Bisphenol A and Regulatory Implications Jason Aungst, Ph.D. Division of Food Contact Notifications (DFCN) Office of Food Additive Safety Center for Food Safety and Applied Nutrition U.S. Food and Drug Administration Presented at the Keller & Heckman 12 th Annual Food Packaging Law Seminar, Crystal City Marriott, Arlington, VA. Oct. 24,2012
Disclaimer The findings and conclusions in this presentation have not been formally disseminated by the FDA and should not be construed to represent any agency determination or policy.
Current Inventory of FCN Program As of October 17, 2012 ● Total No. of FCNs 1236 ● No. of Effective FCNs 941 ● No. of FCNs Withdrawn 273 ● No. of FCNs Not Accepted 9 ● No. of FCNs Superceeded by a New FCN 11 ● No. of FCNs Currently under review 22
FCNs Received by FY • FY 2000 103 120 • FY 2001 81 • FY 2002 106 100 • FY 2003 84 80 • FY 2004 84 • FY 2005 111 60 • FY 2006 114 40 • FY 2007 105 20 • FY 2008 76 0 • FY 2009 78 2000 2002 2004 2006 2008 2010 2012 • FY 2010 96 • FY 2011 90 • FY 2012 107
PNCs Received by FY 140 • FY 2002 41 120 • FY 2003 91 • FY 2004 107 100 • FY 2005 92 80 • FY 2006 106 • FY 2007 106 60 • FY 2008 80 40 • FY 2009 110 • FY 2010 130 20 • FY 2011 130 0 • FY 2012 112 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
DFCN updates from 2011 • Packaging Factors – Consumption and food type distribution factors – Data mining in progress, report will give picture of 2012 food packaging • High pressure processing and migration – Near completion • Diffusion modeling for high barrier films, e.g., PET, Nylon-6, other – In progress, data to be published
FDA regulatory activities on BPA Bisphenol A: http://www.fda.gov/Food/FoodIngredientsPackaging/ucm166145.htm • Monomer found in polycarbonate and as an component for some food-contact substances, such as can coatings and certain resins. • Early 1960s: first authorized by FDA • August 2008: FDA draft safety assessment • October 2008: FDA science board subcommittee review • August and November 2009: FDA “low-dose” updates to the assessment 7
• April 2010: CFSAN documents available for public comment (www.regulations.gov, Docket ID: FDA-2010-N- 0100) • January 2010, March 2012: FDA issued interim updates – “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.” – “FDA is pursuing additional studies to address the uncertainties in the findings” and “supporting reasonable steps to reduce human exposure to BPA” 8
• March 2012: Denied a citizen petition requesting (1) FDA initiate rulemaking to prohibit the use of BPA in human food and packaging, and (2) revoke all food additive regulations that may result in BPA becoming a component of food. – Response available at www.regulations.gov, Docket ID FDA- 2008-P-0577. – Response letter provided background on FDA’s framework for safety evaluation of BPA and an evaluation of additional studies not included in previous assessments 9
• July 2012: In response to a food additive petition, FDA amended its food additive regulations to no longer provide for the use of polycarbonate (PC) resins in infant feeding bottles (baby bottles) and spillproof cups (sippy cups) because these uses have been abandoned (77 FR 41899 (2012 -07-17)). – Petition not related to safety or safety related questions. NOT A BAN. • July 2012: Accepted for review a food additive petition proposing to amend the food additive regulations to no longer provide for the use of BPA-based epoxy resins as coatings in packaging for infant formula because these uses have been abandoned (77 FR 41953 (2012 -07- 17)). – Petition not related to safety or safety related questions 10
Current activities: – continue to consult with other expert agencies in the federal government – continue to monitor the science on the substance or products regulated – conduct studies on the safety of low doses of BPA, including assessment of the novel endpoints where concern have been raised – Provide public updates as significant new information becomes available 11
Research activities at FDA’s National Center for Toxicological Research (NCTR) 12
