Return to Flusilazole Index Page

Activity: Fungicide (azole)
Structure:

Adverse Effects:
Bladder
Body Weight Decrease
Bone developmental - Cleft palate
Brain
Conjoined Twins
Developmental
Eye - Microphthalmia and Coloboma
Kidney
Liver
Reproductive
Teratogenic
Tongue
Environmental

Bladder (click on for all fluorinated pesticides)

-- 2-Year Feeding (oncogenic) - mouse: Systemic NOEL=3.4 mg/kg/day; Systemic LEL=27 mg/kg/day (increased absolute and relative liver weight and increased hepatocellular fatty change in male and females); core grade supplementary (E.I. du Pont de Nemours & Co., Inc., 1985d)
-- 90-Day Feeding - rat: NOEL=125 ppm (6.25 mg/kg/day); LEL=375 ppm (18.75 mg/kg/day) (bladder hyperplasia, elevated cholesterol); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1983a)
-- 90-Day Feeding - dog: NOEL=25 ppm (0.625 mg/kg/day); LEL=125 ppm (3.13 mg/kg/day) (bladder hyperplasia, elevated alanine aminotransferase/serum glutamate pyruvate transaminase, uric acid, decreased total protein Ca albumen, cholesterol, increased liver weight); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1983b)
Ref: US EPA IRIS. NuStar CASRN: 85509-19-9. Available October 6, 2003, at Toxnet.

--The chronic toxicity/carcinogenicity studies in the rat, the target organs identified were consistent with the sub-chronic administration studies, i.e., liver and bladder. Flusilazole was found to be oncogenic at the higher doses, causing bladder transitional cell neoplasia in both sexes and testicular Leydig cell adenoma in males. There is evidence of a proliferative effect of flusilazole in the bladder transitional epithelium, which is likely the mechanism of tumorigenesis. Therefore, the urinary bladder tumors are considered to be caused by an epigenetic, threshold-associated mechanism. Interference of flusilazole with hypothalmic- pituitary-gonadal (HPG) axis is suggested as a possible mechanism of testicular tumor induction. Evidence in support of this theory was provided by a comparative study with the aromatase inhibitor, ketoconazole. Flusilazole did cause a slight reduction in both serum and testicular - testosterone and a dose-dependent decrease in serum estradiol, but was far less potent than ketoconazole. It would avoear reasonable to conclude that a threshold exists for the induction by flusilazole of testicular aienomas. The NOEL for neoplasms was 375 ppm (14.8 and 20.5 mg/kg/day in males and females, respectively). (Page 29)
-- In mouse chronic studies, the target organs were the liver, kidney, urinary bladder and urethra. The incidence of hepatocellular adenomas was increased at L 1000 ppm. Based on the combined results of two studies, the NOEL for oncogenicity in mice is 200 ppm (36 mgrkglday) in females and 500 ppm (73.1 mg/kg/day) for males. Since tumors occurred in excess of the MTD, and were preceded at lower doses by histopathological change consistent with induction-related hepatotoxicity, it is reasonable to conclude that the induction of such tumors is related to cytotoxicity, which demonstrates a clear threshold. (Pages 29-30)
-- Flusilazole was found to exert a clear systemic toxicity on sub-chronic and chronic administration to rats, mice and dogs. A similar pattern of effects was apparent across the three species, with the liver, urinary system and blood system targeted to varying degrees. It was found to be oncogenic at high dose levels in both mice and rats, inducing bladder transitional cell neoplasia in rats and testicular adenoma in male rats and hepatocellular adenomas and carcinomas in mice. (Page 30)
Ref: DuPont Punch (Active ingredient: Flusilazole) and DuPont Charisma (Active ingredients: Flusilazole and Famoxadone): Summary of data compiled in support of a Section 18 Emergency Exemption request for control of Asian soybean rust on soybeans. By DuPont authors: Cosgrove T, Czochor L, Dinter A, Jemberg K, Klemens A, Marcon A, McInnes B, Mullin L, Russell M, Ryan D, Singles S, Vanderbroeck V. Revision No. 1: February 2, 2005.
http://www.fluorideaction.org/pesticides/flusilazole.appendix1.pdf

Blood (click on for all fluorinated pesticides)

-- In a one-year feeding study, dogs were given flusilazole in the diet at concentrations of 0, 5,20, and 75 pprn (MRID 400421 13). There were treatment-related effects on hematological parameters at 75 pprn including increased white blood cell count, ALP activity, and serum cholesterol. Serum total protein and albumin levels were lower in the male high dose group. Relative liver weight was increased at 75 ppm. Treatment-related histopathological changes included liver centrilobular hepatocellular enlargement and centrilobular inflammation and hyperplasia in the lymphoid nodules of the gastric mucosa observed in the high dose. In summary, the effects of feeding flusilazole to dogs for one year were a dose-related trend towards mild to moderate hepatotoxicity and a mild leucocytosis (inflammatory) response. The effects were mainly seen in the high dose group and most pronounced in males. The liver hypertrophy was considered likely to be an adaptive response to increased metabolic demand. Based on minimal liver histology at the mid-dose, 20 ppm (0.7 mgkglday) is considered a NOAEL. (Pages 18-19)
-- Short-term exposure toxicity of flusilazole was investigated in rats (gavage and dietary), mice (dietary), dogs (dietary) and in rabbits (dermal application). The targets identified were the blood system, liver and urinary bladder. The dog was found to be the most sensitive species to the hepatotoxicity and bladder toxicity of flusilazole. Degenerative liver disorder and evidence of cellular proliferation (hyperplasia) in the urinary bladder were seen at 125 ppm (4.3 mgikglday) in the dog. The NOAEL was 0.9 mgkgiday. (Page 29)
Ref: DuPont Punch (Active ingredient: Flusilazole) and DuPont Charisma (Active ingredients: Flusilazole and Famoxadone): Summary of data compiled in support of a Section 18 Emergency Exemption request for control of Asian soybean rust on soybeans. By DuPont authors: Cosgrove T, Czochor L, Dinter A, Jemberg K, Klemens A, Marcon A, McInnes B, Mullin L, Russell M, Ryan D, Singles S, Vanderbroeck V. Revision No. 1: February 2, 2005.
http://www.fluorideaction.org/pesticides/flusilazole.appendix1.pdf

Body Weight Decrease (click on for all fluorinated pesticides)

