Bisphenols

Substances within the bisphenol group are used in the manufacture of plastic articles such as polyvinylchloride (PVC) and polycarbonate. Currently, bisphenol A (BPA) is the substance in the bisphenol group that produced and used in the highest volumes. The use of other bisphenols is small in comparison with BPA (KEMI, 2017).

There is wide use of polycarbonate, with it being used in the manufacture of modern optical media, such as DVDs and CDs, sports equipment, medical and dental devices, building and construction materials, automotive parts and domestic appliances, as well as food containers, such as reusable beverage bottles and some manufacturing equipment. BPA is also used in epoxy resins, such as those used to line food and beverage cans. Small amounts of the BPA contained in these food contact materials migrate into food and beverages stored in materials containing the substance, resulting in human exposure.

BPA is also used in the manufacture of thermal papers, leading to concerns regarding the exposure of cashiers in frequent contact with thermal paper in receipts. Some bisphenols are used as laboratory reagents.

In June 2017, BPA was identified as having endocrine disrupting properties for human health by the Member State Committee of the European Chemicals Agency (ECHA) (ECHA, 2017). Due to its properties as toxic for reproduction, BPA was already listed as a substance of very high concern (SVHC) on the Candidate List under Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

The identification of BPA as a SVHC generates pressure for BPA to be substituted by other bisphenols in the European Union (EU). A number of other bisphenols have been registered under REACH. The Swedish Chemicals Agency has identified over 200 other bisphenols with a chemical structure similar to BPA that can occur on the European market (KEMI, 2017).

According to a survey conducted by ECHA for the European Commission, EU paper manufacturers have started to substitute BPA with BPS, The amount of BPS used as developer in thermal paper on the EU market almost doubled between 2016 and 2017. Reflecting the overall increase in the use of thermal paper in the EU in 2017, BPA use also increased in the same time period.

The market share of BPS-based thermal papers is expected to continue to increase in the coming years, and in particular after 2 January 2020, when BPA can no longer be used in thermal paper in the EU. ECHA notes that substitution of BPA by BPS is worrisome given that ECHA’s Risk Assessment Committee in its opinion on BPA indicated that BPS “is suspected to have many of the same adverse health effects as BPA”. About 30 % of thermal paper in the EU is imported from China, India, Japan, Korea and the US. Unfortunately, information on how the use of different developers in these products changed during the inspected time period was not available for the survey (ECHA, 2018).

To download the list of substances that are currently captured in the bisphenols group, please click here.

The list of bisphenols includes links to information on chemicals provided by ECHA. These include links to Infocards and Brief profiles, where available.

The Infocards quickly display the most prominent hazardous properties of a substance. The ‘Hazard classification and labelling’ section shows the hazards of a substance through a standardised system of statements and pictograms, based on existing EU harmonised classification and labelling (CLH) of the substance. This may be supplemented by Classification and Labelling (C&L) notifications provided by companies under the Classification, Labelling and Packaging (CLP) Regulation (EC) No 1272/2008.

The brief profile goes deeper into the environmental, human health and physico-chemical properties of the chemical, summarizing the non-confidential data on substances held in the ECHA databases, including data provided by third parties.

Aside from these institutional information sources, there is a large body of literature on the toxicity of BPA, including at low doses (see WHO and UNEP, 2012, Gore et al., 2015, Seachrist et al., 2016 and Vandenberg, 2014).

Bisphenol A

There is a large amount of literature on the toxicity of bisphenol A including at low doses [reviewed in WHO and UNEP (2012), Gore et al. (2015), Vandenberg (2014), and EFSA Journal (2015)]. Studies have indicated that it could be associated with increased risk for:

• Fetal development: miscarriages, decreased birth weight at term,
• Reproductive and sexual dysfunctions,
• Breast and prostate cancer or at least significant breast tissue remodelling. Studies have indicated that those effects were associated with gestational and neonatal exposure [Seachrist et al. (2016)].
• Altered immune system activity,
• Obesity and metabolic dysfunctions and diabetes in adults,
• Cardiovascular disease in adults
• Cognitive and behavioural development in young children.

