Table 3.

Definitions of the properties relating to structural alerts and their relevance to confidence.

Criterion	Confidence	Relevance to the Structural Alert in Terms of Possible Uncertainty Affecting Confidence
Purpose	High	The purpose of the structural alert is clearly and unambiguously stated, e.g., toxicity prediction or grouping.
	Moderate	The purpose of the structural alert is broad or ambiguous.
	Low	The purpose of the structural alert is not stated.
Structural Description	High	Unambiguous description of the functional group and/or molecular fragment including modulating factors.
	Moderate	Structural alert is loosely defined with regard to its chemical structure with little or no information regarding modulating factors.
	Low	Poor, or no, description of the structural alert with regard to its chemical structure or modulating factors.
Property Domain	High	A well-defined domain in terms of the complete molecular environment and ranges of physico-chemical and/or structural properties.
	Moderate	Some, but incomplete, definition of the domain for the complete molecular environment. No, or incomplete, definition of the ranges of physico-chemical and/or structural properties.
	Low	No, or very ambiguous, definition of the domain for the complete molecular environment and the ranges of physico-chemical and/or structural properties.
Toxicity or Relationship to Adversity	High	The endpoint, toxicity or adverse effect(s) is clearly and unambiguously stated.
	Moderate	The endpoint, toxicity or adverse effect(s) is general and lacks specificity e.g. in terms of organ or species.
	Low	The endpoint, toxicity or adverse effect(s) is not known or stated.
Species Specificity	High	The species, taxa or groups of organisms, in addition to relevant life stage if important, to which the structural alert is relevant, are identified and clearly stated.
	Moderate	There is some evidence and documentation that the structural alert is associated with the species to which it pertains.
	Low	No evidence is presented for a species-specific response to the structural alert.
Metabolic Domain	High	The metabolic domain is clearly and unambiguously stated e.g., the alert defines whether a chemical does or does not require metabolic activation.
	Moderate	The metabolic domain is ambiguous or poorly defined.
	Low	The metabolic domain is not known or stated.
Mechanistic Interpretation	High	The structural alert is strongly associated with a well-recognised and documented mechanism of action, e.g., a well-developed or OECD endorsed AOP.
	Moderate	The structural alert is possibly associated with a mechanism of action.
	Low	There is no mechanism of action or no documentation associated with the structural alert.
Mechanistic Causality	High	The chemistry captured by the structural alert is strongly associated with the MIE and/or a KE of the mechanism of action.
	Moderate	There is possible, but unsubstantiated, evidence that the chemistry of the structure may be associated with the mechanism of action, for instance evidence of correlation but not causality.
	Low	The chemistry captured by the structure alert has no documented association with the mechanism of action.
Coverage	High	The structural alert has relatively low coverage of alert-specific chemical space which could imply a limited and well-defined domain.
	Moderate	The structural alert has general coverage of alert-specific chemical space with a moderately broad domain.
	Low	The structural alert has high, or undefined, coverage of alert-specific chemical space indicating a broad, unspecific alert.
Performance	High	A statement relating to the predictive performance of the structural alert to assist in understanding the purpose of the alert, i.e., good performance measured by few false positives/negatives for hazard identification, or biased to ensure few false negatives for screening in a tiered approach.
	Moderate	The structural alert has modest (i.e. greater than random but is not 100% accurate) predictive performance.
	Low	The structural alert is not able to distinguish between active and inactive chemicals.
Corroborating Evidence	High	Multiple and confirmatory toxicological data to support the structural alert.
	Moderate	Few toxicological data exist to support the structural alert.
	Low	No toxicological data are available to support the structural alert e.g. for a statistical approach or one derived on hypothetic mechanisms.
Supporting Evidence	High	Multiple and confirmatory evidence from mechanistic information to confirm the mechanistic hypothesis.
	Moderate	Few data exist to support the mechanistic interpretation of the structural alert.
	Low	No mechanistic information is available to support the structural alert.