Bisphenol A (BPA): Use in Food Contact Application

Update on Bisphenol A (BPA) for Use in Food Contact Applications

January 2010; Updated March 30, 2012

• Overview
• Background
• FDA's Current Perspective on BPA
• Additional Studies
• Public Comment and Next Steps for FDA's Assessment of BPA
• Interim Public Health Recommendations
• The Regulatory Framework for BPA
• Collaboration with International Partners

• Original January 2010 update available in PDF (52KB).

Overview

Bisphenol A (BPA) is an industrial chemical that has been present in many hard plastic bottles and metal-based food and beverage cans since the 1960s.

Studies employing standardized toxicity tests have thus far supported the safety of current low levels of human exposure to BPA. However, on the basis of results from recent studies using novel approaches to test for subtle effects, both the National Toxicology Program at the National Institutes of Health and FDA have some concern about the potential effects of BPA on the brain, behavior, and prostate gland in fetuses, infants, and young children. In cooperation with the National Toxicology Program, FDA’s National Center for Toxicological Research is carrying out in-depth studies to answer key questions and clarify uncertainties about the risks of BPA.

In the interim:

• FDA is taking reasonable steps to reduce human exposure to BPA in the food supply. These steps include:
  • supporting the industry’s actions to stop producing BPA-containing baby bottles and infant feeding cups for the U.S. market;
  • facilitating the development of alternatives to BPA for the linings of infant formula cans; and
  • supporting efforts to replace BPA or minimize BPA levels in other food can linings.
• FDA is supporting a shift to a more robust regulatory framework for oversight of BPA.
• FDA is seeking further public comment and external input on the science surrounding BPA.

FDA is also supporting recommendations from the Department of Health and Human Services for infant feeding and food preparation to reduce exposure to BPA.

FDA is not recommending that families change the use of infant formula or foods, as the benefit of a stable source of good nutrition outweighs the potential risk from BPA exposure.

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Background

BPA is an industrial chemical used to make a hard, clear plastic known as polycarbonate, which has been used in many consumer products, including reusable water bottles. BPA is also found in epoxy resins, which act as a protective lining on the inside of metal-based food and beverage cans. These uses of BPA are subject to premarket approval by FDA as indirect food additives or food contact substances. The original approvals were issued under FDA’s food additive regulations and date from the 1960s.

Studies employing standardized toxicity tests used globally for regulatory decision making thus far have supported the safety of current low levels of human exposure to BPA.[1] However, results of recent studies using novel approaches and different endpoints describe BPA effects in laboratory animals at very low doses corresponding to some estimated human exposures.[2] Many of these new studies evaluated developmental or behavioral effects that are not typically assessed in standardized tests.

The National Toxicology Program Center for the Evaluation of Risks to Human Reproduction, part of the National Institutes of Health, completed a review of BPA in September 2008.[3] The National Toxicology Program uses five different terms to describe its level of concern about the different effects of chemicals:  negligible concern, minimal concern, some concern, concern, and serious concern.[4]

In its report on BPA, the National Toxicology Program expressed “some concern for effects on the brain, behavior, and prostate gland in fetuses, infants, and children at current human expo¬sures to bisphenol A.”[5] The Program also expressed “minimal concern for effects on the mammary gland and an earlier age for puberty for females in fetuses, infants, and children at current human exposures to bisphenol A” and “negligible concern” for other outcomes.[6]

The National Toxicology Program does not make regulatory recommendations. With respect to neurological and developmental outcomes of BPA, the Program stated that “additional research is needed to more fully assess the functional, long-term impacts of exposures to bisphenol A on the developing brain and behavior.”[7] The Program also stated:

Overall, the current literature cannot yet be fully inter¬preted for biological or experimental consis¬tency or for relevance to human health. Part of the difficulty for evaluating consistency lies in reconciling findings of different studies that use different experimental designs and different specific behavioral tests to measure the same dimension of behavior.[8]

In August 2008, prior to the release of the final National Toxicology Program report, FDA released a document entitled Draft Assessment of Bisphenol A for Use in Food Contact Applications.[9] This draft assessment was then reviewed by a Subcommittee of FDA’s Science Board, which released its report at the end of October 2008.[10]

Since that time, the Center for Food Safety and Applied Nutrition (CFSAN) within FDA has reviewed additional studies of low-dose toxicity cited by the National Toxicology Program and the Science Board Subcommittee as well as other such studies that have become available. The Center then prepared a document entitled Bisphenol A (CAS RN. 80-05): Review of Low Dose Studies,dated August 31, 2009. In the fall of 2009, FDA’s Acting Chief Scientist asked five expert scientists from across the federal government to provide independent scientific evaluations of this document. In April 2010, FDA made the CFSAN documents available for public comment, and also made public the independent scientific evaluations.