-- 2-Generation Reproduction - rat: Parental NOEL=3.5 mg/kg/day; Parental LEL=19 mg/kg/day (decreased body weight and body weight gain in F1 males during the 90 day feeding study); Reproductive NOEL and LEL could not be determined; Developmental NOEL=0.85 mg/kg/day (hydronephrosis noted at weaning of F2b pups - only trial examined); core grade supplementary (E.I. du Pont de Nemours & Co., Inc., 1986b)
-- Teratology - rat: Maternal NOEL=10 mg/kg/day; Maternal LEL=100 mg/kg/day (increased mortality after day 23 of gestation, prolonged gestation, decreased food consumption and weight gain, increased relative and absolute liver weight); Developmental NOEL (pre and post natal)=2 mg/kg/day; Developmental LEL=10 mg/kg/day (increased incidence of small renal papilla, distended ureter, dilated renal pelvis, decreased pup survival); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1985b)
-- Teratology - rabbit: Maternal NOEL=12 mg/kg/day; Maternal LEL=35 mg/kg/day (decreased food consumption and final body weight were observed at one dose only); Developmental NOEL=12 mg/kg/day; Developmental LEL=35 mg/kg/day (increased resorptions and abortions, and decreased fetal weight); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1985c)
Ref: US EPA IRIS. NuStar CASRN: 85509-19-9. Available October 6, 2003 at Toxnet.

Bone (click on for all fluorinated pesticides)

Abstract: This report describes the first part of a study which was undertaken to examine the teratogenic potential of triazole compounds used as fungicides in agriculture. Pregnant Wistar rats were given single oral dosages of flusilazole or bitertanol on days 9, 10, 11 or 13th of gestation (positive vaginal smear=day 1) at levels of 1/5, 1/10 and 1/50 LD50. The dosages were calculated from the reported LD50 values of 1272 mg/kg for flusilazole and 5000 mg/kg for bitertanol. The results of the study demonstrated that both compounds induce congenital anomalies when given on days 9, 10 or 11th at levels corresponding to 1/5 and 1/10 LD50. The types of the registered malformations after flusilazole treatment were exophthalmus, hypognathia, macroglossia and cleft palate and after bitertanol treatment micro- and acaudia and in rare cases exophthalmus, hypognathia and cleft palate. A clear dose effect relationship was established for both compounds.
Ref: Vergieva T (1990). Teratology 1990 Aug;42(2):27A-28A. Triazoles teratogenicity in rats. Abstract from Toxnet.

• Definitions:
Exophthalmia (n.) The protrusion of the eyeball so that the eyelids will not cover it, in consequence of disease.
Hypognathus - Unequal conjoined twins in which the rudimentary parasite is attached to the mandible of the autosite.
Macroglossia - Excessively large tongue.

Note from FAN - not sure if this is appropriate under this category.
PubMed abstract: Triazole-derivatives are antimycotics used in agriculture as well as in clinical and veterinary therapy. The aim of the present work is the in vitro comparative study of the teratogenic activity of triazole (the parental compound), flusilazole (an agricultural triazole mono-derivative fungicide), and fluconazole (a clinically used bis-triazole derivative). Rat embryos, 9.5 days old (1 to 3 somites) were exposed in vitro to triazole 500 to 5000 microM, flusilazole 3.125 to 250 microM, or fluconazole 62.5 to 500 microM. After 48 h in culture, the embryos were morphologically examined and processed for histologic and biochemical analysis. Flusilazole and fluconazole [antifungal drug] showed similar teratogenic effects (abnormalities at the branchial apparatus level and cell death at the level of the branchial mesenchyme) at concentration levels of 6.25 microM and higher for flusilazole and of 125 microM and higher for fluconazole. By contrast, only slight developmental retardation and blood discoloration were observed at the highest concentrations of triazole, suggesting no teratogenic activity for the triazole group.
Ref: Antifungal triazoles induce malformations in vitro; by Menegola E, Broccia ML, Di Renzo F, Giavini E. Reprod Toxicol 2001 Jul-Aug;15(4):421-7
http://www.fluoridealert.org/pesticides/Flusilazole.PubMed.Abstrcts.htm

• Defintion:
branchial apparatus - Of or pertaining to branchiae or gills. Branchial arches, the bony or cartilaginous arches which support the gills on each side of the throat of fishes and amphibians. Branchial clefts, the openings between the branchial arches through which water passes. Source: Websters Dictionary

Brain (click on for all fluorinated pesticides)

Abstract: Triazole-derivatives alter the pharyngeal apparatus morphogenesis of rodent embryos cultured in vitro. The hindbrain segmentation and the rhombencephalic neural crest cell (NCCs) migration are altered by Fluconazole exposure in vitro. The aim of the present work is to identify if a common pathogenic pathway is detectable also for other molecules of this class of compounds. 9.5 days post coitum (d.p.c.) old rat embryos were exposed in vitro to the teratogenic concentrations of Flusilazole, Triadimefon and Triadimenol and cultured for 24, 48 or 60 h. The expression and localisation of Hox-b1 and Krox-20 proteins (used as markers for hindbrain segmentation) were evaluated after 24 h of culture. The localisation and distribution of NCC was evaluated after 24, 30 and 48 h of culture. The morphology of the embryos was analysed after 48 h, while the branchial nerve structures were evaluated after 60 h of culture. Hindbrain segmentation and NCC migration alteration as well as pharyngeal arch and cranial nerve abnormalities were detected after exposure of the tested molecules. A common severe teratogenic intrinsic property for the tested molecules of this chemical class has been found, acting through alteration of the normal hindbrain developmental pattern.
Reference: Menegola E, Broccia ML, Di Renzo F, Massa V, Giavini E (2005). Study on the common teratogenic pathway elicited by the fungicides triazole-derivatives. Toxicol In Vitro. Sep;19(6):737-48.
Abstract available at:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15913947&query_hl=19

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.

abnormalities at the level of the branchial apparatus; disorganisation and fusions at the level of the cranial nerves; abnormalities in the migration of NCC, not able to form 3 distinct migration stripes from the rhomboencephalon to the branchial apparatus; alteration of the hindbrain segmentation, with reduced and scattered immunolocalised stripes.
Reference: Massa et al. Mechanisms Involved In Triazole-Induced Teratogenesis: In Vitro Study. Toxicol Lett 2003 Sep ;144 (Suppl 1 ):S107

Conjoined Twins (click on for all fluorinated pesticides)

Abstract: This report describes the first part of a study which was undertaken to examine the teratogenic potential of triazole compounds used as fungicides in agriculture. Pregnant Wistar rats were given single oral dosages of flusilazole or bitertanol on days 9, 10, 11 or 13th of gestation (positive vaginal smear=day 1) at levels of 1/5, 1/10 and 1/50 LD50. The dosages were calculated from the reported LD50 values of 1272 mg/kg for flusilazole and 5000 mg/kg for bitertanol. The results of the study demonstrated that both compounds induce congenital anomalies when given on days 9, 10 or 11th at levels corresponding to 1/5 and 1/10 LD50. The types of the registered malformations after flusilazole treatment were exophthalmus, hypognathia, macroglossia and cleft palate and after bitertanol treatment micro- and acaudia and in rare cases exophthalmus, hypognathia and cleft palate. A clear dose effect relationship was established for both compounds.
Ref: Vergieva T (1990). Teratology 1990 Aug;42(2):27A-28A. Triazoles teratogenicity in rats. Abstract from Toxnet.

