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EFSA Journal 2015;13(1):3978

SCIENTIFIC OPINION

Scientific Opinion on the risks to public health related to the presence of

bisphenol A (BPA) in foodstuffs: Executive summary

EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids

(CEF)

2,3

European Food Safety Authority (EFSA), Parma, Italy

BSTRACT

This opinion describes the assessment of the risks to public health associated with bisphenol A (BPA) exposure.

Exposure was assessed for various groups of the human population in three different ways: (1) external (by diet,

drinking water, inhalation, and dermal contact to cosmetics and thermal paper); (2) internal exposure to total

BPA (absorbed dose of BPA, sum of conjugated and unconjugated BPA); and (3) aggregated (from diet, dust,

cosmetics and thermal paper), expressed as oral human equivalent dose (HED) referring to unconjugated BPA

only. The estimated BPA dietary intake was highest in infants and toddlers (up to 0.875 µg/kg bw per day).

Women of childbearing age had dietary exposures comparable to men of the same age (up to 0.388 µg/kg bw per

day). The highest aggregated exposure of 1.449 µg/kg bw per day was estimated for adolescents. Biomonitoring

data were in line with estimated internal exposure to total BPA from all sources. BPA toxicity was evaluated by

a weight of evidence approach. “Likely” adverse effects in animals on kidney and mammary gland underwent

benchmark dose (BMDL

) response modelling. A BMDL

of 8 960 µg/kg bw per day was calculated for

changes in the mean relative kidney weight in a two generation toxicity study in mice. No BMDL

could be

calculated for mammary gland effects. Using data on toxicokinetics, this BMDL

was converted to an HED of

609 µg/kg bw per day. The CEF Panel applied a total uncertainty factor of 150 (for inter- and intra-species

differences and uncertainty in mammary gland, reproductive, neurobehavioural, immune and metabolic system

effects) to establish a temporary Tolerable Daily Intake (t-TDI) of 4 µg/kg bw per day. By comparing this t-TDI

with the exposure estimates, the CEF Panel concluded that there is no health concern for any age group from

dietary exposure or from aggregated exposure. The CEF Panel noted considerable uncertainty in the exposure

estimates for non-dietary sources, whilst the uncertainty around dietary estimates was relatively low.

EY WORDS

Bisphenol A, BPA, exposure, toxicity, health risks, TDI, food contact materials

On request from EFSA, Question No EFSA-Q-2012-00423, adopted on 11 December 2014.

Panel members: Claudia Bolognesi, Laurence Castle, Jean-Pierre Cravedi, Karl-Heinz Engel, Paul Fowler, Roland Franz,

Konrad Grob, Rainer Gürtler, Trine Husøy, Wim Mennes, Maria Rosaria Milana, André Penninks, Franz Roland, Vittorio

Silano, Andrew Smith, Maria de Fátima Tavares Poças, Christina Tlustos, Fidel Toldrá, Detlef Wölfle and Holger Zorn.

Correspondence:

[email protected]

Acknowledgement: The Panel wishes to thank the members of the Working Groups on BPA Exposure and Toxicology: Claire

Beausoleil, Diane Benford, Emma Bradley, Anne Lise Brantsaeter, Gemma Calamandrei, Daniel Doerge, Paul Fowler, Peter

Greaves (until July 2012), Ursula Gundert-Remy, Andrew David Hart, Edel Holene, Trine Husøy, Catherine Leclercq (until

July 2013), Inger Therese Laugsand Lillegaard, Wim Mennes, Ralph Pirow, Maria de Fátima Tavares Poças, Iona Pratt

(deceased in February 2014), Josef Rudolf Schlatter, Catherine Simoneau, Wout Slob, Jacqueline Van Engelen, Henk Van

Loveren, Natalie Von Götz, Detlef Wölfle and Rudolf Antonius Woutersen for the preparatory work on this scientific opinion

and the hearing experts: Jan Alexander, Pasquale Mosesso and Alfonso Siani, and EFSA staff: Davide Arcella, Anna F.

Castoldi, Cristina Croera and Anne Theobald for the support provided to this scientific opinion.

Suggested citation: EFSA CEF Panel (EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids),

2015. Scientific Opinion on the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs: Executive

summary. EFSA Journal 2015;13(1):3978, 22 pp. doi:10.2903/j.efsa.2015.3978

Available online:

www.efsa.europa.eu/efsajournal

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ABLE OF CONTENTS

Abstract .................................................................................................................................................... 1

Background as provided by EFSA ........................................................................................................... 3

Terms of reference as provided by EFSA ................................................................................................ 4

Interpretation of the terms of reference as provided by EFSA ................................................................. 4

Summary .................................................................................................................................................. 5

1. Part I – BPA exposure assessment................................................................................................... 5

1.1.

BPA uses ................................................................................................................................. 5

1.2.

EU Regulatory framework for BPA........................................................................................ 5

1.3.

Potential exposure sources for the general population............................................................ 5

1.4.

General approach for the assessment ...................................................................................... 6

1.5.

Methods .................................................................................................................................. 6

1.6.

Assessment of BPA exposure ................................................................................................. 7

1.6.1. External exposure to BPA .................................................................................................. 7

1.6.1.1. Dietary exposure ........................................................................................................ 7

1.6.1.2. Non-dietary exposure ............................................................................................... 10

1.6.2. Internal exposure to total BPA ......................................................................................... 11

1.6.3. Conclusions ...................................................................................................................... 12

2. Part II – BPA toxicological assessment and risk characterisation ................................................. 13

2.1.

Methods ................................................................................................................................ 13

2.2.

Hazard identification ............................................................................................................. 14

2.2.1. Toxicokinetics .................................................................................................................. 14

2.2.2. General toxicity ................................................................................................................ 15

2.2.3. Reproductive and developmental effects .......................................................................... 15

2.2.4. Neurological, neurodevelopmental and neuroendocrine effects....................................... 16

2.2.5. Immune effects ................................................................................................................. 17

2.2.6. Cardiovascular effects ...................................................................................................... 17

2.2.7. Metabolic effects .............................................................................................................. 17

2.2.8. Genotoxicity ..................................................................................................................... 18

2.2.9. Carcinogenicity................................................................................................................. 18

2.2.10. Proliferative and morphological changes potentially related to tumour induction ........... 18

2.2.11. Mechanistic studies with BPA including epigenetic effects............................................. 19

2.3.

Hazard characterisation ......................................................................................................... 19

2.3.1. Uncertainties in hazard characterisation ........................................................................... 20

2.3.2. Health-based guidance value ............................................................................................ 20

2.4.

Risk characterisation ............................................................................................................. 20

Overall conclusions ................................................................................................................................ 22

Recommendations .................................................................................................................................. 22

EFSA Journal 2015;13(1):3978

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ACKGROUND AS PROVIDED BY

EFSA

Bisphenol A (BPA) is used as a monomer in the manufacture of polycarbonates and epoxy resins and

as an additive in plastics. Polycarbonates are used in food contact materials such as reusable beverage

bottles, infant feeding bottles, tableware (plates and mugs) and storage containers. Epoxy resins are

used in protective linings for food and beverage cans and vats.

BPA is authorised for use as a monomer in plastic food contact materials, in accordance with

Commission Regulation (EU) No 10/2011/EU on plastic materials and articles intended to come into

contact with foodstuffs

. Its use is subject to a specific migration limit SML of 0.6 mg/kg. In addition,

Commission Implementing Regulation (EU) No 321/2011

places a restriction on the use of BPA in

the manufacture of polycarbonate infant feeding bottles.

EFSA has already issued scientific opinions on BPA in 2006, 2008 and in 2010 (EFSA 2006a, 2008;

EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF), 2010).

In its opinion of 2006, EFSA performed a risk characterisation for BPA, including a dietary exposure

assessment and a hazard characterisation. In this opinion, EFSA established a tolerable daily intake

(TDI) for BPA of 0.05 milligram per kilogram (mg/kg) body weight per day, based on the no adverse

effect level of 5 mg/kg body weight per day in multi-generation rodent studies and applying an

uncertainty factor of 100.

A new opinion on the toxicokinetics of BPA was adopted by EFSA in 2008. Here, EFSA reaffirmed

the TDI established in 2006, concluding that age-dependent toxicokinetics differences of BPA in

animals and humans would have no implication for the assessment of BPA previously carried out by

EFSA.

In 2010, the CEF Panel performed a new hazard characterisation of BPA, based on a comprehensive

evaluation of more recent toxicity data. The CEF Panel concluded that no new scientific evidence had

been published since the EFSA opinions of 2006 and 2008 that would call for a revision of the current

TDI. However, it emphasised that there were uncertainties concerning some BPA-related effects of

possible toxicological relevance, in particular biochemical changes in brain, immune-modulatory

effects and enhanced susceptibility to breast tumours emerging from studies on developing animals.

