Read-across for rat oral gavage repeated-dose toxicity for short-chain mono-alkylphenols: A case study

• Published in: Computational toxicology 2017-05, Vol.2, p.1-11
• Main Authors: Mellor, Claire L., Schultz, Terry W., Przybylak, Katarzyna R., Richarz, Andrea N., Bradbury, Steven P., Cronin, Mark T.D.
• Format: Article
• Language: English
• Subjects: Lowest Observed Adverse Effect Level (LOAEL); Mono-alkylphenols; No Observed Adverse Effect Level (NOAEL); Read-across; Repeated-dose toxicity; Uncertainty; Weight-of-evidence (WoE)
• ISSN: 2468-1113; 2468-1113
• DOI: 10.1016/j.comtox.2017.03.003

[Display omitted] •24 short-chain (C4 or less) mono-alkylphenols were selected for read-across.•Alkylphenols exhibit an unspecific, reversible polar narcosis mode of action.•Six analogues with high quality repeated-dose toxicity data serve as source chemicals.•Uncertainty is reduced by the concordance of in vivo, in vitro, ToxCast and in silico data.•A NOAEL of 50mg/kgbw/d may be read across to fill data gaps for untested analogues. Short-chain mono-alkylphenols provide an example of where a category-approach to read-across may be used to estimate the repeated-dose endpoint for a number of derivatives. Specifically, the NOAELs of 50mg/kgbw/d for mono-methylphenols based on a LOAEL of very low systemic toxicity can be read across with confidence to untested mono-alkylphenols in the category. These simple alkylphenols are non-reactive and exhibit an unspecific, reversible polar narcosis mode of toxic action. Briefly, polar narcotics act via unspecific, reversible interactions with biological membranes in a manner similar to cataleptic anaesthetics. The read-across premise includes rapid and complete absorption via the gastrointestinal tract, distribution in the circulatory system, first-pass phase II metabolism in the liver and elimination of sulphates and glucuronides in the urine. Thus, toxicokinetic parameters are considered to be similar and have the same toxicological significance. Six analogues have high quality experimental oral repeated-dose toxicity data (i.e., OECD TG 408 or OECD TG 422). These repeated-dose toxicity test results exhibit qualitative consistency in symptoms. Typical findings include decreased body weight and slightly increased liver and kidney weights which are generally without concurrent histopathological effects. The sub-chronic findings are quantitatively consistent with the No Observed Adverse Effect Level (NOAEL) of ≥50mg/kgbw/d. Chemical similarity between the analogues is readily defined and data uncertainty associated with the similarities in toxicokinetic properties, as well as toxicodynamic properties, are low. Uncertainty associated with mechanistic relevance and completeness of the read-across is low-to-moderate, largely because there is no adverse outcome pathway or intermediate event data. Uncertainty associated with mechanistic relevance and completeness of the read-across is reduced by the concordance of in vivo, in vitro, US EPA toxicity forecaster (ToxCast) results, as well as in silico data. The rat oral repeated