Abstracts
Flusilazole
CAS No. 85509-19-9
For more abstracts search PubMed or Toxnet
 
 

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Adverse Effects

ACTIVITY: Fungicide (azole)

CAS Name: 1-[[bis(4-fluorophenyl)methylsilyl]methyl]-1H-1,2,4-triazole

Structure:


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15913947&query_hl=19

Toxicol In Vitro. 2005. Sep;19(6):737-48.

Study on the common teratogenic pathway elicited by the fungicides triazole-derivatives.

Menegola E, Broccia ML, Di Renzo F, Massa V, Giavini E

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.

 

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15554355

Endocr Res. 2004 Aug;30(3):387-94.

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.

Department of Toxicology, University of Wurzburg, Wurzburg, Germany.

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.

PMID: 15554355 [PubMed - in process]


From Dart Special at Toxnet

Teratology 1990 Aug;42(2):27A-28A

Triazoles teratogenicity in rats.

Vergieva T

Inst. of Hygiene, Sofia, Bulg.

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.

• 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.


Reports available from
The National Technical Information Service
(NTIS)

Order from NTIS by: phone at 1-800-553-NTIS (U.S. customers); (703)605-6000 (other countries); fax at (703)605-6900; and email at orders@ntis.gov. NTIS is located at 5285 Port Royal Road, Springfield, VA, 22161, USA.
Order No. Title Keywords / Abstract

NTIS/OTS0559123

EPA/OTS; Doc #89980000145S

1998 - SUPPORT: A DERMAL DOSE RANGE-FINDING PRENATAL DEVELOPMENTAL TOXICITY STUDY OF FLUSILAZOLE IN RATS, FINAL REPORT, WITH COVER LETTER DATED 3-6-1998 (SANITIZED)

WIL RESEARCH LABORATORIES INC

CONFIDENTIAL
FLUSILAZOLE
HEALTH EFFECTS
REPRODUCTION/FERTILITY EFFECTS
TERATOGENICITY
MAMMALS
RATS
DERMAL
CAS Registry No: 85509-19-9

NTIS/OTS0559123

EPA/OTS; Doc #88970000188S

1997 - INITIAL SUBMISSION: LETTER FROM [] TO USEPA REPORTING PRELIMINARY RESULTS OF RAT PILOT DERMAL DEVELOPMENTAL TOXICITY STUDY WITH FLUSILAZOLE, DATED 5-23-1997 (SANITIZED)

CONFIDENTIAL
FLUSILAZOLE
HEALTH EFFECTS
REPRODUCTION/FERTILITY EFFECTS
TERATOGENICITY
MAMMALS
RATS
DERMAL
CAS Registry No: 85509-19-9

NTIS/OTS0538409-4

EPA/OTS; Doc #89970000022S

1996 - SUPPORT: LETTER FROM [ ] TO USEPA REGARDING ACUTE ORAL TOXICITY OF A SUBSTITUTED HETEROCYCLE AND FLUSILAZOLE, DATED 11-11-96 (SANITIZED)


CONFIDENTIAL
SUBSTITUTED HETEROCYCLE AND FLUSILAZOLE
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
ORAL
GAVAGE
CAS Registry No: 85509-19-9

NTIS/OTS0535921

EPA/OTS; Doc #88-920001537

1992 - INITIAL SUBMISSION: DEVELOPMENTAL TOXICITY STUDY IN RATS GIVEN INF-5829 BY GAVAGE ON DAYS 7-16 OF GESTATION (FINAL REPORT) WITH ATTACHMENTS AND COVER LETTER DATED 03-27-92