Despite the wealth of studies, there are still controversies concerning the toxic effects of BPA. Those are related to some lack of reproducibility of the experimental studies possibly due to different designs as well as on issues related to the analytical procedures used for BPA assays. Several studies (both experimental and human) have focused on perinatal exposure using different doses including low doses and monitoring a variety of outcomes [FitzGerald and Wilks (2014)]. In human there are several cohort studies associating perinatal exposure and child development. In addition, there are cross-sectional studies where associations were found between BPA exposure and metabolic and cardiovascular diseases. The latter studies have established association but cannot reveal a causal link between BPA and a toxic outcome. In conclusion, there is a real concern that BPA exposure could be linked to a variety of health outcomes in human, with different level of evidence depending on the outcome and the exposure period. Other Bisphenols, notably many BPA substitutes structurally similar to BPA, have been less studied although data suggest they are also oestrogenic, and likely to induce similar health effects [Rochester and Bolden (2015), Shalenie et al. (2020)].

BPA elicits a variety of endocrine disrupting effects targeting steroid hormones as well as thyroid hormones. Several studies have explored the mechanisms of endocrine disruption. Initial studies have indicated an interaction with the nuclear ER alpha oestrogen receptor with a relatively low affinity. Further studies have indicated an interaction with other receptors such ERbeta, ERRgamma and GPR32. An unresolved question is which of those receptors is involved in the low dose fetal effects of BPA.

Because of the controversies on BPA toxicity, a collaborative project called CLARITY-BPA was carried out in the US involving both regulatory agencies and academic laboratories [National Toxicology Program Research report 9 (2018)]. Despite the fact that animal treatment was centralised, different outcomes and conclusions were reached by different groups. The core studies run by the FDA found little consistent evidence for toxicity and for non-monotonic dose-response curves when traditional outcomes were examined [Camacho et al. (2019)]. Studies done in academic laboratories found evidence for low-dose effects and non-monotonic dose-response [Prins et al. (2019)]. As an illustration, a recent scientific study, undertaken as part of the CLARITY-BPA project, developed a quantitative assessment of the effects of bisphenol A (BPA) exposure on mammary gland development and found a consistent pattern of non-monotonic dose response relationships on a set of over 90 measurements. This demonstrates a causal relationship between exposure to BPA and the health effects observed [Montévil et al. (2020)]. The reasons for these discrepancies are unclear and they could be related to a non-optimal study design, different health outcomes, different analysis of the data and different interpretation of some data.

Bisphenol S, F and others

Recent studies on BPS toxicity are published. Regarding BPS toxicity on reproduction in humans, maternal prenatal urinary BPS concentrations were consistently associated, but not significantly, with various markers of fetal growth [Ferguson et al. (2018)].

Urinary BPS was correlated with increased gestational age and increased risk of late term birth for girls [Wan et al. (2018)], and with preterm birth [Aung et al. (2019)].

In a EU cohort, no association of bisphenol analogues including BPF with fecundability was reported, but total bisphenols (including 4,4-BPF, BPS, BPB, BPP, BPAF, BPAP, or BPZ) was associated with a longer time to pregnancy in women with inadequate folic acid supplement use [Philips et al. (2018)].

BPF, BPS, BPAF, along with Bisphenol Z (BPZ), Bisphenol E (BPE) and Bisphenol B (BPB) are suspected to be endocrine disrupting chemicals which are oestrogenic [Mesnage et al. (2017)]. In human studies investigating health effects including endocrine effects of BPS and other bisphenols [see review by Pelch et al. (2019)], conflicting results have been reported for an association with obesity, diabetes, fasting blood glucose or insulin resistance for BPA analogs including BPS and BPF. Regarding effects on thyroid, BPS was associated with a suggestive increase in TSH, as well as a decrease in free T4 [Aker et al. (2019)].

