Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information
EU RAR 2008, SCOEL recommendation 2014 and EFSA opinion 2015 concluded that Bisphenol A is not mutagenic.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vitro:

The 2003 EU RAR concluded:

"No human data regarding mutagenicity are available. However, Bisphenol A appears to have demonstrated aneugenic potential in vitro, positive results being observed without metabolic activation in a micronucleus test in Chinese hamster V79 cells and in a non-conventional aneuploidy assay in cultured Syrian hamster embryo cells. Additionally, in cell-free and cellular systems there is information that shows Bisphenol A disrupts microtubule formation. Bisphenol A has been shown to produce adduct spots in a post-labelling assay with isolated DNA and a peroxidase activation system, but it does not appear to produce either gene mutations or structural chromosome aberrations in bacteria, fungi or mammalian cells in vitro. However, some deficiencies in the conduct of these studies have been noted and the negative results cannot be taken as entirely conclusive. Bisphenol A does not appear to be aneugenic in vivo, since a recently conducted, standard mouse bone marrow micronucleus test has given a negative result. Bisphenol A was negative in a briefly reported dominant lethal study in rats but, given the limited details provided, this is not regarded as an adequate negative result. The only other data in somatic cells in vivo are from a 32P-postlabelling assay, which showed that Bisphenol A is capable of producing DNA adduct spots in rat liver following oral administration. These adduct spots were not characterised fully.

Considering all of the available genotoxicity data, and the absence of significant tumour findings in animal carcinogenicity studies (see below), it does not appear that Bisphenol A has significant mutagenic potential in vivo. Any aneugenic potential of Bisphenol A seems to be limited to in vitro test systems and is not of concern. The relevance of the finding that Bisphenol A can produce rat hepatic DNA adduct spots in a postlabelling assay is not entirely clear. However, given the absence of positive results for gene mutation and clastogenicity in cultured mammalian cell tests, it seems unlikely that these are of concern for human health."

 

The 2008 updated EU RAR concluded:

"New data from a study indicating effects of Bisphenol A on meiosis in female mice cannot be taken as conclusive evidence of an effect of Bisphenol A on germ cell meiosis because of the several methodological weaknesses and flaws identified in the study, the reporting inadequacies, and the known mutagenicity and toxicity profile of Bisphenol A. In addition, these findings have not been confirmed in more recent publications. Thus, the original conclusion that Bisphenol A has no significant mutagenic potential in vivo is still valid."

 

Additional recent information concerning the observations reported discussed in the 2008 updated EU RAR was discussed in the initial dossier submitted in 2010:

Two in vivo studies (Hunt et al.(2003) and Susiarjo et al. (2007)) evaluated during the 2008 EU RAR reported that short-term oral exposure to low doses of Bisphenol A (≥ 0.020 mg/kg bw/day) in peripubertal or pregnant mice can interfere with meiotic divisions in development of female germ cells (“egg” or “oocyte”). An increase in hyperploid (aneuploid) metaphase II oocytes was observed following treatment with 0.020 mg/kg bw/day. There was not a significant increase in aneuploid embryos.

Two subsequent in vivo studies (Pacchierotti et al.(2008), Eichenlaub-Ritter et al. (2008)) attempted to replicate these findings. Consistent with the previous findings, they detected no significant effects of Bisphenol A exposure on the frequency of aneuploidy in “zygotes” (fertilised oocytes) produced from female mice treated before puberty or as adults with a similar range of doses. In addition, Eichenlaub-Ritter et al. (2008) found no effects of Bisphenol A exposure on aneuploid oocytes and Pacchierotti et al. (2008) found no increase in aneuploid or diploid sperm following exposure of male mice to Bisphenol A. The authors concluded that the aneuploidy predicted by the Hunt group could not be confirmed.

In addition, in a recent study published by the Hunt group, Muhlhauser et al. (2009), the authors could not replicate their initial findings on “congression failure” but report effects on chromosome alignment and/or spindle formation. The authors state “After publishing our findings [Hunt et al., 2003], we initiated studies to assess the effect of long term Bisphenol A exposure on the growing follicle. To our surprise, levels of Bisphenol A that were sufficient to elicit an effect on meiotic chromosome dynamics during the previous two years of study suddenly produced little or no effect. In an analysis of possible changes in experimental protocol, the only change identified was the lot of animal feed.” The authors report frequencies of abnormal oocytes in the absence and presence of Bisphenol A in two different diets (casein based and soy based). The reported frequencies of abnormal oocytes of the Bisphenol A/casein group are lower than the background value reported in the soy-based diet.

Overall, the initial observations reported by the Hunt laboratory were not reproduced in the same laboratory or in other independent laboratories. Therefore, the conclusion from the 2003 EU RAR and the 2008 EU RAR Update is still valid; Bisphenol A has no significant mutagenic potential in vivo.

 

SCOEL Recommendation 2014 concluded on genotoxicity:

“Considering all of the available genotoxicity data and the absence of significant tumour findings in animal carcinogenicity studies (see Section 3.8), it does not appear that Bisphenol A has significant mutagenic or genotoxic potential in vivo.”

 

EFSA Opinion 2015 concluded on gentoxicity:

“The available data support that Bisphenol A is not mutagenic (in bacteria or mammalian cells), or clastogenic (micronuclei and chromosomal aberrations). The potential of Bisphenol A to produce aneuploidy in vitro was not expressed in vivo. The positive finding in the postlabelling assays in vitro and in vivo is unlikely to be of concern, given the lack of mutagenicity and clastogenicity of Bisphenol A in vitro and in vivo.

Using a WoE approach, the CEF Panel assigned a likelihood level of “unlikely” to Bisphenol A genotoxicity.”

 

Justification for classification or non-classification

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