FDA is continuing to consider the low dose toxicity studies of BPA as well as other recent peer-reviewed studies related to BPA. At this stage, FDA is explaining its current perspective on BPA, its support for further studies, its establishment of a public docket for its assessment of BPA use in food contact applications, its interim public health recommendations, its view of the appropriate regulatory framework for BPA use in food contact applications, and our collaborations with international partners.

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FDA’s Current Perspective on BPA

At this interim stage, FDA shares the perspective of the National Toxicology Program that recent studies provide reason for some concern about the potential effects of BPA on the brain, behavior, and prostate gland of fetuses, infants and children. FDA also recognizes substantial uncertainties with respect to the overall interpretation of these studies and their potential implications for human health effects of BPA exposure. These uncertainties relate to issues such as the routes of exposure employed, the lack of consistency among some of the measured endpoints or results between studies, the relevance of some animal models to human health, differences in the metabolism (and detoxification) of and responses to BPA both at different ages and in different species, and limited or absent dose response information for some studies.

FDA is pursuing additional studies to address the uncertainties in the findings, seeking public input and input from other expert agencies, and supporting a shift to a more robust regulatory framework for oversight of BPA to be able to respond quickly, if necessary, to protect the public.

In addition, FDA is supporting reasonable steps to reduce human exposure to BPA, including actions by industry and recommendations to consumers on food preparation. At this time, FDA is not recommending that families change the use of infant formula or foods, as the benefit of a stable source of good nutrition outweighs the potential risk of BPA exposure.

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Additional Studies

FDA supports additional studies, by both governmental and non-governmental entities, to provide additional information and address uncertainties about the safety of BPA. 

FDA’s Studies.  FDA’s CFSAN and FDA’s National Center for Toxicological Research has been and continues to pursue a set of studies on the exposure to dietary BPA and the safety of low doses of BPA, including assessment of the novel endpoints where concerns have been raised.  These include studies pursued in collaboration with the National Toxicology Program and with support and input from the National Institute for Environmental Health Sciences.

Recent evaluation by the FDA’s CFSAN has:

• Determined that exposure to dietary BPA for infants, the population of most potential concern, is less than previously estimated. The initial FDA exposure estimates were 0.185 micrograms/kg-bw/day for adults and 2.42 micrograms/kg bw/day for infants. The new estimate of average dietary exposure, based on increased data collection, is 0.2-0.4 micrograms/kw-bw/day for infants and 0.1-0.2 micrograms/kg-bw/day for children and adults.

Recent research studies pursued by FDA’s National Center for Toxicological Research have[11-17]:

• Found evidence in rodent studies that the level of the active form of BPA passed from expectant mothers to their unborn offspring, following oral exposure, is so low it could not be measured. The study orally dosed pregnant rodents with 100-1000 times more BPA than people are exposed to through food, and could not detect the active form of BPA in the fetus 8 hours after the mother's exposure.
• Demonstrated that oral BPA administration results in rapid metabolism of BPA to an inactive form. This results in much lower internal exposure of aglycone BPA (i.e., the active form) than what occurs from other routes of exposure such as injection. Primates of all ages were also found to effectively metabolize BPA to its inactive form and excrete it much more rapidly and efficiently than rodents, thus reducing concerns about results from some rodent studies using oral and, particularly, non-oral exposures which result in higher actual internal exposures of rodents than of primates, including humans, exposed to the same dose.
• Developed a physiologically based pharmacokinetic model which can be used to predict the level of internal exposure to the active  and inactive forms of BPA. This model allows comparisons of internal exposure across different ages and routes of exposure (e.g., oral and intravenous routes).  Based on the effects of metabolism, internal exposures to aglycone BPA following oral administration are predicted to be below 1% or less of the total BPA level administered.

The FDA’s National Center for Toxicological Research is continuing with additional studies, including:

• Rodent subchronic studies which are in progress to characterize potential effects, and, where observed, the dose-response relationship in the prostate and mammary glands for orally administered BPA.  In addition, these studies will explore other issues including potential effects of BPA on metabolic changes and cardiovascular endpoints.  These studies will include an in utero phase, mimic bottle feeding in neonates, and employ a dose range that will cover the low doses where effects have been previously reported in some animal studies, as well as higher doses where estrogenic effects have been measured in guideline oral studies. Results from this study are expected to be available to FDA to inform the agency’s decision making starting in 2012.

