bisphenols

This webpage provides information on the HBM4EU priority substance group bisphenols, including information on their use and hazardous properties, as well as summarising existing evidence of human exposure to bisphenols in Europe.

It also summarises the legislative status of bisphenols in the European Union, as well as at national level in European countries.

Open policy questions regarding substances in the bisphenols group are listed. These questions guide work on bisphenols under HBM4EU.

The information on the pages is based on HBM4EU’s scoping document on bisphenols, produced by the project’s Chemical Group Leader on bisphenols, Professor Robert Barouki of Inserm, France.

These pages were last updated on 12 January 2018.

 

Uses of 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).

 

Substances included in the bisphenols group

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

 

Hazardous properties of bisphenols

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). Studies have indicated that exposure to BPA 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, associated with gestational and neonatal exposure;
  • Altered immune system activity;
  • Obesity and metabolic dysfunctions and diabetes in adults;
  • Cardiovascular disease in adults; and
  • Cognitive and behavioural development in young children.

Despite the wealth of studies, there are still uncertainties concerning the toxic effects of BPA. Those are related to some lack of reproducibility of the experimental studies possibly due to differences in study design.

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 humans, there are several cohort studies associating perinatal exposure with impacts on 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 associations, but did not identify a causal link between BPA and a toxic outcome.

In conclusion, there is concern that BPA exposure could be linked to a variety of health outcomes in humans, with different degrees of evidence available for different health outcomes resulting from different periods of exposure.

These concerns have prompted industry to develop BPA substitutes, some of which are also compounds in the bisphenol group. For example, Bisphenol F (BPA) is used in epoxy resins and thermal papers, bisphenol S (BPS) is used in epoxy resins, polycarbonate, polyethersulphone, thermal papers, phenolic resins and polyester resins (INERIS, 2015). Less is known about their toxicity, although initial studies have indicated that they may cause toxic effects that are similar to BPA (Rochester and Bolden, 2015, Auerbach et al., 2016). Little is currently known about the toxicity of other bisphenol substances. In 2013, ANSES published a report entitled “Reprotoxic substances and endocrine disruptors: Compounds in the bisphenols class: bisphenols M, S, B, AP, AF, F and BADGE” (ANSES 2013).

 

Human exposure to bisphenols

There is solid evidence that a large majority of the human population is exposed to BPA. The substance is detected in urine and blood samples from almost all humans, which suggests that most of us are continuously exposed to low doses of the substance (KEMI, 2017).

Many biomonitoring studies are available for BPA. However, the majority of the studies have a single measurement of exposure. While these studies are useful in estimating the exposure to BPA in a particular population and follow time trends, they are not as useful for risk assessment. This is because studies with multiple biological samples have shown that BPA has poor Intra-class Correlation Coefficient (ICC), implying that a single biological measurement can cause exposure misclassification. Further, there is a lack of consensus on how to deal with multiple samples when estimating the correct exposure.

In terms of the comprehensiveness of available data, not all European countries in Europe have biomonitoring data on BPA. In the Democophes study, BPA was biomonitored in human populations in six countries. BPA has also been analysed in a limited number of European birth cohorts in Germany, Norway, Spain and France (Casas et al., 2013).

 

Technical challenges in biomonitoring bisphenols in humans

Although BPA (and to a much lesser extent BPS and BPF) have been assayed in several human biomonitoring studies there is a need to harmonize procedures for sample handling, storage and analytical methodologies. Assays for conjugated and free substances should also be harmonized. 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, but there is a lack of evidence on human exposure to other bisphenols (Chen et al., 2016).

 

Legislative status in the European Union

In the EU, all bisphenols manufactured or imported at volumes over one tonne a year must be registered under REACH.

In addition, specific measures have been taken to limit human exposure to BPA at EU level. BPA is on the REACH Candidate List of substances of very high concern for Authorisation, based on its classification as toxic for reproduction and its endocrine disrupting properties which cause probable serious effects to human health which give rise to an equivalent level of concern to carcinogenic, mutagenic, toxic to reproduction (CMRs category 1A or 1B) substances. The use of BPA in thermal papers is also restricted under REACH and will enter into effect in January 2020.

A number of bisphenols have been or are being assessed under the Community Rolling Action Plan and under the Public Activities Coordination Tool (PACT) List. An overview of activities can be downloaded here.

