Return
to Tetraconazole Index Page
Activity:
Fungicide
(azole)
Structure:
Adverse Effects:
Amyloidosis
Blood
Body Weight Decrease
Bone
Brain
Cancer: Likely to be
Carcinogenic to Humans - LIVER
Cholesterol
Endocrine: Ovary
Endocrine: Pituitary
Endocrine: Prostate
Endocrine: Testicular
Endocrine:
Thymus
Endocrine:
Thyroid
Endocrine: Uterus
Endocrine: Vaginal
Kidney
Liver
Lung
Reproductive/Developmental
Environmental:
Persistent in soil and water sediment
Moderately
toxic to birds
Highly toxic
to fish, aquatic invertebrates, algae/aquatic plants and sediment
dwelling organisms
Hazardous to bees
Moderately toxic to earthworms
Hazard Characterization (Page
13)
1,2,4-triazole (free triazole)
is a metabolite common to a number of triazole-derivative
pesticides, and is found in both mammalian (rat) and plant
metabolism studies. Although for most
pesticides, mammals convert only a small proportion to free
triazole (less than 25%), two
compounds (tetraconazole and flusilazole)
demonstrate relatively high conversion (68-77%) in rat metabolism
studies. As a plant metabolite, and
given the wide use of triazole-derivative pesticides (used
as fungicides on many crops as well as on turf) free triazole
is found in a variety of food commodities, including animal
byproducts. 1,2,4-triazole appears to be relatively stable
in the environment, and may be found in rotational crops
as well as in water...
Source: Human
Health Aggregate Risk Assessment for Triazole-derivative
Fungicide Compounds (1,2,4-Triazole, Triazole Alanine,
Triazole Acetic Acid). US EPA, February 7, 2006.
|
Amyloidosis
(click
on for all fluorinated pesticides)
Chronic & Carcinogenicity Studies.
Findings in other organs included enlarged cervical lymph nodes
at 800 and 1250 ppm, prominent alveolar macrophages in the lungs
of males at 1250 ppm and females of all treated groups, pneumonitis
in females at 800 and 1250 ppm, involution in the thymus of males
at 1250 ppm, and amyloidosis in various
organs of mainly males at 800 and 1250 ppm. ...Dogs received
0, 22.5, 90 or 360 ppm of tetraconazole in the diet for 1 year.
Histopathology detected apparent hepatocyte enlargement, eosinophilic
inclusions in hepatocytes, centrilobular hepatocyte rarefaction,
or centrilobular fat in the liver at 90 and 360 ppm, and cortical
tubular hypertrophy and apoptotic bodies
in the kidneys at 360 and/or 90 ppm. The NOEL was 22.5
ppm (0.7 mg/kg bw/day). (page 5)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Blood
(click
on for all fluorinated pesticides)
• Chronic & Carcinogenicity Studies.
Dogs received 0, 22.5, 90 or 360 ppm of tetraconazole in the diet
for 1 year. Some dogs of each group including control suffered
body weight loss which was more pronounced at 360 ppm. In dogs
at 360 ppm, prolonged activated partial
thromboplastin times, lower albumin and higher globulin and cholesterol
levels, and increased AP, ALT, gamma glutamyl transferase and
ornithine carbamoyl transferase activities, as well as increased
inorganic phosphorus were observed.
-- Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to
males only) of tetraconazole in the diet for 2 years; Mortality
and body weight gain were lower at 640 and 1280 ppm. Slight
anemia at 640 and erythrocyte counts. (page 5)
• Sub-chronic studies. Rats
received 0, 10, 60 or 360 ppm of tetraconazole in the diet for
13 weeks. Slightly lower AP, ALT and AST,
and slightly higher cholesterol and calcium levels (males) were
observed at 360 ppm, and some of these changes
also occurred at 60 ppm.
-- Mice received 0, 5, 25,
125 or 625 ppm of tetraconazole in the diet for 13 weeks. In males
at 625 ppm and females at 125 and 625 ppm, decreased
BUN was detected, and elevated alanine aminotransferase (ALT)
and AST activities were associated
with increased liver weights. (page 4)
Short Term Studies. Male rats received 0, 2, 5, 15 or 40 ppm of
tetraconazole in the diet for 4 weeks. No treatment-induced changes
were observed except for increased plasma
aspartate aminotransferase (AST) and glutamate dehydrogenase at
40 ppm. (page 4)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
1,2,4-triazole -
Hematological changes, including slightly decreased hemoglobin
and/or hematocrit, have also been seen in multiple studies and
species (in rats at doses of 33 mg/kg/day and above, and in mice
at doses of 487 mg/kg/day and above). Studies depicting the effects
of chronic exposure to free triazole or its conjugates are not
currently available.
Ref: Human
Health Aggregate Risk Assessment for Triazole-derivative Fungicide
Compounds (1,2,4-Triazole, Triazole Alanine, Triazole Acetic
Acid). US EPA, February 7, 2006.
Body
Weight Decrease (click
on for all fluorinated pesticides)
-- Reproductive and
developmental toxicity. A developmental toxicity study with rats
given oral gavage doses of 5, 22.5, and 100 mg/kg/day from days
6 through 15 of gestation resulted in a NOAEL for
maternal toxicity of 5 mg/kg/day based upon bwt reduction,
reduced food intake and post-dose salivation at the two higher
doses, as compared with zero-dose controls. The developmental
NOAEL was 22.5 mg/kg/day. Among the highest
dose group there was evidence of minimal increase in the incidence
of supernumerary ribs among the fetuses.
-- A chronic feeding/carcinogenicity study was conducted with
tetraconazole in Crl:CD-l (ICR)BR mice at dietary levels of 10,
90, 800, and 1,250 ppm for 80 weeks. Treatment-related non-neoplastic
changes were also seen at 1,250 ppm in the
lungs, kidneys, testes, epididymides, ovaries
and bone, particularly the cranium;
a compression of the brain was noted in a number of mice reflecting
the extent of cranial
bone changes and an increased thymic involution was seen in male
mice that died on test. The 1,250 ppm dietary level for tetraconazole,
because of the substantial bwt gain changes
and increased mortality (more in males), appeared to be
above the maximum tolerated dose (MTD). At 800 ppm, there were
increases in non neoplastic changes in lungs, kidneys, testes,
epididymides, ovaries and bone. In addition, there was substantial
reduction in weight gain as compared with zero-dose control
animals, but the mortality
rate was unaffected. Eight hundred ppm appeared to be a reasonable
estimate of the MTD for mouse.
Ref: Federal Register: October 14, 1999.
Notice of Filing Pesticide Petitions to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023,
and 7E4830.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Oct14.1999.htm
Reproduction Study Rats received
0, 10, 70 or 490 ppm of tetraconazole in the diet for two generations.
F0 and F1 females at 490 ppm had reduced food consumption, and
lower body weights during premating
and gestation, as did F1 males of this group. Increased mortality
(due to dystocia) and higher liver, kidney
and ovary weights were seen in adults of both generations at 490
ppm. Mating performance and pregnancy rate for both F0
and F1 generations were not affected. A prolonged
gestation period was associated with dystocia, and total
litter loss in some F0 and F1 females at 70 and 490 ppm. Increased
post-implantation loss and/or fetal deaths and consequently reduced
litter size at birth, and lower pup
weight gain during lactation were observed in F1 and F2
pups at 490 ppm. Offspring at 70 and 490 ppm had a slight
retardation of growth and sexual maturation
(delayed vaginal opening and balanopreputial cleavage).
Increased liver weights were seen in F1 and F2 pups at 490 ppm
as well as female pups at 70 ppm at weaning. No external
and internal abnormalities were found for both F1 and F2 pups.
