Chemical Hazard Assessment of Aluminum Phosphates in the Provisional Peer-Reviewed Toxicity Value (PPRTV) Program
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Methods: Repeated dose oral toxicity studies were identified for acidic and basic SALPs; however, limitations of these studies (e.g., lack of primary study reports, limited data reporting, unreliable laboratory reports, etc.) were significant. As a result, screening subchronic and chronic p-RfDs were derived using an alternative read-across approach. The read-across methodology is based on a tiered, weight-of-evidence approach as described in Wang et al. (2012) and Lizarraga et al. (2023) that was used to select the overall most appropriate analogue chemical. In this approach, structural analogues were initially identified using automated screening tools and then reviewed by an experienced chemist to narrow (or expand) the list based on known or expected structure-toxicity relationships, reactivity, and metabolic pathways. Metabolic analogues (metabolites and metabolic precursors) were identified from metabolism simulators and targeted literature searches. Toxicity/mechanistic/mode-of-action (MOA) analogues were identified from in vivo toxicity data and in vitro mechanistic data (e.g., bioactivity data). Availability of toxicity assessments from reliable sources (U.S. EPA IRIS and PPRTV assessments, Agency for Toxic Substances and Disease Registry [ATSDR], and California Environmental Protection Agency [CalEPA]) was determined for candidate analogues for potential use in deriving screening-level provisional toxicity values for aluminum phosphates.
Results: Taken together, the water solubility, bioavailability, and toxicity data indicated that aluminum (from aluminum salts) and sodium and potassium phosphate salts were considered suitable analogues for aluminum phosphates. To adequately protect against all of the potential effects mediated by both the aluminum moiety and the phosphate moiety of aluminum phosphates, the candidate analogue with the most conservative toxicity value was selected as the most suitable analogue for read-across. Comparing aluminum to phosphorus in various aluminum phosphates on a molar basis yields a ratio between 1:1 and 1:3 for most of the included aluminum phosphate salts (and did not exceed 1:4 for any compound). Thus, using a point of departure (POD) based on aluminum (risk value of 1 mg Al/kg-day) compared to a POD based on phosphate (risk value of 4 mg P/kg-day) is more protective. Based on ATSDR (2008) Toxicological Profile for Aluminum, POD was a no-observed-adverse-effects level (NOAEL) of 26 mg Al/kg-day for neurobehavioral effects of aluminum toxicity. This same POD was used in this assessment and a composite uncertainty factor (UF) of 100 was applied based on 10-fold inter- and intra- species extrapolation factors (UFA of 10 and UFH of 10, respectively).
Conclusions: A screening RfD of 3 × 10−1 mg Al/kg-day was estimated for both subchronic and chronic exposure to aluminum phosphates, and the details are presented in a recently-released Provisional Peer Reviewed Toxicity Values (PPRTV) assessment (EPA, 2023). For each specific aluminum phosphate compound included in the assessment, the final RfD in the unit of mg compound/kg-day can be calculated based on the relative Al content in the compound.