• Definitions:
Exophthalmia (n.) The protrusion of the eyeball so that the eyelids will not cover it, in consequence of disease.
Hypognathus - Unequal conjoined twins in which the rudimentary parasite is attached to the mandible of the autosite.
Macroglossia - Excessively large tongue.

Much of what is known about the possible dangers of flusilazole is considered a trade secret -- unavailable even to state agents investigating health complaints. What is known about the fungicide -- which is not approved for use in the United States -- offers little comfort to those who applied it to Florida farmland as an undisclosed ingredient in some lots of Benlate 50 DF. According to a study conducted in Bulgaria, oral doses of flusilazole given to pregnant rats produced congenital defects such as protruding eyes, twins of unequal size joined at the jaw and grossly enlarged tongues...
Ref: Jan Hollingsworth. Fungicide studies offer little comfort. Memo: BURIED SECRETS PURSUING A MEDICAL MYSTERY. December 18, 1995. Tampa Tribune (Florida). page 4.

Developmental (click on for all fluorinated pesticides)

-- Ten developmental toxicity studies were carried out with flusilazole, six in the rat (one dietary, four gavage, and one dermal) and four in the rabbit (one dietary and four gavage). In rats, maternal toxicity included decreased weight gain and food consumption, increased clinical signs, and increased liver weights. Fetal toxicity was evidenced by increased incidences of resorptions, fetal mortality, stunted fetuses, and skeletal variations (delayed ossifications, supernumerary ribs, and renal pelvis variations) and decreased fetal weight. Absent renal papillae occurred at 10 mgkglday and above and cleft palate occurred at 250 mgkg/day. Taken as a whole, the NOEL in rats was 0.5 mg/kg/day by the oral route. By the dermal route 2 mg/kg/day was near a NOAEL based on only placental, but no fetal effects at this dose. (- In a rabbit dietary developmental study the NOEL for the dam was 21.2 mg/kg/day and the developmental NOEL was 2.8 mgkg/day based on decreased litters and increased resorptions. In the first two rabbit gavage studies, the maternal and offspring NOELS were both 12 mg/kg/day. In the second there were increased total resorptions and one malformation (hydrocephaly) at 35 mg/kg/day. In the final rabbit gavage study, the maternal NOEL was 7 mgkglday based on increased clinical signs as 15 mgkglday. The developmental NOEL was 15 mg/kg/day based on increased resorptions at the high dose. Taken as a whole, the rabbit maternal NOEL via the gavage route is 7 mgkg/day and the developmental NOEL is 15 mgikglday. (Page 30)
-- In the feeding study, dietary concentrations were 0,50, 100, 300 and 900 pprn (MRID 00072999). Maternal food consumption was reduced at ≥300 pprn during treatment and maternal body weight gains were reduced at 900 ppm. The number of resorptions was significantly increased at the two highest doses and litter size was reduced at the highest dose. There was a significant dose related increase in stunted fetuses, significant at ≥300 ppm. There were no dose-related incidences of malformations. The incidence of variations (supernumerary and delayed ossifications) was increased at ≥ 100 ppm. The maternal NOEL was 100 pprn - (9 mgkgiday). EPA considered the developmental NOAEL to be 100 ppm (9.0 mg/kg/day) and li the NOEL for malformations to be > 900 pprn (79.2 mg/kg/day) the highest dose tested. (Page 21)
-- In the first of three rat gavage studies, flusilazole was administered by gavage (in corn oil) at concentrations of 0, 10,50 and 250 mgikgiday (MRID 00161 169). Maternal morality and clinical signs occurred at 250 mg/kg/day. Weight gain and food consumption were decreased and liver weight increased at ≥ 50 mg/kg/day group during dosing. In the 250 mg/kg/day group mean fetal body weight was reduced; the incidence of resorptions increased; and the number of live fetuses per litter were reduced. The number of live fetuses was also decreased in the intermediate group. There was a significant increase in malformations (cleft palate and absent renal papillae) at the maternally toxic dose, 250 mg/kg/day. There was an unusually high incidence of external hydrocephaly and distended lateral ventricles in all groups (including controls). However, this finding did not exhibit a definitive dose response and was not reproduced in another study over a similar dose range. Increased fetal variations in all dosed groups were misaligned sternebra, extra ossifications, rudimentary and extra ribs and delayed development consisting of partially ossified sternebra and vertebral arch. The maternal NOEL was 10 rng/kg/day and no fetal NOEL was established (< 10 mg/kg/day). (Page 21)
-- In the second gavage study, flusilazole was administered to rats at doses of 0,0.4,2, 10, 50, and 250 mg/kg/day (MRID 00161170). Maternal findings at 250 mg/kg/day were reduced feed consumption and weight gain and increased liver weights. At 50 mg/kg/day, there was a significant decreased food consumption and weight for the first two days but not thereafter. Relative liver weight was increased also at 50 mg/kg/day. A non-statistically significant increase in stunted fetuses occurred at 2 10 mgkglday. There was a statistically significant increase in malformations (cleft palate) in the maternally toxic, high-dose group. The incidence of total malformations (mostly absent renal papillae) and fetal variations were significantly increased at ≥ 10 mg/kg/day. The maternal NOEL 10 mgkg was based on reduced weight gain, liver weight increases and clinical signs. The developmental NOEL was 2.0 mgkg, based on increased incidence of skeletal variations. (Pages 21-22)
-- The third rat developmental gavage study, was conducted to resolve the biological significance and potential reversibility of the changes to the urinary system (small or no papillae, large renal pelvi and dilated ureter) seen in the previous study (MRID 40640704). Rats were dosed with 0, 0.2,0.4,2, 10, and 100 mg/kg/day and either sacrificed at gestation day 21 or 22 to examine fetuses (Phase 1) or dams were allowed to deliver and raise their young to weaning (Phase 2). Maternal toxicity was evidenced at the high dose in both phases as decreased food consumption and reduced weight gain, clinical signs (Phase 1 only), and death (Phase 2). Minimal maternal toxicity (reduction in weight gain during Phase 2) occurred 10 mg/kg/day. Fetal effects consisted of increased incidence of resorptions and stunted fetuses (100 rng/kg/day), increased numbers of fetuses dead at birth, and lower neonatal survival. In the fetal examinations there was an increased incidence of small renal papillae, dilated ureters and subcutaneous hemorrhage at 2 10 mg/lkg/day and bladder foci at 100 rng/kg/day. There were no apparent treatment-related malformations. The maternal and reproductive/developmental was NOAEL 2.0 mg/kg/day. (Page 22)
-- In the fourth rat gavage study (MRID 45042601), rats were dosed with 0,0.5,2, 10, or 50 mg/kg/day flusilazole on one of the following three schedules: days 6-15G (gestation) and sacrificed day 16G, days 6-15G and sacrificed day 21G, or 6-20G and sacrificed on day 21G. - Results were generally similar between the three designs. Maternal weight gain was affected at ≥10 mg/kg/day. Red vaginal discharge was observed at 2 mg/kg/day. Placental weights were increased at 22 mg/kg/day. Fetal weights were affected at 50 mg/kg/day only in the group dosed from 6-15G and sacrificed at 21G. Fetal resorptions were increased at 210 mgkglday. Fetal variations were increased at ≥2 mg/kg/day. At 50 mg/kg/day there was one malformation (naris atresia). The NOEL for the study was 0.5 mg/kg/day based on minimally increased incidence of red vaginal discharge, increased placental weight and increased fetal variations at 2 mg/kg/day. (Page 22)
-- In a rat dermal developmental toxicity study (MRID 44594201), flusilazole was applied to the skin of pregnant rabbits for six hourslday on days 6 to 19 of gestation at doses of 0, 2, 10, 50, and 250 mg/kg/day. Rats were sacrificed on gestation day 20. Mean maternal weight gains were greatly reduced in the 250 mg/kglday group. There were no abnormal clinical signs at any concentration. Microscopic examination of the dams' livers revealed minimal to mild centrilobular hepatocellular hypertrophy at ≥ 10 mg/kg/day. There were enlarged placenta observable at ≥ 10 mg/kg/day and microscopic placental changes at all dose levels. There were no other maternal effects at 2 mg/kg/day. Fetuses of dams treated with ≥ 10 mg/kg/day had enlarged livers and increased variations (rudimentary ribs and unossified sternebra). The lowest dose (2 rng/kg/day) was considered to approximate a NOAEL with the only effect being microscopically observable placental changes. It was not established whether the effect on placenta represent an adverse effect. Since placenta contains a large amount of cytochrome P-450 enzymes, the possibility of a metabolic/adaptive role should be considered. (Page 22)
Ref: DuPont Punch (Active ingredient: Flusilazole) and DuPont Charisma (Active ingredients: Flusilazole and Famoxadone): Summary of data compiled in support of a Section 18 Emergency Exemption request for control of Asian soybean rust on soybeans. By DuPont authors: Cosgrove T, Czochor L, Dinter A, Jemberg K, Klemens A, Marcon A, McInnes B, Mullin L, Russell M, Ryan D, Singles S, Vanderbroeck V. Revision No. 1: February 2, 2005.
http://www.fluorideaction.org/pesticides/flusilazole.appendix1.pdf

