Investigations of putative reproductive toxicity of low-dose exposures to vinclozolin in Wistar rats.
The current investigation examines whether the fungicide vinclozolin, which has an anti-androgenic mode of action, is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology and histopathological examinations. Doses were chosen to represent an effect level (20 mg/kg bw/d), the current NOAEL (4 mg/kg bw/d), and a dose close to the "ADI" (0.005 mg/kg bw/d) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at the effect level but not at lower exposures. Nipple/areola counts appeared to be the most sensitive measure of effect, followed by male sex organ weights at sexual maturation, and finally gross and histopathological findings. The results indicate the absence of evidence for effects at low or very low dose levels. A non-monotonic dose-response relationship was not evident.
Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen, Germany.
Burkhard
B
Flick
Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen, Germany.
Steffen
S
Schneider
Product Safety, Regulations, Toxicology and Ecology, BASF SE, Ludwigshafen, Germany.
Stephanie
S
Melching-Kollmuss
Chemical Food Safety, Nestlé, Lausanne, Switzerland.
Karma C
KC
Fussell
Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen, Germany.
Sibylle
S
Gröters
Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen, Germany.
Roland
R
Buesen
Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen, Germany.
Volker
V
Strauss
Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen, Germany. bennard.ravenzwaay@basf.com.
Bennard
B
van Ravenzwaay
D000726:Androgen Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009558:Nipples / Q000187:drug effects; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D010080:Oxazoles / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects*
D000726:Androgen Antagonists; D052244:Endocrine Disruptors; D005659:Fungicides, Industrial; D010080:Oxazoles; C025643:vinclozolin
Anti-androgenic; Endocrine disruptor; Experimental test guidelines; Low dose; Non-monotonic dose response; Vinclozolin