Table 1.

Areas of applicability of acute toxicity assessment and examples of uses for in silico methods

Area	Use	Opportunities for In Silico
Product R&D	Scaffold selection	Screening away from off-target acutely toxic compounds; often performed on compounds representing structural scaffolds of potential interest for new product development
	Candidate selection	Choosing from among several molecules within one or more structurally active series with a goal of increasing the probability of technical success of a project by avoiding those having a greater safety liability (i.e., optimizing investment of resources)
	Study design support	Selecting dose ranges, salt forms, and additional endpoints to optimize the design of in vivo and in vitro studies (e.g., in silico results can help identify potential target organs or mechanisms of toxicity, which can then be included as endpoints for investigation)
	Metabolite analysis	Identifying probable test article metabolites and inform on their potential toxicity (e.g., through a bioactivation mechanism)
	Issue resolution	Informing on potential mechanism(s) that could be associated with an observed toxicity; useful for forming hypotheses for testing. Confirmed mechanisms can be screened against to find more suitable candidates
	Scaffold hopping	Identifying alternative structural series which continue to possess desirable properties without the continued presence or degree of undesirable off-target properties
	Weight of evidence	Providing a basis for decisions when little or no data are available that used direct testing methods. Results are also useful for determining whether additional testing is needed
Manufacturing and Process Chemistry	Green chemistry support	Selecting occupationally or environmentally safer starting materials and additives
Occupational Health and Safety	Worker safety	Identifying compounds likely to pose a hazard to workers, e.g., through handling or accidental exposure
	Process control and containment	Informing on the potential need for additional handling precautions
	Exposure limits	Assisting in establishing safe exposure thresholds and limits
	Safety Data Sheet support	Identifying the appropriate GHS classification when in vivo and in vitro test data are limited or do not exist
Product Safety and Registration	Safety data for registration/approval	Supporting product safety assessment (e.g., by providing the likelihood of involvement of a specific mechanism relating to a study finding)
	Product quality and specifications	Supporting setting of limits for contaminants (e.g.,residuals, leachables and extractables, material interaction and degradation products)
	Classification and Labeling	Informing labeling for intended use(s)
Public Health and Safety / Environmental	Classification for product transport	Identifying the appropriate GHS classification, when in vivo and in vitro test data are limited or do not exist, and assignment of the proper packing group.
	Environmental discharge limits / disposal	Assisting in establishing limits and specifications for restricting environmental pollutants
	Accidental release situations	Informing assessments of risk and strategies for mitigation or countermeasures
Emergency Response	Intended or unintended acute exposure	Informing assessments of risk and strategies for mitigation or countermeasures
Military	Protection of military personnel	Identifying hazards and informing assessments of risk and strategies for mitigation or countermeasures (i.e.,tactical preparedness)