Substance Name: 4,4'-isopropylidenediphenol (BPA, Bisphenol A) EC Number: 201-245-8 CAS Number: 80-05-7 MEMBER STATE COMMITTEE SUPPORT DOCUMENT FOR IDENTIFICATION OF 4,4'-ISOPROPYLIDENEDIPHENOL (BPA, BISPHENOL A) AS A SUBSTANCE OF VERY HIGH CONCERN BECAUSE OF ITS ENDOCRINE DISRUPTING PROPERTIES WHICH CAUSE PROBABLE SERIOUS EFFECTS TO HUMAN HEALTH WHICH GIVE RISE TO AN EQUIVALENT LEVEL OF 1 2 CONCERN TO THOSE OF CMR AND PBT/ VPVB SUBSTANCES Adopted on 14 June 2017 1 CMR means carcinogenic, mutagenic or toxic for reproduction 2 PBT means persistent, bioaccumulative and toxic; vPvB means very persistent and very bioaccumulative SVHC SUPPORT DOCUMENT - 4,4'-ISOPROPYLIDENEDIPHENOL (BISPHENOL A) CONTENTS JUSTIFICATION ..................................................................................................................................... 16 1. IDENTITY OF THE SUBSTANCE AND PHYSICAL AND CHEMICAL PROPERTIES . 16 1.1 Name and other identifiers of the substance .............................................................. 16 1.2 Composition of the substance ............................................................................................. 17 1.3 Identity and composition of degradation products/metabolites relevant for the SVHC assessment .............................................................................................................. 17 1.4 Identity and composition of structurally related substances (used in a grouping or read-across approach) .................................................................................. 17 1.5 Physicochemical properties ................................................................................................. 17 2. HARMONISED CLASSIFICATION AND LABELLING .......................................................... 18 3. ENVIRONMENTAL FATE PROPERTIES ................................................................................... 18 4. HUMAN HEALTH HAZARD ASSESSMENT ............................................................................... 18 4.1 Binding of BPA to hormonal receptors ........................................................................... 22 4.2 Effect on the reproductive function ................................................................................. 23 4.2.1 Overview of previous evaluation of BPA’s effect on reproductive function ......................................................................................................................................... 23 4.2.2 Adverse effect: alteration of estrous cyclicity ....................................................... 26 4.2.3 Endocrine disruption in relation to the alteration of the estrous cyclicity .......................................................................................................................................... 29 4.2.4 Summary and discussion .................................................................................................... 45 4.2.5 Summary tables of studies ................................................................................................ 48 4.3 Alteration of mammary gland development ................................................................ 56 4.3.1 Overview of previous evaluation of BPA’s effect on mammary gland ..... 56 4.3.2 Background information on mammary gland development ........................... 57 4.3.3 Adverse effect ............................................................................................................................ 61 4.3.4 MoA (see Figure 13 and Figure 14) ..................................................................................... 62 4.3.5 Summary of the plausible link between adverse effects and endocrine MoA: Effects of BPA on mammary gland ................................................................... 66 4.3.6 Human information ................................................................................................................ 68 4.3.7 Transposition to humans: interpretation issues ................................................... 69 4.3.8 Summary and conclusion .................................................................................................... 70 4.3.9 Summary tables of studies ................................................................................................ 71 4.4 Alteration of brain development and cognitive function ....................................... 93 4.4.1 Overview of previous evaluation and focus on a specific effect ................. 93 4.4.2 Adverse effects ......................................................................................................................... 95 4.4.3 Endocrine disruption ........................................................................................................... 101 4.4.4 Summary and discussion .................................................................................................. 106 4.4.5 Summary tables of studies .............................................................................................. 108 4.5 Metabolism and obesity ........................................................................................................ 121 4.5.1 Overview of previous evaluation of BPA’s effect on metabolism and obesity ......................................................................................................................................... 121 4.5.2 Effects of BPA on glycaemia and insulin synthesis ........................................... 127 4.5.3 Effects of BPA on insulin resistance ........................................................................... 131 4.5.4 Human data ............................................................................................................................... 139 4.5.5 General conclusion on metabolism and obesity .................................................. 141 4.5.6 Summary tables of studies .............................................................................................. 143 4.6 Summary and discussion of human health hazard assessment ...................... 152 2 (204) SVHC SUPPORT DOCUMENT - 4,4'-ISOPROPYLIDENEDIPHENOL (BISPHENOL A) 5. ENVIRONMENTAL HAZARD ASSESSMENT ......................................................................... 153 6. CONCLUSIONS ON THE SVHC PROPERTIES ..................................................................... 153 6.1 CMR assessment ..................................................................................................................... 153 6.2 PBT and vPvB assessment ................................................................................................. 153 6.3 Assessment under Article 57(f) ...................................................................................... 153 6.3.1 Summary of the data on the hazardous properties ..................................................... 153 6.3.2 Equivalent level of concern assessment ........................................................................... 160 6.3.3 Conclusion on the hazard properties and equivalent level of concern assessment .................................................................................................................................. 169 REFERENCES ......................................................................................................................................... 172 3 (204) SVHC SUPPORT DOCUMENT - 4,4'-ISOPROPYLIDENEDIPHENOL (BISPHENOL A) TABLES Table 1: Substance identity .................................................................................... 16 Table 2: Constituents other than impurities/additives ............................................ 17 Table 3: Impurities ................................................................................................. 17 Table 4: Additives ................................................................................................... 17 Table 5: Classification according to Annex VI, Table 3.1 (list of harmonised classification and labelling of hazardous substances) of Regulation (EC) No 1272/2008 (as amended by Commission Regulation (EU) 2016/1179) ................... 18 Table 6: Summary table of proposed ED-mediated MoA of BPA on alteration of estrous cyclicity and its documentation .................................................................. 46 Table 7: Overview of the elements supporting the identification of an alteration of estrous cyclicity as an ED-mediated effect of BPA ................................................... 46 Table 8: Summary table of studies investigating the effects of BPA on the estrous cycle in female animals .......................................................................................... 48 Table 9: Summary of the in vitro studies showing an alteration of the ovarian steroidogenesis function likely to result in disturbance of estrous cyclicity if occurring in vivo . .................................................................................................... 51 Table 10: in vivo evidence for endocrine mechanisms potentially underlying alteration of estrous cyclicity as a consequence of adult exposure to BPA .............. 52 Table 11: Summary of the in vitro study showing an alteration of GnRH activity by BPA ........................................................................................................................ 52 Table 12: Evidence for BPA-induced disturbance of estrous cyclicity in animal models and link with an endocrine