The NOEL was 10 ppm (0.4 mg/kg bw/day) for reproduction and postnatal
toxicity. (page 5-6)
• Developmental Studies Pregnant
rats received 0, 5, 22.5 or 100 mg/kg bw/day of tetraconazole
by gavage on gestation days 6-15. Post-dosing salivation was noted
in dams at 22.5 and 100 mg/kg bw/day. Increased water consumption
at 100 mg/kg bw/day, and decreased food
consumption and body weight gain at 22.5 and 100 mg/kg
bw/day were observed. Liver and kidney weights
were increased in dams at 100 mg/kg bw/day. There were no treatment-related
effects on embryo/fetal loss, litter size and sex ratio of pups.
Variable fetal weights within each
group at 22.5 and 100 mg/kg bw/day might be associated with variation
in degrees of skeletal ossification. Incidences of hydronephrosis
and hydroureter at 100 mg/kg bw/day were increased. The number
of fetuses with supernumerary rib(s) was higher, and ossification
in skeletons tended to be advanced at 100 mg/kg bw/day.
The NOEL was 5 mg/kg bw/day for maternal toxicity, and was 22.5
mg/kg bw/day for fetal development.
-- Pregnant rabbits received 0, 20, 40 or 80 mg/kg bw/day of tetraconazole
in a preliminary study, and 0, 7.5, 15 or 30 mg/kg bw/day in the
main study, by gavage on gestation days 6-18. Rabbits at 80 mg/kg
bw/day showed minimal to nil food intake, body
weight loss and deteriorated condition,
and were sacrificed on day 7 of dosing showing increased early
fetal loss. At 40 mg/kg bw/day, reduced food intake, body
weight loss, lower fecal output and
emaciation occurred
during the dosing period, and increased
liver and kidney weight were observed at necropsy. Abortion, death,
post-implantation loss, and reduced
fetal weight were seen in this group. Food consumption
and body weight gain of dams were lower at 30 mg/kg bw/day.
Incidences of malformation, anomalies and skeletal variants were
low in all groups. The NOEL was 15 mg/kg bw/day for maternal
toxicity, and was 30 mg/kg bw/day for fetal growth/development.
(page 6)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Bone
(click
on for all fluorinated pesticides)
• Metbolism nd Toxicokinetics. Tetraconazole
was broadly distributed to all organs and tissues tested, with
the highest level detected in the liver, followed by kidneys,
gonads, brain and bones. Low residual
levels were still detected in the liver and gastrointestinal tract
(sometimes bones) at 72 hr.
• Chronic & Carcinogenicity Studies.
Dorsal compression was seen in the brain of some mice at 1250
ppm, and thickening of compact bones in
the cranium, ribs and collar bones, myelofibrosis [disease
of the bone marrow], pale, thickened, broken, chipped and/or
overgrown incisors were observed at 800 and 1250 ppm, indicating
abnormal bone metabolism. (pp 4-5)
-- Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to
males only) of tetraconazole in the diet for 2 years... In the
brain of males at 640 and 1280 ppm, dorso-lateral compression,
dilated ventricles, and white thickened
cranium and parietal bones were probably secondary to the osseous
hypertrophy. Increased numbers of rats had pale, thickened
and overgrown incisors at 640 and 1280 ppm. (page 5)
• Developmental Studies Pregnant
rats received 0, 5, 22.5 or 100 mg/kg bw/day of tetraconazole
by gavage on gestation days 6-15. Post-dosing salivation was noted
in dams at 22.5 and 100 mg/kg bw/day. Increased water consumption
at 100 mg/kg bw/day, and decreased food
consumption and body weight gain at 22.5 and 100 mg/kg bw/day
were observed. Liver and kidney weights were increased in dams
at 100 mg/kg bw/day. There were no treatment-related effects on
embryo/fetal loss, litter size and sex ratio of pups. Variable
fetal weights within each group at 22.5 and 100 mg/kg bw/day might
be associated with variation in degrees of skeletal ossification.
Incidences of hydronephrosis
and hydroureter at 100 mg/kg bw/day were increased. The
number of fetuses with supernumerary rib(s) was higher, and ossification
in skeletons tended to be advanced at 100 mg/kg bw/day.
The NOEL was 5 mg/kg bw/day for maternal toxicity, and was 22.5
mg/kg bw/day for fetal development.
-- Pregnant rabbits received 0, 20, 40 or 80 mg/kg bw/day of tetraconazole
in a preliminary study, and 0, 7.5, 15 or 30 mg/kg bw/day in the
main study, by gavage on gestation days 6-18. Rabbits at 80 mg/kg
bw/day showed minimal to nil food intake, body
weight loss and deteriorated condition, and were sacrificed on
day 7 of dosing showing increased early fetal loss. At 40 mg/kg
bw/day, reduced food intake, body weight loss, lower fecal output
and emaciation occurred during the dosing period, and
increased liver and kidney weight were observed
at necropsy. Abortion, death, post-implantation loss, and reduced
fetal weight were seen in this group.
Food consumption and body weight gain of dams were lower at 30
mg/kg bw/day. Incidences of malformation,
anomalies and skeletal variants were low in all groups. The
NOEL was 15 mg/kg bw/day for maternal toxicity, and was 30 mg/kg
bw/day for fetal growth/development. (page 6)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
-- Reproductive and
developmental toxicity. A developmental toxicity study with rats
given oral gavage doses of 5, 22.5, and 100 mg/kg/day from days
6 through 15 of gestation resulted in a NOAEL for maternal toxicity
of 5 mg/kg/day based upon bwt reduction, reduced food intake and
post-dose salivation at the two higher doses, as compared with
zero-dose controls. The developmental NOAEL was 22.5 mg/kg/day.
Among the highest dose group there was evidence of minimal increase
in the incidence of supernumerary ribs among
the fetuses.
-- A chronic feeding/carcinogenicity study was conducted with
tetraconazole in Crl:CD-l (ICR)BR mice at dietary levels of 10,
90, 800, and 1,250 ppm for 80 weeks. Treatment-related non-neoplastic
changes were also seen at 1,250 ppm in the
lungs, kidneys, testes, epididymides, ovaries
and bone, particularly the cranium;
a compression of the brain was noted in
a number of mice reflecting the extent of cranial
bone changes and an increased thymic involution
was seen in male mice that died on test.
The 1,250 ppm dietary level for tetraconazole,
because of the substantial bwt gain changes and increased mortality
(more in males), appeared to be above
the maximum tolerated dose (MTD). At 800 ppm, there were increases
in non neoplastic changes in lungs,
kidneys, testes, epididymides, ovaries and bone.
In addition, there was substantial reduction in weight gain as
compared with zero-dose control animals, but the mortality rate
was unaffected. Eight hundred ppm appeared to be a reasonable
estimate of the MTD for mouse.
Ref: Federal Register: October 14, 1999.
Notice of Filing Pesticide Petitions to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023,
and 7E4830.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Oct14.1999.htm
-- Chronic toxicity.
EPA has established the RfD for tetraconazole at 0.005 mg/kg/day.
This RfD is based on a 2-year chronic toxicity/ carcinogenicity
study in rats with a NOAEL of 0.5 mg/kg/day 10 ppm and an uncertainty
factor of 100 based on osseous hypertrophy
of skull bones at the LOAEL of 3.9 mg/kg/day 80 ppm. Due
to the severity of pup effects in the rat reproduction study,
an additional FQPA safety factor of three has been applied to
the acute and chronic RfD calculations. The percent of acute and
chronic RfD utilized should not exceed 33%.