HASKELL LAB

Benzyl sulfonamide,N-{[(4-methoxy- 6-methyl-1,3,5-triazin-2-yl)amino]carbonyl}-2-
(propylsulfonyloxy) (CAS# 85509-19-9) was evaluated for developmental toxicity in groups of 25 rats (Charles River CD strain) given the test substance by oral gavage on days 7 through 16 of gestation at doses of 0, 30, 200, and 500 mg/Kg body weight. No spontaneous deaths occurred in any of the treatment groups. At 500 mg/Kg/day the dams exhibited decreases in food consumption and body weight gain during the treatment period. No adverse effects were reported in the 30 or 200 mg/Kg groups when compared to the control group. At the 500 and 200 mg/Kg dose level fetal toxicity was expressed as decreased mean fetal body weight, an increased percentage of fetuses with variations per litter, and a significant increase in number of fetuses with unossified or partially ossified sternebrae. The 30 mg/Kg group exhibited fetal variations similar to controls. There were no significant differences in sex ratios of litters between control and treatment groups. The NOEL reported was 200 mg/KG for the dams and 30 mg/Kg for the fetus.

Keywords:
E I DUPONT DE NEMOURS & CO
INF-5829
HEALTH EFFECTS
REPRODUCTION/FERTILITY EFFECTS
TERATOGENICITY
MAMMALS
RATS
ORAL
GAVAGE
CAS Registry No: 85509-19-9

NTIS/OTS0535901

EPA/OTS; Doc #88-920001517

1992 - INITIAL SUBMISSION: NINETY-DAY FEEDING AND ONE-GENERATION REPRODUCTION STUDY IN RATS WITH SILANE, [BIS(4-FLUOROPHENYL)] (METHYL) (1H-
1,2,4-TRIAZOL-1-YLMETHYL) (INH-6573) W-ATTACH

HASKELL LAB

(Methyl)(1H,1,2,4-Triazol-1-ymethyl-INH-6573; 11/29/83, EPA 88- 920001517, Fiche No. OTS0535901] The subchronic toxicity of Silane (CAS# 85509-19-9) was evaluated when fed to groups of sixteen male and sixteen female rats (Charles River CD Strain) in a nutritionally adequate diet at doses of 0, 25, 125, 375, and 750 ppm. At the end of the ninety-day feeding phase, ten rats in each group were sacrificed and processed for histopathological examination. The remaining rats in the 0, 25, 125, and 375 ppm dose groups were used in a one-generation, one-litter reproduction substudy to assess the effects of the test substance on reproductive and lactation performance. Throughout the reproduction substudy, all rats received their respective treatment group's diet. After the last litter was weaned, male and female parent rats were fed control diets for four months. After this recovery phase, bladders were removed from these rats to assess the reversibility of lesions that had been observed in test rats sacrificed at the end of the ninety-day feeding phase of the study. Body weights of dams fed 125, 375, and 750 ppm were decreased compared to controls. Absolute and relative liver weights of male and female rats in the high-dose group were elevated. Relative liver weights of female rats in the 125 and 375 ppm groups were greater than controls but within range of biological variation, therefore the 750 ppm dose level was reported as the effect level for liver weight change. In the reproduction substudy, the dams at the 375 ppm dose level showed decreases in proportion of litters with at least one live pup, percent of pups born alive per litter, and percent of litters surviving until weaning as compared to controls. Male to female sex ratio of litters was not reported. Mean litter weights were similar to controls. All pups were sacrificed after weaning with no pathological examination. No conclusions regarding fertility were given as all groups, especially that of the control and 125 ppm groups were abnormally low. The NOEL was reported to be 125 ppm.

Keywords:
E I DUPONT DE NEMOURS & CO
INH-6573
HEALTH EFFECTS
SUBCHRONIC TOXICITY
MAMMALS
RATS
ORAL
DIET
REPRODUCTION/FERTILITY EFFECTS
CAS Registry No: 85509-19-9

NTIS/OTS0535920

EPA/OTS; Doc #88-920001536

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

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.

