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Read-across of 90-day rat oral repeated-dose toxicity: A case study for selected β-olefinic alcohols

: Przybylak, Katarzyna R.; Schultz, Terry W.; Richarz, Andrea-N.; Mellor, Claire L.; Escher, Sylvia E.; Cronin, M.T.D.


Computational Toxicology 1 (2017), pp.22-32
ISSN: 2468-1113
Journal Article
Fraunhofer ITEM ()
read across; No Observed Adverse Effect Level; β-Olefinic alcohols; weight of evidence; uncertainty

There are no in vivo repeated-dose data for the vast majority of β-olefinic alcohols. However, there are robust and consistent ex vivo data suggesting many of these chemicals are metabolically transformed, especially in the liver, to reactive electrophilic toxicants which react in a mechanistically similar manner to acrolein, the reactive metabolite of 2-propen-1-ol. Hence, an evaluation was conducted to determine suitability of 2-propen-1-ol as a read-across analogue for other β-olefinic alcohols. The pivotal issue to applying read-across to the proposed category is the confirmation of the biotransformation to metabolites having the same mechanism of electrophilic reactivity, via the same metabolic pathway, with a rate of transformation sufficient to induce the same in vivo outcome. The applicability domain for this case study was limited to small (C3 to C6) primary and secondary β-olefinic alcohols. Mechanistically, these β-unsaturated alcohols are considered to be readily metabolised by alcohol dehydrogenase to polarised α,β-unsaturated aldehydes and ketones. These metabolites are able to react via the Michael addition reaction mechanism with thiol groups in proteins resulting in cellular apoptosis and/or necrosis. The addition of the non-animal in chemico reactivity data (50% depletion of free glutathione) reduced the uncertainty so the read-across prediction for the straight-chain olefinic β-unsaturated alcohols is deemed equivalent to a standard test. Specifically, the rat oral 90-day repeated-dose No Observed Adverse Effect Level (NOAEL) for 2-propen-1-ol of 6 mg/kg body weight (bw)/d in males based on increase in relative weight of liver and 25 mg/kg bw/d in females based on bile duct hyperplasia and periportal hepatocyte hypertrophy in the liver, is read across to fill data gaps for the straight-chained analogues.