of fluorosis in these
animals. No evidence of fluorosis was observed in the dog studies.
. In this study a NOAEL of 2.5 mg kg -1 d -1 was established with
nephropathy reported at 12.5 mg kg -1 d -1 .
-- It is considered that cranial osteosclerosis
is likely to represent a fluoride mediated perturbation of bone
metabolism but is not considered to be of concern for human health.
It is also considered that the observed
renal and liver damage is of concern to human health. For professional
operators the ACP considered that the most appropriate
NOAEL to use in risk assessments was the figure of 2.5 mg kg -1
d -1 taken from the one year dog study. Professional operators
would not be expected to use products for prolonged periods, therefore
a value from a one year study would be suitable. The other reported
end points (thyroid tumours and osteosclerosis
were associated with chronic exposure and much higher doses. Acceptable
risk assessments would require a safety margin of about 100 over
the NOAEL 2.5 mg kg -1 d -1 . Consequently these would also offer
a high margin of safety against the longer term end points.
-- One-year Study. A repeat-exposure study using Beagles (4/dose/sex)
is available; it was GLP and OECD Annex V compliant. Animals were
administered either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1
d -1 of dichlofluanid (90 % purity) in capsule form for one year.
The top dose was reduced at week 15 to 37.5 mg kg -1 d -1 because
of excessive toxicity. As a NOEL could not be established with
the initial dosing regime, a subsequent study was carried out
in which 0 or 1.25 mg kg -1 d -1 dichlofluanid was used... The
pathology report on the interim kills revealed "a
whitish hardening" of the cranium (still present at study termination).
At the interim kill, the absolute heart weight was significantly
decreased in both sexes at the top dose only (18 % and 14 % males
and females respectively). The increases in relative liver weight
in both sexes, and relative kidney and brain weight in females,
reported at 4500 ppm reflected the previously noted decreases
in body weight. In males at study termination the absolute organ
weights of the kidney (5 %) and testes (5.6 %) were significantly
increased at the top dose. At study termination the relative testes
weight was increased in the top-dose group (18 %). The reported
increases in relative organ weights reflected the decreases in
body weights noted earlier. Histopathology of the satellite groups
revealed a dose-dependent increase in cranial
osteosclerosis in females, achieving statistical significance
in the middle (8/10) and top-dose groups (9/10) when compared
to control animals (1/10). In males
however a significant increase in cranial osteosclerosis was only
found in the low- (7/10) and top-dose groups (9/10); control (1/10).
An increase in cranial lamellar growth patterns was also reported
in males at the top dose (7/10, and controls 0/10). The
forestomachs of males from the top-dose group were found to have
a higher incidence of hyperkeratosis and acanthosis (0/10 and
5/10 controls and 4500 ppm respectively). The thyroids of males
exhibited follicular cell hypertrophy; 0/50 (control), 2/10 (180
ppm), 1/10 (900 ppm) and 3/10 (4500 ppm). Histopathology of the
main groups (24 months) revealed a significant increase in hyperkeratosis
and acanthosis of the forestomach in males (2/49 and 21/49 controls
and 4500 ppm respectively) and females (0/49 and 12/49 controls
and 4500 ppm respectively). A significant
increase in the incidence of cranial osteosclerosis was apparent
in males of all treatment groups and in females at the top dose.
These data also suggest an increase in severity with increasing
dose. See Table 3.10. A significant
decrease in sternal chondrodystrophy reported in females
of the top-dose group. A significant increase
in cranial lamellar growth patterns was reported in both
sexes at the top dose (45/49 and 37/50 males and females respectively)
compared to the controls (1/49 and 0/50 males and females respectively)...
[Unpublished, 1993(b)]
Dichlofluanid:
Table
3.9 : Fluoride Content Of Bones And Teeth At Study Termination |
males |
site |
0 ppm |
180
ppm |
900
ppm |
4500
ppm |
teeth* |
0.12 |
0.27 |
1.17 |
3.92 |
bones* |
0.43 |
0.97 |
2.91 |
13 |
females |
site |
0 ppm |
180
ppm |
900
ppm |
4500
ppm |
teeth* |
0.11 |
0.32 |
1.12 |
5.36 |
bones* |
0.66 |
1.44 |
3.53 |
11.46 |
*
mg fluoride/g ash |
Dichlofluanid:
Table
3.10 : Incidence And Severity Of Cranial Osteosclerosis |
|
males
(dose ppm) |
females
(dose ppm) |
grade |
0 |
180 |
900 |
4500 |
0 |
180 |
900 |
4500 |
minimal |
0 |
6 |
4 |
0 |
12 |
1 |
1 |
1 |
slight |
11 |
14 |
24 |
4 |
0 |
7 |
13 |
8 |
moderate |
0 |
11 |
6 |
18 |
0 |
10 |
2 |
22 |
marked |
0 |
3 |
0 |
26 |
0 |
2 |
0 |
9 |
severe |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
6 |
total |
11 |
34* |
34* |
49* |
12 |
20 |
16 |
46* |
*
statistically significant |
Dichlofluanid:
Table
3.12 : Incidence Of Skull And Nasal Turbinate Thickness And
Tooth Alveolitis Reported On Necropsy |
|
numbers |
|
controls |
5000
ppm |
pathology |
males |
females |
males |
females |
skull
thickness |
0/45 |
0/46 |
39/42 |
40/40 |
turbinate
thickness |
0/45 |
0/46 |
23/42 |
35/40 |
tooth
alveolitis |
0/45 |
1/46 |
17/42 |
19/40 |
The
fluoride content of teeth and bone was found to be significantly
increased at all doses and time points for both sexes. See Table
3.13.
