Naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- is not genotoxic, provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and reproductive toxicity endpoints, and show that there are no safety concerns for naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- for skin sensitization under the current declared levels of use. The photoirritation/photoallergenicity endpoints were evaluated based on data and ultraviolet/visible (UV/Vis) spectra; naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- is not photoirritating/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class III material, and the exposure to naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- is below the TTC (0.47 mg/day). The environmental endpoints were evaluated; naphtho[2,1-b]furan, dodecahydro-3a,6,6,9a-tetramethyl-, (3aR,5aS,9aS,9bR)- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
In vitro hepatic metabolic clearance data were generated for a diverse set of 207 chemicals to advance the collaborative initiative to establish an internal Threshold of Toxicological Concern (iTTC). The data reported herein are being used for chemical-specific physiologically based pharmacokinetic (PBPK) modeling to convert oral No Observable Adverse Effect Levels (NOAELs) into estimates of internal exposure. Hepatocyte assays were conducted at 2 concentrations (0.1 and 1 µM) using cryopreserved cells from multiple species, ensuring applicability to existing mammalian toxicity studies. The metabolic clearance measurements across chemicals varied significantly, ranging from 0 to 4,294 µl/min/106 cells at 0.1 µM and from 0 to 2,351 µl/min/106 cells at 1 µM. A substantial proportion of the chemicals (68% at 0.1 µM and 62% at 1 µM) exhibited clearance values below 30 µl/min/106 cells. Additionally, we observed a strong correlation (R = 0.8) between intrinsic clearance (CLint) values determined at the 2 concentrations. These data contribute to establishing robust iTTC values that can be utilized for: (i) extrapolating from an oral in vivo study to dermal and inhalation exposures, (ii) risk-based screening of aggregate exposures of a given substance from multiple routes of exposures, and (iii) risk-based screening of human biomonitoring results.
Skin sensitization is a key endpoint for the safety assessment of topical consumer products. Ingredients with the potential to act as skin sensitizers differ markedly in their threshold for induction but can be used safely if their potency is characterized and exposure remains within an appropriate margin of safety. To this end, the fragrance industry co-developed Quantitative Risk Assessment (QRA) which starts with the No-Expected-Sensitization-Induction-Level (NESIL). Historically, QRA relies on a weight of evidence approach based on animal data, human confirmatory tests and read across. To allow an approach based solely on New Approach Methodologies (NAMs), the International Dialogue for the Evaluation of Allergens (IDEA) initiative, developed an extended Reference Chemical Potency List (RCPL) integrating human and animal data to derive potency values (PV). Here, we use PVs to evaluate the suitability of quantitative NAMs, including Defined Approaches (DAs), to derive a Point-of-Departure (NAM-PoD) for skin sensitization potency assessment. Evaluation of NAM-PoD derived by SARA-ICE DA, Regression DA and GARDskin dose-response assay (GSDR), indicates that the sensitization potency of fragrance chemicals can be reliably predicted using each approach. Through comparison of NAM-PoDs with in vivo human sensitization thresholds, NAM-specific adjustment factors were derived to convert NAM-PoDs into NAM-NESILs for QRA.
As part of the evidence integration step of its proposed systematic review protocol supporting chemical risk evaluations under the Toxic Substances Control Act (TSCA), the United States Environmental Protection Agency (EPA) describes a data hierarchy for various sources within the risk assessment. EPA identifies "less preferred" exposure data sources (e.g., modeled data) and "more preferred" sources (e.g., monitoring data). This approach to risk assessment data contrasts with substantial EPA guidance regarding tiered approaches for risk-based decision-making. We examined environmental exposure data for the fragrance material 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[g]-2-benzopyran (HHCB), a TSCA high-priority substance, using EPA's deterministic model the Exposure and Fate Assessment Screening Tool (E-FAST), a publicly available probabilistic environmental exposure model (iSTREEM), and data from the United States Geological Survey's National Water Information System. Exposure estimates for HHCB decreased progressively from deterministic modeling to probabilistic modeling to monitoring data. However, this case study illustrates that higher-tier analyses may reduce uncertainty but may not improve the risk conclusions. Over the course of an iterative risk characterization, the need for higher tier data may be demonstrated. However, in other cases, it may be more efficient and effective to draw risk conclusions at a lower tier of assessment and forego further analysis of existing data.