Keywords:
E I DUPONT DE NEMOURS & CO
INH-6573-39
HEALTH EFFECTS
REPRODUCTION/FERTILITY EFFECTS
TERATOGENICITY
MAMMALS
RATS
ORAL
GAVAGE
CAS Registry No: 85509-19-9

NTIS/OTS0543819

EPA/OTS; Doc #88-920006814

1992 - INITIAL SUBMISSION: TEN DOSE ORAL SUBACUTE TEST WITH INH-6573-25 IN RATS WITH ATTACHMENTS, COVER SHEETS AND LETTER DATED 08-20-92

HASKELL LAB

E I DUPONT DE NEMOURS & CO
INH-6573-25
HEALTH EFFECTS
SUBCHRONIC TOXICITY
MAMMALS
RATS
ORAL
GAVAGE
CAS Registry No: 85509-19-9

NTIS/OTS0555076

EPA/OTS; Doc #88-920008258

1992 - INITIAL SUBMISSION: SUBCHRONIC ORAL TOXICITY STUDY OF SILANE, [BIS(4-
FLUOROPHENYL)](METHYL)(1H-
1,2,4-TRIAZOL-1-
YLMETHYL* IN RATS WITH COVER LETTER DATED 08/20/92

HASKELL LABORATORY

E I DUPONT DE NEMOURS & CO
SILANE, [BIS(4-
FLUOROPHENYL)](METHYL)(1H-
1,2,4-TRIAZOL-1-YL*
HEALTH EFFECTS
SUBCHRONIC TOXICITY
MAMMALS
RATS
ORAL
GAVAGE
CAS Registry No: 85509-19-9

NTIS/OTS0570779

EPA/OTS; Doc #88-920008497

1992 - INITIAL SUBMISSION: LETTER FROM DUPONT CHEM TO USEPA REGARDING EMBRYO-FETAL AND TEROTOGENICITY STUDY OF SILANE* IN RATS WITH COVER LETTER AND ATTACHMENTS DATED 08-20-92

DUPONT CHEM
SILANE, [BIS(4-
FLUROPHENYL)](METHYL)(1H-1,2,4-
TRIAZOL*
HEALTH EFFECTS
REPRODUCTION/FERTILITY EFFECTS
COMBINED TERATOGENICITY/REPRODUCTIVE EFFECTS
MAMMALS
RATS
ORAL
GAVAGE
CAS Registry No: 85509-19-9

NTIS/OTS0570852

EPA/OTS; Doc #88-920008564

1992 - INITIAL SUBMISSION: ACUTE ORAL TOXICITY OF SILANE, [BIS(4-
FLUOROPHENYL](METHYL)(1H-
1,2,4-TRIAZOLE-1-
YLMETHYL)- IN RATS WITH COVER LETTER DATED 08-20-92

HASKELL LABORATORY

DUPONT CHEM
SILANE, [BIS(4-FLUOROPHENYL)](METHYL)(1H,1,2,4-
TRIAZOLE-1-Y*
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
ORAL
GAVAGE
CAS Registry No: 85509-19-9

NTIS/OTS0570685

EPA/OTS; Doc #88-920008403

1992 - INITIAL SUBMISSION: LETTER FROM DUPONT CHEM TO USEPA REGARDING A 4-WEEK AND 90-DAY FEEDING STUDY OF SILANE, [BIS(4-FLUROPHENYL)](METHYL)* IN MICE WITH COVER LETTER DATED 08-20-92

DUPONT CHEM
SILANE, [BIS(4-FLUROPHENYL)](METHYL) 1H-
1,2,4*
HEALTH EFFECTS
SUBCHRONIC TOXICITY
MAMMALS
MICE
ORAL
DIET
CAS Registry No: 85509-19-9

NTIS/OTS0570690

EPA/OTS; Doc #88-920008408

1992 - INITIAL SUBMISSION: LETTER FROM DUPONT CHEM TO USEPA REGARDING 1H-1,2,4-
TRIAZOLE, 1-
(BIS-(FLURPHENYL)METHYL IN RATS WITH COVER LETTER AND ATTACHMENTS DATED 08-20-92

DUPONT CHEM
1H-1,2,4-TRIAZOLE, 1-(BIS-
(FLUORPHENYL)METHYL
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
INHALATION
CAS Registry No: 85509-19-9

NTIS/OTS0543806

EPA/OTS; Doc #88-920006801

1992 - INITIAL SUBMISSION: INHALATION MEDIAN LETHAL CONCENTRATION (LC50) OF INH-6573-43 BY EPA PROCOTOL WITH ATTACHMENTS, COVER SHEET & LETTER