-- Developmental toxicity studies-- a. Rats. In the developmental
study in rats, the maternal (systemic) NOAEL was 5 mg/kg/day,
based on decreased body weight and decreased food consumption
at the LOAEL of 22.5 mg/kg/day. The developmental (fetal) NOAEL
was 22.5 mg/kg/day, based on visceral changes,
supernumerary ribs, and delayed ossification at the LOAEL
of 100 mg/kg/day.
-- Reproductive toxicity study-- Rats. In the 2-generation reproductive
toxicity study in rats, the maternal (systemic) NOAEL was 0.7
mg/kg/day, based on dystocia, delayed vaginal
opening, and increased liver weight
at the LOAEL of 5.9 mg/kg/day. The developmental (pup)
NOAEL was 0.7 mg/kg/day, based on increased time to observation
of balanopreputial skin fold [foreskin] and liver weight
at the LOAEL of 5.9 mg/ kg/day. At the high dose of 35.5 mg/kg/day,
there was a decrease in the mean number of live pups per litter
on lactation days 0 and 4 (precull) in the presence of significant
maternal toxicity.
Ref: Federal Register: December 6, 1999.
Tetraconazole; Pesticide Tolerances for Emergency Exemptions.
Final Rule. http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Dec.1999.htm
Note from EC:
"Dystocia. Literally,
it means difficult labor and practically means abnormally slow
progress of labor. The word comes from the Greek 'dys' meaning
'difficult, painful, disordered, abnormal' and 'tokos' meaning
'birth'. Four potential factors may cause difficult labor characterized
by abnormally slow progress. They may occur separately or together.
1) Uterine contractions may be either too weak or too uncoordinated
to open up the cervix. There may also be inadequate pushing
with voluntary muscles during the second stage of labor. 2)
The baby may be lined up wrong to easily pass through the birth
canal. Alternatively, there may be other problems with the baby
that also retard passage of the baby through the birth canal.
3) The maternal bony pelvis may
be too narrow to allow the baby
to pass through the birth canal. 4) Abnormalities of the birth
canal other than those of the bony pelvis may obstruct fetal
descent. The most common cause
of dystocia is a small bony pelvis and/or insufficiently strong
and coordinated uterine contractions. [drnathan/sitedex.htm]."
- Balanopreputial skin fold-
see: http://www.cirp.org/library/history/hodges1/
Brain
(click
on for all fluorinated pesticides)
1,2,4-triazole targets the nervous
system, both central and peripheral, as
brain lesions (most notably in the cerebellum)
were seen in both rats and mice, and peripheral nerve degeneration
was also seen in the subchronic neurotoxicity study in rats. In
addition, brain weight decreases were
seen in several studies, including in the offspring in the reproductive
toxicity study. In the subchronic/neurotoxicity study, there
is evidence that effects progress over time, with an increase
in incidence of clinical signs (including tremors and muscle fasciculations)
during weeks 8 and 13 that were not seen during earlier evaluations.
Effects were also seen on reproductive organs in both sexes, most
notably ovaries (in rats) and testes (in rats and mice), in both
the reproductive toxicity and subchronic toxicity studies. Hematological
changes, including slightly decreased hemoglobin and/or hematocrit,
have also been seen in multiple studies and species (in rats at
doses of 33 mg/kg/day and above, and in mice at doses of 487 mg/kg/day
and above). Studies depicting the effects of chronic exposure
to free triazole or its conjugates are not currently available.
Ref: Human
Health Aggregate Risk Assessment for Triazole-derivative Fungicide
Compounds (1,2,4-Triazole, Triazole Alanine, Triazole Acetic
Acid). US EPA, February 7, 2006.
• Metbolism nd Toxicokinetics. Tetraconazole
was broadly distributed to all organs and tissues tested, with
the highest level detected in the liver, followed by kidneys,
gonads, brain and bones.
Low residua levels were still detected in the liver and gastrointestinal
tract (sometimes bones) at 72 hr.
• Chronic & Carcinogenicity Studies.
Dorsal compression was seen in the brain
of some mice at 1250 ppm, and thickening
of compact bones in the cranium, ribs and
collar bones, myelofibrosis, pale, thickened, broken, chipped
and/or overgrown incisors
were observed at 800 and 1250 ppm, indicating abnormal
bone metabolism. (pp 4-5)
-- Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to
males only) of tetraconazole in the diet for 2 years...
In the brain of males at 640 and 1280 ppm, dorso-lateral
compression, dilated ventricles, and white
thickened cranium and parietal bones were probably secondary to
the osseous hypertrophy. Increased numbers of rats had
pale, thickened and overgrown incisors at 640 and 1280 ppm. (page
5)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Cancer:
Likely to be Carcinogenic to Humans - LIVER (click
on for all fluorinated pesticides)
Likely
to be Carcinogenic to Humans. Hepatocellular
adenomas, carcinomas and combined adenomas/carcinomas in both
sexes; Crl:CD-1 (ICR) mice.
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
Likely to be carcinogenic to humans.
Reviewed 1/ 11/ 00.
Ref: List of Chemicals Evaluated for Carcinogenic
Potential. Science Information Management Branch, Health Effects
Division, Office of Pesticide Programs, U. S. Environmental Protection
Agency. March 15, 2002.
http://www.biomuncie.org/chemicals_evaluated_for_carcinog.htm
Cancer Classification: Tetraconazole
was classified as —likely to be carcinogenic to humans“
based on the occurrence of liver tumors in male and female mice.
The Carcinogenicity Assessment Review Committee recommended that
a low dose extrapolation model be applied to the experimental
animal tumor data and that quantification of risk be estimated
for male and female mouse liver tumors for Tetraconazole. The
most potent unit risk will be used for the purpose of lifetime
cancer risk assessment by the Agency. In this case, the most potent
unit risk, Q1*, is that for male mouse liver benign and/or malignant
combined tumor rates at 2.30 x 10-2 in human equivalents.
-- The highest estimated cancer risk is
6.7 x 10-4 for mixer/loaders working without gloves, However,
the labeling requires gloves and the estimated cancer risk for
mixer/loaders wearing gloves falls to 7.5 x 10-6. The remaining
risks to agricultural workers applying tetraconazole to sugarbeets
range from 7.5 x 10-6 7.7 x 10-7. Post-application cancer risk
is 5.1 x 10-6 or lower, which does not exceed the Agency‘s
level of concern.
Ref: April 2005. Pesticide Fact Sheet:
Tetraconazole. US EPA.
http://www.fluorideaction.org/pesticides/tetraconazole.epa.2005.facts.pdf
-- Carcinogenicity.
Tetraconazole has not been classified with respect to carcinogenic
potential by EPA. However, based on the tumorigenic results in
the mouse carcinogenicity study, EPA has made an initial determination
that a Q1* should be determined based on the male mouse benign
liver tumors, excluding the highest dose. The Q1* is 0.037
(mg/kg/day)-1.
-- Aggregate cancer risk for U.S. population. Tetraconazole produced
statistically significant increases in male and female mouse liver
adenomas and carcinomas. Based on a determination of the
Q1* for this tolerance setting action only, the Q1* was determined
to be 3.7 x 10-2 based on benign tumors in males with the exclusion
of the high dose group. The cancer risk for the U.S. population
is, without adjustment, 2.5 x 10-6. Because this is an emergency
exemption use of tetraconazole, it is considered appropriate to
divide the cancer risk by a factor of 14 [5 years for potential
emergency exemption use/70 years lifetime = 1/14]. The adjusted
cancer risk for the U.S. population is 1.8 x 10-7 and this adjusted
cancer risk is below EPA's level of concern.