Dichlofluanid:
Table
3.13 : Fluoride Content of Bones and Teeth (mg g -1 ash) |
|
teeth |
bone |
|
week
53 |
week
104 |
week
53 |
week
104 |
dose |
male |
female |
male |
female |
male |
female |
male |
female |
0 |
0.4 |
0.4 |
0.2 |
0.3 |
1.1 |
0.9 |
1.1 |
1.2 |
200 |
0.7 |
0.6 |
0.7 |
0.8 |
2.4 |
1.5 |
3.6 |
2.9 |
1000 |
2.2 |
2.1 |
2.4 |
2.2 |
6 |
4.3 |
8.3 |
7.3 |
5000 |
10.9 |
9.9 |
15.7 |
13.8 |
17.4 |
14.5 |
18.7 |
17.5 |
Ref:
January 2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The Health and Safety Executive Biocides
& Pesticides Assessment Unit, Magdalen House, Stanley Precinct
Bootle Merseyside L20 3QZ Available from: Department for Environment,
Food and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Brain
(click
on for all fluorinated pesticides)
-- Mouse Carcinogenicity
Study A 2-year OECD-compliant carcinogenicity study carried out
to GLP is available. Animals (SPF mice B63CF1 60 sex/group) received
dietary administration of either 0, 200, 1000 or 5000 ppm dichlofluanid
(89-93 % purity); equivalent to 50.1, 273.9 or 1731.3 and 63.7,
337 or 1872.7 mg kg -1 d -1 in females and males respectively.
The scheduled study termination was after 104 weeks, with an interim
kill at 52 weeks; all animals were necropsied plus any dying or
sacrificed intercurrently... There were effects on both the relative
and absolute organ weights. The following absolute organ weights
were reduced : brain (5 % males and 6 %
females), spleen (14 % females), and kidney (18 % females)
at the top dose.
-- There were effects on both the relative and absolute organ
weights. In males, at the top dose, there were significant
decreases in the absolute organ weights of the lung (20
%), brain (8 %) and testes (6 %).
In females at the top dose there were significant decreases in
the absolute organ weights of the brain
(8 %), spleen (42 %) and kidney (18 %). The relative organ
weights of the brain (13 %), liver
(44 %), spleen (36 %) and testes (5 %) were increased in males
at the top dose. In females the relative brain
(7 %) and liver (47 %) weights were increased and the kidney
(6 %) and ovary weights (28 %) were decreased. No incidences of
toxicologically significant histopathology (liver included) were
reported.
Ref:
January 2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The Health and Safety Executive Biocides
& Pesticides Assessment Unit, Magdalen House, Stanley Precinct
Bootle Merseyside L20 3QZ Available from: Department for Environment,
Food and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Carginogenic
(click
on for all fluorinated pesticides)
PubMed abstract: Seven
different endpoints for detection of genotoxicity
have been used to demonstrate the DNA-altering properties
of Dichlofluanid, a fungicide commonly used in viticulture pest
control. Each endpoint (DNA synthesis inhibition test, alkaline
viscosimetry, umu-test, alkaline filter elution, FADU-test, 32P-postlabeling,
and electron microscopy) shows clear evidence of genotoxicity.
These data indicate that application of
the fungicide dichlofluanid may be mutagenic and/or carcinogenic
for exposed humans.
Ref: Environ Mol Mutagen 1991;17(1):20-6.
Genotoxicity
of the fungicide dichlofluanid in seven assays; by Heil J,
Reifferscheid G, Hellmich D, Hergenroder M, Zahn RK.
Endocrine:
Ovary (click
on for all fluorinated pesticides)
-- Two-year Study.
The following study is considered to be flawed due to the lack
of histopathological evaluation and it was not GLP compliant.
Beagles (4/sex/group) received dietary administration of either
0, 100, 300, 1000 or 3000 ppm dichlofluanid (90 % purity); equivalent
to 3.6, 10.5, 34 and 107 mg kg -1 d -1 (males) and 3.4, 11, 34
and 101.4 mg kg -1 d -1 (females) respectively,
for a two year study period... Absolute organ weights in males
of the liver, lung, spleen, kidneys, adrenals, pancreas and heart
were all decreased at 3000 ppm; the greatest being a 35 % decrease
in testes weight. Decreases in relative organ weights were reported
in males in the thyroid, heart, spleen and testes (20 % at 3000
ppm) at the top dose. The relative kidney and liver weights were
elevated at both 1000 (21 and 3.4 %) and 3000 ppm (18 and 10 %).
In females absolute organ weights were reduced : the thyroid in
all treatment groups, by 32-36 %; ovaries 31-55 % from 100 ppm;
and heart by 14-27 % at 1000 and 3000 ppm. The absolute spleen
weights were raised in females at 1000 ppm and above by
18-20 %. In females there was a slight increase in the relative
organ weights of the pancreas above 1000 ppm and spleen weight
was elevated by 25 and 60 % at 1000 and 3000 ppm. A decrease
in ovary weight was reported at all doses (55 % at 3000 ppm).
