TABLE I2.
Uncertainties identified and their impact on the outcome of the hazard identification and characterisation.
| Description of the uncertainty | Impact on the hazard identification and characterisation a | |
|---|---|---|
| Chemical composition and analytical methods | ||
| Dosing and chemical composition | Uncertainty associated with the dose in the critical studies used in the risk assessment | 1 – Low impact. Many of the studies are conducted using gavage dosing |
| Hazard identification and characterisation | ||
| ADME | ADME in relation to the critical studies | 1 – Low impact. TK data on rat are available by gavage or i.v. route. Only one in vivo study was identified in mice (oral exposure). One In vitro study showed that the TBBPA glucuronidation abilities in mice was 1.1‐fold those observed in human |
| Relevance in humans, genetic background/susceptibility/sensitive populations | 0 – Negligible impact. Immature metabolism for young children could lead to underestimation of the risk. This is covered in the default UF for intraindividual variability | |
| Accumulation potential | 0 – Negligible impact. Studies in rats with single and repeated exposure show rapid clearance. Data on bioaccumulation indicates that TBBPA is weakly bioaccumulative compared to HBCDDs or PBDEs | |
| Little information on transfer rate to animal products | 0 – Negligible impact. No studies are available but no impact on the risk assessment | |
| Transfer via mother's milk | 0 – Negligible impact. Based on studies in rats, low levels of TBBPA in the pups have been detected | |
| Toxicity studies in experimental animals: critical endpoints and critical study design | Limitations in the study design of the studies that can result in uncertainties |
Carcinogenicity: 0 – Negligible impact. The critical rat study was conducted by NTP (2014) and considered to be of high quality. The mouse study was compromised by high mortality in the top dose group and is not considered to be a critical study Neurotoxicity: 1 – Low impact. The critical study (Kim et al., 2015) is a one dose level study |
| Relevance for humans of the adverse effect/biomarkers of adversity |
Carcinogenicity: 0 – Negligible impact. The uterine tumours reported in rats are relevant for humans Neurotoxicity: 0 – Negligible impact. The effect in the critical study (increased anxiety and decreased interest in social interaction) is indicative of disturbances of social behaviour and is considered adverse. Moreover, mechanistic data, indicating epigenetic modifications at lower doses of TBBPA, provide supporting evidence that exposure to TBBPA has adverse effects on the nervous system in mammals |
|
| Effects tested only in one species, one sex or certain age groups or at one time point |
Carcinogenicity: 0 – Negligible impact. Both male and female rats and mice were tested Neurotoxicity: 1 – Low impact. Only M pups tested in the critical study (Kim et al., 2015) |
|
| Consistency between studies on same/similar endpoints: high dose versus low dose |
Carcinogenicity: 0 – Negligible impact. Not relevant Neurotoxicity: 0 – Negligible impact. Different effects were seen at similar levels in different studies |
|
| Genotoxicity | Uncertainty in the assessment of genotoxicity | 0 – Negligible impact. Based on the evidence available, TBBPA is not genotoxic (see Section 3.1.2.6 ) |
| Selection of reference point | NOAEL/LOAEL approach | 2 – Moderate impact. No NOAEL could be identified in the critical study (Kim et al., 2015). One dose level study |
| Weaknesses in non‐critical studies and uncertainty about whether the endpoints they tested might have been critical if the weaknesses were not present |
2 – Moderate impact. Four studies involved dosing TBBPA to mice via drinking water (Zatecka et al., 2013; Li et al., 2022; Xiong et al., 2023; Song et al., 2024). These studies reported effects on the thyroid, neurotoxicity/neurodevelopment or reproduction toxicity at exceptionally low effect levels whereas other studies where TBBPA was administered by gavage have reported effects only at three orders of magnitude higher dose levels. The CONTAM Panel noted that the studies were generally well conducted. However, the concentrations in drinking water were not confirmed by analysis of TBBPA, which may be important, e.g. because of the low solubility of TBBPA in water. The authors reported that the daily intake in μg/kg bw per day was estimated based on the daily water consumption and body weight. This may be the case for dams but not for the pups, as no drinking water consumption was measured. The CONTAM Panel considered therefore that there is a high level of uncertainty regarding the doses received by the animals, and no NOAELs/LOAELs were identified, or dose–response assessment performed. If effects occurred at the levels reported in these studies, the impact on the hazard assessment and TDI would be high, but the impact on the risk characterisation would be moderate due to the low exposure estimates 1 – Low impact. The lowest LOAEL was identified from a one dose level study (Rock et al., 2019, 1st experiment) for an increased level of activity in the running wheel apparatus. The relevance for humans and adversity of this effect was considered uncertain 1 – Low impact. Increasing evidence of the sensitivity of the developing brain to chemical exposure, including MOA studies with TBBPA reported in the Opinion. These indicate some probability that relevant effects of TBBPA may be found at lower dose levels in future, though these might be intermediate rather than apical |
|
Abbreviations: ADME, absorption, distribution, metabolism, excretion; BMD, benchmark dose; BMDL, Benchmark Dose Lower Confidence Limit; BMR, Benchmark Response; DSB, double strand breaks; MOA, mode of action; NTP, National Toxicology Program; OECD, Organisation for Economic Co‐operation and Development; SSB, single strand breaks; TDI, Tolerable Daily Intake; TK, Toxicokinetic; UF, Uncertainty factor.
0 – Uncertainty with negligible impact; 1 – Uncertainty with low impact; 2 – Uncertainty with medium impact; 3 – Uncertainty with high impact.