The Minnesota and South
Dakota Departments of Agriculture have requested a quarantine
exemption for the use of flusilazole (Punch 3.3EC) and a flusilazole
+ famoxadone premix (Charisma 1.7 EC) on soybeans to control Asian
soybean rust (Federal
Register, September 21, 2005).
1. EPA should have
presented information in the docket on the available animal studies
conducted with flusilazole for this exemption request. It should
have also included known effects on humans. Without this information,
the public is left uninformed of the potential consequences of
2. Flusilazole, a triazole
(or azole) fungicide, presents too many risks for it to be used
for this exemption request. It may be an endocrine disruptor,
a teratogen, and a carcinogen. It is also persistent in soil.
3. Flutriafol, another
triazole (or azole) pesticide, has also been requested for exemption
use on soybean - please see my comments
submitted to Docket OPP-2005-0243. Can the public expect adverse
effects from flutriafol and flusilazole to be additive when both
are applied to soybean? Will the risks be additive when other
foods treated with triazole pesticides are consumed?
Flusilazole MAY BE AN ENDOCRINE DISRUPTOR.
According to Appendix
One, "Summary of data compiled in support of a Section
18 Emergency Exemption" by DuPont: "In the final two-year
feeding study in the rat, flusilazole was found to induce testicular
adenomas in males... Flusilazole caused reduction in both serum
and testicular testosterone and estradiol.. Flusilazole was
found to be oncogenic at the higher doses, causing bladder transitional
cell neoplasia in both sexes and testicular Leydig cell adenoma
in males (pages 28 and 29)."
Available at http://www.fluorideaction.org/pesticides/flusilazole.appendix1.pdf
According to Trosken
et al. (2004), in vitro data on flusilazole indicate it may
be a potent inhibitor of aromatase.
Reference: Comparative assessment of the inhibition of recombinant
human CYP19 (aromatase) by azoles used in agricultre and as
drugs for humans. Endocrine Research, August; 30(3):387-94.
Abstract at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15554355&query_hl=15
According to a 2002
European Commission report, "Although fish early life-stage
tests provide useful information on sensitive life stages of
fish, for flusilazole in particular the risk assessment has
explicitly identified fish and other aquatic species to be at
risk from agricultural use of this a.s., and there is evidence
that flusilazole may have specific effects on the reproductive
process. Therefore the SCP cannot conclude that a NOEC based
on a fish early life-stage test for a single species is necessarily
adequate in this particular case to ensure sufficient protection
of fish populations from adverse effects on reproduction.
-- The monograph (volume 3, pp. 230-233) identified aquatic
species, and fish in particular, as possibly at risk from flusilazole.
In addition, a dose-dependent decrease in serum estradiol levels
by flusilazole, considered to be indicative of aromatase inhibition,
was observed in studies with rats (volume 3, p. 73). Aromatase
inhibition is significant for reproduction since aromatization
of testosterone is the process by which oestrogen is formed
in vertebrates (Trant et al. 1997). This reaction is mediated
by the cytochrome P450 aromatase. It has been shown that oestrogen
(i.e., oestradiol) plays a major role in the reproductive physilogy
of all vertebrates, including gamete development and maturation,
and induces the hepatic synthesis of the yolk precursor, vitellogenin.
Studies in which fish have been exposed to aromatase inhibitors
suggest that aromatase activity, specificity or expression levels
vary with maturation stage and among species (Bl‡zquez
et al. 2001, Zerulla et al. 2002). ... Neither of the above
tests was designed to investigate possible effects on reproductive
output or mating behaviour of adult fish. Given that there is
evidence that flusilazole is an aromatase inhibitor, there are
specific concerns that reproduction could be adversely affected
by this substance. Therefore potential effects on mating behaviour,
time to sexual maturity, reproductive output and timing, fertilisation
success, and sex ratio of offspring are also of concern and
should be explicitly addressed by a test designed for this purpose.
July 2002 - Opinion of the Scientific Committee on Plants on
specific questions from the Commission concerning the evaluation
of flusilazole in the Council Directive 91/414/EEC. European
Commission. Health & Consumer Protection Directorate-General.
Available at http://www.fluorideaction.org/pesticides/flusilazole.eu.july.2002.pdf
Flusilazole MAY BE A TERATOGEN.
Menegola et al. reported in 2005: Triazole-derivatives alter
the pharyngeal apparatus morphogenesis of rodent embryos cultured
in vitro. The hindbrain segmentation and the rhombencephalic
neural crest cell (NCCs) migration are altered by Fluconazole
exposure in vitro. The aim of the present work is to identify
if a common pathogenic pathway is detectable also for other
molecules of this class of compounds. 9.5 days post coitum (d.p.c.)
old rat embryos were exposed in vitro to the teratogenic concentrations
of Flusilazole, Triadimefon and Triadimenol and cultured for
24, 48 or 60 h. The expression and localisation of Hox-b1 and
Krox-20 proteins (used as markers for hindbrain segmentation)
were evaluated after 24 h of culture. The localisation and distribution
of NCC was evaluated after 24, 30 and 48 h of culture. The morphology
of the embryos was analysed after 48 h, while the branchial
nerve structures were evaluated after 60 h of culture. Hindbrain
segmentation and NCC migration alteration as well as pharyngeal
arch and cranial nerve abnormalities were detected after exposure
of the tested molecules. A common severe
teratogenic intrinsic property for the tested molecules of this
chemical class has been found, acting through alteration of
the normal hindbrain developmental pattern.