Given several methodological shortcomings in the studies showing these effects, the CEF Panel

concluded that the relevance of these findings for human health could not be assessed, but that it

would reconsider its opinion should any new relevant data became available. A CEF Panel member

expressed a minority opinion based on those uncertainties.

In 2011, EFSA was asked to provide scientific advice in relation to possible divergences between the

conclusions of the EFSA Scientific Opinion on BPA of September 2010 and those in the reports on

BPA published in September 2011 by the French Agency for Food, Environmental and Occupational

Health and Safety (ANSES). On 1 December 2011, EFSA published a Panel statement on BPA (EFSA

Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF), 2011a) in which

the information in the ANSES report was considered not to change the views that the CEF Panel

expressed in 2010. However, concerning additional data in recent literature, the CEF Panel stated that

it would need further time for a more in-depth review of the new studies. The CEF Panel also

underlined that there are ongoing low-dose studies at National Center for Toxicological Research/FDA

and at National Toxicological Program/National Institute of Environmental Health Sciences which

aim to address, at least in part, the current uncertainties regarding the potential health effects of BPA.

Commission Regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food. OJ

L 12, 15.1.2011, p. 1 – 89.

Commission Implementing Regulation (EU) No 321/2011 of 1 April 2011 amending Regulation (EU) No 10/2011 as regards the restriction

of use of Bisphenol A in plastic infant feeding bottles. OJ L87, 2.4.2011, p. 1 – 2.

EFSA Journal 2015;13(1):3978

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The ANSES risk assessment of BPA (including exposure assessment from the diet as well as from

other routes) was finalised during the preparation of this scientific opinion and was published in April,

2013 (ANSES, 2013).

After its 2011 scientific advice on BPA, EFSA noted that its latest exposure assessment to BPA

through dietary sources dates back to 2006, and needed to be updated in the light of the data since then

available. The relevance of a dietary exposure assessment versus a more general exposure assessment

via various routes of exposure should also be explored. Also, in line with the 2011 conclusions of the

CEF Panel, it is advisable for EFSA to undertake a full re-evaluation of the safety of BPA, based on

all the most recent experimental evidence.

ERMS OF REFERENCE AS PROVIDED BY

EFSA

In accordance with Article 29 (1) of Regulation (EC) No 178/2002

, the European Food Safety

Authority asks its Scientific Panel on Food Contact Materials, Enzymes, Flavourings and Processing

Aids (CEF) to provide by December 2014 a scientific opinion on the risks for public health related to

the presence of bisphenol A in foodstuffs.

In particular, the opinion should:



evaluate the toxicity of BPA for humans, including specific (vulnerable) groups of the

population (e.g. pregnant women, infants and children, etc.) and considering all the relevant

toxicological information available;

carry out an exposure assessment on the basis of the occurrence data available in the public

domain and other occurrence data that may be available, and quantify as far as possible not

only dietary exposure but also exposure from non-dietary sources;

consider specifically the exposure situation for the supposedly most vulnerable groups of the

population (e.g. pregnant women, infants and children, etc.) and take into account, if available,

biomonitoring data when assessing the exposure and compare the results with the calculated

exposure; and

characterise the human health risks of BPA taking into account specific groups of the

population.



NTERPRETATION OF THE TERMS OF REFERENCE AS PROVIDED BY

EFSA

A three-step approach has been taken by the CEF Panel in developing this full risk assessment of

BPA. As a first step, the CEF Panel endorsed its draft exposure assessment in July 2013 and released it

for public consultation (25 July – 15 September, 2013; http://www.efsa.europa.eu/en/

consultationsclosed/call/140117.htm). Secondly, on 12 December 2013 the CEF Panel endorsed its

draft assessment of BPA health risks addressing specifically BPA hazard assessment and risk

characterisation, and subsequently issued it for public consultation (17 January – 13 March, 2014;

http://www.efsa.europa.eu/en/consultationsclosed/call/130725.htm). Following the comments received

during the two public consultations the CEF Panel has now completed and adopted the full opinion on

the risk assessment of BPA. In addition, EFSA has compiled a technical report listing all the

comments received both on the draft BPA exposure assessment and the draft assessment of BPA

health risks, and has explained whether and how they have been taken into account in the final

opinion.

Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general

principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in

matters of food safety. OJ L31, 1.2.2002, p. 1–24

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UMMARY

This scientific opinion deals with the assessment - by the EFSA CEF Panel - of the risks to public

health associated with BPA exposure. It consists of three separate documents:



Executive summary, which includes the sections in the opinion relevant to both Parts I and II,

i.e. abstract, background, terms of reference (ToR), interpretation of the ToR and summary of

Parts I and II;

Part I - Exposure assessment, exposure conclusions, list of references and appendices.

Part II - Toxicological assessment and risk characterisation, their conclusions,

references and appendices.

Part I – BPA exposure assessment

list of



Part I of this opinion addresses the second and third part of the terms of reference. It presents an

exposure evaluation to BPA based on the occurrence data available in the public domain and other

occurrence data that have been collected through a call for data. Furthermore it includes a

quantification not only of the dietary exposure, but also of the exposure from non-dietary sources.

Particular focus is on the exposure for subgroups in the human population, based on different age

classes. The opinion also considers biomonitoring data to support the exposure estimates obtained by

calculation, based on the information on occurrence.

1.1.

BPA uses

BPA (chemical formula C

, CAS No 80-05-7 and EC No 201-245-8) is an organic chemical

used in the manufacture of polycarbonate (PC) plastics, epoxy resins and other polymeric materials

and also for certain paper products (thermal paper e.g. for cash receipts). PC is used for manufacturing

food and liquid containers, such as tableware (plates and mugs), microwave ovenware, cookware and

reservoirs for water dispensers, as well as for non-food applications, such as toys and pacifiers with

PC shields. BPA-based epoxyphenolic resins are used as protective linings for food and beverage cans

and as a coating on residential drinking water storage tanks and supply systems. Additionally, BPA

may be used upstream in the process of manufacturing of some raw materials, which are then used to

produce food contact materials. BPA is also used in the manufacturing of a number of non-food-

related applications, e.g. epoxy resin-based paints, medical devices, surface coatings, printing inks and

flame retardants.

1.2.

EU Regulatory framework for BPA

BPA is authorised for use as a monomer in plastic food contact materials, in accordance with

Commission Regulation (EU) No 10/2011/EU on plastic materials and articles intended to come into

contact with foodstuffs

. Its use is subject to a specific migration limit (SML) of 0.6 mg/kg. In

addition, Commission Implementing Regulation (EU) No 321/2011

placed a restriction on the use of

BPA in the manufacture of PC infant feeding bottles which was introduced in 2011 on the basis of the

precautionary principle.

1.3.

Potential exposure sources for the general population

The general population can be exposed to BPA via food/drinking water and/or via the use of non-food

consumer products such as thermal paper, toys, etc.. Environmental sources can include surface water

(during swimming) and outdoor air (inhalation of aerosols). In addition, BPA from epoxy-based

floorings, adhesives, paints, electronic equipment and printed circuit boards may be released into

Commission Regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into

contact with food. OJ L 12, 15.1.2011, p. 1 – 89.

Commission Implementing Regulation (EU) No 321/2011 of 1 April 2011 amending Regulation (EU) No 10/2011 as

regards the restriction of use of Bisphenol A in plastic infant feeding bottles. OJ L87, 2.4.2011, p. 1 – 2.

EFSA Journal 2015;13(1):3978

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indoor air (including airborne dust) and dust. Environmental sources can potentially contribute to oral

and dermal exposure, as well as inhalation to BPA.

1.4.

General approach for the exposure assessment

This opinion presents a detailed analysis of data on food consumption and BPA occurrence in food

that have become available since the previous EFSA evaluation in 2006. Unlike the opinion adopted in

2006, the present opinion also addresses the contribution of non-food sources to the overall exposure

to BPA.

Average and high total chronic BPA exposures were assessed in different age classes, including

consideration of those groups that may be more vulnerable: infants, children and women of

childbearing age (in order to address potential exposure in the fetus and in breastfed infants), whereas

the assessment of BPA exposure in specific disease states, occupational exposure of workers handling

BPA containing products, or acute exposure to BPA were not developed in this opinion.

The exposure assessment involved the estimation of consumer exposure in terms of the following

three different metrics:



External exposure to BPA (in Part I – Exposure assessment)

The assessment of external exposure considered the different routes (ingestion, inhalation, dermal

uptake) and sources (e.g. diet, drinking water, air, thermal paper). It estimated the source-specific

doses reaching the physical barriers in the gastrointestinal and respiratory tracts and of the skin. Route-

specific external exposures to BPA were calculated via the so-called forward modelling approach by

multiplying source concentrations with the corresponding use frequencies (e.g., food intake, handling

of thermal paper).