-- Reproductive toxicity study-- Rats. In the 2-generation reproductive
toxicity study in rats, the maternal (systemic) NOAEL was 0.7
mg/kg/day, based on dystocia, delayed vaginal
opening, and increased liver weight
at the LOAEL of 5.9 mg/kg/day. The developmental (pup) NOAEL was
0.7 mg/kg/day, based on increased time to observation of
balanopreputial skin fold and liver
weight at the LOAEL of 5.9 mg/ kg/day. At the high dose of 35.5
mg/kg/day, there was a decrease in the mean number of live pups
per litter on lactation days 0 and 4 (precull) in the presence
of significant maternal toxicity.
Ref: Federal Register: December 6, 1999.
Tetraconazole; Pesticide Tolerances for Emergency Exemptions.
Final Rule.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Dec.1999.htm
Chronic & Carcinogenicity Studies.
In a carcinogenicity study, mice received 0, 10, 90, 800 or 1250
ppm of tetraconazole in the diet for 80 weeks. ... Benign
and malignant liver cell tumors were increased at 800
and 1250 ppm, and resulted in the high mortality at 1250 ppm.
The NOEL was 10 ppm (1.4 mg/kg bw/day). (page 5)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Cholesterol
(click
on for all fluorinated pesticides)
-- Chronic toxicity.
A 12-month chronic oral toxicity study in Beagle dogs was conducted
with technical tetraconazole at dose levels of 0.7, 2.8, and 5.6
mg/kg/day (22.5, 90, and 360 ppm dietary concentrations, respectively).
At the highest dose, liver and kidney weights
and cholesterol levels were elevated,
and liver injury occurred based upon
increased levels of GPT, -GT and OCT. The no effect level
was 0.7 mg/kg/day, as compared with zero-dose control animals.
Ref: Federal Register: October 14, 1999.
Notice of Filing Pesticide Petitions to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023,
and 7E4830.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Oct14.1999.htm
Developmental
(click
on for all fluorinated pesticides)
• Developmental Studies Pregnant
rats received 0, 5, 22.5 or 100 mg/kg bw/day of tetraconazole
by gavage on gestation days 6-15. Post-dosing salivation was noted
in dams at 22.5 and 100 mg/kg bw/day. Increased water consumption
at 100 mg/kg bw/day, and decreased food
consumption and body weight gain at 22.5 and 100 mg/kg
bw/day were observed. Liver and kidney weights
were increased in dams at 100 mg/kg bw/day. There were
no treatment-related effects on embryo/fetal loss, litter size
and sex ratio of pups. Variable fetal weights
within each group at 22.5 and 100 mg/kg bw/day might be associated
with variation in degrees of skeletal ossification. Incidences
of hydronephrosis and hydroureter at
100 mg/kg bw/day were increased. The number
of fetuses with supernumerary rib(s) was higher, and ossification
in skeletons tended to be advanced at 100 mg/kg bw/day.
The NOEL was 5 mg/kg bw/day for maternal toxicity, and was 22.5
mg/kg bw/day for fetal development.
-- Pregnant rabbits received 0, 20, 40 or 80 mg/kg bw/day of tetraconazole
in a preliminary study, and 0, 7.5, 15 or 30 mg/kg bw/day in the
main study, by gavage on gestation days 6-18. Rabbits at 80 mg/kg
bw/day showed minimal to nil food intake, body
weight loss and deteriorated condition, and were sacrificed
on day 7 of dosing showing increased early fetal loss. At 40 mg/kg
bw/day, reduced food intake, body weight
loss, lower fecal output and emaciation occurred during
the dosing period, and increased liver and
kidney weight were observed at necropsy. Abortion, death, post-implantation
loss, and reduced fetal weight were seen in this group.
Food consumption and body weight gain of dams were lower at 30
mg/kg bw/day. Incidences of malformation,
anomalies and skeletal variants were low in all groups. The
NOEL was 15 mg/kg bw/day for maternal toxicity, and was 30 mg/kg
bw/day for fetal growth/development. (page 6)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Endocrine:
Ovary (click
on for all fluorinated pesticides)
A chronic feeding/carcinogenicity study was conducted with tetraconazole
in Crl:CD-l (ICR)BR mice at dietary levels of 10, 90, 800, and
1,250 ppm for 80 weeks. Treatment-related non-neoplastic changes
were also seen at 1,250 ppm in the lungs, kidneys,
testes, epididymides,
ovaries and bone, particularly the cranium;
a compression of the brain was noted in a number of mice reflecting
the extent of cranial bone changes and an increased
thymic involution was seen in male mice
that died on test.
The 1,250 ppm dietary level for tetraconazole, because of the
substantial bwt gain changes and increased mortality (more in
males), appeared to be above the maximum tolerated dose (MTD).
At 800 ppm, there were increases in non neoplastic changes in
lungs, kidneys, testes, epididymides,
ovaries and bone.
In addition,
there was substantial reduction in weight gain as compared with
zero-dose control animals, but the mortality rate was unaffected.
Eight hundred ppm appeared to be a reasonable estimate of the
MTD for mouse.
Ref: Federal Register: October 14, 1999.
Notice of Filing Pesticide Petitions to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023,
and 7E4830.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Oct14.1999.htm
• Metbolism nd Toxicokinetics. Tetraconazole
was broadly distributed to all organs and tissues tested, with
the highest level detected in the liver, followed by kidneys,
gonads, brain and bones.
Low residual levels were still detected in the liver and gastrointestinal
tract (sometimes bones) at 72 hr.
• Chronic & Carcinogenicity Studies.
An absence of corpora lutea in ovaries
and thin uterus in females were seen at 800 and 1250 ppm. ...
Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to males
only) of tetraconazole in the diet for 2 years... At interim sacrifice,
female rats showed an absence of corpora lutea in the ovaries
and a decrease in the incidence of epithelial mucification in
cervix and vagina in all treated groups, and squamous metaplasia
in the endometrial glands of the uterus at 80 and 640 ppm. At
the end of the study, females showed thickened uterus at 640 ppm
and males showed a higher incidence of enlarged cervical lymph
nodes at 640 and 1280 ppm, along with cystic sinuses at 1280 ppm.
(page 5)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Endocrine:
Pituitary (click
on for all fluorinated pesticides)
• Chronic & Carcinogenicity Studies.
Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to males
only) of tetraconazole in the diet for 2 years... Pituitary
weights were reduced, with enlarged or vacuolated cells in the
pars anterior in males at 640 and 1280 ppm. (page 5)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Endocrine:
Prostate (click
on for all fluorinated pesticides)
Chronic & Carcinogenicity Studies.
There were small and flaccid testes with
reduced spermatogenesis, absence of spermatozoa in epididymides,
and small and flaccid prostate and
seminal vesicles with reduced secretion at 800 and 1250
ppm, and interstitial
cell hyperplasia and prominent multinucleate spermatids in the
testes at 1250 ppm. (page
5)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Endocrine:
Testicular
(click on for all fluorinated pesticides)
-- A chronic feeding/carcinogenicity
study was conducted with tetraconazole in Crl:CD-l (ICR)BR mice
at dietary levels of 10, 90, 800, and 1,250 ppm for 80 weeks.
Treatment-related non-neoplastic changes were also seen at 1,250
ppm in the lungs, kidneys,
testes, epididymides, ovaries and bone,
particularly the cranium;
a compression of the brain was noted in a number of mice reflecting
the extent of cranial bone changes and an increased thymic involution
was seen in male mice that died on test. The 1,250 ppm dietary
level for tetraconazole, because of the
substantial bwt gain changes and increased mortality (more
in males), appeared to be above the maximum tolerated dose
(MTD). At 800 ppm, there were increases in non neoplastic changes
in lungs, kidneys,
testes, epididymides, ovaries and bone.