In vivo scientific evidences were also released recently on BPS and organs or systems such as the mammary gland, female reproductive system, the male reproductive system and on metabolism and obesity.  A developmental toxicity study on BPS according to OECD guideline 414 in pregnant rats did not reveal any reproductive, developmental or teratogenic effects (ECHA Dissemination, 2018). However, different academic papers studied the effects of BPS on male reproductive function and suggest a coherent picture of the alterations in spermatogenesis after BPS exposure in both rat and mice [Shi et al. (2018), Horan et al. (2018), Shi et al. (2017), Ullah et al. (2018), Shi et al. (2019)].

Among evidenced effects reported on female reproductive study in animals, are alteration of the pattern of oocyte maturation/meiosis and/or folliculogenesis, and, in a lesser extent, the timing of puberty. [Shi et al. (2017 and 2019), Nourian et al. (2017), Ijaz et al. (2019), Ahsan et al (2018), Horan et al.  (2018), Nevoral et al. (2018)].

BPB, BPE, BPF display anti-androgenic activities in some settings [Rosenmai et al. (2014)]. Moreover a study on BPS and BPAF exposure showed that it can modify the histology of zebra fish testes and ovaries and influence homeostasis of testosterone and oestradiol, and parental exposure to environmentally relevant concentration of BPAF results in delayed hatching of the offspring [Shi et al. (2015)]. BPS and BPF induce proliferation and migration of breast cancer cells via the oestrogen receptor dependent pathway in vitro [Kim et al. (2017)].

A new text-mining tool was developed to explore the literature and attempt link bisphenols to adverse outcome pathways (AOP-helpFinder). Using this tool as well as systems biology approaches, it was found that BPS could be linked to pathways leading to obesity [Carvaillo et al. (2019)] and BPF to AOP networks leading to thyroid cancer [Rugard et al.(2020)]. These data and others suggest that the safety of BPA substituents is not clear at this stage.

BPA is used in certain plastics, epoxy resins and thermal papers and is among the highest volume of chemicals produced world-wide. There is evidence that contamination can occur through different routes, including food, water, air and skin (particularly in occupational exposure of cashiers). BPA has a relatively short half-life (hours); it is conjugated and believed to be inactive in that form, but there is concern that it may be locally deconjugated at the tissue level. There is a clear advantage in measuring free and conjugated forms both to address the possibility of external contamination during the assay and to better assess the active form of the substance.

There is solid evidence that a large majority of the human population is exposed to BPA. Many biomonitoring studies are available for bisphenol A (BPA) but the majority of the studies have a single measurement of exposure. These studies are useful in estimating the exposure to BPA in a particular population and follow time trends but not for risk assessment. Studies with multiple biological samples (usually pregnancy cohorts) have shown that BPA has poor Intraclass Correlation Coefficient (ICC) and therefore a single biological measurement can cause exposure misclassification. Further, there is a lack of consensus on how to deal with multiple samples in estimating the correct exposure. In addition, not all countries in Europe have biomonitoring data available on BPA. In DEMOCOPHES^[1], seventeen European countries participated, but BPA was added for a group of only 6 countries. BPA is analysed in very few European birth cohorts in Germany, Norway, Spain and France [Casas et al. (2013)].

Bisphenol F (BPF), Bisphenol S (BPS), and Bisphenol AF (BPAF) are among the main substitutes of BPA [Chen et al. (2016); Gao et al. (2020); Yang Y et al. (2019)]. Studies in food revealed that BPS and some other bisphenols can be detected besides BPA in a large number of foodstuffs at low concentrations [Vinas et al. (2010); Liao and Kannan, (2013, 2014)].

As part of the national biomonitoring program, the Esteban cross-sectional study has measured, for the first time in the continental French population, the levels of impregnation with bisphenols A, S and F. The measurement of urinary concentrations of bisphenols was based on a subsample of 500 children and 900 adults, aged 6 to 74, included in the study between April 2014 and March 2016. Bisphenols A, S and F were detected in almost all samples; the geometric mean in BPA was 2.25 and 2.69 μg / g creatinine, respectively, in children and adults; equivalent to 0.44 and 0.53 μg / g creatinine for bisphenol S (BPS), and 0.26 and 0.31 μg / g creatinine for bisphenol F (BPF). Impregnation with bisphenols was higher in children than in adults. The results obtained were close to those observed in North American countries [Santé Publique France (2019)].