The changes in organ weight in females preclude the setting of
a NOEL. [Unpublished, 1969]
Ref:
January 2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The Health and Safety Executive Biocides
& Pesticides Assessment Unit, Magdalen House, Stanley Precinct
Bootle Merseyside L20 3QZ Available from: Department for Environment,
Food and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
PubMed Abstract: Two
types of reactions were observed on the alteration of Drosophila
vitellogenesis [established
biomarker for estrogen action] by the four fungicides
used in this study. Dithane M45 resulted in stimulation associated
with egg retention. However, the other three fungicides (Benlate,
Bouillie bordelaise and Euparene) resulted in inhibition to a
varying degree. Although the inhibition was comparatively limited
due to Benlate it induced an egg retention. The inhibition was
very high due to Bouillie bordelaise and Euparene [dichlofluanid].
With Bouillie bordelaise an egg retention occured together with
the reduction of vitellogenesis and
caused an increase in the rate of the follicle resorption. The
latter depended on the duration of treatment. With
Euparene [dichlofluanid], no egg retention was observed and the
toxicity was only noticed on vitellogenesis.
Ref: J Environ Sci Health B 1997 May;32(3):411-28.
[Ovarian activity of Drosophila melanogaster Meigen (Diptera),
during a chronic intoxication with four fungicides: anatomical
and cytological study] [Article in French] by Marchal-Segault
D, Lauge G.
Dichlofluanide has
been reported as a hormonal active substance
in the environment in a review of the German Umweltbundesambt
(Schramm et al., 1996). However, a concentration range for which
this "hormonal activity" was found, was not reported
(page 44). [Schramm K.-w., thumm W. * Kettrup A. (1996). Hormonal
active substances in the environment: exposition, impact and detection.
Expert Round. Endocrinically active chemicals in the environment.
UBA Texte 3/96. Umweltbundesamt, Germay.]
Ref: RIVM report 601506005. BIOCIDES (II).
Refined aquatic environmental risk assessment of 28 priority biocides.
B.J.W.G. Mensink. November 2000. RIVM = Rijksinstituut voor Volksgezondheid
en Milieu. National Institute of Public Health and the Environment.
http://www.rivm.nl/bibliotheek/rapporten/601506005.pdf
Endocrine-
Pituitary
(click
on for all fluorinated pesticides)
-- One-year Study A
repeat-exposure study using Beagles (4/dose/sex) is available;
it was GLP and OECD Annex V compliant. Animals were administered
either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid
(90 % purity) in capsule form for one year. The top dose was reduced
at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity...
The pituitary glands of several animals
from the top-dose group were found to have mild to severe hyperplasia
(2 males and 2 females) of large pale staining cells (basophils)
in the pars distailis, among pituitary basophils are the thyrotrophs.
Testicular degeneration was noted in 2 animals receiving 37.5
mg kg -1 d -1 , the lesion was widespread and of moderate/severe
grade. Thymic atrophy was also reported in males receiving 37.5
mg kg -1 d -1 (3/4 animals).
-- Rat Two-Year Combined Chronic Toxicity And Carcinogenicity
Study A 2-year combined chronic toxicity and carcinogenicity study
is available. This study was carried out to EPA guidelines and
was both GLP and Annex V compliant. Wistar rats (BOR:WISW strain,
50 group/sex, plus 10/sex group interim kill) received dietary
administration of either 0, 180, 900 or 4500 ppm dichlofluanid
(89-93 % purity). This was equivalent to 9.4, 54.4 or 301.3 mg
kg -1 d -1 and 13.5, 73.1 or 420.7 mg kg -1 d -1 for males and
females respectively. Those animals scheduled as interim kills
were sacrificed after 53 weeks and study termination was scheduled
for 106 weeks. Interim blood samples were taken at weeks 26, 53
and 79 for clinical chemistry and haematology. Urinalysis was
also carried out at these time points. Deaths were reported in
both the satellite and main groups. In the main study the terminal
mortalities were 12 %, 18 %, 30 % and 16 % at 0, 180, 900 and
4500 ppm in males and 26 %, 26 %, 22 % and 20 % at 0, 180, 900
and 4500 ppm in females.... No treatment-related neoplastic alterations
were reported in the satellite group. Tumours found were a malignant
lymphoma (male 4500 ppm), a malignant fibrosarcoma of the skin
(male 4500 ppm) and a benign pituitary adenoma
(female 180 ppm). In the main group, treatment-related
tumours of the thyroid were noted.
Ref: January 2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The Health and Safety Executive Biocides
& Pesticides Assessment Unit, Magdalen House, Stanley Precinct
Bootle Merseyside L20 3QZ Available from: Department for Environment,
Food and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Endocrine:
Suspected Disruptor (click
on for all fluorinated pesticides)
Dichlofluanide
has been reported as a
hormonal active substance in the environment in
a review of the German Umweltbundesambt (Schramm et al., 1996).
However, a concentration range for which this "hormonal activity"
was found, was not reported (page 44).
[Schramm K.-w., thumm W. * Kettrup A. (1996).
Hormonal active substances in the environment: exposition, impact
and detection. Expert Round. Endocrinically active chemicals in
the environment. UBA Texte 3/96. Umweltbundesamt, Germay.]
Ref: RIVM report 601506005. BIOCIDES (II).