Endocrine Disruptor (click on for all fluorinated pesticides)

Abstract: Azoles (imidazoles and triazoles) are used as antifungal agents in agriculture and in medicine, and also for antiestrogen therapy, e.g., for breast cancer treatment. Antifungal activity is based on inhibition of fungal CYP51 (lanosterol 14alpha-demethylase), and estrogen biosynthesis reduction is due to azole inhibition of CYP19 (aromatase). Inhibition of aromatase by antifungal agents is usually an unwanted side effect and may cause endocrine disruption. A fluorimetric assay based on human recombinant CYP19 enzyme with dibenzylfluorescein as a substrate was used to compare the inhibitory potency of 22 azole compounds. Dose responses were established and duplicate datasets were analyzed with a nonlinear mixed-effects model with cumulative normal distribution for the logarithm of concentration. IC50 values (50% inhibitory concentration) of 13 fungicides used in agriculture ranged more than 700-fold, starting from 0.047 microM. The potency of seven human drugs spanned more than 7000-fold, starting from 0.019 microM. Most potent fungicides included prochloraz, flusilazole, and imazalil, and most potent medicinal antifungals were bifonazole, miconazole, and clotrimazole. These in vitro data indicate that the top-ranking azoles used as antifungal agents or drugs are as potent inhibitors of aromatase as are antiestrogen therapeutics used to treat breast cancer. These putative effects of azole agents and drugs on steroid biosynthesis and sex hormone balance should be considered when used in human subjects and also in wildlife exposed to azole fungicides used in agriculture.
Ref: Comparative assessment of the inhibition of recombinant human CYP19 (aromatase) by azoles used in agriculture and as drugs for humans. Trosken ER, Scholz K, Lutz RW, Volkel W, Zarn JA, Lutz WK. Endocr Res. 2004 Aug;30(3):387-94.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15554355

• Definition of aromatase inhibition: Prevention of the formation of estradiol, a female hormone, by interfering with an aromatase enzyme. Aromatase inhibition is a type of hormone therapy used in postmenopausal women who have hormone-dependent breast cancer.

Endocrine: Testicular (click on for all fluorinated pesticides)

