title: Combination effects of azole fungicides in male rats in a broad dose range.
abstract: Two 28-day feeding studies were performed in male rats to investigate combination effects of azole fungicides in a broad dose range. Following separate administration of cyproconazole, epoxiconazole, prochloraz, propiconazole, and tebuconazole at five dose levels, the first three compounds were selected to be administered in two different mixtures at three dose levels including very low doses. Here we present the data obtained by clinical observations, pathology, histopathology, clinical chemistry and haematology. The liver was the common main target organ of all compounds and their mixtures. In addition, epoxiconazole exhibited an effect on the adrenals. Furthermore, food consumption and efficiency and body weight (gain) were affected. Adverse effects of the combinations were observed at dose levels at which the individual substances caused similar effects. No evidence of adverse effects was found at dose levels below the previously established NOAELs. Our findings indicate that the concept of dose additivity appears sufficiently protective for risk assessment of the fungicides examined. Besides toxicological testing, tissue residues of the azole compounds in liver, testis and kidney were determined revealing remarkable differences following administration of the single substances and of the mixtures.
authors.affiliation: Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, D-10589 Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, D-10589 Berlin, Germany. Electronic address: philip.marx-stoelting@bfr.bund.de.
authors.forename: P
authors.initials: P
authors.lastname: Marx-Stoelting
authors.affiliation: Institute for Veterinary Pathology, Schönhauser Strasse 62, D-13127 Berlin, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Haider
authors.affiliation: Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, D-10589 Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Heise
authors.affiliation: Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, D-10589 Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kneuer
authors.affiliation: Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, D-10589 Berlin, Germany; Faculty for Veterinary Medicine, Free University of Berlin, Königsweg 67, 14163 Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ladwig
authors.affiliation: Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, D-10589 Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Banneke
authors.affiliation: Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, D-10589 Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Rieke
authors.affiliation: Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, D-10589 Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Niemann
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D001393:Azoles / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D002149:Energy Intake / Q000187:drug effects; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017208:Rats, Wistar; D018570:Risk Assessment / Q000379:methods; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D001393:Azoles; D005659:Fungicides, Industrial
keywords: Azole fungicides; Liver; Low dose effects; Mixture toxicity; Short term toxicity