Refined aquatic environmental risk assessment of 28 priority biocides.
B.J.W.G. Mensink. November 2000. RIVM = Rijksinstituut voor Volksgezondheid
en Milieu. National Institute of Public Health and the Environment.
http://www.rivm.nl/bibliotheek/rapporten/601506005.pdf
Endocrine:
Testicular
(click on for all fluorinated
pesticides)
-- One-year Study.
A repeat-exposure study using Beagles (4/dose/sex) is available;
it was GLP and OECD Annex V compliant. Animals were administered
either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid
(90 % purity) in capsule form for one year. The top dose was reduced
at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity.
As a NOEL could not be established with the initial dosing regime,
a subsequent study was carried out in which 0 or 1.25 mg kg -1
d -1 dichlofluanid was used... There were also non-significant
decreases in both absolute and relative
thyroid weights (39 % and 33 % respectively) and testes
weights (25 % and 15 % respectively). Two animals were
found to have bilateral testicular degeneration;
no control animals were reported with bilateral
testicular degeneration. In females absolute (15-60 %)
and relative (25-150 %) ovary weights were
increased in all treatment groups. These increases were not dose
related or statistically significant...
Minimal to severe thyroid follicular cell degeneration was reported
in all animals from the top-dose group and one male from the middle-dose
group. The pituitary glands of several animals from the top-dose
group were found to have mild to severe hyperplasia (2 males and
2 females) of large pale staining cells (basophils) in the pars
distailis, among pituitary basophils are the thyrotrophs.
Testicular degeneration was noted
in 2 animals receiving 37.5 mg kg -1 d -1 , the lesion was widespread
and of moderate/severe grade. Thymic atrophy
was also reported in males receiving 37.5 mg kg -1 d -1
(3/4 animals). In the second study (0 or 1.25 mg kg -1 d -1 ),
no obvious treatment-related effects were reported in the clinical
chemistry, haematology or urinalysis parameters measured. At necropsy
the following findings were reported. Both absolute and relative
testes weights were decreased (29 % and
25 % respectively). However in the absence of a dose response
(when compared to the higher doses used in the first study), and
as the weights were within the range of historical control values,
this observation was not thought to be of toxicological significance.
No statistically significant treatment-related organ weight changes
were reported in females. Inspection of the data revealed absolute
and relative ovary weight increases (60
% and 175 % respectively). The large SD values and small
numbers make it difficult to assess the significance of these
data. One incidence of testicular degeneration
was reported at necropsy in both control and treated animals.
Overall the ACP concluded that the ovarian
weight increases were not relevant and that a NOAEL of
2.5 mg kg -1 d -1 could be determined from these studies. [Unpublished,
1992] ... In males at study termination the absolute organ weights
of the kidney (5 %) and testes (5.6 %) were
significantly increased at the top dose. At study termination
the relative testes weight was increased
in the top-dose group (18 %)...
-- Two-year Study. The following study is considered to be flawed
due to the lack of histopathological evaluation and it was not
GLP compliant. Beagles (4/sex/group) received dietary administration
of either 0, 100, 300, 1000 or 3000 ppm dichlofluanid (90 % purity);
equivalent to 3.6, 10.5, 34 and 107 mg kg -1 d -1 (males) and
3.4, 11, 34 and 101.4 mg kg -1 d -1 (females) respectively, for
a two year study period... Absolute organ weights in males of
the liver, lung, spleen, kidneys, adrenals, pancreas and heart
were all decreased at 3000 ppm; the greatest
being a 35 % decrease in testes weight. Decreases in relative
organ weights were reported in males in the
thyroid, heart, spleen and testes
(20 % at 3000 ppm) at the top dose. The relative kidney and liver
weights were elevated at both 1000 (21 and 3.4 %) and 3000 ppm
(18 and 10 %). In females absolute organ weights were reduced
: the thyroid in all treatment groups, by
32-36 %; ovaries 31-55 % from 100 ppm;
and heart by 14-27 % at 1000 and 3000 ppm. The absolute spleen
weights were raised in females at 1000 ppm and above by 18-20
%. In females there was a slight increase in the relative organ
weights of the pancreas above 1000 ppm and spleen weight was elevated
by 25 and 60 % at 1000 and 3000 ppm. A decrease in ovary weight
was reported at all doses (55 % at 3000 ppm). The changes in organ
weight in females preclude the setting of a NOEL. [Unpublished,
1969]
-- -- Dichlofluanid (unspecified purity) was given by gavage
at 200 mg kg -1 in DMSO (4 or 5 animals). Autoradiography of 3
H-thymidine labeled samples was used to measure
testicular DNA synthesis. Dichlofluanid was reported to
cause a statistically significant decrease in the incorporation
of 3 H-thymidine into DNA and was therefore positive. [Unpublished,
1977]
Ref:
January 2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The Health and Safety Executive Biocides
& Pesticides Assessment Unit, Magdalen House, Stanley Precinct
Bootle Merseyside L20 3QZ Available from: Department for Environment,
Food and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Endocrine:
Thyroid
(click on for
all fluorinated pesticides)
-- Professional
operators would not be expected to use products for prolonged
periods, therefore a value from a one year study would be suitable.
The other reported end points (thyroid tumours
and osteosclerosis) were associated with chronic exposure and
much higher doses. Acceptable risk assessments would require a
safety margin of about 100 over the NOAEL 2.5 mg kg -1 d -1 .