HASKELL LAB

E I DUPONT DE NEMOURS & CO
INH-6573-43
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
INHALATION
CAS Registry No: 85509-19-9

NTIS/OTS0570678

EPA/OTS; Doc #88-920008396

1992 - INITIAL SUBMISSION: ACUTE ORAL TOXICITY OF N7872-25 IN MALE AND FEMALE RATS WITH COVER LETTER DATED 08-20-92

HASKELL LABORATORY

DUPONT CHEM
N7872-25
HEALTH EFFECTS
ACUTE TOXICITY
MAMMALS
RATS
ORAL
GAVAGE
CAS Registry Nos:
10605-21-7
85509-19-9

NTIS/OTS0570781

EPA/OTS; Doc #88-920008499

1992 - INITIAL SUBMISSION: LETTER FROM DUPONT CHEM TO USEPA REGARDING 90-DAY FEEDING STUDY AND ONE-GENERATION REPRODUCTION STUDY IN RATS WITH COVER LETTER AND ATTACHMENTS DATED 08-20-92

DUPONT CHEM
SILANE, [BIS(4-
FLUROPHENYL)](METHYL)(1H,2,4-
TRIAZOL*
HEALTH EFFECTS
SUBCHRONIC TOXICITY
MAMMALS
RATS
ORAL
DIET
REPRODUCTION/FERTILITY EFFECTS
TERATOGENICITY
CAS Registry No: 85509-19-9

Other studies performed for US EPA:

MRID 44302410. O'Neill, A. (1994) Inhalation Median Lethal Concentration (LC50) Study with DPX-JE874-158 in Rats. DuPont Haskell Laboratory Report HLR 791-93.

MRID 40042109. Turner, R. (1985) Inhalation Median Lethal Concentration (LC50) of INH- 6573. DuPont Haskell Laboratory Report HLR 1-85.

MRID 40042106. Wylie, C. (1984) Median Lethal Dose (LD50) in Rats. DuPont Haskell Laboratory Report HLR 433-83.

MRID 40042107 Gargus, J. and J. Sutherland (1983) Acute Skin Absorption LD50 Test on Rabbits. Haskell Laboratory Report HLO 288-83.

MRID 40357501 Dashiell, 0. (1982) INH-6573 Eye hitation Test in Rabbits. DuPont Haskell Laboratory Report HLR 582-82. To be submitted with registration application. Clouzeau, J. (1991) Acute Dermal Imtation in the Rabbit. 7443 TAL. /-

MRID 40357502 Dashiell, 0. (1982) IN H6573 Primary Skin Imtation and Sensitization Test on Guinea Pigs. DuPont Haskell Laboratory Report HLR 626-82.

SUBCHRONIC TOXICITY

MRIDs 00072421 and 00161400. Pastoor, T. (1983) Ninety-day Feeding and One-Generation Reproduction Study in Rats with Silane. DuPont Haskell Laboratory Report 483-83

MRID 400421 11. Pastoor, T. (1983) Four-week Range Finding and Ninety-Day Feeding in Mice with Silane, [Bis(4-Fluorophenyl)](methyl) (1H-1,2,4-biazol-I-methyl) (IN H-6573). DuPont Haskell Laboratory Report HLR 341-83.

MRID 41514901. Keller, D. (1990) Subchronic Oral Toxicity: 90-Day Study with DPX- H6573-193 Feeding Study in Mice. DuPont Haskell Laboratory Report HLR 60-90.

MRID 00161 168. Rickard, R. (1983) Three-month Feeding Study in Dogs with Silane (INH- 6573). DuPont Haskell Laboratory Report HLR 461-83.

MRID 400421 19. Sarver, J. (1986) Twenty-one Day Dose Dermal Toxicity Study with INH- 6573-82 in Rabbits. DuPont Haskell Laboratory Report HLR 744-86.

