Adverse Effects
Tetraconazole
CAS No.
112281-77-3

 
 

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]
 
Fluoride Action Network | Pesticide Project | 315-379-9200 | pesticides@fluoridealert.org