Synthesis and Toxicity Evaluation of <i>p</i> -Phenylenediamine-Quinones
Pranav Nair, Jianxian Sun, Lin-Na Xie, Lisa M. Kennedy, Derek Kozakiewicz, Sonya Kleywegt, Chunyan Hao, Hannah Byun, Holly Barrett, Joshua Baker, J. J. Monaghan, Erik T. Krogh, Datong Song, Hui Peng
Abstract
N -(1,3-Dimethylbutyl)- N′ -phenyl- p -phenylenediamine-quinone (6PPD-Q), the tire rubber-derived transformation product of 6PPD, was recently discovered to cause the acute mortality of coho salmon ( Oncorhynchus kisutch ). Aiming to identify potential replacement antiozonants for 6PPD that do not produce toxic quinones, seven PPD-quinones with distinct side chains were synthesized to investigate their structure-related toxicities in vivo using rainbow trout ( Oncorhynchus mykiss ). While 6PPD-Q exerted high toxicity (96 h LC 50 = 0.35 μg/L), toxicity was not observed for six other PPD-quinones despite their similar structures. The fish tissue concentrations of 6PPD-Q after sublethal exposure (0.29 μg/L) were comparable to the other PPD-quinones, which indicated that bioaccumulation levels were not the reason for the selective toxicity of 6PPD-Q. Hydroxylated PPD-quinones were detected as the predominant metabolites in fish tissue. Interestingly, a single major aromatic hydroxylation metabolite was detected for the alternate PPD-quinones, but two abundant OH-6PPD-Q isomers were detected for 6PPD-Q. MS 2 spectra confirmed that hydroxylation occurred on the alkyl side chain for one isomer. The structurally selective toxicity of 6PPD-Q was also observed in a coho salmon (CSE-119) cell line, which further supports its intrinsic toxicity. This study reported the selective toxicity of 6PPD-Q and pinpointed the possibility for other PPDs to be applied as potential substitutes of 6PPD.