Registration Dossier

Administrative data

Description of key information

A developmental neurotoxicity study indicated no effect up to the highest dose tested; 2250 ppm (corresponding to 164 mg/kg/day during gestation and 410 mg/kg/day during lactation).

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
164 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

A robust study in rats conducted under OECD and US EPA guidelines (Stump, 2009) reported no evidence of developmental neurotoxicity at any of the tested concentrations of Bisphenol A. Bisphenol A was continuously administered to rat dams during gestation and lactation via test diets containing 0, 0.15, 1.5, 75, 750, and 2250 ppm Bisphenol A. Reduced body weight and body weight gain was observed in dams and F1 males and females at 750 and 2250 ppm Bisphenol A. There were no effects observed at any exposure level in the neurobehavioural and neuropathological evaluations of F1 animals. A systemic NOAEL of 75 ppm (corresponding to 5.85 mg/kg/day during gestation and 13.1 mg/kg/day during lactation) for reduction in body weight and weight gain of dams and offspring was determined. A NOAEL for developmental neurotoxicity of 2250 ppm (corresponding to 164 mg/kg/day during gestation and 410 mg/kg/day during lactation) in offspring was determined, as there was no evidence of developmental neurotoxicity at any tested dose, including the highest dose of 2250 ppm Bisphenol A.

EFSA Opinion 2015 Conclusions on neurological, neurodevelopmental and neuroendocrine effects.

"There are indications from prospective studies in humans that prenatal Bisphenol A exposure (Bisphenol A exposure during pregnancy) may be associated with altered child behaviour in a sex-dependent manner. However, the associations were not consistent across the studies and it cannot be ruled out that the results are confounded by diet or concurrent exposure factors. The associations reported do not provide sufficient evidence to infer a causal link between Bisphenol A exposure during pregnancy or childhood and neurodevelopmental effects in humans.

A number of new studies report changes that may indicate effects of Bisphenol A on brain development (effect on neurogenesis and on gene expression, neuroendocrine effects, effects on the morphology of certain brain regions, etc.). Whether such changes are mechanistically related to the neurobehavioral responses reported following exposure is attempted addressed by some studies but with inconsistent results.

Several new animal studies investigated anxiety-like behaviour, learning and memory, social behaviour and sensory-motor function. Some studies report changes in anxiety-like behaviour after Bisphenol A exposure. Some, but not all, studies reported significant impairment of either learning and/or memory capacities. A few studies also report effects on social behaviour and sensory-motor function. However, the studies present methodological shortcomings, such as small sample size, lack of consideration of the litter effect, not properly controlled variability of exposure through diet and inadequate statistics. Using a WoE approach, the CEF Panel assigned a likelihood level of “as likely as not” to neurological, neurodevelopmental and neuroendocrine effects of Bisphenol A level for this endpoint is less than "likely" (see Appendix A), this endpoint was not taken forward for assessing the toxicological reference point, but was taken into account in the evaluation of uncertainty for hazard characterisation and risk characterisation (Section 4.3)."

Recent information taken into account for the dossier update.

There are two recent studies in the context of the US NTP CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) study (Rebuli et al 2015 and Johnson et al 2015). To address potential neurobehavioral effects, the present studies were conducted as part of the CLARITY-Bisphenol A (Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity) program. The impact of perinatal Bisphenol A exposure (2.5, 25, or 2500 µg/kg body weight (bw)/day) on behaviors related to anxiety and exploratory activity was assessed in juvenile (pre-pubertal) and adult NCTR Sprague-Dawley rats of both sexes. Ethinyl estradiol (EE; 0.5 µg/kg bw/day) was used as a reference estrogen. Exposure spanned gestation and lactation with dams gavaged from gestational day 6 until birth, and then the offspring gavaged directly through weaning (n = 12/sex/group).

Behavioral assessments included open field, elevated plus maze, and zero maze. Anticipated sex differences in behavior were statistically identified or suggested in most cases. No consistent effects of Bisphenol A were observed for any endpoint, in either sex, at either age compared to vehicle controls; however, significant differences between Bisphenol A-exposed and EE-exposed groups were identified for some endpoints. These data do not indicate Bisphenol A-related effects on anxiety or exploratory activity in these developmentally exposed rats (Rebuli et al 2015; for further details on the study see chapter toxicity to reproduction)

At adulthood, offspring were tested for seven days in the Barnes maze. No consistent or robust effect was observed. The 2500 Bisphenol A group sniffed more incorrect holes on day 7 only than those in the control, 2.5 Bisphenol A, and EE groups. The 2500 Bisphenol A females were less likely than control females to locate the escape box in the allotted time (p value = 0.04). Although 2.5 Bisphenol A females exhibited a prolonged latency, the effect did not reach significance (p value = 0.06), whereas 2.5 Bisphenol A males showed improved latency compared to control males (p value = 0.04); the significance of this result is uncertain. No differences in serum testosterone concentration were detected in any male or female treatment groups (Johnson et al 2015; for further details on the study see chapter toxicity to reproduction).

Justification for classification or non-classification

Bisphenol A is included in Annex VI of Regulation (EC) No 1272/2008. No classification regarding Neurotoxicity is required. No classification required.