Internal exposure to total BPA (in Part I – Exposure assessment)

The assessment of internal exposure to total BPA considered the route- and source-specific absorption

fractions to estimate the doses that passed the physical barriers to enter the body. For this purpose

exposure from all sources and over all routes were combined.

These internal doses are expressed as doses of total BPA (as no differentiation is made between the

unconjugated and conjugated BPA). As BPA is completely eliminated via urine, the sum of these

internal doses is directly comparable to exposure estimates obtained by the so-called backward

modelling approach from urinary biomonitoring data.



Aggregated exposure to unconjugated BPA (in Part II – Toxicological assessment and risk

characterisation)

The assessment of aggregated exposure used physiologically based pharmacokinetic (PBPK)

modelling to translate the contributions from the relevant sources (diet and house dust for the oral

route, thermal paper and cosmetics for the dermal route) into a toxicologically relevant dose metric,

the area under the curve (AUC) for the serum concentration of unconjugated BPA. A translation into

AUC is necessary because, in contrast to dermally absorbed BPA, orally (i.e. gastrointestinally)

absorbed BPA is subjected to the first-pass metabolism before entering the systemic circulation. Based

on the AUC information, external dermal exposures (thermal paper, cosmetics) were converted to

equivalent oral exposures which could then be summed up with the external oral exposures (diet,

house dust) to obtain aggregated exposure estimates.

1.5.

Methods

Literature sources.

A thorough literature search was performed by an independent contractor to

retrieve scientific studies relevant to the following categories: analytical methods for BPA in food,

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human biomonitoring of BPA, occurrence of BPA in drinking water, food contact materials, food,

non-food materials (such as indoor air, dust, thermal printed paper, dental materials and medical

devices) and in the environment. The search using the terms “bisphenol”, “BPA” alone or combined

with “food” or “migration” or “water” was conducted on these databases: ISI Web of Knowledge-Web

of Science, Elsevier Science Direct, Elsevier Scopus, EBSCOhost—OmniFile Full Text Select (H.W.

Wilson), SpringerLink, Taylor & Francis online, Wiley Interscience. In addition, members of the CEF

Panel’s Working Group on BPA Exposure searched the scientific literature for additional relevant

information, e.g. parameters used to estimate skin absorption and physiological data, etc..

The publications were then screened against the following eligibility criteria: (i) only primary research

studies, (ii) language (at least abstract in English), (iii) publication date between January 2006 and

December 2012 (papers published outside this period were considered only if they provided data in

areas where no or very few data were available (e.g. data on human milk) or to complete the European

dataset (e.g. biomonitoring data); (iv) geographical origin of the samples and sample type (only

European data were used if available); (v) quality of the analytical methods employed. Also grey

literature was considered as specified in the methodology of Part I of this opinion.

EFSA call for data.

Data were also retrieved through a call for data that EFSA launched in July 2012

in relation to (i) the occurrence of BPA in food and beverages; (ii) BPA migration from food contact

materials; and (iii) BPA occurrence in food contact materials. Details on the eligibility and inclusion

of data received from the call for data are given in Appendix B of Part I of this opinion.

1.6.

1.6.1.

Assessment of BPA exposure

External exposure to BPA

1.6.1.1. Dietary exposure

Dietary exposure to BPA has been estimated in different population groups by combining information

on BPA occurrence in food with the corresponding consumption levels. Average exposure was

assessed based on average concentration and average consumption data, while high exposure was

based on average concentration and high consumption.

A total of 2 516 samples (many of which were pooled samples from the French total diet study) of

food and beverages were selected as the basis to assess BPA concentrations in the different food

categories. Data on BPA concentrations from the literature and from the call for data did not show

major differences and were therefore merged for each food category to be used in the exposure

calculations.

Left-censored data, i.e. from samples with concentrations below the limit of detection (LOD) or

quantification (LOQ), were handled through the substitution method. The lower bound (LB) was

obtained by assigning a value of zero to all the samples reported as less than the left-censoring limit,

the middle bound (MB) by assigning half of the left-censoring limit, and the upper bound (UB) by

assigning the left-censored limit (LOD or LOQ) as the sample result.

Significant differences in BPA concentration between canned and non-canned food were observed in a

large majority of food categories, with higher BPA concentrations in the canned food. Seven out of 17

canned food categories presented a MB average BPA concentration above 30 µg/kg (“Grain and grain-

based products”, “Legumes, nuts and oilseeds”, “Meat and meat products”, “Fish and other seafood”,

“Herbs, spices and condiments”, “Composite food”, and “Snacks, desserts, and other foods”). Lower

levels were found in other categories. The average (MB) BPA concentration was lower than 3 µg/kg in

canned beverages (water, alcoholic and non-alcoholic beverages, fruit and vegetables juices). Among

the 19 non-canned food categories, the highest levels of BPA were found in the categories “Meat and

meat products” and “Fish and other seafood” with average (MB) BPA concentrations of 9.4 and 7.4

µg/kg, respectively. When comparing European with non-European concentration data for food,

average BPA levels were mostly in the same range.

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Biomonitoring studies suggested higher levels of BPA in colostrum (produced during the first five

days after delivery) compared with mature human milk. Due to the very limited availability of

European data on colostrum, the CEF Panel took into account also the data from a Japanese study,

despite its severe limitations (analytical determination of BPA by ELISA and long storage time of

samples). Overall, an average total BPA concentration of 3 µg/L and a modelled high concentration

estimate of 5.8 µg/L in colostrum were used for exposure assessment during the first five days of life.

Based on different studies, the average and high concentrations of total BPA in mature human milk

were estimated to be 1.1 µg/L and 4.0 µg/L, respectively.

BPA migration data from food contact materials into food simulants, retrieved from the literature and

EFSA’s call for data, were used to assess the exposure of specific groups of consumers. In particular,

average BPA migration levels were derived for the following PC articles: water coolers with PC

reservoirs (0.81 µg/L in water), PC water kettles (0.11 µg/L in warm water), PC filters (0.04 µg/L in

water), PC tableware and cookware (0.09 and 0.29 µg/L, respectively, in foods that can be consumed

hot).

Data from the EFSA Comprehensive European Food Consumption Database (hereafter called the

Comprehensive Database) were used to assess dietary exposure to BPA in all age groups, excluding

infants aged 0 to 6 months. Consumption data observed in toddlers were used as an estimate of

consumption in infants aged 6 to 12 months since no data were available for the latter age class.

Consumption data from a total of 32 different dietary surveys carried out in 22 different Member

States covering more than 67 000 individuals are included in the Comprehensive Database. In the

present assessment the adult age group has been broken down in the following subgroups, comprising

women from 18 to 45 years (child- bearing age), men from 18 to 45 years, adults from 45 to 65 years,

and elderly and very elderly (65 years and over). Only a limited number of dietary surveys in the

Comprehensive Database have information on the type of packaging (canned or non-canned, in

particular).

In the case of infants a consumption of 150 g/kg bw per day was used as a standard for both human

milk and infant formula with the exception of breastfed infants over their first five days of life for

whom the consumption was assumed to be 75 g/kg bw per day.

Two scenarios were developed to consider the higher levels of BPA in canned foods compared with

non-canned foods. In scenario 1 only foods specifically codified as canned in the dietary survey are

assigned the corresponding occurrence level for BPA. In scenario 2 any food category (at the lowest

available level of food category classification) which has been codified as canned in at least one

survey is always considered to be consumed as canned in all dietary surveys included the

Comprehensive Database.

Due to a low percentage of left censored samples, in particular among canned foods, the techniques

used to model data below the LOD or LOQ had a small impact on the average concentration in the

different food categories and, consequently, on the exposure. Therefore, middle bound average BPA

concentration values were used in the final exposure assessment.

Dietary exposure for the population groups older than 6 months

The modelled dietary exposure (MB) obtained by scenario 2, for infants (6 to 12 months), toddlers (12

to 36 months) and other children (3 to 10 years) ranged from 290 to 375 ng/kg bw per day for the

average exposure and from 813 to 857 ng/kg bw per day for the high exposure, respectively.

Additional dietary exposure from a number of food contact articles was also assessed in specific

population groups. The highest estimated high exposure from PC tableware and cookware was

observed for infants and toddlers (14 ng/kg bw per day for PC tableware and 46 ng/kg bw per day for

cookware). The highest estimated exposures to BPA migrating from water coolers with PC reservoirs

and PC filters into drinking water were also observed in infants and toddlers (22 ng/kg bw per day for

water coolers and 3.8 ng/kg bw per day for PC filters). High estimated exposure in residents of

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buildings with old water pipes repaired with epoxy resins was up to 29 ng/kg bw per day in infants and

toddlers.