• Rodent behavioral/neuroanatomical pilot studies which are also already in progress as part of the sub-chronic study to characterize dose levels at which behavioral, neuroanatomical, neurochemical and hormonal endpoints may be affected by developmental exposure to BPA.  These data are intended to evaluate possible effects of exposure to BPA during development that have been reported in some published studies on sexually dimorphic behavioral endpoints such as anxiety, as well as on standard developmental neurotoxicity tests.  Results from these studies are expected to be available to FDA to inform the agency’s decision making starting in 2012.

Other Studies.  Other studies on the safety of BPA are also underway.  For example, the National Toxicology Program/Food and Drug Administration (NTP/FDA) will conduct a long-term toxicity study of BPA in rodents to assess a variety of endpoints including novel endpoints where concerns have been raised. NTP/FDA will collaborate with the National Institute of Environmental Health Sciences by providing animals and tissues to a consortium of researchers with interest in studying a variety of additional toxicological areas.  

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Public Comment and Next Steps for FDA’s Assessment of BPA

On April 5, 2010 the FDA  opened a public docket (FDA-2010-N-0100) for comment on BPA.  The docket contains the Center for Food Safety and Applied Nutrition’s review of the low dose toxicity studies and recently published studies, the five expert reviews, other relevant material, and public comments.

FDA will also continue to consult with other expert agencies in the federal government, including the National Institutes of Health (and National Toxicology Program), Environmental Protection Agency, Consumer Product Safety Commission, and the Centers for Disease Control and Prevention. 

Based on this outside input and the results of new studies, FDA will update its assessment of BPA and will be prepared to take additional action if warranted.  As the scientific field is evolving rapidly, FDA anticipates providing further updates on BPA to the public as significant new information becomes available.

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Interim Public Health Recommendations

At this interim stage, FDA supports reasonable steps to reduce exposure of infants to BPA in the food supply.  In addition, FDA will work with industry to support and evaluate manufacturing practices and alternative substances that could reduce exposure to other populations.

Infants.  Infants are a potentially sensitive population for BPA because (1) their neurological and endocrine systems are developing; and (2) their hepatic system for detoxification and elimination of such substances as BPA may be immature.

• FDA is supporting the industry’s actions to stop producing BPA-containing bottles and infant feeding cups for the U.S. market. FDA understands that the major manufacturers of these products have stopped selling new BPA-containing bottles and infant feeding cups for the U.S. market. Glass and polypropylene bottles and plastic disposable “bag” liners have long been alternatives to polycarbonate nursing bottles.  

• FDA is facilitating the development of alternatives to BPA for the linings of infant formula cans.  FDA has already noted increased interest on the part of infant formula manufacturers to explore alternatives to BPA-containing can linings, and has received notifications for alternative packaging.  The agency is supporting efforts to develop and use alternatives by (1) working with manufacturers regarding the regulatory status and safety of alternative liners; (2) giving technical assistance to those wishing to prepare applications for approval of alternatives; and (3) expeditiously reviewing any such new applications for alternatives. Because reliable can lining materials are a critical factor in ensuring the quality of heat processed liquid infant formula, safe replacement of such materials requires not only that they both be safe for food contact but also allow for processing that is fully functional in protecting the safety and quality of the infant formula itself. 

The American Academy of Pediatrics and other health authorities recommend breastfeeding as the optimal nutrition for infants.  Infant formula, including infant formula packaged in cans, is a safe and acceptable alternative that provides known nutritional benefits and prevents life-threatening nutritional deficiencies. 

FDA is not recommending that families change the use of infant formula or foods, as the benefit of a stable source of good nutrition outweighs the potential risk of BPA exposure. 

Other Advice.  FDA is supporting recommendations by the Department of Health and Human Services for infant feeding and food preparation to reduce exposure to BPA.

The Regulatory Framework for BPA

Current BPA food contact uses were approved under food additive regulations issued more than 40 years ago.  This regulatory structure limits the oversight and flexibility of FDA.  Once a food additive is approved, any manufacturer of food or food packaging may use the food additive in accordance with the regulation.  There is no requirement to notify FDA of that use. For example, today there exist hundreds of different formulations for BPA-containing epoxy linings, which have varying characteristics.  As currently regulated, manufacturers are not required to disclose to FDA the existence or nature of these formulations.  Furthermore, if FDA were to decide to revoke one or more approved uses, FDA would need to undertake what could be a lengthy process of rulemaking to accomplish this goal.