-- A second, two-year chronic toxicity and carcinogenicity flusilazole feeding study was carried out in the rat to achieve an MTD (MRID 42613202). Rats were fed diets containing 0, 125, 375, and 750 pprn flusilazole for two years. Toxicologically significant effects of treatment with flusilazole were seen at every dose level in this study. The following were also observed: mortality (5) and induced hepatocellular hypertrophy, fatty change and mixed cell foci, testicular interstitial cell hyperplasia and interstitial cell adenomas in males; decreased mean final body weight and hepatocellular centrilobular hypertrophy in females; and increased mean absolute and relative liver weights, hepatocellular lamellar bodies, urinary bladder mucosal hyperplasia, and --. transitional cell neoplasms in both sexes. There was no NOEL for non-neoplastic lesions in either sex. The NOEL for neoplasms was 375 pprn (14.8 and 20.5 mgikglday in males and females, respectively). - (Page 18)
-- In the rat, target organs were consistent with the subchronic administration studies, i.e., liver and bladder. Flusilazole was oncogenic at the higher doses, causing bladder transitional cell neoplasia in both sexes and testicular Leydig cell adenomas in males... Based on subsequent mechanistic work (see mechanistic section that follows) interference of flusilazole with hypothalmic-pituitary-gonadal (HPG) axis is a possible mechanism of testicular tumor induction. Therefore, it is reasonable to conclude that a threshold exists for the induction by flusilazole of testicular adenomas. The NOEL for neoplasms was 375 pprn (14.8 and 20.5 mglkglday in males and females, respectively). (Page 19)
SUPPLEMENTARY MECHANISTIC STUDIES
---- A 90-day study (MRID 42613204) was conducted to investigate mechanisms of toxicity (hepatotoxicity) and oncogenicity (urinary bladder transitional cell tumors and testicular Leydig cell adenomas) of flusilazole in the rat. Since genotoxicity tests were negative, a non-genotoxic mechanisms of tumor induction were investigated i.e., increased cellular proliferation rates due to irritation or chronic toxicity, and peroxisome proliferation-mediated events. Flusilazole was administered to rats in the diet at concentrations of 0, 10, 125, 375 and 750 ppm. Rats were sacrificed after 1 or 2 weeks or 1.5 or 3 months. Liver weight increases correlated well with the observed cytochrome P-450 induction. It was concluded from these results that the liver toxicity seen in this study and therefore the long-term studies also was due to the observed induction of cytochrome P-450 causing proliferation of the SER and hepatocellular hypertrophy. In the urinary bladder, there was a clear proliferative response following treatment with flusilazole. Serum hormone levels were not significantly altered in this study. It was suggested that the mechanism may lie in the ability to inhibit cytochrome P-450 activity thereby inhibiting steroidogenesis. An additional study was carried out to further investigate the possible mechanism of testicular adenoma induction. The results of this study support the proposal that the toxicity of flusilazole results from effects on cytochrome P-450, and direct toxic effects on the bladder. (Page 28)
---- In the final two-year feeding study in the rat, flusilazole was found to induce testicular adenomas in males. A possible non-genotoxic mechanism for such tumor induction was investigated (HLR 410-93). Flusilazole has been shown to inhibit cytochrome P-450 by the same mechanism as ketoconazole (an anti-tumor agent used in the treatment of human testicular carcinoma). In an in vivo experiment, rats were treated twice daily with either 0, 10,25, 75 or 125 mg/kg/day of flusilazole or 0, 10, 25,50 or 100 mg/kg/day of ketoconazole for 14 days. In an in vitro experiment, Leydig cells were isolated from rats and cultured with ketoconazole or flusilazole and the concentrations of steroids were measured. In the in vivo study, relative accessory sex gland weights were reduced with ketoconazole, but not flusilazole. It was concluded that either the flusilazole was less potent than ketoconazole or operated by another mechanism. Ketoconazole produced a decrease in serum testosterone and related steroids. Flusilazole caused reduction in both serum and testicular testosterone and estradiol, but was far less potent than ketoconazole. It was proposed that this data supported the theory that flusilazole could induce Leydig cell tumors by decreasing testosterone and estradiol synthesis thus disrupting the HPT axis. (Page 28)
-- The chronic toxicity/carcinogenicity studies in the rat, the target organs identified were consistent with the sub-chronic administration studies, i.e., liver and bladder. Flusilazole was found to be oncogenic at the higher doses, causing bladder transitional cell neoplasia in both sexes and testicular Leydig cell adenoma in males. There is evidence of a proliferative effect of flusilazole in the bladder transitional epithelium, which is likely the mechanism of tumorigenesis. Therefore, the urinary bladder tumors are considered to be caused by an epigenetic, threshold-associated mechanism. Interference of flusilazole with hypothalmic- pituitary-gonadal (HPG) axis is suggested as a possible mechanism of testicular tumor induction. Evidence in support of this theory was provided by a comparative study with the aromatase inhibitor, ketoconazole. Flusilazole did cause a slight reduction in both serum and testicular - testosterone and a dose-dependent decrease in serum estradiol, but was far less potent than ketoconazole. It would appear reasonable to conclude that a threshold exists for the induction by flusilazole of testicular aienomas. The NOEL for neoplasms was 375 ppm (14.8 and 20.5 mglkgiday in males and females, respectively). (Page 29)
Ref: DuPont Punch (Active ingredient: Flusilazole) and DuPont Charisma (Active ingredients: Flusilazole and Famoxadone): Summary of data compiled in support of a Section 18 Emergency Exemption request for control of Asian soybean rust on soybeans. By DuPont authors: Cosgrove T, Czochor L, Dinter A, Jemberg K, Klemens A, Marcon A, McInnes B, Mullin L, Russell M, Ryan D, Singles S, Vanderbroeck V. Revision No. 1: February 2, 2005.
http://www.fluorideaction.org/pesticides/flusilazole.appendix1.pdf

Eye - Microphthalmia and Coloboma (click on for all fluorinated pesticides)

Parents believe that exposure to Flusilazol during pregnacy resulted in severe eye deformities such as microphthalmia (small eyes) and coloboma, a defect in the structure of the eyes.
Ref: Scottish Daily Record & Sunday Mail Ltd. - Sunday Mail. October 15, 2000
http://www.fluoridealert.org/pesticides/Flusilazole.Scot.EYE.2000.htm

• Definitions:
Coloboma - A defect of the iris caused by a failure of the eyeball to fuse properly during fetal development. These are developmental anomalies and do not worsen as the child grows older.
Microphthalmia - An unnatural smallness of the eyes, occurring as the result of disease or of imperfect development.

Abstract: This report describes the first part of a study which was undertaken to examine the teratogenic potential of triazole compounds used as fungicides in agriculture. Pregnant Wistar rats were given single oral dosages of flusilazole or bitertanol on days 9, 10, 11 or 13th of gestation (positive vaginal smear=day 1) at levels of 1/5, 1/10 and 1/50 LD50. The dosages were calculated from the reported LD50 values of 1272 mg/kg for flusilazole and 5000 mg/kg for bitertanol. The results of the study demonstrated that both compounds induce congenital anomalies when given on days 9, 10 or 11th at levels corresponding to 1/5 and 1/10 LD50. The types of the registered malformations after flusilazole treatment were exophthalmus, hypognathia, macroglossia and cleft palate and after bitertanol treatment micro- and acaudia and in rare cases exophthalmus, hypognathia and cleft palate. A clear dose effect relationship was established for both compounds.
Ref: Vergieva T (1990). Teratology 1990 Aug;42(2):27A-28A. Triazoles teratogenicity in rats. Abstract from Toxnet.