The modelled dietary exposure obtained by scenario 2, for adolescents, adults (including women of

childbearing age) and elderly/very elderly, ranged from 116 to 159 ng/kg bw per day for the average

exposure and from 335 to 388 ng/kg bw per day for the high exposure, respectively. Additional dietary

exposure from a number of food contact articles was also assessed in specific population groups

within this population. Estimated exposure from PC kettles ranged from 2 to 3.2 ng/kg bw per day

with the highest values being observed in adults and the elderly due to their higher consumption of

coffee and tea.

Under scenario 1, non-canned “meat and meat products” turned out to be a major contributor to BPA

average exposure in the large majority of countries and age classes. Canned foods contributed to less

than 50 % to the average exposure for all age classes. “Vegetables and vegetable products” was the

only canned food category that contributed up to 25-50 % exposure in some population groups.

Under scenario 2, canned products dominated in all surveys, with canned “vegetables and vegetable

products”, “meat and meat products” and “composite food” being the major sources of average BPA

exposure. The contribution of BPA from non-canned foods ranged from 10 to 25 % exposure, with

“Meat and meat products” being the major contributor among the non-canned food categories as for

scenario 1.

Exposure from non-canned meat and meat products and fish had not been anticipated until the 2013

report of ANSES on concentrations of BPA in French food. Investigation of these findings is currently

underway in France (see https://info.agriculture.gouv.fr/gedei/site/bo-agri/instruction-2014-994), but

until further results are available there is no substantiated explanation for the presence of unconjugated

BPA in foods of animal origin. It may be due to migration from any food contact materials or from

articles used in the processing of the product or deconjugation of conjugated BPA occurring during

processing of the sample. The CEF Panel considered that accumulation of BPA in animal tissues was

not a likely explanation, given the extensive data showing rapid metabolism and elimination of BPA in

various animal species.

Overall, among the population older than 6 months, infants and toddlers presented the highest

estimated average (375 ng/kg bw per day) and high (857 ng/kg bw per day) dietary exposure. The CEF

Panel considered that this was mainly due to their higher consumption of foods and beverages per kg

bw.

Dietary exposure for infants aged 0-6 months

For breastfed infants, the estimated average dietary exposure was 225, 165 and 145 ng/kg bw per day

for infants in the first five days of life, infants from 6 days up to 3 months and infants 4-6 months,

respectively. The estimated high dietary exposure was 435, 600 and 528 ng/kg bw per day,

respectively. The CEF Panel noted that, due to the lack of recent European data related to colostrum,

the estimated dietary exposure in the first five days of life was based on BPA concentration in samples

collected in Japan in 2000 and generated using ELISA methodology. The CEF Panel noted these

severe limitations and the resulting uncertainties in the estimates for this age group.

Average and high additional exposure to infants that would derive from the consumption of herbal tea

prepared with water heated in a PC kettle would be as low as 6 and 12 ng/kg bw per day, respectively.

In the case of formula-fed infants (0-6 months), the estimated average and high exposures were 30 and

80 ng/kg bw per day, respectively. These estimates are based on the assumption that non-PC baby

bottles and water containing low BPA levels were used to reconstitute the infant formula. Additional

dietary exposure may occur in specific population groups due to the use of old PC bottles bought

before the 2011 ban (estimated high exposure: 731 ng/kg bw per day). The percentage of infants to

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which these cases would apply is unknown. If this percentage was higher than 5 % in some countries,

it would lead to a high dietary exposure which is significantly higher than 80 ng/kg bw per day.

Dietary exposure from further sources in other specific population groups of infants was also assessed:

exposure for infants fed powdered formula reconstituted with water heated in PC kettles was 53 ng/kg

bw per day (average) and 94 ng/kg bw per day (high).

Compared with the assessment of dietary exposure to BPA estimated by EFSA in 2006 (up to 11 000

ng/kg bw per day in infants aged 3 months in one of the scenarios considered), the current estimate in

the population 0 to 6 months is far lower, due to the improvement of data compared with 2006, which

previously led to very conservative assumptions in relation to BPA concentration in infant formula and

to BPA migration from PC bottles.

1.6.1.2. Non-dietary exposure

The non-dietary sources considered for this assessment were thermal paper, indoor/outdoor air

(including air-borne dust), dust, toys and articles which may be mouthed, and cosmetics. An average

and a high scenario were made for all sources. For the average scenario, average values for all

parameters, including parameters describing frequency of use, were chosen. For the high scenario, the

same average parameters were used for absorption rates and occurrence data, but the frequency of use

parameters was modified to account approximately for the highest 95

percentile among the EU

population, in line with the methodology used to assess dietary exposure.

Data on occurrence, migration and transfer of BPA from non-food sources are scarce. The following

concentration data were selected from the scientific literature and other risk assessment reports to

calculate exposure in the EU: for air 1 ng/m

; for dust 1 460 µg/kg, and for cosmetics (such as body

wash, and body lotions, etc.) 31 µg/kg. A migration of 0.14 µg/toy product into saliva over a 24 h

period was assumed. The transfer of BPA from thermal paper to fingers was estimated to be 1.4

µg/finger considering 10 s of contact with paper. Handling events were assumed as 1 per day for

adolescents and adults to assess average exposure and as 4.6 per day to assess high exposure. For

children the handling events were assumed as 0.5 time per day for average exposure and 2 times per

day for high exposure. The thermal paper was assumed to be handled mainly by the fingertips of three

fingers of one (average exposure) or two hands (high exposure).

The estimates of external non-dietary exposure according to source and exposure route are as follows:

Dust ingestion:

for the average scenario the derived exposure values ranged from 0.6 ng/kg bw per day

in adults to 8.8 ng/kg bw per day in infants. The CEF Panel considered that these are likely to be

overestimated, because in the original studies soil and dust ingestion rates could not be determined

separately, and so conservative assumptions were made when deriving the dust ingestion rates. In the

high exposure scenario the exposure ranged from 1.0 ng/kg bw per day (adults) to 14.6 ng/kg bw per

day (infants).

Mouthing of toys:

exposure values of 0.2 and 0.01 ng/kg bw per day for the average exposure scenario

and 0.6 and 0.01 ng/kg bw per day for the high exposure scenario for infants’ and toddlers’ exposure,

respectively, to rattles (as a proxy for PC mouthing toys) were derived.

Air inhalation:

the average exposure values ranged from 0.2 (adults) to 0.7 ng/kg bw per day (toddlers

and infants), whereas high exposure levels ranged from 0.3 (adults) to 1.4 ng/kg bw per day (infants).

Dermal exposure to thermal paper:

this scenario applied only to subjects older than 3 years. From

average assumptions, exposures of 68.8, 93.8 and 58.9 ng/kg bw per day were derived for children,

adolescents and adults, respectively. For the high exposure, values ranged from 542 (adults) to

863 ng/kg bw per day (adolescents).

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Dermal exposure to cosmetics:

average exposure ranged from 2.0 (adults) to 4.8 ng/kg bw per day

(infants). High exposure ranged from 4.0 (adults) to 9.4 ng/kg bw per day (infants).

The CEF Panel noted that the average values for dust and thermal paper differed by a factor 10 from

the respective high values. This is due to highly conservative assumption for dust ingestion and

frequency of and number of fingers handling thermal paper when assessing high exposure.

1.6.2.

Internal exposure to total BPA

The external exposure values to BPA as derived by forward calculation were transformed into internal

exposure levels by applying route- and source-specific absorption fractions, namely 100 % absorption

for both ingestion and inhalation, 10 % for dermal absorption of BPA from thermal paper and 50 %

for dermal absorption of BPA from cosmetics. The internal levels of total BPA summed up over

different routes were only used to validate external exposure estimates, by means of a comparison with

daily urinary excretion of total BPA from biomonitoring studies. Internal levels of total BPA were not

used for risk characterisation, which only focuses on the toxicologically active unconjugated fraction

of BPA.

By forward modelling, the average internal exposure (expressed as ng/kg bw per day) to total BPA

ranged from 42 to 387 for the overall age class “Infants”, and amounted to 384 for toddlers and 301

for children 3–10 years old. For the adolescents, women of childbearing age, and all the adult

populations internal total BPA exposures were estimated to be in the range of 124 to 172 ng/kg bw per

day. The high internal exposure to total BPA for the overall class of infants ranged from 101 to

878 ng/kg bw per day, and for toddlers and children 3–10 years old it was estimated around

870 ng/kg bw per day. Lower levels were estimated for adolescents, women of childbearing age, and

all the adult populations (between 393 and 473 ng/kg bw per day).

