Bisphenol A and Regulatory Implications Jason Aungst, Ph.D. - - PowerPoint PPT Presentation

Presented at the Keller & Heckman 12th Annual Food Packaging Law Seminar, Crystal City Marriott, Arlington, VA.

• Oct. 24,2012

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

Bisphenol A and Regulatory Implications

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• No. of FCNs Withdrawn 273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

• FY 2001

81

• FY 2002

106

• FY 2003

84

• FY 2004

84

• FY 2005

111

• FY 2006

114

• FY 2007

105

• FY 2008

76

• FY 2009

78

• FY 2010

96

• FY 2011

90

• FY 2012

107

20 40 60 80 100 120 2000 2002 2004 2006 2008 2010 2012

PNCs Received by FY

• FY 2002

41

• FY 2003

91

• FY 2004

107

• FY 2005

92

• FY 2006

106

• FY 2007

106

• FY 2008

80

• FY 2009

110

• FY 2010

130

• FY 2011

130

• FY 2012

112

20 40 60 80 100 120 140 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

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• 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

• f 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”

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• 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

• f additional studies not included in previous

assessments

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• 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

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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

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Research activities at FDA’s National Center for Toxicological Research (NCTR)

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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.

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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

15

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

• r associations in epidemiological studies
• Start of dosing: August 2012

Next Steps for BPA

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• 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

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

Dietary Concentration tiers (ppb) Estimated Daily Intake tiers (EDI in μg/person/day) - Adult EDI Tier Values (μg/kg bw/day) 0.5 1.5 0.025 50 150 2.5 1000 3000 50

Considerations in identifying a potential safety concern

• r 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

• r 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.