Read-across of 90-day rodent repeated-dose toxicity: A case study for selected simple aryl alcohol alkyl carboxylic acid esters

Abstract

Aryl alcohol alkyl carboxylic acid esters constitute a wide-employed class of fragrance materials. Outcomes presented within this study illustrate formulation of a read-across protocol for 90-day, repeat-dose toxicity within a series of these compounds, extending in scope to the dodecanoic acid esters of both benzyl and 2-phenylethyl alcohol. Central to the filling of data gaps is the hypothesis that adverse impact-mediated through mechanisms analogous to narcosis-associated non-specific basal cytotoxicity-is as a consequence of the hydrolysis of parent compounds to their corresponding alcohol. High-quality in vivo data (equivalent to either OECD Test Guideline 408 or 411) relating the toxicodynamic and toxicokinetic profiles of benzyl alcohol, 2-phenylethyl alcohol and benzyl acetate within rodents were retrieved, permitting extrapolation to each ester derivative with great confidence. NOAEL values of 250-500 mg/kg/day were assigned to esters, with a greater toxicity present within females. In order to greater enhance reliability, further theoretical support for the read-across prediction is provided through the integration, where appropriate, of in vitro and in silico data.

Integration of read-across and artificial neural network-based QSAR models for predicting systemic toxicity: A case study for valproic acid

“…analogue identification and analogue evaluation) is emphasized in all of these documents, but a definitive protocol has not been established. Recently, a series of case studies focusing on repeated-dose toxicity has provided some operative examples of a read-across protocol (Firman et al, 2018;Przybylak et al, 2017;Schultz et al, 2017). However, these protocols are applicable only to a chemical with a simple structure for which analogues can be easily chosen (e.g., analogues with a different number of carbon atoms in the alkyl chain of n-alkanols).…”

Clustering a Chemical Inventory for Safety Assessment of Fragrance Ingredients: Identifying Read-Across Analogs to Address Data Gaps

“…A case study for selected simple aryl alcohol alkyl carboxylic acid esters has been reported. 46 This case study reports that in vivo assessment of the toxico-kinetics of 2-phenylethyl propionate has not been reported. However, evidence derived from in vitro studies in both rat liver and intestine tissue samples and artificial gastric juices, demonstrated that the ester readily undergoes hydrolysis to phenethyl alcohol and propionic acid.…”

“…Results of 90-day repeated-dose study of dermally administered 2-phenylethyl alcohol in male and female Sprague–Dawley rats is further reported. 46 On the basis of body weight abnormalities observed at the higher concentrations, a NOAEL of 0.50 mL/kg/day or 500 mg/kg/day was reported. In the same paper, the 90-day dietary repeated-dosed toxicity of propionic acid in male and female Sprague–Dawley rats revealed a minor decrease in body weight in the higher-dose male group, together with a 12% reduction in kidney size, whereas at the high dose, females displayed increased mass in heart and liver; the NOAEL for males and females were noted as 1250 mg/kg/day and 2500 mg/kg/day, respectively.…”

Incorporating lines of evidence from New Approach Methodologies (NAMs) to reduce uncertainties in a category based read-across: A case study for repeated dose toxicity

“…A number of case studies of read-across for repeated dose toxicity (Schultz et al, 2017a,b;Przybylak et al, 2017;Mellor et al, 2017;Firman et al, 2018) have provided the catalyst for the understanding of weaknesses in read-across. Most specifically, these weaknesses are seen as being potentially restrictive towards regulatory acceptance (Chesnut et al, 2018;Escher et al, 2019).…”

“…It is acknowledged that, in the strictest sense, existing data are not NAMs, but it is our assumption that they provide useful and useable lines of evidence that will support an overall weight of evidence for a read-across. They were used by Schultz et al, (2017a,b), Przybylak et al, (2017), Mellor et al, (2017) and Firman et al, (2018) for this purpose, without being termed NAMs.…”