The estimates for the average and high internal exposure to total BPA in the general population, as

obtained by the forward modelling approach, were compared with the biomonitoring estimates. The

focus is on total BPA (conjugated plus unconjugated) in order to provide validation for the external

exposure levels.

A relatively large amount of information on urinary BPA concentration was available for Europe

covering all age classes: children (except 1–3-year-old toddlers), adolescents, and 18–75-year-old

adults.

Average and high urinary concentrations of total BPA were multiplied by age-specific urinary output

rates to obtain estimates of daily urinary excretion for the different age groups. Since absorbed BPA is

rapidly removed from circulation via conjugation and subsequent renal excretion, the estimates of

daily urinary excretion can be used as estimates of daily BPA exposure.

For the average exposure, the following biomonitoring estimates (expressed as ng/kg bw per day)

were derived: <10 (infants 1–2 months old), 107 (children 3–5 years old), 49 (children 5–10 years

old), 48 (adolescents), 39 (adults including women of childbearing age), and 56 (the elderly). The

biomonitoring estimates (expressed as ng/kg bw per day) for high BPA exposure were 161 (infants 1–

2 months old), 676 (children 3–5 years old), 380 (children 5–10 years old), 256 (adolescents), 290

(adults including women of childbearing age), and 203 (the elderly).

By comparing estimated internal exposure with biomonitoring data, the forward modelling approach

gave about 4-fold higher estimates (42–387 vs. <10–107 ng/kg bw per day) than the biomonitoring

approach for average exposure, and about 2-fold higher for high exposure, demonstrating quite a good

agreement between these two approaches. The different statistical procedures used to derive central

tendencies and the scenarios for modelling the dietary and non-dietary exposure may contribute to the

observed differences. The CEF Panel also noted that there are considerable uncertainties in both

estimates.

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1.6.3.

Conclusions

The assessment of external exposure to BPA from all sources showed that diet is the main source in all

population groups. Specifically, canned food and non-canned meat and meat products are the two

main dietary contributors to external BPA exposure in the large majority of countries and age classes.

While canned food as a main source of dietary exposure to BPA is confirmed by the data presented in

this opinion, exposure from non-canned meat and meat products and fish had not been anticipated

until the 2013 report of ANSES on concentrations of BPA in French food (see above). Investigation of

these findings is currently under way, but, until further results are available, there is no substantiated

explanation for the presence of unconjugated BPA in foods of animal origin.

Among the population older than six months, infants (6-12 months) and toddlers had the highest

estimated external average (0.375 µg/kg bw per day) and high (0.857 µg/kg bw per day) dietary

exposure. This was mainly due to their higher consumption of foods and beverages per kilogram body

weight. The modelled dietary exposure for adolescents, adults (including women of childbearing age)

and elderly/very elderly ranged from 0.116 to 0.159 µg/kg bw per day for the average external

exposure and from 0.335 to 0.388 µg/kg bw per day for the high exposure, respectively. Dietary

exposure to BPA estimated by EFSA in 2006 in the population older than six months was far higher

(up to 5.3 µg/kg bw per day in toddlers) compared with the current assessment (up to 0.857 µg/kg bw

per day for the high exposure of toddlers), owing to the lack of data at that time which led to the use of

very conservative assumptions in relation to both the level of consumption of canned food and the

estimated BPA concentration in these foods.

The current much higher data availability than in 2006 has made it possible for the CEF Panel to carry

out a more refined dietary exposure assessment for infants. According to the current estimate, BPA

exposure for infants up to six months (0.03 to 0.225 µg/kg bw per day for average external exposure)

is much lower than that estimated by EFSA in 2006 for infants within six months of age (≤

11 µg/kg bw per day). This was due to the use at that time of very conservative assumptions in relation

to BPA concentration in infant formula and to BPA migration from PC bottles to account for the lack

of data.

Dietary external exposure in women of childbearing age (0.132 and

average and high exposure, respectively) was similar to that of men

0.335 µg/kg bw per day for average and high external exposure,

differences may be related to women consuming different food items,

surveys.

0.388 µg/kg bw per day for

of the same age (0.126 and

respectively). The minimal

as reported in the individual

The uncertainty around the estimates of dietary exposure was judged as relatively low compared to

non-dietary sources of exposure such as thermal paper.

Thermal paper was the second largest source of external exposure in all population groups above three

years of age. The modelled estimates for 3–10-year-old children, adolescents, adults (including

women of childbearing age) and elderly/very elderly ranged from 0.059 to 0.094 µg/kg bw per day for

the average exposure and from 0.542 to 0.863 µg/kg bw per day for the high external exposure,

respectively. The CEF Panel considers that more data would be needed for BPA absorption through

the skin, on skin metabolism and for patterns of thermal paper handling by the general population in

order to provide a refined estimate of exposure through this source to reduce the uncertainty in the

estimate.

In children under the age of three years (except for infants in the first few days of life) dust was the

second largest source of external exposure to BPA and ranged from 0.009 to 0.015 µg/kg bw per day

for average and high external exposure, respectively.

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Average external exposure to BPA from non-dietary sources such as toys and cosmetics was estimated

to be less than 0.001 µg/kg bw per day and 0.005 µg/kg bw per day, respectively, in all population

groups.

For the four age classes covering infants from 1 day up to 6 months, the average internal exposure to

total BPA, as estimated by forward modelling, ranged from 0.042 µg/kg bw per day to 0.226 µg/kg bw

per day. The average internal exposure for the population older than six months ranged from 0.301 to

0.387 µg/kg bw per day in children aged 3 to 10 years and infants aged 6 to12 months and from 0.124

to 0.172 µg/kg bw per day in the elderly/very elderly and adolescents.

For the four age classes covering infants from 1 day up to 6 months the high internal exposure to total

BPA ranged from 0.101 µg/kg bw per day to 0.621 µg/kg bw per day. The high internal exposure for

populations older than six months ranged from 0.873 to 0.878 µg/kg bw per day in toddlers and infants

aged 6 to 12 months, and from 0.393 to 0.473 µg/kg bw per day in men and adolescents.

Internal exposures to total BPA, as estimated by forward modelling, are in good agreement with the

backward-modelling estimates obtained from urinary biomonitoring, suggesting that it is likely that no

major exposure sources have been missed for the forward-modelled exposure assessment. It is,

however, important to highlight the fact that the internal exposure estimation of total BPA includes

conservative assumptions resulting in likely overestimation of exposure that could in theory have

hidden other possible sources of exposure. The CEF Panel noted also that there are considerable

uncertainties in the forward and backward estimates of internal exposure.

The CEF Panel additionally carried out an assessment of aggregated dietary and non-dietary exposure

to unconjugated BPA using PBPK modelling. This aggregated exposure assessment included diet and

house dust (the main oral-route sources) as well as thermal paper and cosmetics (the main dermal-

route sources).

Part II – BPA toxicological assessment and risk characterisation

Part II of this opinion addresses the first and the fourth part of the terms of reference, i.e. BPA hazard

assessment, and the risk characterisation for human health associated with BPA exposure.

2.1.

Methods

Literature sources:

A thorough and extensive literature search was outsourced by EFSA to cover the

period from August 2010 to December 2012. The publications were searched on five online

databases—namely PubMed, ScienceDirect, Scopus from Elsevier, Web of Knowledge/Science from

the Institute for Scientific Information, and the Directory of Open Access Journals (DOAJ)—using the

search strings “bisphenol” or “BPA” (without any additional search terms). Additional sources of

information were the list of published scientific studies on BPA submitted by Réseau Environnement

Santé to the European Commission (EC) and received by EFSA on 19 February 2013; pre-(July)2010

studies previously identified as key studies by various risk assessment bodies including EFSA; pre-

(July)2010 studies not previously evaluated by EFSA because they did not match the inclusion criteria

established for the 2010 opinion, e.g. non-oral studies, single-dose studies, studies addressing BPA

exposure only during adult age and genotoxicity studies (searched from 2006 onwards); and some

studies available in 2013 (as per the literature search carried out by an EFSA contractor) selected on a

case-by-case basis (based on expert judgement) based on their relevance to critical review questions

and/or their methodological soundness. The literature cited in the comments of the public consultation

and therefore published by the closing date of the consultation (17 March 2014) was an additional

source of evidence.

The studies used for the hazard identification and characterisation of BPA were then grouped

according to 10 macro-areas of interest, including toxicokinetics and metabolism, general toxicity,

reproductive and developmental effects. The studies grouped by macro-area were assigned to the

working group on BPA toxicology for evaluation, including appraisal of their strengths and

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weaknesses.