• Definitions:
Exophthalmia (n.) The protrusion of the eyeball so that the eyelids will not cover it, in consequence of disease.
Hypognathus - Unequal conjoined twins in which the rudimentary parasite is attached to the mandible of the autosite.
Macroglossia - Excessively large tongue.

Much of what is known about the possible dangers of flusilazole is considered a trade secret -- unavailable even to state agents investigating health complaints. What is known about the fungicide -- which is not approved for use in the United States -- offers little comfort to those who applied it to Florida farmland as an undisclosed ingredient in some lots of Benlate 50 DF. According to a study conducted in Bulgaria, oral doses of flusilazole given to pregnant rats produced congenital defects such as protruding eyes, twins of unequal size joined at the jaw and grossly enlarged tongues...
Ref: Jan Hollingsworth. Fungicide studies offer little comfort. Memo: BURIED SECRETS PURSUING A MEDICAL MYSTERY. December 18, 1995. Tampa Tribune (Florida). page 4

Kidney (click on for all fluorinated pesticides)

-- 2-Generation Reproduction - rat: Parental NOEL=3.5 mg/kg/day; Parental LEL=19 mg/kg/day (decreased body weight and body weight gain in F1 males during the 90 day feeding study); Reproductive NOEL and LEL could not be determined; Developmental NOEL=0.85 mg/kg/day (hydronephrosis noted at weaning of F2b pups - only trial examined); core grade supplementary (E.I. du Pont de Nemours & Co., Inc., 1986b)
-- Teratology - rat: Maternal NOEL=10 mg/kg/day; Maternal LEL=100 mg/kg/day (increased mortality after day 23 of gestation, prolonged gestation, decreased food consumption and weight gain, increased relative and absolute liver weight); Developmental NOEL (pre and post natal)=2 mg/kg/day; Developmental LEL=10 mg/kg/day (increased incidence of small renal papilla, distended ureter, dilated renal pelvis, decreased pup survival); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1985b)
Ref: US EPA IRIS. NuStar CASRN: 85509-19-9. Available October 6, 2003, at Toxnet.

• Definitions:
-- Hydronephrosis: Pathological chronic enlargement of the collecting channels of a kidney, leading to compression and eventual destruction of kidney tissue, and diminishing kidney functionning.
-- renal papilla - Renal Papillary Necrosis Alternate Names : Necrosis - Renal Papillae, Renal Medullary Necrosis Definition A disorder of the kidney involving death of some or all of the renal papillae.

Liver (click on for all fluorinated pesticides)

-- Oral RfD Summary: Critical Effect Experimental Doses. Liver cell enlargement. 1-Year Dog Feeding Study. du Pont, 1985. NOEL: 5 ppm (0.2 mg/kg/day) LEL: 20 ppm (0.7 mg/kg/day).
-- Nustar was administered in the diet at 0, 5, 20, or 75 ppm (0, 0.2, 0.7, or 2.5 mg/kg bw/day) to 5 dogs/sex/dose for 1 year. Hypertrophy of the centrilobular hepatocytes was noted in both sexes at the mid- and high-dose levels. Changes observed only at the high dose were consistent with hepatotoxicity and inflammation. In males these included: increased WBC counts due to increased neutrophils, monocytes and eosinophils; increased alkaline phosphatase and decreased cholesterol and total protein; and hepatocytic vacuolation. Increased liver weight and centrilobular inflammation of the liver occurred in both males and females. Thus, the NOEL and LEL for systemic toxicity are 5 ppm (0.2 mg/kg/day) and 20 ppm (0.7 mg/kg/day), respectively. [E.I. du Pont de Nemours and Company. 1985. MRID No. 40042113. Available from EPA. Write to FOI, EPA, Washington, DC 20460.]
-- 2-Year Feeding (oncogenic) - rat: No increase in neoplastic lesions at any dose; Systemic NOEL=0.46 mg/kg/day; Systemic LEL=2.3 mg/kg/day (hepatic changes in females at 1 year, including increased relative liver weight and hepatocellular hypertrophy); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1986a)
-- Teratology - rat: Maternal NOEL=10 mg/kg/day; Maternal LEL=100 mg/kg/day (increased mortality after day 23 of gestation, prolonged gestation, decreased food consumption and weight gain, increased relative and absolute liver weight); Developmental NOEL (pre and post natal)=2 mg/kg/day; Developmental LEL=10 mg/kg/day (increased incidence of small renal papilla, distended ureter, dilated renal pelvis, decreased pup survival); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1985b)
-- 2-Year Feeding (oncogenic) - mouse: Systemic NOEL=3.4 mg/kg/day; Systemic LEL=27 mg/kg/day (increased absolute and relative liver weight and increased hepatocellular fatty change in male and females); core grade supplementary (E.I. du Pont de Nemours & Co., Inc., 1985d)
-- 90-Day Feeding - dog: NOEL=25 ppm (0.625 mg/kg/day); LEL=125 ppm (3.13 mg/kg/day) (bladder hyperplasia, elevated alanine aminotransferase/serum glutamate pyruvate transaminase, uric acid, decreased total protein Ca albumen, cholesterol, increased liver weight); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1983b)
Ref: US EPA IRIS. NuStar CASRN: 85509-19-9. Available October 6, 2003, at Toxnet.

-- Short-term exposure toxicity of flusilazole was investigated in rats (gavage and dietary), mice (dietary), dogs (dietary) and in rabbits (dermal application). The targets identified were the blood system, liver and urinary bladder. The dog was found to be the most sensitive species to the hepatotoxicity and bladder toxicity of flusilazole. Degenerative liver disorder and evidence of cellular proliferation (hyperplasia) in the urinary bladder were seen at 125 ppm (4.3 mgikglday) in the dog. The NOAEL was 0.9 mgkgiday. (Page 29)
Ref: DuPont Punch (Active ingredient: Flusilazole) and DuPont Charisma (Active ingredients: Flusilazole and Famoxadone): Summary of data compiled in support of a Section 18 Emergency Exemption request for control of Asian soybean rust on soybeans. By DuPont authors: Cosgrove T, Czochor L, Dinter A, Jemberg K, Klemens A, Marcon A, McInnes B, Mullin L, Russell M, Ryan D, Singles S, Vanderbroeck V. Revision No. 1: February 2, 2005.
http://www.fluorideaction.org/pesticides/flusilazole.appendix1.pdf

