6-hydroxy-2-naphthoic acid

Endpoint summary

Description of key information

Data are limited for Toxicokinetic properties of the subject substance (6-hydroxy-2-naphthoic acid; 6-HNA) and the read-across substance (3-hydroxy-2-naphthoic acid; 3-HNA).  However, a combination of data from studies conducted on 6-HNA and 3-HNA, as well as studies on the the metabolism of another group of structurally similar substances, the isomers of naphthoic acid (1- and 2- isomers), conclusions can be drawn regarding Toxicokinetics, metabolism and distribution of 6-HNA.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

PRIMARY EVIDENCE:

While there are limited data for the metabolism/toxicokinetics of either the substance of record (6-hydroxy-2-naphthoic acid; 6 -HNA) and the read-across substance (3-hydroxy-2-naphthoic acid; 3 -HNA), there are data regarding the metabolism of a structurally-related group of substances. The common structural component of all of the substances referenced in this Weight of Evidence approach is the naphthalene ring.

The Toxicokinetics of the naphthalene substructure are very well understood (Preuss et al., 2003). Naphthalene is first epoxidized via Cytochrome P450, and is then either conjugated to glutathione, or proceeds to a hydroxylated form with is then glucuronidated (Klaassen, 2001, p. 215; IARC Monograph 82). While naphthalene has known toxicological concerns (it classified by IARC as Category 2B ["possibly carcinogenic to humans"]), 6 -HNA, 3 -HNA and naphthoic acid (both the 1- and 2 -isomers) do not pass through the naphthoquinone intermediate, which is considered the putative carcinogenic entity. This is supported by the lack of in vitro genotoxicity of both 6 -HNA and 3 -HNA in the presence of mammalian metabolic systems (please see Section 7.6 of the dossier).

Progressing toward the structure of the substance of record (6 -HNA) and the read-across molecule (3 -HNA), the structural isomers 1 - and 2 -naphthoic acid differ structurally from 6 -HNA and 3 -HNA in the absence of the hydroxyl group present at the 2 -position, and the absolute position of the carboxylic acid group. Detoxification of exogenous substances can happen via two types of reactions: transformation or conjugation. Transformation (Phase I) reactions directly convert substances into more readily excretable metabolites through slight changes in structure (i.e., introduction of hydroxyl groups into non-reactive aromatic compounds). Conjugation pathways involve the linkage of exogenous substances to other molecules which make them more readily excretable (glutathione conjugation, glucuronidation). Glucuronidation represents a generic detoxification pathway, as it is relatively non-specific. It is known that cyclic structures with primary and/or tertiary carboxylic acid groups are metabolized via O-glucuronidation pathways (Tukey and Strassburg, 2000). Because the metabolism of 1- and 2 -naphthoic acid is primarily through the route of glucuronic acid conjugation to the carboxylic acid group (Klaassen, 2001), it is the similarity in reactivities of the carboxylic acid group that drives this read-across. Despite the difference in the absolute position of the carboxylic acid group, the reactivities of all four substances can be considered similar based on their similarities in pKa:

Substance	pKa
6 -hydroxy-2 -naphthoic acid	4.89
3 -hydroxy-2 -naphthoic acid	2.7
1 -naphthoic acid	3.70
2 -naphthoic acid	4.07

Because all of the pKa's are below neutral (7.0), they would all be expected to be in the same state of dissocation in biological systems. This would imply similar reactivities, meaning that there would be a high probability for a common detoxification mechanism. Detoxification (biotransformation and excretion) of any substance suggests that bioaccumulation does not occur. Even the less hydrophilic naphthalene is not known to bioaccumulate (IARC Monograph 82).

SECONDARY EVIDENCE

The read-across substance, 3 -HNA, has been used in clinical settings as a Cholagogue/Choleretic. Use of this substance as a direct pharmacological agent presumes metabolism/excretion.

As further evidence that naphthalenic structures are metabolized/excreted, the pharmacological agent Cinacalcet contains a naphthalene substructure which is oxidized to dihydrodiols, which are then excreted in urine and bile as glucuronide conjugates (Kumar et al., 2004).

CONCLUSION:

There are no direct data regarding the absorption rate of the substance of record (6 -HNA), the read-across candidate (3 -HNA), or the other structural analogues. The conclusion that 6 -HNA represents a "Low Bioaccumulation Potential" is derived from professional opinion based on the overall weight of evidence. The weight of evidence approach suggests that substances with naphthalenic substructures are metabolized/excreted, and therefore pose a low potential for bioaccumulation.