In vitro

studies and studies on the mechanisms of action of BPA were used primarily as

supplementary information for the toxicological evaluation.

2.2.

Hazard identification

For the hazard identification of BPA, the Weight of Evidence (WoE) approach was structured in such

a way as to facilitate consistent treatment of the evidence and to document this in a tabular format, as

described in more detail in Appendix A of this opinion. The WoE evaluation for each toxicological

endpoint was divided into one or several parts addressing different questions considered by the CEF

Panel to be relevant for hazard identification of BPA, e.g. “Is there an association between BPA

exposure and reproductive effects in humans?”. As already indicated, the conclusions of earlier

assessments by EFSA in 2006 and/or 2010 were taken as a starting point for each question.

Subsequently, for each question, the relevant publications were organised into a number of “lines of

evidence”, addressing different findings or considerations that provide an answer to the question

concerned. The strengths and weaknesses of each line of evidence, and of the evidence underpinning

the earlier assessments, were briefly summarised in a tabular format, to facilitate a conclusion to be

drawn on the likelihood that exposure to BPA was associated with a particular effect. This conclusion

was categorised depending on the strength of the overall experimental evidence for the effect, as

follows. Note that, on this scale, "As likely as not" means a level of likelihood between "Unlikely" and

"Likely", where it is about equally likely that BPA causes, or does not cause, the effect.

Box 1. Set of standard terms used for expressing the overall likelihood in the WoE tables.

Likelihood

Very likely

Likely

From “-as likely as not- to likely”

As likely as not

From “unlikely to –as likely as not-”

Unlikely

Very unlikely

The CEF Panel would like to underline that this classification applies solely to BPA hazard

identification and not to the assessment of human risks from BPA exposure.

This approach was adopted independently for (1) human studies reporting effects of BPA, (2) animal

studies and (3)

in vitro

studies, where considered appropriate. An overall conclusion was then drawn

regarding the likelihood that BPA could be associated with the effect in question in the human

population, based on a WoE approach in humans, animals and/or

in vitro

studies.

The toxicokinetics of BPA were similarly reviewed using the conclusions of previous evaluations and

the results of new toxicokinetic studies on BPA published since the 2010 EFSA opinion on BPA. In

this case, however, a WoE approach was not found to be necessary to reach an overall conclusion on

the toxicokinetics of BPA in humans and experimental animals.

The conclusions of the CEF Panel on the hazard identification step for BPA in relation to each

endpoint considered are summarised in the following sections.

2.2.1.



Toxicokinetics

Species- and life-stage dependent differences in the toxicokinetic profile of BPA must be

considered when comparing toxicokinetic data from different species.

Conjugation to BPA-glucuronide is the major metabolic pathway of BPA in humans, non-

human primates and rodents. Glucuronidated BPA is a biologically inactive form of BPA at

the oestrogen receptors (ERs); however it cannot be excluded that the glucuronidated form

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may have effects at ER independent sites. BPA can also be conjugated via sulfation to a

lower extent.



The oral systemic bioavailability of unconjugated BPA in adults is: 2.8 % in rats, 0.45 % in

mice and 0.9 % in monkeys, based on oral versus intravenous toxicokinetic data.

Unconjugated BPA and BPA-conjugates are observable at low concentrations in the

amniotic fluid of rats and monkeys in comparison with serum levels. In early pregnancy

exposure of the fetus might be greater compared with later pregnancy after i.v. exposure to

BPA.

BPA is present in rat milk from BPA-treated dams in both unconjugated and conjugated

forms. In rat milk, BPA-glucuronide comprises about 80 % of the total BPA concentration.

Pup exposure via lactation is low, i.e. about 1/300 of the maternal dose. Unconjugated BPA

has also been reported in human milk.

BPA-conjugating enzymes (UDP-glucuronyl-transferases (UGT) and sulfotransferases

(SULT)) are polymorphic in humans. The default intraspecies uncertainty factors used to

derive a health-based guidance value are considered sufficient to account for possible

differences in rates of metabolism of BPA between human individuals.

A solid base of toxicokinetic studies in various laboratory animal species provides internal

dose metrics for neonatal-to-adult stages and for different routes of exposure. Moreover,

PBPK models have been developed to predict the internal exposures in laboratory animals

and humans in a route-specific manner.

Overall, this body of information permits extrapolation to humans and the application of the

human equivalent dose (HED) concept for providing HEDs for points of departure derived

from critical animal data. This was achieved by estimating human equivalent dose factors

(HEDF) from the ratio of the Area Under the Curve (AUC) for the test species and AUCs for

humans.

Available experimental evidence indicates a 24-h percutaneous penetration of BPA across

human skin of 2.3–8.6 %. For exposure scenarios with dermal contact to thermal paper, the

CEF Panel used a conservative value of 10 % dermal absorption. The CEF Panel did not

consider skin metabolism (conservative decision). For scenarios with aggregated oral and

dermal exposures, PBPK modelling was used to estimate the internal dose metrics (AUCs)

for unconjugated BPA, with which equivalent oral exposures were subsequently calculated.

General toxicity

BPA was found to affect kidney and liver weight in parental animals and in all the

generations of rats and mice examined in multi-generation studies. These effects were

considered by EFSA (2006, 2010) as relevant systemic effects for the identification of a

NOAEL. In mice the increased kidney weight was associated with nephropathy at the

highest BPA dose. Liver weight was increased in rats (relative weight) and mice (both

absolute and relative weight). The latter species also showed hepatocellular hypertrophy.

The CEF Panel re-confirmed that the changes in the kidney and liver are critical endpoints in

BPA toxicity and therefore took them forward for hazard characterisation.

Reproductive and developmental effects

Only limited conclusions can be drawn from human studies on the likelihood of associations

between BPA exposure during pregnancy and disturbed foetal growth, or maternal and infant

decreased thyroid function. The evidence is not sufficient to infer a causal link between BPA

exposure and reproductive effects in humans.



2.2.2.



2.2.3.



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

Data considered in previous EFSA opinions show that BPA is a reproductive toxicant at high

dose levels. On balance, the evidence from new lower dose (below 3.6 mg/kg bw per day,

that corresponds to the NOAEL for general toxicity transformed in HED) animal studies for

changes in reproductive function arising from in utero exposure to BPA remains

contradictory and highly variable between studies. Furthermore, the biological relevance to

humans of some of the effects of BPA exposure observed in some animal studies (e.g.

reduced ano-genital distance in females) is not well understood. The CEF Panel noted that

there is some evidence for effects of BPA exposure on several parameters indicative for

changes in the reproductive system in adult male animals at dose levels below 3.6 mg/kg bw

per day, although these effects were modest. It is not possible to conclude that these changes

are reflective of changes in reproductive performance, since the studies rarely included a

forced/continuous breeding phase in adulthood to establish reduced fertility. However, in

several multi-generation studies no effects were observed at dose levels as low as 3

g/kg

bw per day up to at least 50 mg/kg bw per day.

The CEF Panel re-confirmed that BPA is a reproductive toxicant at high dose levels.

Using a WoE approach, the CEF Panel assigned a likelihood level of “as likely as not” to

reproductive and developmental effects of BPA at low doses (below the HED of 3.6 mg/kg

bw per day). Since the likelihood level for this endpoint is less than "likely" (see Box 1), this

endpoint was not taken forward for assessing the toxicological reference point, but was taken

into account in the evaluation of uncertainty for hazard characterisation and risk

characterisation.

Neurological, neurodevelopmental and neuroendocrine effects

There are indications from prospective studies in humans that prenatal BPA exposure (BPA

exposure during pregnancy) may be associated with altered child behaviour in a sex-

dependent manner. However, the associations were not consistent across the studies and it

cannot be ruled out that the results are confounded by diet or concurrent exposure factors.

The associations reported do not provide sufficient evidence to infer a causal link between

BPA exposure during pregnancy or childhood and neurodevelopmental effects in humans.

A number of new studies report changes that may indicate effects of BPA on brain

development (effect on neurogenesis and on gene expression, neuroendocrine effects, effects

on the morphology of certain brain regions, etc.). Whether such changes are mechanistically

related to the neurobehavioral responses reported following exposure is attempted addressed

by some studies but with inconsistent results.

Several new animal studies investigated anxiety-like behaviour, learning and memory, social

behaviour and sensory-motor function. Some studies report changes in anxiety-like

behaviour after BPA exposure. Some, but not all, studies reported significant impairment of

either learning and/or memory capacities. A few studies also report effects on social

behaviour and sensory-motor function. However, the studies present methodological

shortcomings, such as small sample size, lack of consideration of the litter effect, not

properly controlled variability of exposure through diet and inadequate statistics. Moreover

the results from different studies are inconsistent.