LONGTERM TOXICITY AND CARCINOGENICITY

MRID 00148511. Pastoor, T. (1984) Long-term Feeding and Two-generation, Four-litter Reproduction Study in Rats with Silane, [Bis(4-Fluorophenyl)](methyl) (1H-1,2,4-Triazol-I- ylmethy1)-(INH-6573). DuPont Haskell Laboratory Report HLR 281-84 MRID 42613202. Keller, D. (1992) Oncogenicity Study with DPX-H6573-194 (Flusilazole) 2-year Feeding in Rats. DuPont Haskell Laboratory Report HLR 527-92.

MRID 400421 14. Brock, W. (1985) Long-term Feeding Study in Mice with INH-6573. DuPont Haskell Laboratory Report HLR 278-85.

MRID 42613201. Keller, D. (1992) Oncogenicity Study with DPX-H6573-193 (Flusilazole) 18-month Feeding in Mice. DuPont Haskell Laboratory Report HLR 35-92.

MRID 400421 13 O'Neal, F. (1985) One-year Feeding Study in Dogs with IN H-6573. DuPont r Haskell Laboratory Report HLR 461-85.

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

MRIDs 00072421,00161400. Pastoor, T. (1983) Ninety-day Feeding and One-generation Reproduction Study in Rats with Silane. DuPont Haskell Laboratory Report HLR 483-83.

MRID 0014851 1 Pastoor, T. (1984) Long-term Feeding and Two-generation, Four-litter Reproduction Study in Rats with Silane, [Bis(4-Fluorophenyl)](methyl) (1H-1,2,4-Triazol-1- ylmethy1)-(INH-6573. DuPont Haskell Laboratory Report HLR 281-84

MRID 41684601. Mullin, L. (1990) Reproductive and Fertility Effects with Flusilazole Multigeneration Reproduction Study in Rats. DuPont Haskell Laboratory Report HLR 424- 90.

MRID 00072999. Alvarez, L. (1984). Developmental Toxicity Study in Rats Given INH- 6573-66 in the Diet on Days 7-16 of Gestation. DuPont Haskell Laboratory Report HLR 431- 84.

MRID 00161 169. Lamontia, C. (1983) Embryo-fetal Toxicity and Teratogenicity Study of INH-6573-39 by Gavage in the Rat. DuPont Haskell Laboratory Report HLR 444-83.

MRID 001 61 170. Lamontia, C. (1 984) Embryo-Fetal Toxicity and Teratogenicity Study of INH-6573-39 by Gavage in the Rat. DuPont Haskell Laboratory Report HLR 142-84.

MRID 40640704. Alvarez, L. (1985) INH-6573: Prenatal and Postnatal Toxicity Study in Rats Dosed by Gavage on Days 7-16 of Gestation. DuPont Haskell Laboratory Report 654-85.

MRID 45042601. Munley, S. (2000) Flusilazole Technical: Developmental Toxicity Study in Rats. DuPont-2287. MRID 44594201. Schardein, J. (1998) A Dermal Prenatal Development Toxicity Study of Flusilazole in Rats. DuPont Haskell Laboratory Report HLO-1998-01504 Revised.

MRID 00154930. Alvarez, L. (1985) INH-6573 Developmental Toxicity Study in Rabbits Treated by Diet on Days 7-19 of Gestation. DuPont Haskell Laboratory Report 337-85.

MRID 00148512. Solomon, H. (1984) Developmental Toxicity Study in Rabbits Given INH- 6573 by Gavage on Days 7-19 of Gestation: DuPont Haskell Laboratory Report HLR 333-84.

MRID 00154929. Zellers, J. (1985) INH-6573. Developmental Toxicity Study (Supplemental) in Rabbits Dosed by Gavage on Days 7-19 of Gestation. DuPont Haskell Laboratory Report HLR 669-85. ,p

To be submitted with registration application. Alvarez, L. (1990) Teratogenicity Study of DPX-H6573-66 in Rabbits. DuPont Haskell Laboratory Report HLR 216-90.

GENOTOXICITY

MRID 00161 171. Donovan, S. (1982) Mutagenicity Evaluation in Salmonella typhimurium [of Silane]: MR No. 4581-047. DuPont Haskell Laboratory Report No. 61 1-82.