^[1] Demonstration Of A Study To Coordinate And Perform Human Biomonitoring On A European Scale – DEMOCOPHES (2010) http://www.eu-hbm.info/democophes

Although BPA (and to a much lesser extent BPS and BPF) have been assayed in several Human Biomonitoring studies there is a need to harmonise procedures for sample handling, storage and analytical methodologies. However, assays for conjugated and free substances should also be harmonised. The same holds true for other bisphenols.

Furthermore, external contamination during sample collection, handling and analysis is an important criteria during the evaluation of studies to be considered both for assigning reference values (HBM values) and risk assessment. For BPF and BPS, there are few biomonitoring studies available (see below) but there is a lack of literature for other bisphenols [Chen et al. (2016)].

Following on the Advisory Board’s advice to strengthen the science-policy interface, HBM4EU developed a strategic and systematic approach to outreach and align science and policy. A legislative mapping exercise was done by RPA Consultants, providing relevant public policy processes that may benefit from the knowledge generated under HBM4EU. The documents are available for consultation here, with the tables presented here.

Regulatory measures have been taken at the EU level while additional measures have been taken in certain countries. In the EU, bisphenol A is regulated under REACH (1907/2006/EC). EU law regulates BPA in plastic materials and articles intended to come into contact with food [Commission Regulation (EU) No 10/2011], and since 2011 BPA has been banned from infant feeding bottles across Europe [Commission Directive 2011/8/EU]. In 2018, the EU further restricts the use of bisphenol A in in certain food-contact materials. A specific migration limit (SML) for BPA in varnishes and coating has been introduced and the SML for BPA in the Plastics Regulation has been revised. [Commission Regulation (EU) 2018/213]. Additional measures have been taken in several countries. For example, France banned BPA in all food contact materials [French Law No 2012-1442], other countries like Denmark, Belgium and Sweden, banned it in those materials intended for children under 3.

Since 2017 BPA is on the Candidate List of substances of very high concern for Authorisation (SVHC candidates) as it is classified toxic for reproduction. France has prepared a dossier for the identification of BPA as a human ED-SVHC substance, and Germany for the identification as an environmental ED-SVHC substance. In June 2017, ECHA identified BPA as a substance of very high concern (SVHC) due to alleged endocrine disrupting (ED) effects for human health and the environment [ECHA (2017)]. In October 2019, ECHA prioritised BPA for toughest EU restrictions by proposing its use should be subject to prior authorisation.

There are also controversies between different agencies concerning the most protective Total Daily Intake (TDI). Furthermore, BPA is also present in thermal papers and exposure of cashiers has been assessed and led to a proposal for restriction and substitution. Different committees of ECHA have analysed the benefits and costs of restrictions and sent their conclusion to the European Commission. BPA is restricted in the EU in thermal paper since 2016. The ban has taken effect in January 2020, giving companies time to phase it out and find a safer alternative. BPA is being primarily replaced by BPS in thermal paper, however it is likely not a safer alternative. In Switzerland, BPS is banned from thermal paper (at a concentration equal to or greater than 0.02% by weight) as well, as of June 2020.

Currently in the EU, there is a limit on the amount of BPA that is allowed to leach out of toys for children up to the age of three and in any toys that are intended to be placed in a child’s mouth. The migration limit has been decreased to 0.04 mg/l in toys [Commission Directive (EU) 2017/898].

BPA regulation is actively debated across the world. BPS and BPF are the major BPA substituents with distinct industrial applications. Much less is known about their putative toxicity and their presence in human matrices, although initial studies have indicated that they may display toxic effects that are similar to BPA [Rochester and Bolden (2015), Auerbach et al. (2016)]. ECHA has started the process for a harmonised classification and labelling on reproductive toxicity for BPS[1]. The consultation period was closed on February 2020. In addition, a similar consultation recently finished for BPAF[2]. Other bisphenol compounds are also manufactured and little is known about their toxicity and diffusion at this stage.