In addition,
there was substantial reduction in weight gain as compared with
zero-dose control animals, but the mortality rate was unaffected.
Eight hundred ppm appeared to be a reasonable estimate of the
MTD for mouse.
-- At 90 ppm, non-neoplastic changes were detected in
bone and the
epididymides
in addition to liver changes. No treatment-related findings were
seen in mice treated at 10 ppm (approximately 1.5 mg/kg/ day),
and this dose level was defined as the NOAEL.
Ref: Federal Register: October 14, 1999.
Notice of Filing Pesticide Petitions to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023,
and 7E4830.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Oct14.1999.htm
-- Reproductive toxicity study-- Rats. In the 2-generation reproductive
toxicity study in rats, the maternal (systemic) NOAEL was 0.7
mg/kg/day, based on dystocia, delayed vaginal
opening, and increased liver weight
at the LOAEL of 5.9 mg/kg/day. The developmental (pup) NOAEL was
0.7 mg/kg/day, based on increased time to observation of
balanopreputial skin fold [foreskin]
and liver weight at the LOAEL of
5.9 mg/ kg/day. At the high dose of 35.5 mg/kg/day, there was
a decrease in the mean number of live pups per litter on lactation
days 0 and 4 (precull) in the presence of significant maternal
toxicity.
Ref: Federal Register: December 6, 1999.
Tetraconazole; Pesticide Tolerances for Emergency Exemptions.
Final Rule. http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Dec.1999.htm
• Balanopreputial
skin fold- see: http://www.cirp.org/library/history/hodges1/
• Metbolism nd Toxicokinetics. Tetraconazole
was broadly distributed to all organs and tissues tested, with
the highest level detected in the liver, followed by kidneys,
gonads, brain and bones.
Low residual levels were still detected in the liver and gastrointestinal
tract (sometimes bones) at 72 hr.
• Chronic & Carcinogenicity Studies.
There were small and flaccid testes
with reduced spermatogenesis, absence of
spermatozoa in epididymides, and small and flaccid prostate and
seminal vesicles with reduced secretion at 800 and 1250
ppm, and interstitial cell hyperplasia and
prominent multinucleate spermatids in the testes at 1250
ppm. (page 5)
•
Reproduction Study Rats received
0, 10, 70 or 490 ppm of tetraconazole in the diet for two generations.
Offspring at 70 and 490 ppm had a slight
retardation of growth and sexual maturation
(delayed vaginal opening and balanopreputial cleavage*).
Increased liver weights were seen in F1 and F2 pups at 490 ppm
as well as female pups at 70 ppm at weaning. No external
and internal abnormalities were found for both F1 and F2 pups.
The NOEL was 10 ppm (0.4 mg/kg bw/day) for reproduction and postnatal
toxicity. (page 5-6)
• Sub-chronic studies. Rats
received 0, 10, 60 or 360 ppm of tetraconazole in the diet for
13 weeks. Enlarged or swollen liver was seen at 360 ppm. Increased
liver weight was associated with minimal centrilobular hepatocyte
enlargement at 60 and 360 ppm, and a higher incidence of liver
fat deposition at 360 ppm. Increased kidney weight in females
and reduced testes weight in males
were also observed at 360 ppm. The NOEL was 10 ppm (0.7 mg/kg
bw/day).
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Definition: balanopreputial.
Relating to or situated near the glans
penis and the foreskin .
Endocrine:
Thymus (click
on for all fluorinated pesticides)
-- A chronic feeding/carcinogenicity
study was conducted with tetraconazole in Crl:CD-l (ICR)BR mice
at dietary levels of 10, 90, 800, and 1,250 ppm for 80 weeks.
Treatment-related non-neoplastic changes were also seen at 1,250
ppm in the lungs, kidneys,
testes, epididymides, ovaries and
bone, particularly the cranium;
a compression of the brain was noted in a number of mice reflecting
the extent of cranial bone changes and an increased
thymic involution was seen in male mice that
died on test.
The 1,250 ppm
dietary level for tetraconazole, because of the substantial bwt
gain changes and increased mortality (more
in males), appeared to be above the maximum tolerated dose
(MTD). At 800 ppm, there were increases in non neoplastic changes
in lungs, kidneys,
testes, epididymides, ovaries and bone.
In addition, there was substantial reduction in weight gain as
compared with zero-dose control animals, but the mortality rate
was unaffected. Eight hundred ppm appeared to be a reasonable
estimate of the MTD for mouse.
Ref: Federal Register: October 14, 1999.
Notice of Filing Pesticide Petitions to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023,
and 7E4830.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Oct14.1999.htm
Endocrine:
Thyroid (click
on for all fluorinated pesticides)
Chronic & Carcinogenicity Studies.
Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to males
only) of tetraconazole in the diet for 2 years... Cystic follicular
hyperplasia and follicular epithelial hypertrophy
were increased in the thyroid of males at 1280 ppm. Tumor
incidences were not increased by treatment. The NOEL was 10 ppm
(0.4 mg/kg bw/day).
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
-- The class of compounds
(triazoles) to which tetraconazole belongs is known to induce
liver microsomal enzymes. The follicular
cell hypertrophy and cystic follicular hyperplasia of the thyroid
seen in male rats at 1,280 ppm are also likely to be linked
to the hepatic changes. Compounds such as phenobarbital are also
known to induce thyroid changes in rats due to increased hepatic
clearance of thyroxin, mediated by hepatic enzyme induction.
Ref: Federal Register: October 14, 1999.
Notice of Filing Pesticide Petitions to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023,
and 7E4830.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Oct14.1999.htm
Endocrine:
Uterus (click
on for all fluorinated pesticides)
Chronic & Carcinogenicity Studies.
Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to males
only) of tetraconazole in the diet for 2 years... At interim sacrifice,
female rats showed an absence of corpora lutea in the ovaries
and a decrease in the incidence of epithelial mucification in
cervix and vagina in all treated groups, and squamous
metaplasia in the endometrial glands of the uterus at 80 and 640
ppm. At the end of the study, females showed thickened uterus
at 640 ppm and males showed a higher incidence of enlarged
cervical lymph nodes at 640 and 1280 ppm, along with cystic sinuses
at 1280 ppm. (page 5)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Endocrine:
Vaginal and
Reproductive
(click
on for all fluorinated pesticides)
Reproductive
toxicity study-- Rats. In the 2-generation reproductive
toxicity study in rats, the maternal (systemic) NOAEL was 0.7
mg/kg/day, based on dystocia, delayed vaginal
opening, and increased liver weight
at the LOAEL of 5.9 mg/kg/day. The developmental (pup) NOAEL was
0.7 mg/kg/day, based on increased time to observation of
balanopreputial skin fold
[foreskin] and liver weight
at the LOAEL of 5.9 mg/ kg/day. At the high dose of 35.5 mg/kg/day,
there was a decrease in the mean number of live pups per litter
on lactation days 0 and 4 (precull) in the presence of significant
maternal toxicity.
Ref: Federal Register: December 6, 1999.
Tetraconazole; Pesticide Tolerances for Emergency Exemptions.
Final Rule.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Dec.1999.htm
Reproduction Study Rats received
0, 10, 70 or 490 ppm of tetraconazole in the diet for two generations.
Offspring at 70 and 490 ppm had a slight
retardation of growth and sexual maturation
(delayed vaginal opening and balanopreputial
cleavage). Increased liver weights were seen in
F1 and F2 pups at 490 ppm as well as female pups at 70 ppm at
weaning. No external and internal abnormalities were found
for both F1 and F2 pups. The NOEL was 10 ppm (0.4 mg/kg bw/day)
for reproduction and postnatal toxicity. (page 5-6)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
•
Note from EC:
"Dystocia. Literally,
it means difficult labor and practically means abnormally slow
progress of labor. The word comes from the Greek 'dys' meaning
'difficult, painful, disordered, abnormal' and 'tokos' meaning
'birth'. Four potential factors may cause difficult labor characterized
by abnormally slow progress. They may occur separately or together.
