Registration Dossier

Toxicological information

Carcinogenicity

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Description of key information

Dietary carcinogenicity studies in rats and mice concluded that Bisphenol A was not carcinogenic in either species. No inhalation or dermal carcinogenicity studies were available, although in repeat exposure inhalation toxicity studies, Bisphenol A did not exhibit properties that raised concern for potential carcinogenicity. Overall, Bisphenol A has no carcinogenic potential. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The 2003 EU RAR concluded:

"There are no human data contributing to the assessment of whether or not Bisphenol A is carcinogenic, but a dietary carcinogenicity study in rats and mice concluded that Bisphenol A was not carcinogenic in either species because the tumour findings were not considered toxicologically significant. No inhalation or dermal carcinogenicity studies were available, although in repeat exposure inhalation toxicity studies, Bisphenol A did not exhibit properties that raised concern for potential carcinogenicity. Taking into account all the animal data available, it was concluded that the animal evidence suggests that Bisphenol A does not have carcinogenic potential."

The 2008 updated EU RAR concluded:

"The new information on the potential carcinogenic and/or promoting effects of Bisphenol A in prenatal and neonatal rat models supports the original conclusion that Bisphenol A does not possess any significant carcinogenic potential. This is based on one new study in which the full carcinogenic potential of Bisphenol A on the mammary gland was examined in a prenatal model. This study claimed that Bisphenol A induced preneoplastic and neoplastic lesions of the mammary gland, but its validity was hampered by serious methodological limitations and its findings are inconsistent with the absence of preneoplastic lesions of the mammary gland in the offspring from several standard multi-generation studies in rats and mice. Other new studies suggest that prenatal or neonatal exposure to Bisphenol A does not exert promoting activity on the carcinogenesis induced by established carcinogens/initiators in specific organs."

Recent data taken into account for the dossier update:

A recent study by US NCTR (Delclos et al 2014) investigated mammary gland proliferation in rats. This study was evaluated by SCOEL and EFSA. Ethinyl oestradiol was used as a positive control of the estrogenic effects of Bisphenol A. The dose-matched vehicle control was carboxymethylcellulose. The doses were: (i) Bisphenol A 2.5, 8, 25, 80, 260, 840, 2700, 100 000, 300 000 μg/kg bw per day, (ii) Vehicle, (iii) EE2 0.5, 5 μg/kg bw per day. The study included a naïve control group and doses were administered by oral gavage. The protocol and methods, including statistical analysis were of the high quality and robust with treatment, body weight and litter randomisation and appropriate inclusion and exclusion criteria established prior to the start of the study. The target unit for analysis was 20 litters and 18-23 were achieved. F0 females were dosed from GD 6 up to labour onset and pups from PND 1 until tissue harvesting, up to PND 90. Additional groups were exposed from GD 6 to PND 21 for histopathological examination of the mammary glands.

Overall conclusion concerning mammary gland: "Taking the incidences, the statistical testing results, and all pathologists and study authors opinions together, the authors of the NTP report (Gu and Mitkus, 2013), concluded that the evidence for duct hyperplasia in the mammary gland of females on either PND 21 or PND 90 was weak. They considered it an equivocal finding that may be the reflection of normal variability and/or a reflection of limits in tissue processing. Bisphenol A did not cause duct hyperplasia in the mammary glands of male rats, while conversely the reference estrogen EE2 induced hyperplasia in the male but not the female mammary gland".

SCOEL Recommendation 2014 concluded on carcinogenicity:

"Thus, there is currently no convincing evidence of carcinogenicity of Bisphenol A when administered either during the adulthood or perinatally. However, as concluded by EFSA (2014), there are some data (including the data by Delclos et al 2014) that raise some concern for Bisphenol A effects on mammary gland cell proliferation after pre- and perinatal exposure. Whether this is linked to increased cancer incidence in later life or not remains to be shown."

EFSA Opinion 2015 concluded:

Proliferative and morphological changes potentially related to carcinogenesis

"Earlier evidence for Bisphenol A effects on cell proliferation and differentiation in the mammary gland and other tissues (e.g. prostate or testis) has been supported by recent studies. The proliferative changes in the mammary gland reported in these new studies, including a non-human primate study, are insufficient to conclude that there is a link to cancer development in later life. However, there might be a possible role of Bisphenol A in increasing the susceptibility to mammary gland carcinogenesis later in life.

The proliferative responses and possibly enhanced sensitivity to mammary gland carcinogens seen in animal studies might be of relevance for human health and are therefore included in the risk assessment.

Using a WoE approach, the CEF Panel assigned a likelihood level of “likely” to Bisphenol A induced proliferative changes in the mammary gland. Therefore, this endpoint was brought forward for hazard characterisation and for uncertainty analysis.

The CEF Panel considered that the evidence for proliferative changes induced by Bisphenol A in other organs (e.g. prostate or testis) is currently too limited to reach any conclusion."

Carcinogenicity:

“Very few epidemiological studies published to date have investigated a possible association between exposure to Bisphenol A and incidence of certain cancers, specifically breast cancer and meningioma. These studies do not allow any conclusion to be drawn regarding the carcinogenicity of Bisphenol A in humans.

Bisphenol A was not carcinogenic in two standard oral carcinogenicity studies in rats and mice. In a more recent study, female but not male mice, exposed to approximately 10 mg/kg bw per day Bisphenol A from in utero up to postnatal day (PND) 21, developed significantly more hepatocellular tumours (adenomas and carcinomas together) with or without preneoplastic lesions after a stop-exposure period of 10 months. Additional rodent studies on perinatal exposure to Bisphenol A investigated the potential carcinogenic effect in mammary gland. Due to weaknesses in these studies the results do not provide convincing evidence that Bisphenol A is carcinogenic to the liver during adult life or in mammary gland following perinatal exposure.

Using a WoE approach, the CEF Panel assigned a likelihood level of “unlikely to - as likely as not -” to carcinogenic effects of Bisphenol A. Since the likelihood level for this endpoint is less than "as likely as not” (see Appendix A), this endpoint was not taken into account in the evaluation of uncertainty for hazard characterisation and risk characterisation.“

Justification for classification or non-classification

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