Using a WoE approach, the CEF Panel assigned a likelihood level of “as likely as not” to

neurological, neurodevelopmental and neuroendocrine effects of BPA. Since the likelihood

level for this endpoint is less than "likely" (see Box 1), this endpoint was not taken forward

for assessing the toxicological reference point, but was taken into account in the evaluation

of uncertainty for hazard characterisation and risk characterisation.



2.2.4.



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2.2.5.



Immune effects

Based on recent studies, there are indications that BPA exposure may be linked to

immunological outcomes in humans, although these studies had limitations and confounding

factors may have been present. A causal link between BPA exposure during pregnancy or in

childhood and immune effects in humans cannot be established.

Studies in animals lend support to the possibility of immunological effects of BPA.

However, most of these studies suffered from shortcomings in experimental design and

reporting. Although dose-responses could not be confidently established in most studies, a

dose-related effect was observed for allergic lung inflammation.

Using a WoE approach, the CEF Panel assigned a likelihood level of “-as likely as not- to

likely” to immunotoxic effects of BPA. Since the likelihood level for this endpoint is less

than "likely" (see Box 1), this endpoint was not taken forward for assessing the toxicological

reference point, but was taken into account in the evaluation of uncertainty for hazard

characterisation and risk characterisation.

Cardiovascular effects

All but one study, among the newly considered human studies in relation to cardiovascular

effects since the 2010 EFSA opinion, are cross-sectional and thus unsuitable to study BPA

exposure-disease associations on their own. There are indications from one prospective study

that BPA may be associated with such effects but overall a causal link between BPA

exposure and cardiovascular effects in humans cannot be established.

There are insufficient animal data to suggest that BPA has an effect on cardiac function or

causes cardiotoxicity.

Using a WoE approach, the CEF Panel assigned a likelihood level of “as likely as not” to

cardiovascular effects of BPA. Since this likelihood level is less than “likely”, this endpoint

was not taken forward for risk characterisation. It cannot be ruled out that the observed

association between exposure to BPA and cardiovascular effect in the epidemiological

studies is confounded by diet or other concurrent exposure factors. This association does not

provide sufficient evidence to infer a causal link between BPA exposure and cardiovascular

effects in humans. Since there is also a lack of information on the dose-relationship for this

association, and since there were only very limited number of animal studies on this

endpoint, this endpoint was not included in the uncertainty analysis.

Metabolic effects

Of the reviewed human studies on metabolic effects only two were prospective while 22

were cross-sectional and thus not suitable on their own to study exposure-disease

associations. Inconsistent with the results of cross-sectional studies one prospective study

found that a higher BPA concentration in maternal urine during pregnancy was associated

with a lower level of obesity in daughters. A causal link between BPA exposure and

metabolic effects in humans cannot be established.

A number of studies in pre- and postnatally exposed rats and mice indicate that BPA

exposure could have an effect on metabolic function as evidenced by effects on glucose or

insulin regulation or lipogenesis, and body weight gain (short-term studies). However,

based on the results from other studies with a longer duration (e.g. 90 days) there is no

convincing evidence that BPA is obesogenic after intrauterine exposure or in longer-term

studies.



2.2.6.



2.2.7.



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

Using a WoE approach, the CEF Panel assigned a likelihood level of “as likely as not” to

metabolic effects of BPA. Since the likelihood level for this endpoint is less than "likely"

(see Box 1), this endpoint was not taken forward for assessing the toxicological reference

point, but was taken into account in the evaluation of uncertainty for hazard characterisation

and risk characterisation.

Genotoxicity

The available data support that BPA is not mutagenic (in bacteria or mammalian cells), or

clastogenic (micronuclei and chromosomal aberrations). The potential of BPA 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 BPA in vitro and in vivo.

Using a WoE approach, the CEF Panel assigned a likelihood level of “unlikely” to BPA

genotoxicity.

Carcinogenicity

Very few epidemiological studies published to date have investigated a possible association

between exposure to BPA and incidence of certain cancers, specifically breast cancer and

meningioma. These studies do not allow any conclusion to be drawn regarding the

carcinogenicity of BPA in humans.

BPA 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 BPA 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 BPA investigated the potential carcinogenic effect in mammary gland. Due to

weaknesses in these studies the results do not provide convincing evidence that BPA 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 BPA. Since the likelihood level for this endpoint is less

than "as likely as not” (see Box 1), this endpoint was not taken into account in the evaluation

of uncertainty for hazard characterisation and risk characterisation.

Proliferative and morphological changes potentially related to carcinogenesis

Earlier evidence for BPA 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 however insufficient to conclude that there is a link to cancer

development, although there might be a possible role of BPA 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 BPA

induced proliferative changes in the mammary gland. Therefore, this endpoint was brought

forward for hazard characterisation and for uncertainty analysis.

2.2.8.



2.2.9.



2.2.10.



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

The CEF Panel considered that the evidence for proliferative changes induced by BPA in

other organs (e.g. prostate or testis) is currently too limited to reach any conclusion.

Mechanistic studies with BPA including epigenetic effects

Mechanistic studies published since 2010 continue to support the conclusion that BPA

affects a number of receptor-dependent and independent signalling pathways, resulting in

effects on hormone homeostasis and gene expression as well as in cytogenetic and epigenetic

effects.

The CEF Panel confirmed its conclusion in its opinion of 2010 that no single clearly defined

mode of action of BPA can be identified that can contribute substantially to the

understanding of the potential effects of BPA in humans.

Hazard characterisation

2.2.11.



2.3.

The WoE approach to hazard identification has been used to identify the critical toxicological effects

for BPA, following prenatal or postnatal exposure, or both. The subsequent step in the risk assessment,

namely hazard characterisation, was carried out for only those endpoints for which the overall

likelihood for the specific effect was considered as “likely”. Dose-response relationships (hazard

characterisation) were examined for the studies considered by the CEF Panel to be the most reliable, in

order to provide a reference point for the derivation of a health-based guidance value.

The CEF Panel considered that the “likely” effects indicative of general toxicity in rats and mice that

were already described in the EFSA 2010 opinion should be maintained as a critical endpoint for risk

assessment of BPA. Additionally the CEF Panel concluded that BPA-induced effects on the mammary

gland of rats, mice and monkeys exposed pre- or perinatally were “likely” effects. These latter

conclusions resulted from the CEF Panel’s evaluation of new evidence published since EFSA’s

previous risk assessment in 2010 and of earlier studies using the subcutaneous route of administration

(not considered in the EFSA 2010 opinion). The CEF Panel also considered that recent scientific

literature has provided additional indications (compared with its 2010 evaluation) of reproductive and

developmental effects at doses of BPA below the NOAEL for general toxicity as well as neurological/

neurodevelopmental/neuroendocrine, immune-modulatory and metabolic effects. In light of the

methodological shortcomings identified in the evaluated studies, the CEF Panel considered that none

of these effects could be considered as “likely” by the WoE approach. Instead, they were considered in

a thorough and structured uncertainty analysis, the results of which were taken into account in hazard

and risk characterisation.

The CEF Panel has carried out dose-response (Benchmark Dose [BMD]) modelling on the data for

general toxicity and for the proliferative changes in the mammary gland. The analysis of the mammary

gland data revealed large differences in the BMD estimates obtained with the various models and wide

BMD confidence intervals obtained with some of the models. These estimates could not be used for

the derivation of a health-based guidance value. Therefore, the proliferative changes in the mammary

gland were taken into account in the evaluation of uncertainty for hazard characterisation and for risk

characterisation.

The CEF Panel therefore used only the endpoint “general toxicity” for risk characterisation,

specifically the mean relative kidney weight in a two-generation study in mice, and calculated a

BMDL

of 8 960 µg/kg bw per day.

Subsequent to the 2010 opinion, new toxicokinetic data have become available which allow a more

accurate substance-specific extrapolation of data from animals to humans, using the human equivalent

dose (HED) approach. The human equivalent dose factor (HEDF) of 0.068 for oral exposure of adult

mice was applied to the BMDL

of 8 960 µg/kg bw per day, which results in a HED of 609 µg/kg bw

per day. The CEF Panel decided to use the HED value of 609 µg/kg bw per day as the reference point

for establishing a health-based guidance value for BPA.

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The CEF Panel also developed criteria

for nonmonotonic dose responses (NMDRs) and reviewed

studies reporting a NMDR for BPA. None of the studies fulfils these criteria. Overall the CEF Panel

concluded that the available data do not provide evidence that BPA exhibits a NMDR for the

endpoints considered (reprotoxicity/development, neurotoxicity/behavioural effects, metabolic effects,

proliferative changes in mammary gland).