1) Uterine contractions may be either too weak or too uncoordinated
to open up the cervix. There may also be inadequate pushing
with voluntary muscles during the second stage of labor.
2) The baby may be lined up wrong to easily pass through the
birth canal. Alternatively, there may be other problems with
the baby that also retard passage of the baby through the birth
canal.
3) The maternal bony pelvis may be too narrow to allow the baby
to pass through the birth canal.
4) Abnormalities of the birth canal other than those of the
bony pelvis may obstruct fetal descent. The
most common cause of dystocia is a small bony pelvis and/or
insufficiently strong and coordinated
uterine contractions.
[drnathan/sitedex.htm]."
-- Balanopreputial
skin fold- see:
http://www.cirp.org/library/history/hodges1/
Kidney
(click
on for all fluorinated pesticides)
Chronic Toxicity: The liver and
kidney are the primary target organs of tetraconazole.
Ref: April 2005. Pesticide Fact Sheet: Tetraconazole.
US EPA.
http://www.fluorideaction.org/pesticides/tetraconazole.epa.2005.facts.pdf
• Metbolism and Toxicokinetics. Tetraconazole
was broadly distributed to all organs and tissues tested, with
the highest level detected in the liver, followed by kidneys,
gonads, brain and bones. Low residual levels
were still detected in the liver and gastrointestinal tract (sometimes
bones) at 72 hr.
• Chronic & Carcinogenicity Studies.
Dogs received 0, 22.5, 90 or 360 ppm of tetraconazole in the diet
for 1 year. Histopathology detected apparent hepatocyte enlargement,
eosinophilic inclusions in hepatocytes, centrilobular hepatocyte
rarefaction, or centrilobular fat in the liver at 90 and 360 ppm,
and cortical tubular hypertrophy and apoptotic
bodies in the kidneys at 360 and/or 90 ppm. The NOEL was
22.5 ppm (0.7 mg/kg bw/day). (page 5)
• Sub-chronic studies. Rats received 0, 10, 60 or
360 ppm of tetraconazole in the diet for 13 weeks. Enlarged or
swollen liver was seen at 360 ppm. Increased liver weight was
associated with minimal centrilobular hepatocyte enlargement at
60 and 360 ppm, and a higher incidence of liver fat deposition
at 360 ppm. Increased kidney weight in females
and reduced testes weight in males
were also observed at 360 ppm. The NOEL was 10 ppm (0.7 mg/kg
bw/day).
-- Mice received 0, 5, 25, 125 or 625 ppm of tetraconazole in
the diet for 13 weeks. Some males at 625
ppm showed lymphocyte aggregation and foci in the kidneys. The
NOEL was 5 ppm (1 mg/kg bw/day). (page 4)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Liver
(click on for
all fluorinated pesticides)
Likely
to be Carcinogenic to Humans. Hepatocellular
adenomas, carcinomas and combined adenomas/carcinomas in both
sexes; Crl:CD-1 (ICR) mice.
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
Likely to be carcinogenic to humans. Reviewed
1/ 11/ 00.
Ref: List of Chemicals Evaluated for Carcinogenic
Potential. Science Information Management Branch, Health Effects
Division, Office of Pesticide Programs, U. S. Environmental Protection
Agency. March 15, 2002.
http://www.biomuncie.org/chemicals_evaluated_for_carcinog.htm
• Metbolism nd Toxicokinetics. Tetraconazole
was broadly distributed to all organs and tissues tested, with
the highest level detected in the liver,
followed by kidneys, gonads, brain and bones.
Low residual levels were still detected in the liver and gastrointestinal
tract (sometimes bones) at 72 hr.
• Chronic & Carcinogenicity Studies.
Dogs received 0, 22.5, 90 or 360 ppm of tetraconazole in the diet
for 1 year. Histopathology detected apparent
hepatocyte enlargement, eosinophilic inclusions in hepatocytes,
centrilobular hepatocyte rarefaction, or centrilobular fat in
the liver at 90 and 360 ppm, and cortical tubular hypertrophy
and apoptotic bodies in the kidneys
at 360 and/or 90 ppm. The NOEL was 22.5 ppm (0.7 mg/kg
bw/day). (page 5)
-- In a carcinogenicity study, mice received 0, 10, 90, 800 or
1250 ppm of tetraconazole in the diet for 80 weeks. In the liver,
increased weight and masses and enlarged
and discoloured liver were noted at 90 ppm and above with a dose-related
increase in the incidence and degree of generalised hepatocyte
enlargement, vacuolation, fat deposition and bile duct hyperplasia
at 90 ppm (males) and higher doses. There were also
increased basophilic hepatocyte foci, eosinophilic hepatocytes,
pericholangitis, granulomatous inflammation and pigmented macrophages
in mice at 800 and 1250 ppm. Hepatocyte
necrosis was detected in some females
of each treated group (page 4) ... Benign and malignant
liver cell tumors were increased at 800 and 1250 ppm,
and resulted in the high mortality at 1250 ppm. The NOEL was 10
ppm (1.4 mg/kg bw/day). (page 5)
• Sub chronic studies. Mice
received 0, 5, 25, 125 or 625 ppm of tetraconazole in the diet
for 13 weeks. In males at 625 ppm and females at 125 and 625 ppm,
decreased BUN was detected, and elevated alanine aminotransferase
(ALT) and AST activities were associated
with increased liver weights. Mice at 625 ppm exhibited
pale and enlarged liver with lobular markings
accentuated. Hepatocyte enlargement was
a major finding in the majority of mice at 25 ppm and above. Hepatocyte
necrosis, degeneration or congestion developed at 125 and
625 ppm, and a higher incidence of hepatocyte
vacuolation appeared at 625 ppm.
Some males at 625 ppm showed lymphocyte aggregation and foci in
the kidneys. The NOEL was 5 ppm (1 mg/kg bw/day). (page
4)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
-- Carcinogenicity.
Tetraconazole has not been classified with respect to carcinogenic
potential by EPA. However, based on the tumorigenic results in
the mouse carcinogenicity study, EPA has made an initial determination
that a Q1* should be determined based on the male mouse benign
liver tumors, excluding the highest dose. The Q1* is 0.037
(mg/kg/day)-1.
-- Aggregate cancer risk for U.S. population. Tetraconazole produced
statistically significant increases in male and female mouse liver
adenomas and carcinomas. Based on a determination of the
Q1* for this tolerance setting action only, the Q1* was determined
to be 3.7 x 10-2 based on benign tumors in males with the exclusion
of the high dose group. The cancer risk for the U.S. population
is, without adjustment, 2.5 x 10-6. Because this is an emergency
exemption use of tetraconazole, it is considered appropriate to
divide the cancer risk by a factor of 14 [5 years for potential
emergency exemption use/70 years lifetime = 1/14]. The adjusted
cancer risk for the U.S. population is 1.8 x 10-7 and this adjusted
cancer risk is below EPA's level of concern.
-- Reproductive toxicity study-- Rats. In the 2-generation reproductive
toxicity study in rats, the maternal (systemic) NOAEL was 0.7
mg/kg/day, based on dystocia, delayed vaginal
opening, and increased liver weight
at the LOAEL of 5.9 mg/kg/day. The developmental (pup) NOAEL was
0.7 mg/kg/day, based on increased time to observation of
balanopreputial skin fold and liver
weight at the LOAEL of 5.9 mg/ kg/day. At the high dose of 35.5
mg/kg/day, there was a decrease in the mean number of live pups
per litter on lactation days 0 and 4 (precull) in the presence
of significant maternal toxicity.
