title: Comparing effect levels of regulatory studies with endpoints derived in targeted anti-androgenic studies: example prochloraz.
abstract: Prochloraz is an imidazole fungicide, and its regulatory toxicological data package has been primarily generated in the 1990s. More recently, studies have been published demonstrating an interaction with hormone receptors/steroidogenesis and effects with an endocrine mode of action. In the present study, prochloraz has been investigated in a comprehensive in vivo study including relevant elements of current regulatory reproduction toxicity studies and additional mechanistic parameters. Prochloraz was administered per gavage in oil from GD 6 to PND 83 to pregnant and lactating Wistar rats and their respective offspring, at doses of 0.01 mg/kg bw/day (acceptable daily intake of prochloraz), 5 mg/kg bw/day [expected no-observed-effect-level (NOEL)] and 30 mg/kg bw/day. At 30 mg/kg bw/day maternal and offspring effects (decreased viability, lower number of live offspring) were seen including a delayed entry into male puberty (+1 day) accompanied by lower male offspring body weights, increased anogenital distance/index in females and transiently retained nipples in males at PND 12 (not seen at PND 20). The only finding at the "expected NOEL" was increased incidences of transiently retained nipples in males which are not considered adverse. No effects were seen in the low-dose group. There was no evidence for a non-monotonic dose-response curve or effects at low levels.
authors.affiliation: Product Safety, Regulations, Toxicology and Ecology, BASF SE, Ludwigshafen am Rhein, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Melching-Kollmuss
authors.affiliation: Chemical Food Safety, Nestlé, Lausanne, Switzerland.
authors.forename: Karma C
authors.initials: KC
authors.lastname: Fussell
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Buesen
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Groeters
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Strauss
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany. bennard.ravenzwaay@basf.com.
authors.forename: Bennard
authors.initials: B
authors.lastname: van Ravenzwaay
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D054750:Ecotoxicology / Q000331:legislation & jurisprudence / Q000379:methods*; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood / Q000139:chemically induced; D005327:Fetal Resorption / Q000097:blood / Q000139:chemically induced; D005659:Fungicides, Industrial / Q000097:blood / Q000592:standards / Q000633:toxicity*; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D007774:Lactation; D008297:Male; D008956:Models, Chemical; D057466:Nonsteroidal Anti-Androgens / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011628:Puberty, Delayed / Q000097:blood / Q000139:chemically induced; D011897:Random Allocation; D017208:Rats, Wistar; D066007:Toxicokinetics; D014564:Urogenital Abnormalities / Q000097:blood / Q000139:chemically induced; D015430:Weight Gain / Q000187:drug effects
chemical_list: D052244:Endocrine Disruptors; D005659:Fungicides, Industrial; D007093:Imidazoles; D057466:Nonsteroidal Anti-Androgens; C045362:prochloraz
keywords: Anti-androgenicity; Low dose; Prochloraz; Reference value; Reproductive toxicology