Update on Bisphenol A for Use in Food Contact Applications U.S. Food and Drug Administration January 2010

Overview

Bisphenol A (BPA) is an industria l chemical that has been presen t in many hard plastic bottles

and metal-based food and bevera ge cans since the 1960s.

Studies employing standardized toxi city tests have thus far suppor ted 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, bot h the National Toxicology Program at the National

Institutes of Health and FDA have some concern about the potential effect s 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 Toxicologi cal 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 hum an exposure to BPA in the food supply. These steps include:

o supporting the industry’s actions to stop producing BPA-containing baby bottles and infant feeding cups for the U.S. market;

o facilitating the development of alternatives to BPA for the linings of infant formula cans; and

o supporting efforts to replace BPA or minimize BPA levels in other food can linings.

• FDA is supporting a shift to a more robust re gulatory framework for oversight of BPA.

• FDA is seeking further public comment a nd external input on the science surrounding

BPA.

FDA is also supporting recommendations from th e 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.

Background

BPA is an industrial chemical used to make a hard, clear plastic known as polycarbonate, which has been used in many consumer products, incl uding reusable water bottles and baby bottles. BPA is also found in epoxy resins, which act as a protective lining on the inside of metal-based food and beverage cans. Thes e uses of BPA are subject to premarket approval by FDA as

indirect food additives or food contact substances. The origin al approvals were issued under FDA’s food additive regulations and date from the 1960s.

1Studies employing standardized toxicity tests us ed globally for regulator y decision making thus far have supported the safe ty of current low levels of human exposure to BPA. 1 However, results of recent studies using novel approaches and different e ndpoints describe BPA effects in laboratory animals at very low doses corres ponding to some estimated human exposures. 2 Many

of these new studies evaluated de velopmental or behavioral effect s that are not typically assessed

in standardized tests.

The National Toxicology Program Center for the Evaluation of Risk s 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 te rms to describe its level of concern about the

different effects of chemicals: negligible concern, minimal c oncern, 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 fetuse s, infants, and children at current human exposures 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 bi s phenol 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 interpreted for biological or experimental consistency or for relevance to human health. Part of the difficulty for evaluating consistency lies in reconciling findings of different studies that use different

1 See, e.g., European Food Safety Authority. Toxicokinetics of Bisphenol A, Scientific Opinion of the Panel on Food additives, Flavouri ngs, Processing aids and Materials in Contact with Food, Adopted 9 July 2008, The EFSA Journal 2008. Available online at http://www.efsa.europa.eu/cs/BlobServer/Scie ntific_Opinion/afc_ej 759_bpa_%20toxicokinetics _op_en.pdf?ssbinary=true.

2 See, e.g. vom Saal FS, Akingbemi BT, Belc her SM et al. Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at cu rrent 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.

2experimental designs and different specific behavioral tests to measure the same dimension

of behavior. 8

In August 2008, prior to the re lease of the final National To xicology Program report, FDA

released a document entitled Draft Assessment of Bisphenol A for Use in Food Contact Applications

. 9 This draft assessment was then revi ewed by a Subcommittee of FDA’s Science Board, which released its repor t at the end of October 2008. 10

Since that time, the Center for Food Safety a nd Applied Nutrition within FDA has reviewed additional studies of low-dose toxicity cite d 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, F DA’s Acting Chief Scientist asked five expert scientists from across the federal gove rnment to provide independent scientific

evaluations of this document.

FDA is continuing to consider th e low dose toxicity studies of BP A as well as other recent peerreviewed studies related to BPA. At this st age, FDA is explaining its current perspective on BPA, its support for further studies, its intent to solicit and consider public comment before revising its assessment of BPA use in food cont act applications, its interim public health recommendations, its view of th e appropriate regulatory framewor k for BPA use in food contact applications, and our planned collabor ations with international partners.

FDA’s Current Perspective on BPA

At this interim stage, FDA shares the perspectiv e of the National Toxicolo gy Program that recent studies provide reason for some concern abou t the potential effects of BPA on the brain, behavior, and prostate gland of fetuses, infant s and children. FDA also recognizes substantial uncertainties with respect to the overall interp retation of these studies and their potential implications for human health eff ects of BPA exposure. These uncerta inties relate to issues such as the routes of exposure employed, the lack of consistency among some of the measured endpoints or results between stud ies, the relevance of some an imal 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.

8 Ibid.

9 U.S. Food and Drug Administration, Draft Assessment of Bisphenol A for Use in Food Contact Applications , 14 August 2008 (Available online at http://www.fda.gov/ohrms/dockets/AC/08/briefing/2008- 0038b1_01_02_FDA%20BPA%20Draft%20Assessment.pdf).

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 (Available online at http://www.fda.gov/ohrms/ dockets/ac/08/briefing/ 2008-4386b1-05.pdf).

3FDA is pursuing additional studie s to address the uncertainties in the findings, seeking public input and input from other expe rt agencies, and supporting a shif t 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 step s to reduce human exposure to BPA, including actions by industry and recommendations to cons umers 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.

