Lessons Learned from Read-Across Case Studies for Repeated-Dose Toxicity

Schultz, TW and Cronin, MTD Lessons Learned from Read-Across Case Studies for Repeated-Dose Toxicity http://researchonline.ljmu.ac.uk/id/eprint/6732/ Article LJMU has developed LJMU Rese

Schultz, TW and Cronin, MTD

Lessons Learned from Read-Across Case Studies for Repeated-Dose Toxicity http://researchonline.ljmu.ac.uk/id/eprint/6732/

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Schultz, TW and Cronin, MTD (2017) Lessons Learned from Read-Across Case Studies for Repeated-Dose Toxicity Regulatory Toxicology and

Pharmacology, 88 pp 185-191 ISSN 0273-2300

LJMU Research Online

Lessons Learned from Read-Across Case Studies for Repeated-Dose Toxicity

2016; Shah et al., 2016; van Ravenzwaay et al., 2016) More recently, Ball et al., (2016)

prediction are likely to vary little, as the aim of a RA is to provide a prediction(s) that is

Table 1 Summary of the main findings of the read-across case studies for repeated dose chronic toxicity

Summary of Weight(s) of Evidence To Support Read-Across for the Category

Conclusion Regarding Uncertainty

straight- Absorbed from the gut; distributed in the blood

in solution; first pass metabolism leads mainly

to the corresponding carboxylic acid; subsequent mitochondrial β-oxidation to CO2

 No systemic toxicity; no chemical reactivity or receptor-mediated interactions; nonpolar narcosis is a probable mode-of action

Chemistry: High Toxicokinetics: Medium Toxicodynamics:

In vivo: High

In vitro: High

Overall: High

Same as performing an OECD TG 408 test

2- Absorbed from the gut; distributed in the blood

in solution; first past metabolism leads mainly to glucuronidation; subsequent elimination in the urine

 No systemic toxicity; no chemical reactivity or receptor-mediated interactions; probable mode-

of action is nonpolar narcosis

Chemistry: High Toxicokinetics: Medium Toxicodynamics:

 Absorbed from the gut; distributed in the blood

in solution; first past metabolism leads to the corresponding α, β-unsaturated aldehyde or α, β-unsaturated ketone

Chemistry: High Toxicokinetics: Medium Toxicodynamics:

In vivo: Medium

In vitro: High

Overall:

Straight-chain β -olefinic alcohols: same as

performing an OECD TG

408 test;

 The corresponding α, β-unsaturated derivatives are the definitive electrophilic toxicants; likely

mode-of action is Michael addition; in vivo

potency is related to relative thiol reactivity

Straight-chain β-olefinic alcohols: high

Branched-chain β -olefinic alcohols: medium

branched-chain β -olefinic alcohols: 2-propen-1-ol is the worst case scenario

 No systemic toxicity; no chemical reactivity; no relevant receptor-mediated interactions;

probable mode-of action is polar narcosis

Chemistry: High Toxicokinetics: Medium Toxicodynamics:

In vivo: High

Overall: High

Same as performing an OECD TG 408 test

132

by-chemical assessments based on animal testing to assessments by interpolation within a

reproduced To meet these requirements for transparency and reproducibility, clear

related to the quality of the read across data (e.g., 90-day oral repeated-dose no observable

The assessment of uncertainty associated with a similarity justification is shown to include

of toxicologically-relevant in vitro or NAM data to support mechanistic plausibility, the

Predictions from RA are more likely to be acceptable when undertaken on an

same, i.e highly similar chemistry and similar mechanistic plausibility in the form of an

the WoE for the RA justification through the results from toxicologically-relevant alternative

data were used to support a mode of toxic action developed from non-mammalian data or a

case studies demonstrated that, in reality, neither is ideal for RA Broad definitions of

cooperative review of case studies on grouping methods (such as RA) have increased

2 on one-to-one (analogue) or many-to-one (category) basis rather than a one to many

Palmer, J., Pamies, D., Penman, M., Richarz, A.-N., Russo, D.P., Stuard, S.B.,

G.P 2016 Grouping 34 chemicals based on mode of action using connectivity

European Chemicals Agency (ECHA), 2015 Read-Across Assessment Framework (RAAF)

Organisation for Economic Co-operation and Development (OECD), 2007 Guidance on

Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides

Patlewicz, G., Ball, N., Boogaard, P.J., Becker, R.A and Hubesch, B 2015 Building

Shah, I., Liu, J., Judson, R.S., Thomas, R.S and Patlewicz, G 2016 Systematically