Consequently these would also offer a high margin of safety against
the longer term end points.
-- Carcinogenicity - The only carcinogenicity data relate to the
oral route of exposure, with studies performed in the rat and
mouse. No evidence of carcinogenic potential was observed in the
mouse. However, in the rat dichlofluanid was found to cause an
increase in the incidence of thyroid follicular
cell tumours at the highest dose level of 300-420 mg kg
-1 d -1 . These tumours occurred at a single site, were of late
onset and generally benign pathology. Dichlofluanid has been thoroughly
examined for genotoxic potential and the available data indicate
that dichlofluanid was not an in vivo somatic cell or germ cell
mutagen. The results of the histopathological examination of the
thyroid follicular cell tumours are consistent with a non-genotoxic
aetiology. Overall, it can be concluded that dichlofluanid is
a non-genotoxic rat thyroid follicular cell
carcinogen.
-- Dichlofluanid was found to cause an increase in the incidence
of thyroid tumours at highest dose
level of 300-420 mg kg -1 d -1 . These tumours occurred at a single
site, were of late onset and generally benign pathology. These
pathology findings are indicative of a non-genotoxic aetiology,
consistent with the overall conclusions from the genotoxicity
studies. Rat thyroid tumours arise
as a secondary consequence of perturbations in thyroid hormone
homeostasis, leading to prolonged stimulation of the thyroid gland
via a positive feedback mechanism. Interspecies comparisons of
the relative sensitivities of thyroid hormone homeostasis to disturbance
by xenobiotics have shown that humans are markedly less sensitive
than rats. Overall, the ACP considered that the rat thyroid follicular
tumours would not be relevant to human health if they were due
to treatment-related hormone imbalance. However it concluded that
the in vitro studies did not convincingly demonstrate inhibition
of thyroid peroxidase. Whilst it seemed probable that the mechanism
was non-genotoxic, a more convincing explanation of the mechanism
was required.
-- One-year Study. A repeat-exposure study using Beagles (4/dose/sex)
is available; it was GLP and OECD Annex V compliant. Animals were
administered either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1
d -1 of dichlofluanid (90 % purity) in capsule form for one year.
The top dose was reduced at week 15 to 37.5 mg kg -1 d -1 because
of excessive toxicity. As a NOEL could not be established with
the initial dosing regime, a subsequent study was carried out
in which 0 or 1.25 mg kg -1 d -1 dichlofluanid was used... Levels
of the thyroid hormones T3 (28 %) and T4
(37 %) were elevated at study termination in animals receiving
37.5 mg kg -1 d -1 . At necropsy, treatment-related pathology
findings were reported in males receiving 37.5 mg kg -1 d -1 .
Externally one animal was pale with discoloration of the kidney,
liver and thyroid which was also
reduced in size. There were also non-significant decreases in
both absolute and relative thyroid weights
(39 % and 33 % respectively) and testes
weights (25 % and 15 % respectively). Two animals were found to
have bilateral testicular degeneration; no control animals were
reported with bilateral testicular degeneration. In females absolute
(15-60 %) and relative (25-150 %) ovary weights were increased
in all treatment groups. These increases were not dose related
or statistically significant... Minimal
to severe thyroid follicular cell degeneration was reported
in all animals from the top-dose group and one male from the middle-dose
group. The pituitary glands of several animals
from the top-dose group were found to have mild to severe hyperplasia
(2 males and 2 females) of large pale staining cells (basophils)
in the pars distailis, among pituitary basophils are the thyrotrophs...
The thyroids of males exhibited follicular
cell hypertrophy; 0/50 (control), 2/10 (180 ppm), 1/10
(900 ppm) and 3/10 (4500 ppm)... In the thyroid
gland a statistically significant increase in the lesion described
as a focal follicular growth anomaly was established in
both sexes at the top dose. In males the following data were presented
: 1/50 (controls); 1/50 (180 ppm); 2/50 (900 ppm); and 3/49 (4500
ppm) and in females the data were : 0/50 (controls); 0/50 (180
ppm); 2/50 (900 ppm); and 4/49 (4500 ppm)... Two females sacrificed
in extremis were found to have thyroid follicular
cell carcinoma; one animal from each of the middle- and
top-dose groups. No statistically significant neoplastic events
were reported. However, a significant trend
in the distribution of thyroid adenomas was found in both sexes.
A NOEL could not be set due to the effects of excess fluoride
and cranial osteosclerosis at the lowest dose. The NOEL for neoplasms
could be set at 900 ppm (equivalent to 54.4 and 73.1 mg kg -1
d -1 for males and females respectively) due to the increase in
thyroid tumours seen at the top dose.