2.3.1.

Uncertainties in hazard characterisation

The overall uncertainty evaluation included the effects on the mammary gland as well as on the

reproductive, metabolic, neurobehavioural and immune systems. The CEF Panel concluded that the

health-based guidance value should cover the lowest dose in the dose range for which the likelihood

approaches “likely” from the overall uncertainty evaluation, taking into account uncertainty of all the

evaluated endpoints as well as their relevance and adversity to humans. The uncertainty evaluation

approached “likely” in the (HED) dose range of 100–1000 µg/kg bw per day. The CEF Panel therefore

decided that the uncertainty regarding the above mentioned effects at the HED of 100 µg/kg bw per

day and higher should be taken into account when establishing a health-based guidance value by

including an extra factor in establishing the TDI. Thus, as the reference point was 609 µg/kg bw per

day based on the mean relative kidney weight and the lower end of the dose-range for which the

uncertainty evaluation for other endpoints approached “likely” is 100 µg/kg bw per day, a factor of 6

was applied.

2.3.2.

Health-based guidance value

In deriving a health-based guidance value, the CEF Panel used an uncertainty factor of 2.5 for inter-

species differences (1 for toxicokinetics and 2.5 for toxicodynamics, reflecting the fact that

toxicokinetic differences have been addressed by use of the HED approach) and an uncertainty factor

of 10 for intra-species differences. In addition, the CEF Panel considered that the extra factor of 6

should be included to take into account the uncertainty in the database, i.e. mammary gland and

reproductive, neurobehavioural, immune and metabolic systems.

The CEF Panel applied, therefore, an overall uncertainty factor of 150 to the HED of 609 µg/kg bw

per day and established a temporary Tolerable Daily Intake (t-TDI) for external oral exposure to BPA

in humans of 4 µg/kg bw, based on the mean relative kidney weight effect in mice. The CEF Panel

designated the TDI as temporary, pending the outcome of the long-term study in rats involving

prenatal as well as postnatal exposure to BPA, currently being undertaken by NTP/FDA.

2.4.

Risk characterisation

The following table shows the aggregate exposures figures that were used for the risk characterisation.

(i) at least two adjacent doses departing from monotonicity or support for the NMDR from a similar study (same species,

similar treatments, similar sampling time) on the same effect (this criteria is relevant to reduce the chance for an incidental

finding).

(ii) a plausible underlying mode of action/overarching concept;

(iii) the reliability of the study and the relevance of the effect for human health should be considered as medium or high (as

expressed in Appendix B and C); the reliability of the study results should also include an appropriate statistical treatment of

the reported data

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Table 1:

Summary table on average (A) and high (H) exposure (µg/kg bw per day) from

dietary and non-dietary sources to BPA in the different age groups of the general population.

Dermal doses are expressed as equivalent oral doses as obtained by PBPK modelling.

Dietary

Oral

Food &

beverage

0.225

0.435

0.165

0.6

0.145

0.528

0.03

0.08

0.375

0.857

0.375

0.857

0.290

0.813

0.159

0.381

0.132

0.388

0.126

0.335

0.126

0.341

0.116

0.375

Non-dietary

Dermal

Thermal

Cosmetics

paper

0.053

0.424

0.113

1.036

0.071

0.650*

0.071

0.650

0.071

0.650*

0.071

0.650*

0.008

0.016

0.015

0.029

0.012

0.024*

0.012

0.024

0.012

0.024

0.012

0.024*

Age group

Infants 1-5 days

(breastfed)

Infants 6 days - 3 months

(breastfed)

Infants 4-6 months (breastfed)

Infants 0-6 months (formula

fed)

Infants 6-12 months

Toddlers 1-3 years

Children 3-10 years

Adolescents 10-18 years

Women 18-45 years

Men 18-45 years

Other adults 45-65 years

Elderly and very elderly

65 years and over

Exposure

level

Oral

Dust &

Toys

0.009

0.015

0.009

0.015

0.009

0.015

0.009

0.015

0.007

0.012

0.003

0.005

0.002

0.003

0.0006

0.001

0.0006

0.001

0.0006

0.001

0.0006

0.001

Sum of

non-dietary

0.009

0.015

0.009

0.015

0.009

0.015

0.009

0.015

0.007

0.012

0.064

0.445

0.13

1.068

0.084

0.675*

0.084

0.675

0.084

0.675*

0.084

0.675*

* It is assumed that the dermal exposures as expressed as equivalent oral doses for the age group men 18-45 years also are

representative for the age groups women 18-45 years, other adults 45-65 years, and elderly and very elderly 65 years and

over, assuming that the toxicokinetics are not significantly different between these age groups.

Comparison of the estimates for high dietary exposure for all age groups with the t-TDI of 4 µg/kg bw

per day showed that the dietary exposure in all age groups (including the most exposed groups, i.e. 6-

12 months infants and toddlers with levels of 0.857 µg/kg bw per day) was more than 4-fold below the

t-TDI, indicating no health concern from dietary exposure alone. The additional contribution from

other oral sources, like dust and toys mouthing (high exposure up to 0.015 µg/kg bw per day), did not

change this conclusion.

Comparison of the aggregated estimates for exposure to dietary and non-dietary sources of “children

3-10 years” and adolescents with the t-TDI showed that even when the high exposure estimates for

dietary and non-dietary sources are combined, the aggregated exposure for children 3-10 years

(0.813 + 0.445 = 1.258 µg/kg bw per day) and adolescents (0.381 + 1.068 = 1.449 µg/kg bw per day)

will be approximately 3-fold below the t- TDI.

The aggregated high dietary and non-dietary exposures (including oral and dermal sources) for women

(0.388 + 0.675 = 1.063 µg/kg bw per day) and men (0.335 + 0.675 = 1.010 µg/kg bw per day) are

mostly identical and they are lower than those for adolescents and children 3-10 years. The CEF Panel

considered that the exposure estimates (up to approximately 1 µg/kg bw per day) for men and for

women including pregnant women and prenatally exposed children, will be approximately 4-fold

below the t-TDI of 4 µg/kg bw per day.

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Having evaluated the overall uncertainty of this assessment, the upper bound of the uncertainty

interval for dietary BPA exposure alone did not exceed the t-TDI for any age group. Upper bounds for

the uncertainty of high but not average aggregate exposure estimates to BPA exceed the t-TDI but the

lower bounds are considerably lower than the t-TDI. The wide uncertainty intervals are caused by

uncertainty about the magnitude of external exposure to BPA from thermal paper, about the proportion

of the amount of BPA which is absorbed through the skin, and about the choice of PBPK model for

converting dermal exposures to oral equivalents.

VERALL CONCLUSIONS

The CEF Panel concludes that the dietary exposure to BPA for the highest exposed groups, which

includes infants, children and adolescents, is below the t-TDI of 4 µg/kg bw per day, indicating that

there is no health concern for BPA at the estimated levels of exposure. These conclusions also apply to

prenatally exposed children and to the elderly.

In addition, the CEF Panel concludes that the central estimates for aggregated exposure to BPA via the

dietary and non-dietary sources (dust, toys, cosmetics and thermal paper) for the highest exposed

groups, which includes infants, children and adolescents, is also below the t-TDI of 4 µg/kg bw per

day, indicating that the health concern for BPA is low at the estimated levels of exposure. However,

the CEF Panel noted that there is a considerable uncertainty in the exposure estimate for the non-

dietary sources.

ECOMMENDATIONS

Reflecting the uncertainties surrounding this risk assessment of BPA as outlined in the previous

Section, the CEF Panel considers that further research in the following areas would be useful:



Further work to refine the Human Equivalent Dose approach used in this opinion to

extrapolate from experimental results in animals to humans, including further refinement

of the toxicokinetics of unconjugated BPA in mice

Further refinement of the human PBPK modelling applied in the opinion

Further studies on the frequency and extent of dermal contact with BPA containing

materials

Further studies on the extent of dermal absorption following exposure to BPA by the

dermal route in humans and the toxicokinetics of BPA following dermal absorption in

humans and experimental animals.

Mechanistic studies in the kidney to determine the mode of action of BPA in this organ

Further research on the significance of proliferative and morphological changes in

mammary gland following exposure to BPA and the possible relevance for the

development of breast cancer

Further research on the potential adverse health effects of BPA for which there are

uncertainties and that were therefore not definitely considered as “likely” in this opinion,

in particular reproductive, neurobehavioural, immunological and metabolic endpoints,

using validated, robust methodology

Further investigations designed to explore the occurrence of non-monotonic dose

responses following in vivo exposure to BPA

Investigations to clarify the extent and the sources of unconjugated BPA in meat and fish



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