Reference: Menegola E, Broccia ML, Di Renzo F, Massa V, Giavini
E (2005). Study on the common teratogenic pathway elicited by
the fungicides triazole-derivatives. Toxicol In Vitro. Sep;19(6):737-48.
Abstract available at:
Massa et al reported
in 2003: abnormalities at the level of the branchial apparatus;
disorganisation and fusions at the level of the cranial nerves;
abnormalities in the migration of NCC, not able to form 3 distinct
migration stripes from the rhomboencephalon to the branchial
apparatus; alteration of the hindbrain segmentation, with reduced
and scattered immunolocalised stripes.
Reference: Mechanisms Involved In Triazole-Induced Teratogenesis:
In Vitro Study. Toxicol Lett 2003 Sep ;144 (Suppl 1 ):S107
in 1990: Pregnant Wistar rats were given single oral dosages
of flusilazole or bitertanol on days 9, 10, 11 or 13th of gestation
(positive vaginal smear=day 1) at levels of 1/5, 1/10 and 1/50
LD50. The dosages were calculated from the reported LD50 values
of 1272 mg/kg for flusilazole and 5000 mg/kg for bitertanol.
The results of the study demonstrated that both compounds induce
congenital anomalies when given on days 9, 10 or 11th at levels
corresponding to 1/5 and 1/10 LD50. The types of the registered
malformations after flusilazole treatment were exophthalmus,
hypognathia, macroglossia and cleft palate and after bitertanol
treatment micro- and acaudia and in rare cases exophthalmus,
hypognathia and cleft palate. A clear dose effect relationship
was established for both compounds.
Reference: Triazoles teratogenicity in rats. Teratology 1990
The Scottish Daily
Record & Sunday Mail Ltd. October 15, 2000, reported: "Parents
believe that exposure to Flusilazol during pregnancy resulted
in severe eye deformities such as microphthalmia (small eyes)
and coloboma, a defect in the structure of the eyes."
Available at - http://www.fluoridealert.org/pesticides/flusilazole.scot.eye.2000.htm
Flusilazole may be
implicated in the rare eye defects found in the Benlate poisoning
incidents in Florida. It has been reported by Jan Hollingsworth
in a December 18, 1995, Tampa Tribune (Florida) news report
that flusilazole was an "undisclosed ingredient in some
lots of Benlate 50 DF." Reference: Fungicide studies offer
little comfort. Memo: buried secrets pursuing a medical mystery.
MAY BE A CARCINOGEN.
-- Flusilazole was
found to exert a clear systemic toxicity on sub-chronic and
chronic administration to rats, mice and dogs. A similar pattern
of effects was apparent across the three species, with the liver,
urinary system and blood system targeted to varying degrees.
It was found to be oncogenic at high dose levels in both mice
and rats, inducing bladder transitional cell neoplasia in rats
and testicular adenoma in male rats and hepatocellular adenomas
and carcinomas in mice. (Page 30)
Reference: DuPont Punch (Active ingredient: Flusilazole) and
DuPont Charisma (Active ingredients: Flusilazole and Famoxadone):
Summary of data compiled in support of a Section 18 Emergency
Exemption request for control of Asian soybean rust on soybeans.
By DuPont authors: Cosgrove T, Czochor L, Dinter A, Jemberg
K, Klemens A, Marcon A, McInnes B, Mullin L, Russell M, Ryan
D, Singles S, Vanderbroeck V. Revision No. 1: February 2, 2005.
Available at: http://www.fluorideaction.org/pesticides/flusilazole.appendix1.pdf
IS PERSISTENT IN SOIL.
Its potential to
leach into groundwater needs clarification. Flutriafol is another
triazole (or azole) pesticide requested for exemption use on
soybean. Flutriafol is extremely persistent and water contamination
(page 51): [Flutriafol] is extremely persistent in soil and
will accumulate following repeated annual applications. Soil
residues also demonstrate the potential to be mobile. Although
the fate and behaviour of flutriafol in water has not been evaluated
and no data are available from natural water monitoring, the
high spray application rate and the use on cereals, indicated
that water contamination is likely.
Reference: Evaluation on: Flutriafol. October 1996. Issue No.
158, UK Department for Environment, Food and Rural Affairs,
Pesticides Safety Directorate, Mallard House, Kings Pool, 3
Peasholme Green, York YO1 7PX.
Available at: http://www.pesticides.gov.uk/PSD_PDFs/Evaluations/158_flutriafol.pdf
Note: This comment
is listed in the Federal Register as Docket