Pharmacokinetics of BPA: oral (and non-oral) routes of administration • Oral administration results in rapid metabolism of BPA to an inactive form in rodents and primates. • Primates of all ages were effectively metabolize and excrete BPA much more rapidly and efficiently than rodents. • The level of the active form of BPA passed from rodent mothers to fetus is so low it could not be measured. • Data used to develop a physiologically based pharmacokinetic (PBPK) model that can be used to predict the level of internal exposures . 13
Toxicological studies Rodent subchronic study • Characterize guideline-based endpoints, and potential effects in the prostate, mammary glands, metabolic changes, and cardiovascular endpoints • Dosing from in utero (maternal gavage) to completion of study including direct neonatal administration • Broad BPA dose range: 2.5 – 2,700 μg/kg bw/day, 100 and 300 mg/kg bw/day • 2 doses of reference estrogen (ethinyl estradiol) • Preliminary results were presented at the 2012 Society of Toxicology Annual Meeting Rodent behavioral/neuroanatomical pilot studies • Uses animals and tissues from the subchronic study • Evaluate possible effects of exposure to BPA during development 14
NIEHS/NTP FDA/NCTR CLARITY-BPA Study • NTP-funded 2-year core BPA toxicity study in rats – Developmental exposure included – Broad BPA dose range: 2.5 – 25,000 μg/kg bw/day – 2 doses of reference estrogen (ethinyl estradiol) – Standard chronic toxicity endpoints, 1 and 2 year necropsies • Consortium: 12 NIEHS-funded investigators – Grants selected after NIEHS study section review and feasibility review – Range of molecular, structural, and functional endpoints – Endpoints related to reported effects of BPA in animal models or associations in epidemiological studies • Start of dosing: August 2012 15
Next Steps for BPA • Continue to monitor the science on the substance or products regulated • NCTR studies will be published and assessed in FDA’s ongoing review of BPA • Provide public updates as significant new information becomes available • CLARITY-BPA study represents a potential new model for possible use in collaboration with regulatory agencies to fill knowledge gaps and inform a safety assessment • FDA will continue to engage with other federal and international agencies in monitoring the state of the science concerning BPA 16
Food contact materials for infants Background:January 2010 FDA risk management update on BPA – supporting 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
Infants are not “little adults” – Unique population – Developmental, physiological, toxicological differences – Sole source consumption – not typical of food contact materials – Mass of food consumption and body mass different as compared to an adult • Infant formula contact materials as example
Exposure • Pediatricians recommend formula (or breastmilk) as sole-source nutrition until 6 months of age. • NHANES data for 6 month old = highest consumption (0.9 kg/day) to body weight (6.3 kg) ratio Safety testing tiers • Current guidance tiers listed as ppb or µg/person/day based on adult bw and consumption – µg/kg bw/d is independent of age and more relevant to toxicological testing Estimated Daily Dietary Intake tiers (EDI in EDI Tier Values Concentration tiers μg/person/day) - (μg/kg bw/day) (ppb) Adult 0.5 1.5 0.025 50 150 2.5 1000 3000 50
Considerations in identifying a potential safety concern or need for additional information • Do the available toxicity data (or lack thereof) or chemical structure suggest a concern for developmental toxicity, e.g., neurotoxicity, nephrotoxicity, immunotoxicity, reproductive toxicity, or other endpoints? • What, if any, positive endpoints identified in a juvenile or adult animal toxicity study might be expected to result in a different effect or change in magnitude or sensitivity of effect in a neonate? • What other data may be useful in informing age- or species-dependent differences, e.g., ADME, MOA, PK/PD, TK/TD? • Do the available data/testing address the concern identified? Can the available information address the variability or differences between infants and adults? • For uncertainties in data interpretation or if additional testing is determined necessary, may consider the DFCN prenotification consultation (PNC) process for guidance.
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