title: Metabolomics as read-across tool: A case study with phenoxy herbicides.
abstract: New technologies, such as metabolomics, can address chemical grouping and read across from a biological perspective. In a virtual case study, we selected MCPP as target substance and MCPA and 2,4-DP as source substances with the goal to waive a 90-day study with MCPP. In order to develop a convincing case to show how biological data can substantiate read across, we used metabolomics on blood samples from the 28-day studies to show the qualitative and quantitative similarity of the substances. The 28-day metabolome evaluation of source substances and the target substance indicate liver and kidneys as target organs. 2,4-DP was identified as the best source substance. Using the information of the 90-day 2,4-DP study, we predicted MCPP's toxicity profile at 2500 ppm: reduced food consumption and body weight gain, liver and kidney weight increases with clinical-pathology changes and a moderate red blood cell parameter reduction. NOEL prediction for MCPP was below that of 2,4-DP (<500 ppm), and similar to that of MCPA (≥150 ppm). Qualitatively, these predictions are comparable to the results of the real MCPP 90-day study in rats (reduced food consumption and body weight gain, weight increases and clinical-pathology changes in liver and kidneys, reduced red blood cells values). Quantitatively, the predicted NOAEL (150 ppm) is similar to the actual study (NOEL = 75 ppm, NOAEL ≤ 500 ppm). Thus, the 90-day rat toxicity study of MCPP could have been waived and substituted by the 90-day results of 2,4-DP by using metabolome data of 28 day studies.
authors.affiliation: BASF SE, Ludwigshafen, Germany. Electronic address: bennard.ravenzwaay@basf.com.
authors.forename: B
authors.initials: B
authors.lastname: van Ravenzwaay
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sperber
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Lemke
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Fabian
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Faulhammer
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kamp
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Mellert
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Strauss
authors.affiliation: Metanomics GmbH, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Strigun
authors.affiliation: Metanomics GmbH, Berlin, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Peter
authors.affiliation: Metanomics GmbH, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Spitzer
authors.affiliation: Metanomics GmbH, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Walk
mesh_terms: D000818:Animals; D001682:Biological Availability; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006540:Herbicides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D055432:Metabolomics; D015394:Molecular Structure; D010636:Phenols / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D006540:Herbicides; D010636:Phenols; C042329:phenoxy radical
keywords: Metabolomics; Prediction; REACH; Rat; Read across; Toxicity