Additional Studies

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

FDA’s Studies. FDA’s National Center for Toxicologica l Research is pursuing a set of studies on the safety of low doses of BPA, including a ssessment of the novel endpoints where concerns have been raised. These include studies pursu ed in collaboration with the National Toxicology Program and with support and input from the National Institute for Environmental Health Sciences. Depending on the results, each could influence regulatory decisions about BPA.

FDA’s studies include:

• Physiologically based pharmacokinetic modeling studies in both rodents and nonhuman primates are under way to predict internal exposure of BPA in both the free and conjugated forms, and to provide data on the magnitude of inter-individual differences.

These data will facilit ate comparisons of exposure across all stages of development and development of relationships between th e results of rodent and nonhuman primate feeding studies, and will allow comparisons of internal doses of BP A when given by oral and intravenous routes. This approach has been identified as critical in order to fully evaluate the potential human health implications of st udies that have used novel endpoints or non-oral dosing, particularly in rodents, which may metabolize BPA differently than humans. These data will also allow the agency to assess the magnitude of the potential differential exposur e (and risk) to neonates. Results from this study are expected to be available to FDA to inform the agency’s decisionmaking starting in spring

2010.

• Rodent subchronic studies are in progress to characteri ze potential eff ects, 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 cardi ovascular 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 decisionmaking starting in 2012.

4• Rodent behavioral/neuro anatomical pilot studies are also already in progress as part of the sub-chronic study to charac terize 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 this study are expected to be available to FDA to inform the agency’s decisionmaking starting in 2012.

Other Studies. Other studies on the safety of BPA are also underway. For example, the

National Institute of Environmenta l Health Sciences has recently announced that it is providing $30 million in funding to study BPA, which include s support both for FDA studies and external

grants.

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

FDA will open a public docket for comment on BPA. The docket will contain the Center for Food Safety and Applied Nutrition’s review of the low dose toxicity studies and recently published studies, the five expert reviews, and other relevant material. The agency welcomes comments on these documents, other available ev idence, and the agency’s regulatory options. This docket will be open for public comment for 60 days.

FDA will also continue to consult with othe r expert agencies in the federal government, including the National Institutes of Health (a nd National Toxicology Program), Environmental Protection Agency, Consumer Product Safety Co mmission, 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.

Interim Public Health Recommendations

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

Given that these are preliminary steps being taken as a precaution, it is important that no harmful changes be made in food packaging or consum ption, whether by industry or consumers, that could jeopardize either food safety or reduce access to and intake of food needed to provide good nutrition, particularly for infants.

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 is immature.

5• FDA is supporting the industry’s actions to stop producing BPA-cont aining bottles and infant feeding cups for the U.S. market. FDA understands that over the past year, 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 alte rnatives 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 inte rest 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 manufact urers regarding the re gulatory status and safety of alternative liners; (2) giving tec hnical assistance to those wishing to prepare applications for approval of alternatives; a nd (3) expeditiously re viewing any such new applications for alternatives. Because reliable can lining materials are a critical factor in ensuring the quality of heat pr ocessed 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 protec ting the safety and qua lity 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 benefi ts and prevents lifethreatening nutritiona l 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 Populations. With respect to uses of BPA in packaging of food intended for other populations, FDA will support changes in food can linings and manufacturing to replace BPA or minimize BPA levels where the changes can be accomplished while still protecting food safety and quality. FDA will support efforts to develop alternatives for other can lining applications similar to those which are already being tested for liquid infant formula packaging. Reliable can lining materials are a critical f actor in ensuring the quality of heat processed foods. Therefore, FDA will work to encourage and facilitate changes that minimize exposure to BPA and avoid other adverse impacts on food safety or quality.

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

The Regulatory Framework for BPA

Current BPA food contact uses we re approved under food additive regulations issued more than 40 years ago. This regulatory structure limits the oversight and flexibil ity 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 requirem ent to notify FDA of that use. For example,

67 today there exist hundreds of different formul ations for BPA-containing epoxy linings, which have varying characteristics. As currently regulated, manufacturer s are not required to disclose

to FDA the existence or nature of these formula tions. Furthermore, if FDA were to decide to revoke one or more approved us es, FDA would need to undertake what could be a lengthy process of rulemaking to accomplish this goal.

Since 2000, FDA has regulated new food cont act 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 bei ng 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 si gnificant safety concern;

• FDA can require additional studies by indivi dual 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 evaluati on 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 no tification for their currently marketed uses of BPA-containing materials.

In addition, FDA will explore additional opti ons to regulate BPA under the more modern

framework.

Collaboration with International Partners

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

For example, FDA has participated with Health Ca nada in encouraging indus try 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 is planning to support and participate in an upcoming planned Expert Consultation on BPA to be convened by Wo rld Health Organization and the Food and Agriculture Organization of the United Nations. Information about this expert consultation is

available from the WHO web site: http://www.who.int/foodsafety/fs_management/infosan_archives/en/