[1] ECHA 2019; BPS – CLH report Proposal for Harmonised Classification and Labelling Based on Regulation (EC) No 1272/2008 (CLP Regulation), Annex VI, Part 2

[2] ECHA 2019; BPAF – CLH report Proposal for Harmonised Classification and Labelling Based on Regulation (EC) No 1272/2008 (CLP Regulation), Annex VI, Part 2

Regarding actions at national level, several countries have restrictions on the use of BPA in food contact materials and in pacifiers and teething rings. Occupational exposure limits are also in placed in several countries.

Food contact materials, pacifiers and teething rings

France banned BPA in all food contact materials as of January 2015 (French Law No 2012-1442). Baby bottles made from bisphenol A (BPA) were banned in France under law No 2010-729 of 30 June 2010. Law No 2012-1442 of 24 December 2012 then expanded the scope of the ban to include all food packaging, containers and utensils, as well as teethers and soother shields.

In Denmark, BPA has been prohibited in food contact materials intended to come into contact with children under three since 2010. The Danish Environmental Protection Agency produced a publication titled “Background for national legislation on bisphenol A (BPA) in EU and EFTA countries” in 2014 (Danish Environmental Protection Agency, 2014).

From January 2013, Belgium banned the use of BPA in food contact materials intended for children less than three years old and in plastic articles like spoons and plates for the same age group.

In Austria, it is prohibited to manufacture pacifiers and teething rings with bisphenol A or place them on the market, following Federal Law Gazette Part II, No.327/2011.

In 2012, the Swedish Chemicals Agency (KEMI) produced a background report on BPA in cash receipts in support of a proposal for a ban of BPA in thermal paper (KEMI, 2012). The legislative process was then put on hold, pending the outcome of the proposal for a restriction on BPA in thermal paper under REACH. This restriction has subsequently been agreed. From January 2013, Sweden banned BPA in varnish and coatings in food contact materials intended for 0-3 year olds. Sweden banned the use of bisphenol A (BPA) in epoxy resins in water pipe linings from 1 September 2016.

Denmark has set an Occupational Exposure Limit (OEL) of 3 mg/m3 for BPA, based on the general national OEL for organic dust of 3 mg/m3. In Germany, Switzerland, Finland and Austria the OELs is set at 5 mg/m³.

There are several critical questions concerning bisphenols that need to be resolved.

The first is whether different regulations in different countries lead to different internal exposure values and whether the increasingly frequent use of substituents has led to increased exposure and to the presence of mixtures of bisphenols in humans.

The second is to identify safety values taking into consideration the accumulating knowledge on Bisphenol toxicity, particularly at low doses. A third question is whether substitutes are safer than BPA considering their hazardous properties and current and expected exposure to those compounds.

Specific policy-related questions are:

1. What is the current exposure of the EU population to BPA, BPS and BPF?
2. Do different regulatory controls across the EU concerning in particular BPA lead to different exposures?
3. Are bisphenols (BPA and substitutes) exposure levels of concern for health?
4. Is occupational exposure of cashiers (BPA and substitutes) a health concern?
5. What is the toxicity of BPA substitutes?
6. Are health risks age and gender-dependent?
7. Can we find evidence for low-dose effects within mixtures?
8. How can HBM feed into the assessment of the Tolerable Daily Intake (TDI) for BPA, as set by the European Food Safety Authority (EFSA)?
9. Is it important to eliminate legacy BPA from material cycles (i.e. waste till receipt rolls) when implementing a circular economy in order to protect human health?

Please click here to access the Substance Report.

In the interest of transparency and accountability, HBM4EU invites interested stakeholders to submit comments on the scoping document on Bisphenols.

All submitted comments will be made available for download on this webpage and will be taken into consideration by the HBM4EU consortium, where possible.

Please click here to submit your comments.