Reproductive (click on for all fluorinated pesticides)

the effects of flusilazole on reproductive parameters were investigated in one single-generation and two multigeneration studies. In the single-generation study, there were effects on pup viability and weights. In the first multigeneration study, there was no parental toxicity demonstrated at doses up to 250 ppm. Offspring findings, mostly at the high dose level included reduced number of live pups at birth and reduced viability during lactation. The NOEL r- for this study was 50 ppm based on perinatal effects. The same dose levels were used in the second study. Minimal signs of treatment-related effects seen in the 50 (not significant) and 250 pprn parental animals consisted of body weight effects in parental females. A significant increase in gestation length and periparturient deaths occurred in the high dose group. This finding was consistent with reduced viability of pups at birth. In addition, pups did not thrive and reduced weight gain and survival was recorded for litters of dams fed 250 pprn in all matings. The NOEL for reproductive/offspring effects was 50 ppm. (Pages 20-21)
Ref: DuPont Punch (Active ingredient: Flusilazole) and DuPont Charisma (Active ingredients: Flusilazole and Famoxadone): Summary of data compiled in support of a Section 18 Emergency Exemption request for control of Asian soybean rust on soybeans. By DuPont authors: Cosgrove T, Czochor L, Dinter A, Jemberg K, Klemens A, Marcon A, McInnes B, Mullin L, Russell M, Ryan D, Singles S, Vanderbroeck V. Revision No. 1: February 2, 2005.
http://www.fluorideaction.org/pesticides/flusilazole.appendix1.pdf

-- Although fish early life-stage tests provide useful information on sensitive life stages of fish, for flusilazole in particular the risk assessment has explicitly identified fish and other aquatic species to be at risk from agricultural use of this a.s., and there is evidence that flusilazole may have specific effects on the reproductive process. Therefore the SCP cannot conclude that a NOEC based on a fish early life-stage test for a single species is necessarily adequate in this particular case to ensure sufficient protection of fish populations from adverse effects on reproduction.
-- The monograph (volume 3, pp. 230-233) identified aquatic species, and fish in particular, as possibly at risk from flusilazole. In addition, a dose-dependent decrease in serum estradiol levels by flusilazole, considered to be indicative of aromatase inhibition, was observed in studies with rats (volume 3, p. 73). Aromatase inhibition is significant for reproduction since aromatization of testosterone is the process by which oestrogen is formed in vertebrates (Trant et al. 1997). This reaction is mediated by the cytochrome P450 aromatase. It has been shown that oestrogen (i.e., oestradiol) plays a major role in the reproductive physilogy of all vertebrates, including gamete development and maturation, and induces the hepatic synthesis of the yolk precursor, vitellogenin. Studies in which fish have been exposed to aromatase inhibitors suggest that aromatase activity, specificity or expression levels vary with maturation stage and among species (Bl‡zquez et al. 2001, Zerulla et al. 2002).
-- ... Neither of the above tests was designed to investigate possible effects on reproductive output or mating behaviour of adult fish. Given that there is evidence that flusilazole is an aromatase inhibitor, there are specific concerns that reproduction could be adversely affected by this substance. Therefore potential effects on mating behaviour, time to sexual maturity, reproductive output and timing, fertilisation success, and sex ratio of offspring are also of concern and should be explicitly addressed by a test designed for this purpose.
Ref: July 2002 - Opinion of the Scientific Committee on Plants on specific questions from the Commission concerning the evaluation of flusilazole in the Council Directive 91/414/EEC. European Commission. Health & Consumer Protection Directorate-General.
http://www.fluorideaction.org/pesticides/flusilazole.eu.july.2002.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.

Teratogenic (click on for all fluorinated pesticides)

Abstract: Triazole-derivatives alter the pharyngeal apparatus morphogenesis of rodent embryos cultured in vitro. The hindbrain segmentation and the rhombencephalic neural crest cell (NCCs) migration are altered by Fluconazole exposure in vitro. The aim of the present work is to identify if a common pathogenic pathway is detectable also for other molecules of this class of compounds. 9.5 days post coitum (d.p.c.) old rat embryos were exposed in vitro to the teratogenic concentrations of Flusilazole, Triadimefon and Triadimenol and cultured for 24, 48 or 60 h. The expression and localisation of Hox-b1 and Krox-20 proteins (used as markers for hindbrain segmentation) were evaluated after 24 h of culture. The localisation and distribution of NCC was evaluated after 24, 30 and 48 h of culture. The morphology of the embryos was analysed after 48 h, while the branchial nerve structures were evaluated after 60 h of culture. Hindbrain segmentation and NCC migration alteration as well as pharyngeal arch and cranial nerve abnormalities were detected after exposure of the tested molecules. A common severe teratogenic intrinsic property for the tested molecules of this chemical class has been found, acting through alteration of the normal hindbrain developmental pattern.
Reference: Menegola E, Broccia ML, Di Renzo F, Massa V, Giavini E (2005). Study on the common teratogenic pathway elicited by the fungicides triazole-derivatives. Toxicol In Vitro. Sep;19(6):737-48.
Abstract available at:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15913947&query_hl=19

abnormalities at the level of the branchial apparatus; disorganisation and fusions at the level of the cranial nerves; abnormalities in the migration of NCC, not able to form 3 distinct migration stripes from the rhomboencephalon to the branchial apparatus; alteration of the hindbrain segmentation, with reduced and scattered immunolocalised stripes.
Reference: Massa et al. Mechanisms Involved In Triazole-Induced Teratogenesis: In Vitro Study. Toxicol Lett 2003 Sep ;144 (Suppl 1 ):S107

Abstract: This report describes the first part of a study which was undertaken to examine the teratogenic potential of triazole compounds used as fungicides in agriculture. Pregnant Wistar rats were given single oral dosages of flusilazole or bitertanol on days 9, 10, 11 or 13th of gestation (positive vaginal smear=day 1) at levels of 1/5, 1/10 and 1/50 LD50. The dosages were calculated from the reported LD50 values of 1272 mg/kg for flusilazole and 5000 mg/kg for bitertanol. The results of the study demonstrated that both compounds induce congenital anomalies when given on days 9, 10 or 11th at levels corresponding to 1/5 and 1/10 LD50. The types of the registered malformations after flusilazole treatment were exophthalmus, hypognathia, macroglossia and cleft palate and after bitertanol treatment micro- and acaudia and in rare cases exophthalmus, hypognathia and cleft palate. A clear dose effect relationship was established for both compounds.
Ref: Vergieva T (1990). Teratology 1990 Aug;42(2):27A-28A. Triazoles teratogenicity in rats. Abstract from Toxnet.

• Definitions:
Exophthalmia (n.) The protrusion of the eyeball so that the eyelids will not cover it, in consequence of disease.
Hypognathus - Unequal conjoined twins in which the rudimentary parasite is attached to the mandible of the autosite.
Macroglossia - Excessively large tongue.