BPA, BPS and 4,4′-dihydroxybiphenyl (BP4,4’) are authorised for use in food contact materials in the EU under Regulation 10/2011/EU, relating to plastic materials and articles intending to come into contact with foodstuffs. In January 2011, the European Commission adopted Directive 2011/8/EU, prohibiting the use of BPA for the manufacture of polycarbonate infant feeding bottles. The European Food Safety Authority (EFSA) has conducted a range of work on BPA in food contact materials, with documentation available on the EFSA webpages on BPA.

A number of bisphenols are subject to control under health and safety legislation, environmental legislation and consumer legislation, as a result of their classification under the CLP Regulation. Please click on the links below to view tables identifying relevant substances and legislation.

Regarding BPA, in 2014 the Scientific Committee on Occupational Exposure Limits (SCOEL) recommended an occupational exposure limit value of 2 mg/m3 over an 8 hour time weighted average for BPA (SCOEL, 2014). Due to uncertainties related to the short half-life of BPA and resulting variation in the urinary excretion over the course of the day, as well as limited data on the toxicokinetics of BPA after inhalation or dermal exposure, no BLV was proposed. A biological guidance value (BGV) of 7 μg/l was recommended for the identification of potentially occupationally exposed from the occupationally non-exposed.

In 2017, Directive 2017/164/EU established an indicative occupational exposure limit value of 2 mg/m3 over 8 hours for BPA.

 

Legislative status in European countries

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.

 

Occupational exposure limits

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. 

 

Policy questions on bisphenols

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 reflect on the implications that growing evidence regarding the toxicity of bisphenols at low doses might have for current toxicity references values.

A third question is whether the substitutes being used to replace BPA are safe, considering their hazardous properties and current and expected exposure.

Specific actions required to enable HBM4EU to address these broader questions are listed below.

  1. To identify existing analytical methods to monitor BPA, BPS, BPF and possibly other bisphenols in human matrices, as well as the necessary gaps to be fulfilled in terms of method development and validation.
  2. To urgently harmonize procedures for sample handling, storage and analytical methodologies for BPA, BPS and BPF to minimize external contamination. To encourage European countries to participate in inter-laboratory comparisons.
  3. To map available biomonitoring data on bisphenols in Europe, to find out which countries lack this kind of data and to evaluate the quality of the available data such that the design of future biomonitoring studies can be improved accordingly.
  4. To use available biomonitoring data on bisphenols to key questions including: What are the minimum number of samples required per individual to estimate the correct exposure to BPA? How to deal with multiple samples in estimating the correct exposure?
  5. To follow the time and spatial trends for human exposure to bisphenols in order to answer the following questions: What is the current exposure of the EU population to BPA, BPS and BPF and possibly other bisphenols? What are the reference values for the EU population?
  6. To determine whether different regulatory controls across European countries results in different level of human exposure.
  7. To assess whether current or expected exposure levels of BPS and BPF are of concern for health and to identify the relationship with external exposure via the environment and workplace. Key questions include: what is the toxicity of BPA substitutes? Is there a gender difference in relation to health risks? What are the most exposed sub-groups? What is the evidence for low-dose effects? Are Adverse Outcome Pathways for those compounds similar to those of BPA?
  8. To identify effect biomarkers associated to bisphenol exposure and to determine whether those effect markers are common to all bisphenol compounds
  9. To identify exposure pathways for bisphenols and to determine the toxicokinetic characteristics of bisphenols.
  10. To determine the effect of combined exposures to substance mixtures within the bisphenol family and with other families. To establish whether combined effects should be taken into account when developing health guidance relevant to the contamination of food, and consumer exposure via cosmetics and the use of plasticizers in products.
  11. To derive EU-wide human biomonitoring health-based guidance values for BPA and other bisphenols. To consider how such values might inform an assessment of the Tolerable Daily Intake (TDI) for BPA of 4 μg/kg/day as set by EFSA?
  12. To determine the age and gender specific health effects of BPA.
  13. To establish whether the occupational exposure of cashiers to BPA substitutes is a health concern, since PBA will be banned from use in thermal papers from January 2020.
  14. As longer term goal, it will be important to investigate the impact of implementing a circular economy on human exposure to BPA, due to the recycling of material cycles containing legacy BPA.

 

References

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 ToxCastTM 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

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.