To be submitted with registration application. Vlachos, D. (1989). Evaluation of INH-6573-82 in the In Vitro Assay for Chromosome Aberrations in Human Lymphocytes. DuPont Haskell Laboratory Report HLR 745-86 Revision I.

MRID 00161 172. McCooey, K. (1983) CHOiHGPRT Assay for Gene Mutation [using Silane]. DuPont Haskell Laboratory Report HLR 449-83.

MRID 400421 17. Chromey, N. (1983) Unscheduled DNA SynthesisRat Hepatocytes in vitro. DuPont Haskell Laboratory Report HLR 209-83

To be submitted with registration application. Vlachos, D. (1989). Mouse Bone Marrow Micronucleus Assay of INH-6573-69. DuPont Haskell Laboratory Report HLO 437-84 Revision 1.

MRID 00161 173. Cortina, T. (1983) In vivo Bone Marrow Chromosome Study in Rats with H# 14,728: Final Report: HLA Project No. 201-614.

METABOLISM

MRID 400421 15. Anderson, J. et al., (1986) Metabolism of [Carbon 141-DPX-H6573 in Rats. DuPont AMR 196-128.

MECHANISTIC STUDIES

MRID 42613204. Keller, D. (1992) Mechanisms of Toxicity: 90-day Feeding Study in Rats with DPX-H6573-194 (Flusilazole): Revision No. 1. DuPont Haskell Laboratory Report HLR 628-92.

To be submitted with registration application. Cook, J. (1993) Mechanisms of Rat Leydig Cell Tumor Induction by DPX-H6573-193 (Flusilazole) (Revision 1) Supplement to Oncogenicity Study with DPX-H6573-194 (Flusilazole) Two-Year Feeding Study in Rats (HLR 527-92). DuPont Haskell Laboratory Report HLR 410-93.

WORKER EXPOSURE

To be submitted with registration application. Old, J. et al. (2002) Monitoring Exposure of I- Workers During Mixing, Loading, and Application Using Flusilazole 25EW Fungicide for Control of Cereal Diseases in the UK: Field Phase and Routine Analysis. Inveresk Report No. 20690 DuPont-3899.

FOLIAR DISSIPATION

To be submitted with registration application. Smyser, B. (1992) Dissipation of Flusilazole from Wheat Forage. DuPont Report AMR 1855-90.

DuPont states: The following reports have not been submitted to US EPA, but are available for review upon request.

Brodsky, J. 1991. Determination of Residues of Flusilazole (DPX-H6573) in Soybeans by GC-MS following Treatment with "Punch CS" (Season 1990 - France). Battelle-Institut E.V. Frankfurt, Germany. BE-A-I I-91-01-BF. Unpublished.

DuPont Brazil Study Numbers: RBR-04-276, RBR-04-277, RBR-04-278; Study Director: AndrC Luis Moraes. 2004. Unpublished.

San Juan, M., Morre, J. 2004. Magnitude of Residues of DPX-H6573 (Flusilazole) in Cultivars of Soybean (Glycine mat L. Merr.) for the Registration of the Product FUSION@ (Fungicide) (Flusilazole 12.5% + Carbendazim 25% SC) Trials canied out in the Argentine Republic Season 2003. DuPont Argentina Study Number: 005-2004. Unpublished.

Garbers, H.V. 2003. Determination of Flusilazole and Carbendazim Residues in Soya. SABS, Pretoria, South Africa. Report No. 721412126256iW393. . Unpublished.

 

From Dart Special at Toxnet

Toxicol Lett 2003 Sep ;144 (Suppl 1 ):S107

Mechanisms Involved In Triazole-Induced Teratogenesis: In Vitro Study.

Massa V, Broccia ML, Di Renzo F, Menegola E, Giavini E

University of Milan- Department of Biology, 20133 Milan, Italy.

