Chemical Hazard Assessment of PXE (1-Phenyl-1-(2,4-dimethylphenyl)-ethane) in the Provisional Peer-Reviewed Toxicity Value (PPRTV) Program
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Background and Purpose: 1-Phenyl-1-(2,4-dimethylphenyl)-ethane (PXE; CASRN 6165-52-2), is a sediment contaminant with no reported commercial uses. Due to its detection at Superfund sites, PXE was nominated for assessment by the U.S. EPA Provisional Peer-Reviewed Toxicity Value (PPRTV) Program. From surveying toxicity values sources (e.g., U.S. EPA Integrated Risk Information System [IRIS], Health Effects Assessment Summary Tables [HEAST], Agency for Toxic Substances and Disease Registry [ATSDR], etc.), no existing toxicity values were available for PXE. Therefore, this assessment was developed in order to determine whether available data were adequate to derive provisional RfDs or RfCs (p-RfDs or p-RfCs) and/or cancer risk estimates for PXE.
Methods: Literature searches were conducted to identify the repeated-dose, short-term, subchronic, chronic, or reproductive/developmental toxicity studies that could be used to derive provisional toxicity values for PXE using chemical-specific data. However, no studies were identified regarding the toxicity or carcinogenicity of PXE in humans or animals after oral or inhalation exposure. Therefore, a read-across evaluation was attempted. In this method, analogues were identified on the basis of three similarity contexts (structural, metabolic, and toxicity/mode-of-action [MOA]). Initially, automated tools (e.g., OECD QSAR Toolbox, ChemIDPlus, the US EPA Comptox Chemistry Dashboard) were employed to generate a list of potential structural analogues, which underwent refinement through the application of a chemist with expertise. Metabolic analogues (metabolites and/or metabolic precursors) were identified using metabolism simulators and targeted literature searches. The identification of analogues relevant to toxicity/MOA was attempted based on evaluation of in vivo toxicity and in vitro mechanistic and bioactivity data for PXE. Candidate analogues identified by these methods were searched to determine the availability of toxicity values from reliable sources (e.g., IRIS and PPRTV assessments, ATSDR, California Environmental Protection Agency [CalEPA]).
Results: The lack of toxicity data for PXE prevented the direct derivation of provisional values using chemical-specific data. Employing read-across approaches, 59 candidate analogues were identified: 26 structural, 33 metabolic, and zero mechanistic/MOA analogues. Searches of EPA, ATSDR, and CalEPA databases did not, however, identify relevant toxicity values for any of the candidate analogues of PXE. Therefore, no suitable analogues were identified from which to derive screening-level provisional toxicity values for PXE.
Conclusions: The available database of relevant studies was inadequate to directly derive provisional oral or inhalation toxicity values or cancer risk estimates for PXE using chemical-specific data. Read-across approaches identified 59 potential candidate analogues; however, none of these had available oral or inhalation toxicity values. Consequently, applying read-across approaches did not facilitate the derivation of screening-level toxicity values for PXE.
Disclaimer: The views expressed are those of the authors and do not necessarily reflect the views and policies of the US EPA.