Since 2000, FDA has regulated new food contact substances through the Food Contact Notification Program.  Under this program:

• FDA receives notification from each manufacturer of the basis for the safe use of a food contact substance, detailing the conditions of the substance’s use, allowing the agency and public to know how much is being used, and for what applications;

• FDA can work with individual manufacturers to minimize exposure if a potential or actual safety concern is identified after approval;

• FDA can require the submission of additional safety and exposure data from individual manufacturers to address a significant safety concern;

• FDA can require additional studies by individual manufacturers to address a significant safety concern;  and

• If FDA were to reach a conclusion that revocation of one or more approved uses is justified, FDA could quickly protect the public by revoking the use through a notice published in the Federal Register.

Given concern about BPA, and the ongoing evaluation of and studies on its safety, FDA believes that the more modern framework is more robust and appropriate for oversight of BPA than the current one.

FDA will encourage manufacturers to voluntarily submit a food contact notification for their currently marketed uses of BPA-containing materials.

In addition, FDA will explore additional options to regulate BPA under the more modern framework.

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Collaboration with International Partners

FDA will continue to participate in discussions with our international regulatory and public health counterparts who have also been engaged in assessing the safety of BPA. 

For example, FDA has participated with Health Canada in encouraging industry efforts to refine their manufacturing methods for the production of infant formula can linings to minimize migration of BPA into the formula. 

In addition, FDA actively supported and participated in the Expert Consultation on BPA convened by World Health Organization and the Food and Agriculture Organization of the United Nations on November 2-5, 2010, in Ottawa, Canada. Information about this expert consultation and the report of the meeting is available from the WHO web site .

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[1]See, e.g., European Food Safety Authority.  Toxicokinetics of Bisphenol A, Scientific Opinion of the Panel on Food additives, Flavourings, Processing aids and Materials in Contact with Food, Adopted 9 July 2008 , The EFSA Journal 2008.

[2]See, e.g. vom Saal FS, Akingbemi BT, Belcher SM et al. Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure, Reproductive Toxicology 2007;24:131-8.

[3]NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Bisphenol A, NIH Publication No. 08-5994, September 2008.

[4]Ibid, page 6.

[5]Ibid.

[6]Ibid.

[7]Ibid, page 20.

[8]Ibid.

[9]U.S. Food and Drug Administration, Draft Assessment of Bisphenol A for Use in Food Contact Applications, 14 August 2008.

[10]FDA Science Board Subcommittee on Bisphenol A.  Scientific Peer-Review of the Draft Assessment of Bisphenol A for Use in Food Contact Applications, 31 October 2008. 

[11]Doerge D.R., Twaddle N.C., Woodling K.A., Fisher J.W.  Pharmacokinetics of bisphenol A in neonatal and adult rhesus monkeys, Toxicology and Applied Pharmacology 2010; 248: 1–11.

[12]Doerge D.R., Twaddle N.C., Vanlandingham M., Fisher J.W. Pharmacokinetics of Bisphenol A in neonatal and adult CD-1 mice: Inter-species comparisons with Sprague-Dawley rats and rhesus monkeys, Toxicology Letters 2011; 207: 298– 305.

[13]Doerge D.R., Twaddle N.C., Vanlandingham M., Brown R.P., Fisher J.W. Distribution of bisphenol A into tissues of adult, neonatal, and fetal Sprague–Dawley rats, Toxicology and Applied Pharmacology 2011; 255: 261–270. 

[14]Doerge D.R., Vanlandingham M., Twaddle N.C., Delclos K.B. Lactational transfer of bisphenol A in Sprague–Dawley rats, Toxicology Letters 2010; 199: 372–376. 

[15]Twaddle N.C., Churchwell M.I., Vanlandingham M., Doerge D.R. Quantification of deuterated bisphenol A in serum, tissues, and excreta from adult Sprague Dawley rats using liquid chromatography with tandem mass spectrometry, Rapid Communications in Mass Spectrometry 2010; 24: 3011–3020.

[16]Doerge D.R., Twaddle N.C., Vanlandingham M., Fisher J.W. Pharmacokinetics of bisphenol A in neonatal and adult Sprague-Dawley rats, Toxicology and Applied Pharmacology 2010; 247: 158–165.

[17]Fisher J.W., Twaddle N.C., Vanlandingham M., Doerge D.R.  Pharmacokinetic Modeling:  Prediction and Evaluation of Route Dependent Dosimetry of Bisphenol A in Monkeys with Extrapolation to Humans, Toxicology and Applied Pharmacology 2011; 257; 122-136.