Triazole-derivatives are antimycotic compounds used in agricolture as well as in clinical and veterinary therapy. Literature data, confirmed by results obtained in our previous studies, showed severe alterations at the level of the branchial apparatus after triazoles in vitro exposure (hypoplasia of I and II branchial arches, fusion between I and II branchial arches). Our previous works on Fluconazole (FLUCO) showed that FLUCO exposure is able to alter the morphogenesis of the branchial apparatus modifying the rhomboencephalic neural crest cells (NCC) migration in rat embryos cultured in vitro. The hindbrain segmentation was also altered by FLUCO. The aim of the present work was to extend the study of the mechanisms to other molecules of this class to verify if different molecules of the same family have the same target. For this purpose 9.5 d.p.c. old rat embryos were exposed in vitro to Flusilazole (25 uM), Triadimefon (250 uM) and Triadimenol (125 uM). The morphology of the embryos was analysed after 48 hours of culture. Some embryos cultured for 60 hours were immunostained using antibodies anti-160 kDa neurofilament in order to evaluate the cranial nerve structures. The localisation and distribution of NCC was evaluated after 24, 30 and 48 hours of culture, using the specific immunostaining of CRAB proteins. The expression and localisation of Hox bl and Krox 20 proteins (used as markers for the study of the correct hindbrain segmentation) was evaluated using whole mount immunostaining after 24 hours of culture. The obtained results showed very similar effects after exposure to Flusilazole, Triadimefon and Triadimenol: 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. The collected data suggest a common target for all the examined molecules: the observed branchial abnormalities are due to anomalous NCC migration related to an incorrect organisation and specification of the rhomboencephalon.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11489598&dopt=Abstract

Reprod Toxicol 2001 Jul-Aug;15(4):421-7

Antifungal triazoles induce malformations in vitro.

Menegola E, Broccia ML, Di Renzo F, Giavini E.

Department of Biology, University of Milan, Italy.

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 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.


PMID: 11489598 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10794648&dopt=Abstract

J Agric Food Chem 1999 Jun;47(6):2439-46

Metabolism of [(14)C]flusilazole in the goat.

Anderson JJ, Shalaby LM, Berg DS.

Experimental Station, DuPont Agricultural Products, Wilmington, Delaware 19880-0402, USA.

[Phenyl(U)-(14)C] and [triazole(3)-(14)C]flusilazole ([(bis 4-fluorophenyl)]methyl(1H-1,2,4-triazole-1-ylmethyl)silane; I) were extensively metabolized when fed to lactating goats (Capra hircus). The primary metabolites identified in goat tissues and milk were bis(4-fluorophenyl)(methyl)silanol (II) and 1H-1,2,4-triazole (III). Concentrations of total radiolabeled residues in the milk ranged from 0.09 to 0.74 microg/mL. Concentrations of radiolabeled residues found in tissues when the [(14)C] label was in the phenyl or triazole position, respectively, were 13.5 and 3.54 microg/g (liver), 8.74 and 0.75 microg/g (kidney), 0.41 and 0.52 microg/g (leg muscle), and 4.07 and 0.94 microg/g (back fat). Urine contained an additional major metabolite identified as [bis(4-fluorophenyl)](methyl)silylmethanol (IV) and its glucuronic acid conjugate (V). With either labeled form of flusilazole, the majority of the recovered radiolabel was excreted in urine or feces.


PMID: 10794648 [PubMed - indexed for MEDLINE]


From Toxline at Toxnet  

Pesticide residues in food - 1995. Toxicology evaluations (1996) pp 157-79

Flusilazole

Authors: FAO and WHO working groups

Levels that cause no toxic effect. Mouse: 25 ppm, equal to 3.4 mg/kg bw per day (18-month study of toxicity and carcinogenicity). Rat: 10 ppm, equal to 0.4 mg/kg bw per day (two-year study of toxicity and carcinogenicity); 5 ppm, equal to 0.34 mg/kg bw per day (maternal toxicity in a two-generation study of reproductive toxicity); 50 ppm, equal to 4 mg/kg bw per day (two-generation study of reproductive toxicity); 4.6 mg/kg bw per day (embryo- or fetotoxicity in a study of developmental toxicity); 100 mg/kg bw per day (teratogenicity in a study of developmental toxicity). Rabbit: 12 mg/kg bw per day (maternal and embryo- or fetal toxicity in a study of developmental toxicity); 15 mg/kg bw per day (teratogenicity in a study of developmental toxicity). Dog: 5ppm, equal to 0.14 mg/kg bw per day (one-year study of toxicity). Estimate of acceptable daily intake for humans. 0-0.001 mg/kg bw.