[Unpublished, 1993(b)]
Table
3.19 : Thyroid Hormone Levels
During The Study |
|
T3
(ng 100 ml -1 ) |
T4
(mg 100 ml -1 ) |
day |
0 |
4500
ppm |
% |
0 |
4500
ppm |
% |
7 |
55.2 |
45.7 |
-17.3 |
3.9 |
2.6 |
-32 |
21 |
52.9 |
45.3 |
14.5 |
4.2 |
3.5 |
-16 |
63 |
67.6 |
61.8 |
-8.7 |
5.7 |
5.1 |
-11.5 |
Table
3.20 : Thyroid Weights At Day
7 |
dose
ppm |
control |
150 |
500 |
1500 |
4500 |
weight
mg |
10 |
14 |
13 |
15 |
16 |
% increase |
- |
40 |
30 |
50 |
60 |
Ref:
January 2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The Health and Safety Executive Biocides
& Pesticides Assessment Unit, Magdalen House, Stanley Precinct
Bootle Merseyside L20 3QZ Available from: Department for Environment,
Food and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
In July 1998, discussing
this pesticide because it was an Accession Treaty priority for
A, the CMR Group agreed to classify it with Xn; R20 : Xi; R36
: R43 : N; R50-53. Symbols Xn and N. R-phrases 20-36-43-50/53.
S-phrases (2-)24-37-60-61. The proposal was sent to DG XI and
included in the 25th ATP. Regarding carcinogenicity, S argued
that the evidence was too weak for classification; tumour findings
were limited to high dose groups. B expressed doubts about the
aetiology of the rat thyroid tumours and, in relation to this,
UK noted that dichlofluanid was an inhibitor
of thyroid peroxidase. As the carcinogenicity issue was
not problematic under the Accession Treaty, the Group agreed to
conclude the present discussion with no classification for carcinogenicity.
However, dichlofluanid would be referred back to the Pesticides
Group for further consideration of carcinogenicity classification.
A explained that the thyroid tumours seen in rats were limited
to high dose groups and suggested classification with Carc Cat
3; R40. A also noted cranial effects in rodents that justify R48/22.
B, with support from IRL, P and E, considered the mechanism of
tumour induction to involve liver enzyme induction which did not
justify classification for carcino-genicity because it was not-relevant
to humans. UK noted, however, data suggesting
inhibition of thyroid peroxidase which would justify classification.
The Group agreed that more information was required from Industry
on these issues. A and UK offered to send their interpretation
of the data made available by Ind.
Ref: EUROPEAN COMMISSION DIRECTORATE GENERAL
JRC JOINT RESEARCH CENTRE Institute for Health and Consumer Protection
Unit: Toxicology and Chemical Substances European Chemicals Bureau
ECBI/12/99 Rev. 1 31.03.1999 SUMMARY RECORD Meeting of the Commission
Working Group on the Classification and Labelling of Dangerous
Substances Pesticides ECB Ispra, 18-20 November 1998
Genotoxic
/ Potent Cytoxicant
(click on for all fluorinated
pesticides)
Abstract:
The cytotoxicity
and lipid peroxidation of pesticides containing a halogen group
were examined in isolated rat hepatocytes. We examined 9 pesticides
of 3 different representative chemical families... The contents
of the hydroperoxides in phospholipid, phosphatidylcholine hydroperoxide
(PCOOH) and phosphatidylethanolamine hydroperoxide (PEOOH) were
determined by the HPLC-chemiluminescence (CL-HPLC) method, which
is sensitive and specific for lipid hydroperoxide. Chlorothalonil,
dichlofluanid and captan were
the most potent cytotoxicants evaluated by lactate dehydrogenase
(LDH) leakage. PCP, NIP and CNP exhibited intermediate
cytotoxicity. PCNB, fthalide and chlomethoxynil showed low cytotoxicity.
The cellular phospholipid hydroperoxide
(PCOOH and PEOOH) levels were remarkably increased by chlorothalonil
(PCOOH, 23 times and PEOOH, 7 times), dichlofluanid
(PCOOH, 523 times and PEOOH, 22 times) and captan (PCOOH,
518 times and PEOOH, 16 times) as compared with the control group.
The PCOOH content was slightly increased by PCP (4.8 times) and
NIP (6.3 times), whereas the other 4 pesticides did not change
the phospholipid hydroperoxide level. Severe
cytotoxicity was observed with a remarkable increase of phospholipid
hydroperoxide by
chlorothalonil, dichlofluanid and
captan.
Ref: Biol Pharm Bull 1997 Mar;20(3):271-4.
Cytotoxicity
of organochlorine pesticides and lipid peroxidation in isolated
rat hepatocytes; by Suzuki T, Komatsu M, Isono H.
Abstract:
Seven different endpoints for detection of genotoxicity have been
used to demonstrate the DNA-altering properties of Dichlofluanid,
a fungicide commonly used in viticulture pest control. Each endpoint
(DNA synthesis inhibition test, alkaline viscosimetry, umu-test,
alkaline filter elution, FADU-test, 32P-postlabeling, and electron
microscopy) shows clear evidence of genotoxicity.
These data indicate that application of the fungicide dichlofluanid
may be mutagenic and/or carcinogenic for exposed humans.
Ref: Environ Mol Mutagen 1991;17(1):20-6.
Genotoxicity
of the fungicide dichlofluanid in seven assays; by
Heil J, Reifferscheid G, Hellmich D, Hergenroder M, Zahn RK.
Kidney
(click on for all fluorinated
pesticides)
--
In the chronic
studies, the most consistent findings were
cranial osteosclerosis in the rat, and findings consistent with
fluorosis in a 2-year mouse study. Clinical chemistry findings
with supportive histopathology were observed in a 1-year study
in the dog which were indicative of
renal and liver damage.
A detailed assessment of cranial osteosclerosis
was performed in a 2-year study in the rat; a LOEL was
established at 10-14 mg kg -1 d -1..