Ref: Federal Register: December 6, 1999.
Tetraconazole; Pesticide Tolerances for Emergency Exemptions.
Final Rule.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Dec.1999.htm
-- Subchronic toxicity.
A 90-day oral subchronic toxicity study was conducted with technical
grade tetraconazole in rats at 10, 60, and 360 ppm in the diet.
Treatment related increased liver weights and centrilobular
hepatocyte enlargement were observed at the two highest
dose levels. The NOAEL was 10 ppm (0.8 mg/kg/day), by comparison
with data from the zero-dose control group.
-- A 90-day oral subchronic toxicity study was conducted in mice
with dietary concentrations of technical grade tetraconazole at
5, 25, 125, and 625 ppm. The two highest dosages resulted in liver
enlargement, accentuated lobular markings and liver pallor. Microscopic
tissue alterations related to tetraconazole were liver
enlargement at the three highest doses and single
cell necrosis/degeneration and/or areas of necrosis at
the two highest doses. The NOAEL was 5 ppm (1 mg/kg/ day).
-- Chronic toxicity. A 12-month chronic oral toxicity study in
Beagle dogs was conducted with technical tetraconazole at dose
levels of 0.7, 2.8, and 5.6 mg/kg/day (22.5, 90, and 360 ppm dietary
concentrations, respectively). At the highest dose, liver
and kidney weights and cholesterol
levels were elevated, and liver injury
occurred based upon increased levels of GPT, -GT and
OCT. The no effect level was 0.7 mg/kg/day, as compared with zero-dose
control animals.
-- A chronic (full-lifetime) feeding/carcinogenicity study was
conducted with Crl:CD(SD)BR rats fed tetraconazole at dietary
levels of 10, 80, 640, and 1,280 ppm for 104 weeks in males and
10, 80, and 640 ppm for 104 weeks in females. In the liver,
changes such as hepatocyte enlargement
and increased incidence of eosinophilic
hepatocytes, seen at doses of 80, 640, or 1,280 ppm were
associated with hepatic enzyme induction.
-- At 90 ppm, non-neoplastic changes were detected in bone
and the epididymides in addition to
liver changes. No treatment-related findings were seen
in mice treated at 10 ppm (approximately 1.5 mg/kg/ day), and
this dose level was defined as the NOAEL. In this same study,
an increased incidence of benign liver
cell tumors was observed in males and females fed 800 ppm, and
an increased incidence of benign and malignant liver cell tumors
in males and females given 1,250 ppm. These tumors were associated
with increased signs of hepatotoxicity including hepatocyte vacuolation
and fat deposition at 90, 800, and 1,250 ppm; granulomatous inflammation,
pigmented macrophages, bile duct hyperplasia and pericholangitis
in mice given 800 and 1,250 ppm. In addition, there was evidence
of treatment-related hepatocellular enlargement and increased
numbers of altered foci of eosinophilic and basophilic hepatocytes
in both sexes given 800 and 1,250 ppm; eosinophilic
hepatocytes were noted in male (only) mice receiving 90
ppm.
-- Tetraconazole is a triazole, and this class of compounds is
known to induce liver microsomal
enzymes. A special mechanistic study was conducted in order to
more fully determine the potential role of microsomal enzyme induction
by tetraconazole administered in the diet upon the formation of
tumors in mouse. Dietary administration of tetraconazole to mice
for 4 weeks results in the induction of cytochrome P450-related
activities, as well as the concentrations of microsomal protein
and cytochrome P450, and of the phase II activity, and p-nitrophenol
UDP- [[Page 55720]] glucuronyl transferase activity. The effects
of tetraconazole on the cytochrome P450-dependent MFO system were
somewhat different from those of phenobarbital. Many of these
enzymes have not been as well- characterized in mice compared
to rats. However, the phase II enzyme activity increases were
similar to those of phenobarbital. It is concluded from these
studies that prolonged induction of liver
microsomal enzymes and/or production of sustained liver injury
can lead to the formation of liver
tumors in mice.
Ref: Federal Register: October 14, 1999.
Notice of Filing Pesticide Petitions to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023,
and 7E4830.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Oct14.1999.htm
Lung
(click
on for all fluorinated pesticides)
Chronic & Carcinogenicity Studies.
Findings in other organs included enlarged cervical lymph nodes
at 800 and 1250 ppm, prominent alveolar
macrophages in the lungs of males at 1250 ppm and females of all
treated groups, pneumonitis in females at 800 and 1250 ppm,
involution in the thymus of males at 1250 ppm, and amyloidosis
in various organs of mainly males at 800 and 1250 ppm.
(page 5)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Reproduction
(click
on for all fluorinated pesticides)
Reproduction Study. Rats received
0, 10, 70 or 490 ppm of tetraconazole in the diet for two generations.
F0 and F1 females at 490 ppm had reduced food consumption, and
lower body weights during premating
and gestation, as did F1 males of this group. Increased mortality
(due to dystocia) and
higher liver, kidney and ovary weights were seen in adults of
both generations at 490 ppm. Mating performance and pregnancy
rate for both F0 and F1 generations were not affected. A prolonged
gestation period was associated with dystocia, and total
litter loss in some F0 and F1 females at 70 and 490 ppm. Increased
post-implantation loss and/or fetal deaths and consequently reduced
litter size at birth, and lower pup
weight gain during lactation were observed in F1 and F2
pups at 490 ppm. Offspring at 70 and 490 ppm had a slight
retardation of growth and sexual maturation (delayed vaginal opening
and balanopreputial cleavage). Increased
liver weights were seen in F1 and F2 pups at 490 ppm as well as
female pups at 70 ppm at weaning. No external and internal
abnormalities were found for both F1 and F2 pups. The NOEL was
10 ppm (0.4 mg/kg bw/day) for reproduction and postnatal toxicity.
(page 5-6)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
1,2,4-triazole -
Effects were also seen on reproductive organs in both sexes, most
notably ovaries (in rats) and testes (in rats and mice),
in both the reproductive toxicity and subchronic toxicity studies....
Ref: Human
Health Aggregate Risk Assessment for Triazole-derivative Fungicide
Compounds (1,2,4-Triazole, Triazole Alanine, Triazole Acetic
Acid). US EPA, February 7, 2006.
Reproductive
toxicity study-- Rats. In the 2-generation reproductive
toxicity study in rats, the maternal (systemic) NOAEL was 0.7
mg/kg/day, based on dystocia, delayed vaginal
opening, and increased liver weight
at the LOAEL of 5.9 mg/kg/day. The developmental (pup) NOAEL was
0.7 mg/kg/day, based on increased time to observation of
balanopreputial skin fold
[foreskin] and liver weight
at the LOAEL of 5.9 mg/ kg/day. At the high dose of 35.5 mg/kg/day,
there was a decrease in the mean number of live pups per litter
on lactation days 0 and 4 (precull) in the presence of significant
maternal toxicity.
Ref: Federal Register: December 6, 1999.
Tetraconazole; Pesticide Tolerances for Emergency Exemptions.
Final Rule.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Dec.1999.htm
•
Note from EC:
"Dystocia. Literally,
it means difficult labor and practically means abnormally slow
progress of labor. The word comes from the Greek 'dys' meaning
'difficult, painful, disordered, abnormal' and 'tokos' meaning
'birth'. Four potential factors may cause difficult labor characterized
by abnormally slow progress. They may occur separately or together.