From Dart Special at Toxnet

Chemically Induced Birth Defects 1993;2:675-721

Pesticides.

Schardein JL

International Research and Development Corporation, Mattawan, MI.

Medical Subject Headings (MeSH):
Pregnancy
Animal
Human
Female
Pesticides/*TOXICITY
*Abnormalities, Drug-Induced
2,4,5-Trichlorophenoxyacetic Acid/TOXICITY
Insecticides/TOXICITY

Substance (CAS Registry Number): [Too many to list]

Sodium fluoroacetate (62-74-8)

[Note: the following organofluorines were included]
Diflubenzuron (35367-38-5)
Ethalfluralin (55283-68-6)
Flusilazole (85509-19-9)
Gliftor (8065-71-2) - [Synonym: 1-Chloro-3-fluoro-2-propanol mixt. with 1,3-difluoro-2-propanol]
N-Methyl-N- 1-naphthyl fluoroacetamide [Nissol] (5903-13-9)
Sarin [Synonym: (+-)-Isopropyl methylphosphonofluoridate] (107-44-8)
Sodium fluoroacetate (62-74-8)
Sodium hexafluorosilicate [also known as Sodium fluorosilicate] (16893-85-9)
Soman [Synonym: 1,2,2-Trimethylpropyl methylphosphonofluoridate] (96-64-0)
Sulfuryl fluoride (2699-79-8)
Trifluralin (1582-09-8)


From Toxline at Toxnet

FAO Plant production and protection paper Vol:100/2 (1988) pp 117-39

Flusilazole

Authors: FAO and WHO working groups

Level causing no toxicological effect Mouse: 25 ppm in the diet, equal to 3.4 mg/kg bw/day Rat: 10 ppm in the diet, equal to 0.45 mg/kg bw/day Dog: 5 ppm in the diet, equal to 0.14 mg/kg bw/day Estimate of acceptable daily intake for humans 0-0.001 mg/kg bw. Studies which will provide information valuable in the continued evaluation of the compound 1. Observations in humans. 2. Toxicity of the biotransformation products.


Helpful background reading:

2002 - Zerulla M, Lþnge R, Steger-Hartmann T, Panter G, Hutchinson T,and Dietrich DR.
Morphological sex reversal upon short-term exposure to endocrine modulators in juvenile fathead minnow (Pimephales promelas).
Toxicology Letters 131: 51-63.

2001 - Bl‡zquez M, Felip A, Zanuy S, Carrillo M, Piferrer F.
Critical period of androgen-inducible sex differentiation in a teleost fish, the European sea bass.
Journal of Fish Biology 58: 342-358.

1998 - Nagel, R. and Isberner, K.
Testing of chemicals with fish Ð a critical evaluation of tests with special regard to zebrafish.
In: Braunbeck,T., Hinton, D.E. and Streit, B.: Fish Ecotoxicology. Basel, pp337-352.

1997 - Peter, H. and Heger, W.
Long-term effects of chemicals in aquatic ecosystems.
In: SchŸŸrmann, G. and Markert, B. (Eds.) Ecotoxicology. New York and heidelberg, pp 571-586.

1997 - Trant JM, Lehrter J, Gregory T, Nunez S, and Wunder J.
Expression of cytochrome P450 aromatase in the channel catfish, Ictalurus punctatus.
J. Steroid Biochem. Molec. Biol. 61: 393-397.

1977 - Macek, K.J. and Sleight, B.H.
Utility of toxicity tests with embryos and fry of fish in evaluating hazard associated with the chronic toxicity of chemicals to fishes.
Eds. F.L. Meyer and J.L. Hamelink, pp.137 Ð 146. ASTM STP 634. Philadelphia: ASTM 1977.

1977 - Mc Kim, J.M.
Evaluation of tests with early life stages of fish for predicting long-term toxicity.
J. Fish Res Bd Can. 34: 1148 Ð 1154.

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