-- A detailed assessment of cranial osteosclerosis was performed
in a rat 2-year study (summarised in section 3.3.5.1) in which
a LOEL was established at 10-14 mg kg -1 d -1 . A clear increase
in the incidence of cranial osteosclerosis was observed in the
low- and middle-dose groups, with almost all animals affected
at the top dose. These findings are likely to be secondary to
fluorosis in these animals. In terms of interspecies comparisons,
in a mouse 2- year study, thickening of both the appositional
bone of the cranial vault and nasal turbinates, and tooth alveolitis
were observed at the top dose of 1,731-1,873 mg kg -1 d -1 . These
findings are also considered to be a secondary consequence of
fluorosis in these animals. No evidence of fluorosis was observed
in the dog studies. It is considered that these findings are likely
to represent a fluoride mediated perturbation of bone metabolism
but are not considered to be of concern for human health.
It is considered that the observed liver and renal damage is of
concern to human health.
-- In a 1-year dog study clinical chemistry findings with supportive
histopathology, indicative of nephrotoxicity
and liver damage, were observed. In this study a NOAEL
of 2.5 mg kg -1 d -1 was established.
-- Two-year Study The following study is considered to be flawed
due to the lack of histopathological evaluation and it was not
GLP compliant. Beagles (4/sex/group) received dietary administration
of either 0, 100, 300, 1000 or 3000 ppm dichlofluanid (90 % purity);
equivalent to 3.6, 10.5, 34 and 107 mg kg -1 d -1 (males) and
3.4, 11, 34 and 101.4 mg kg -1 d -1 (females) respectively, for
a two year study period. Interim blood sampling was carried out
at 6 weeks, 6 months and 12 months for haematology, with interim
clinical chemistry analysis being performed at 12 months... Changes
reported in clinical chemistry parameters at 3000 ppm including
increased ALP, ALT, bilirubin, cholesterol levels and BSP retention
time, indicative of impaired hepatic function...
Against a background of variable data, increases in serum creatinine
(27 % males and 33 % females, at 3000 ppm) and urea levels (34
% males and 50 % females, at 3000 ppm) were reported, this being
suggestive of impaired renal function.
Direct measurements of kidney function at study termination revealed
a decrease in both p-aminohippuric acid (PAH) and inulin clearance;
(5 and 17 %) in males and (19 and 32 %) females at 24 months at
3000 ppm. These data provide further evidence for impaired
renal function... The relative kidney and liver weights
were elevated at both 1000 (21 and 3.4 %) and 3000 ppm (18 and
10 %).
Ref:
January 2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The Health and Safety Executive Biocides
& Pesticides Assessment Unit, Magdalen House, Stanley Precinct
Bootle Merseyside L20 3QZ Available from: Department for Environment,
Food and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Liver
(click on for all fluorinated
pesticides)
--
In the chronic
studies, the most consistent findings were
cranial osteosclerosis in the rat, and findings consistent with
fluorosis in a 2-year mouse study. Clinical chemistry findings
with supportive histopathology were observed in a 1-year study
in the dog which were indicative of
renal and liver damage. A
detailed assessment of cranial osteosclerosis
was performed in a 2-year study in the rat; a LOEL was
established at 10-14 mg kg -1 d -1..
-- A detailed assessment of cranial osteosclerosis was performed
in a rat 2-year study (summarised in section 3.3.5.1) in which
a LOEL was established at 10-14 mg kg -1 d -1 . A clear increase
in the incidence of cranial osteosclerosis was observed in the
low- and middle-dose groups, with almost all animals affected
at the top dose. These findings are likely to be secondary to
fluorosis in these animals. In terms of interspecies comparisons,
in a mouse 2- year study, thickening of both the appositional
bone of the cranial vault and nasal turbinates, and tooth alveolitis
were observed at the top dose of 1,731-1,873 mg kg -1 d -1 . These
findings are also considered to be a secondary consequence of
fluorosis in these animals. No evidence of fluorosis was observed
in the dog studies. It is considered that these findings are likely
to represent a fluoride mediated perturbation of bone metabolism
but are not considered to be of concern for human health.
It is considered that the observed liver and renal damage is of
concern to human health.
-- In a 1-year dog study clinical chemistry findings with supportive
histopathology, indicative of nephrotoxicity
and liver damage, were observed. In this study a NOAEL
of 2.5 mg kg -1 d -1 was established.
Ref:
January 2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The Health and Safety Executive Biocides
& Pesticides Assessment Unit, Magdalen House, Stanley Precinct
Bootle Merseyside L20 3QZ Available from: Department for Environment,
Food and Rural Affairs, Pesticides Safety Directorate, Mallard
House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Contamination
(click
on for all fluorinated pesticides)
Wood preservative ruined 200
homes
By: Christian Ege Jørgensen,
The Danish Ecological Council.
A
wood preservative with the active ingredient dichlofluanid (a
sulfamide fungicide) has created a disaster in Denmark. It was
marketed in Denmark under the retail product name "Rentolin",
and without a warning against indoor uses. (In other EU countries
the product name may be different. We know that some wood preservatives
containing dichlofluanid are marketed as e.g. "Preventol"
and "Flourofolpet").