PubMed abstract: Triazole-derivatives are antimycotics used in agriculture as well as in clinical and veterinary therapy. The aim of the present work is the in vitro comparative study of the teratogenic activity of triazole (the parental compound), flusilazole (an agricultural triazole mono-derivative fungicide), and fluconazole (a clinically used bis-triazole derivative). Rat embryos, 9.5 days old (1 to 3 somites) were exposed in vitro to triazole 500 to 5000 microM, flusilazole 3.125 to 250 microM, or fluconazole 62.5 to 500 microM. After 48 h in culture, the embryos were morphologically examined and processed for histologic and biochemical analysis. Flusilazole and fluconazole [antifungal drug] showed similar teratogenic effects (abnormalities at the branchial apparatus level and cell death at the level of the branchial mesenchyme) at concentration levels of 6.25 microM and higher for flusilazole and of 125 microM and higher for fluconazole. By contrast, only slight developmental retardation and blood discoloration were observed at the highest concentrations of triazole, suggesting no teratogenic activity for the triazole group.
Ref: Antifungal triazoles induce malformations in vitro; by Menegola E, Broccia ML, Di Renzo F, Giavini E. Reprod Toxicol 2001 Jul-Aug;15(4):421-7
http://www.fluoridealert.org/pesticides/Flusilazole.PubMed.Abstrcts.htm

Much of what is known about the possible dangers of flusilazole is considered a trade secret -- unavailable even to state agents investigating health complaints. What is known about the fungicide -- which is not approved for use in the United States -- offers little comfort to those who applied it to Florida farmland as an undisclosed ingredient in some lots of Benlate 50 DF. According to a study conducted in Bulgaria, oral doses of flusilazole given to pregnant rats produced congenital defects such as protruding eyes, twins of unequal size joined at the jaw and grossly enlarged tongues...
Ref: Jan Hollingsworth. Fungicide studies offer little comfort. Memo: BURIED SECRETS PURSUING A MEDICAL MYSTERY. December 18, 1995. Tampa Tribune (Florida). page 4.

Parents believe that exposure to Flusilazol during pregnacy resulted in severe eye deformities such as microphthalmia (small eyes) and coloboma, a defect in the structure of the eyes.
Ref: Scottish Daily Record & Sunday Mail Ltd. - Sunday Mail. October 15, 2000
http://www.fluoridealert.org/pesticides/Flusilazole.Scot.EYE.2000.htm

• Definitions:
Coloboma - A defect of the iris caused by a failure of the eyeball to fuse properly during fetal development. These are developmental anomalies and do not worsen as the child grows older.
Microphthalmia - An unnatural smallness of the eyes, occurring as the result of disease or of imperfect development.

Abstract. Silane,[Bis(4-Flouorophenyl)] (Methyl)(1H,1,2,4-Triazol-1-ymethyl-INH-6573 (CAS# 85509-19-9) was evaluated to determine its embryo-fetal toxicity and teratogenic potential when administered by oral gavage to twenty-five rats (Charles River CD strain) per treatment group on days 7 through 16 of gestation at doses of 0, 10, 50, and 250 mg/kg body weight. At 250 mg/kg maternal deaths occurred and overt toxicity expressed as decreased body weight gain and feed consumption and by a significant increase of chromodacryorrhea, chromorhinorrhea, wet and stained underbodies, and alopecia. Slight maternal toxicity at 50 mg/kg was expressed as a significant decrease in feed consumption. The mean relative liver weight was significantly increased in the 250 and 50 mg/kg treatment groups. No maternal toxicity was noted at 10 mg/kg and below. Embryo-fetal toxicity was noted at all treatment levels. At 250 mg/kg a decrease in fetal body weight and an increase in fetal deaths were reported. The incidence of skeletal variations were increased significantly above controls at all treatment levels. An increase in fetal head malformations were reported in all groups, including controls. Male to female sex ratios of litters were not reported. Due to the incidence of fetal head malformations across all groups, no NOEL was reported in this study.
Ref: 1992 - INITIAL SUBMISSION: EMBRYO-FETAL TOXICITY AND TERATOGENICITY STUDY OF INH-6573-39 BY GAVAGE IN THE RAT (FINAL REPORT) WITH ATTACHMENTS AND COVER LETTER DATED 03-27-92. HASKELL LAB [E I DUPONT DE NEMOURS & CO]. Report No. NTIS/OTS0535920 from The National Technical Information Service.

Tongue (click on for all fluorinated pesticides)

Abstract: This report describes the first part of a study which was undertaken to examine the teratogenic potential of triazole compounds used as fungicides in agriculture. Pregnant Wistar rats were given single oral dosages of flusilazole or bitertanol on days 9, 10, 11 or 13th of gestation (positive vaginal smear=day 1) at levels of 1/5, 1/10 and 1/50 LD50. The dosages were calculated from the reported LD50 values of 1272 mg/kg for flusilazole and 5000 mg/kg for bitertanol. The results of the study demonstrated that both compounds induce congenital anomalies when given on days 9, 10 or 11th at levels corresponding to 1/5 and 1/10 LD50. The types of the registered malformations after flusilazole treatment were exophthalmus, hypognathia, macroglossia and cleft palate and after bitertanol treatment micro- and acaudia and in rare cases exophthalmus, hypognathia and cleft palate. A clear dose effect relationship was established for both compounds.
Ref: Vergieva T (1990). Teratology 1990 Aug;42(2):27A-28A. Triazoles teratogenicity in rats. Abstract from Toxnet.

• Definitions:
Exophthalmia (n.) The protrusion of the eyeball so that the eyelids will not cover it, in consequence of disease.
Hypognathus - Unequal conjoined twins in which the rudimentary parasite is attached to the mandible of the autosite.
Macroglossia - Excessively large tongue.

Much of what is known about the possible dangers of flusilazole is considered a trade secret -- unavailable even to state agents investigating health complaints. What is known about the fungicide -- which is not approved for use in the United States -- offers little comfort to those who applied it to Florida farmland as an undisclosed ingredient in some lots of Benlate 50 DF. According to a study conducted in Bulgaria, oral doses of flusilazole given to pregnant rats produced congenital defects such as protruding eyes, twins of unequal size joined at the jaw and grossly enlarged tongues...
Ref: Jan Hollingsworth. Fungicide studies offer little comfort. Memo: BURIED SECRETS PURSUING A MEDICAL MYSTERY. December 18, 1995. Tampa Tribune (Florida). page 4.