ANSES, 2013, Reprotoxic substances and endocrine disruptors: Compounds in the bisphenols class: bisphenols M, S, B, AP, AF, F and BADGE, French Agency for food, environmental and occupational health and safety, Paris, France

Auerbach, S., Filer, D., Reif, D., Walker, V., Holloway, A. C., Schlezinger, J., Srinivasan, S., Svoboda, D., Judson, R., Bucher, J.R., Thayer, K. A. (2016). Prioritizing Environmental Chemicals for Obesity and Diabetes Outcomes Research: A Screening Approach Using ToxCast^TM High-Throughput Data. Environmental Health Perspectives, 124(8), 1141–1154. http://doi.org/10.1289/ehp.1510456

Casas, M., Chevrier, C., Den Hond, E., Fernandez, M. F., Pierik F., Philippat, C., Slama, R. Toft, G., Vandentorren, S., Wilhelm, M., Vrijheid, M. (2013) Exposure to brominated flame retardants, perfluorinated compounds, phthalates and phenols in European birth cohorts: ENRIECO evaluation, first human biomonitoring results, and recommendations, International Journal of Hygiene and Environmental Health, 216 (3), 230-242. ISSN 1438-4639, https://doi.org/10.1016/j.ijheh.2012.05.009

Chen, D., Kannan, K., Tan H., Zheng, Z., Feng, Y-L., Wu, Y., Widelka, M. (2016) Bisphenol Analogues Other than BPA: Environmental Occurrence, Human Exposure, and Toxicity – A Review, Environmental Science & Technology, 50 (11), 5438-5453. http://doi.org/10.1021/acs.est.5b05387

Danish Environmental Protection Agency (2014) Background for national legislation on bisphenol A (BPA) in EU and EFTA countries, Environmental project No. 1552, 2014, Danish Environmental Protection Agency, Denmark

Demonstration Of A Study To Coordinate And Perform Human Biomonitoring On A European Scale – DEMOCOPHES (2010) http://www.eu-hbm.info/democophes

ECHA (2017) MSC unanimously agrees that Bisphenol A is an endocrine disruptor, ECHA/PR/17/12

ECHA (2018) BPA being replaced by BPS in thermal paper, ECHA survey finds, ECHA/NR/18/31

FitzGerald RE., Wilks MF. (2014) Bisphenol A—why an adverse outcome pathway framework needs to be applied. Toxicology Letters, 230, 368–74. https://doi.org/10.1016/j.toxlet.2014.05.002

Gore, A. C., Chappell, V. A., Fenton, S. E., Flaws, J. A., Nadal, A., Prins, G. S.,Topari,J., Zoeller, R. T. (2015). EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocrine Reviews, 36(6), E1–E150. http://doi.org/10.1210/er.2015-1010

INERIS. 2015, Données technico-économiques sur les substances chimiques en France: Bisphénols F et S, DRC-14-136881-02238A, 54 p., INERIS, France

KEMI (2010) Bisfenol A I kassakvittin – rapport fran ett regeringsuppdrag – Rapport Nr 4/12, KEMI, Sweden

KEMI (2017) Bisfenoler – en kartlaggning och analys, KEMI, Sweden

Rochester, J. R., & Bolden, A. L. (2015). Bisphenol S and F: A Systematic Review and Comparison of the Hormonal Activity of Bisphenol A Substitutes. Environmental Health Perspectives, 123(7), 643–650. http://doi.org/10.1289/ehp.1408989

SCOEL (2014) Recommendation from the Scientific Committee on Occupational Exposure Limits for Bisphenol-A, SCOEL/SUM/113, June 2014

Seachrist, D. D., Bonk, K. W., Ho, S.-M., Prins, G. S., Soto, A. M., & Keri, R. A. (2016). A Review of the Carcinogenic Potential of Bisphenol A. Reproductive Toxicology (Elmsford, N.Y.), 59, 167–182. http://doi.org/10.1016/j.reprotox.2015.09.006

Vandenberg, L. N. (2014). Low-dose effects of hormones and endocrine disruptors. Vitam Horm, 94, 129-65.DOI:10.1016/B978-0-12-800095-3.00005-5

WHO and UNEP (2012) State of the Science of Endocrine Disrupting Chemicals, 2012. Edited by A Bergman, JJ Heindell, S Jobling, KA Kidd, RT Zoeller.