-- Around 200 people used Rentolin indoors and suffered serious
injury. Many houses are now uninhabitable, and several people
suffer from chronic diseases. Some have the diagnosis of MCS [Multiple
Chemical Sensibility], meaning that they have violent reaction
to all kinds of volatile chemical substances, natural and manmade
as well. The sufferers have now formed a union of "Rentolin-injured"
people, and have sued the importer. However he escaped to the
United States. Experts are not unanimous that the said injuries
were caused by dichlofluanid, but to us it appears to be the most
likely explanation. Danish EPA finds it more probable that the
organic solvent (a kind of white spirit) in Rentolin caused the
disorders. But if so, we find it hard to understand why similar
disorders have not been seen with indoor use of other products
containing organic solvents, such as floor varnishes. The Rentolin
case is probably the worst chemical disaster Denmark has seen
for decades. We have urged the Danish EPA to make a thorough investigation
of the causes, but still this has not been done. Now the same
demand has been raised in the Danish parliament.
According to the EU, dichlofluanid is being used in Ireland, UK,
Luxembourg, Germany, Austria, France, Spain, Portugal, Italy,
and Greece. It is not included in any of the lists for European
re-assessment of active ingredients under 91/414, though. As for
Sweden we know that Rentolin was always marketed with the label
"Only for outdoor use", but we do not know about other countries.
Dichlofluanid is on the EU list of hazardous substances, classified
as an allergen and hazardous to the environment.
We have already informed NGOs in other countries via the EEB chemicals
group and the PAN-Europe (Pesticide Action Network). We recommend
that NGOs investigate whether similar injuries have been found
in other countries. If investigations show that dichlofluanid
caused such disorders a joint call for a ban on the production
and use of dichlofluanid in Europe must be considered.
Ref:
Issue 17, Chemical Awareness (2001)
http://www.chemical-awareness.com/news.php?nid=18&aid=433
Chemical
Awareness is financially supported by the Danish Environmental
Protection Agency, the Swedish National Chemicals Inspectorate
and the Swedish Society for Nature Conservation.
http://www.fluorideaction.org/pesticides/dichlofluanid.denmark.poiso.htm
Environmental
(click
on for all fluorinated pesticides)
Very high toxicity to aquatic
organisms.
Ref: Examples
of substances requiring particular attention. Swedish
National Chemicals Inspectorate in collaboration with the
Swedish Environmental Protection Agency and the Swedish
National Board of Occupational Safety and Health. NATIONAL
CHEMICALS INSPECTORATE. Order No 510 622. Second, revised
edition, 1998.
Dichlofluanid
is toxic to the freshwater algae Scenedesmus subspicatus
which had 96 h EbC50 and ErC50 values of > 1 mg l -1
; this was the highest concentration tested. Dichlofluanid
is toxic to Daphnia magna, with an acute study resulting
in a 48 h EC50 value of 0.42 mg ai l -1 and a NOEC of 0.07
mg l -1 . In a chronic study, Daphnia reproduction was inhibited
by 51.7 % at 0.2 mg ai l -1 . Acute toxicity studies on
the rainbow trout and blue gill sunfish resulted in 96 h
LC50 values of 0.010 and 0.030 mg ai l -1 respectively,
with NOECs of < 0.024 and < 0.0026 mg l -1 for bluegill
sunfish and rainbow trout respectively. A study investigating
the effects of dichlofluanid on carp resulted in a NOEC
of 0.05 mg l -1 ... Although no marine
data were submitted, dichlofluanid was shown to be highly
toxic to aquatic organisms. The species
most sensitive to chronic effects was Daphnia magna, with
a 24 - d NOEC (reduced reproduction) of 40 µg ai l
-1 .
anuary
2003 - Evaluation
on: Booster biocides in antifouling products. Full review
of Dichlofluanid. No. 206. Evaluation of Fully Approved
or Provisionally Approved Products. Prepared by : The Health
and Safety Executive Biocides & Pesticides Assessment Unit,
Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ
Available from: Department for Environment, Food and Rural
Affairs, Pesticides Safety Directorate, Mallard House, Kings
Pool, 3 Peasholme Green, York YO1 7PX, UK.
Organic
booster biocides were recently introduced as alternatives
to organotin compounds in antifouling products, after restrictions
imposed on the use of tributyltin (TBT) in 1987. Replacement
products are generally based on copper metal oxides
and organic biocides. This ban has led to an increase in
alternative coating products containing the above biocides.
The most commonly used biocides in
antifouling paints are: Irgarol 1051, diuron, Sea-nine
211, dichlofluanid, chlorothalonil,
zinc pyrithione, TCMS (2,3,3,6-tetrachloro-4-methylsulfonyl)
pyridine, TCMTB [2-(thiocyanomethylthio) benzothiazole],
and zineb. Since 1993, several studies
have demonstrated the presence of these biocides in European
coastal environment as a result of their increased use.
More recently, the presence of these biocides was also revealed
in waters from Japan, United States, Singapore, Australia
and Bermuda. This paper reviews the currently available
data on the occurrence of these biocides in the aquatic
environment. Some data dealing with the environmental fate,
partitioning, behaviour and risk assessment of antifouling
paint booster biocides are also reported in order to discuss
the detected levels of contamination.
Ref:
Worldwide occurrence and effects of antifouling paint booster
biocides in the aquatic environment: a review. I.
K. Konstantinou, and T. A. Albanis. Environment International;
Volume 30, Issue 2 , April 2004, Pages 235-248.
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