1) Uterine contractions may be either too weak or too uncoordinated
to open up the cervix. There may also be inadequate pushing
with voluntary muscles during the second stage of labor.
2) The baby may be lined up wrong to easily pass through the
birth canal. Alternatively, there may be other problems with
the baby that also retard passage of the baby through the birth
canal.
3) The maternal bony pelvis may be too narrow to allow the baby
to pass through the birth canal.
4) Abnormalities of the birth canal other than those of the
bony pelvis may obstruct fetal descent. The
most common cause of dystocia is a small bony pelvis and/or
insufficiently strong and coordinated
uterine contractions.
[drnathan/sitedex.htm]."
-- Balanopreputial
skin fold- see:
http://www.cirp.org/library/history/hodges1/
Environmental
(click
on for all fluorinated pesticides)
Tetraconazole
is considered moderately toxic to
birds and highly toxic to fish,
aquatic invertebrates, algae/aquatic plants and sediment
dwelling organisms. Tetraconazole
has been shown to be hazardous to bees,
when they are exposed through oral or contact means. (page
21)
Persistent
in water sediment.
For the most part, sediments were anaerobic, and the majority
of the radioactivity found was parent compound indicating
very little metabolism of tetraconazole under anaerobic
conditions. For the whole water/sediment systems, half-lives
were calculated as 382 and 318 days for the pond and runoff
system respectively demonstrating the persistence of tetraconazole
in such systems. (page 18-19)
Persistent
in soil.
The other two field studies determined tetraconazole residues
in soil samples obtained from field tests where tetraconazole
was applied as a single dose. The tests were conducted over
1 year to 67 weeks and covered 5 soil types. Both these
studies indicated very little movement of tetraconazole
with no residues being detected below 10 cm. Degradation
rates varied significantly between the soils and half lives
ranged from 0.79 weeks (5.5 days) to 69 weeks (483 days).
Despite rapid initial degradation in some of the soils,
tetraconazole was clearly persistent
as over the course of the studies, insufficient degradation
occurred to allow a DT90 to be calculated (page 19). The
main concern is with persistence and accumulation in soils
and further work in this area is recommended with
any future application involving an extension to higher
rates and more frequent applications. (page 21)
Toxic
to fish.
Fish: Acute toxicity tests were performed on freshwater
fish under static renewal or flow through conditions. On
the basis of these results, tetraconazole
is considered toxic to fish with 96 h LC50s ranging from
>2.5-4.3 mg ac/L. Fathead minnow was tested for
toxicity to their early life stages. This test established
a 34 day NOEC of 1.09 ppm and a LOEC of 3.21 ppm. An acute
toxicity study was performed on each of the metabolites
SLM-2 and SLM-6 on rainbow trout. The results indicate that
metabolite SLM-6 is practically non-toxic to fish whereas
metabolite SLM-2 has a 96 h LC50 of 24 mg/L. (page 20)
Toxic
to very toxic to aquatic invertebrates.
Tetraconazole and formulated product were tested acutely
on one freshwater invertebrate (Daphnia) under static conditions
and one salt water species of mysid shrimp under static
conditions. The 48 h EC/LC50 values derived for daphnia
and mysid shrimp were 1.8-3.0 and 0.42 mg ac/L, respectively,
indicating tetraconazole is toxic
to very toxic to aquatic invertebrates. Daphnia were
further tested chronically under static renewal conditions.
The 21-d EC50 (reproduction) was estimated to be 0.73 mg/L.
The NOEC (21-d) was determined to be 0.56 ppm. An acute
toxicity study of each of the metabolites SLM-2 and SLM-6
indicates that SLM-6 is practically non-toxic to Daphnia
while SLM-2 has an acute toxicity of 48 h LC50 of 68 mg/L.
A 28 day chronic toxicity study was carried out on the larvae
of the sediment dwelling organisms midge Chironomous riparius.
A 28 day LC50 of 5.3 mg/L for the emergence and development
rates indicates that tetraconazole is toxic to Chironomous
riparius. (page 20)
Moderately
toxic to earthworms.
Four toxicity studies on earthworms indicate that tetraconazole
was moderately toxic to earthworms with a 14 d LD50 of 71
mg/kg and a corresponding NOEC of 32 mg/kg. (page 20)
Ref:
August
2005 - Evaluation of Tetraconazole in the product Domark
40ME Fungicide. Australian Pesticides and Veterinary Medicines
Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
Threatened
and Endangered Species Concern in the US.
-- The black-footed ferret is
possibly collocated in a total of 13 counties in three states
(MT, NE, and WY) based on EFED‘s LOCATES Database. There
may be a potential for indirect adverse effects based on an
endpoint of increased length of gestation. It is possible
that the availability of prey for the black-footed ferret
could be reduced. The black-footed ferret
feed on prairie dogs and other small mammals that may chronically
contain tetraconazole residues.
-- The US Fish and Wildlife Service is currently considering
a petition to delist the Preble‘s
mouse. This petition is based on the review of available
information which indicates that the Preble's mouse is not
a discrete taxonomic entity, does not meet the definition
of a subspecies, and was listed in error. Risk refinements
will not be necessary if this species is removed from the
list. A final rule will be made in May 2005 (FR Vol. 70. No.
21. February 2, 2005).
Ref: April 2005. Pesticide
Fact Sheet: Tetraconazole. US EPA.
http://www.fluorideaction.org/pesticides/tetraconazole.epa.2005.facts.pdf
|
A
February
16, 2005,
check at the Code
of Federal Regulations for Tetraconazole: this fungicide
is permitted in or on 10
food
commodities in the United States.
The
following list identifies these crops for which EPA has set
pesticide tolerances. |
[Code
of Federal Regulations]
[Title 40, Volume 22]
[Revised as of July 1, 2004]
From the U.S. Government Printing Office via GPO Access
[CITE: 40CFR180.557]
[Page 503]
TITLE 40--PROTECTION OF ENVIRONMENT
CHAPTER I--ENVIRONMENTAL PROTECTION AGENCY (CONTINUED)
PART 180_TOLERANCES AND EXEMPTIONS FROM TOLERANCES FOR PESTICIDE
CHEMICALS
IN FOOD--Table of Contents
Subpart C_Specific Tolerances
Sec. 180.557 Tetraconazole; tolerances for residues.
(a) General. [Reserved]
(b) Section 18 emergency exemptions. Time-limited
tolerances are
established for residues of the fungicide tetraconazole [(+/-)-2-(2,4-
dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl) propyl 1, 1,2,2-
tetrafluoroethyl ether] in connection with the use of the
pesticide
under section 18 emergency exemptions granted by EPA. The
tolerances
will expire and be revoked on the date specified in the following
table. |
Commodity |
As
of October 15,
2003
PPM |
As
of February 16,
2005
PPM |
Expiration/
Revocation Date |
Beet, sugar,
dried pulp |
0.20 |
0.20 |
12/31/05
|
Beet, sugar,
molasses |
0.30 |
0.30 |
12/31/05 |
Beet, sugar,
roots |
0.10 |
0.10 |
12/31/05
|
Beet, sugar,
tops |
6.0 |
6.0 |
12/31/05
|
Cattle,
fat |
0.60 |
0.60 |
12/31/05 |
Cattle,
kidney |
0.20 |
0.20 |
12/31/05 |
Cattle,
liver |
6.0 |
6.0 |
12/31/05
|
Cattle,
meat byproducts, except kidney and liver |
0.03 |
0.030 |
12/31/05
|
Cattle,
meat |
0.03 |
0.030 |
12/31/05
|
Milk |
0.05 |
0.050 |
12/31/05
|
(c)
Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved] |
|