P R O C E E D I N G S
Greeting and Housekeeping
CHEESEMAN: Good morning. I'm Mitchell Cheeseman. I am the Director of the Division of Food Contact Substance Notification Review at FDA. I just want to start by giving you a little bit of housekeeping information.
We have question cards, if you have not already received some of those. They are multicolored question cards and you can get another set down front. There is a box to place the completed cards in, if you have any questions. They are color-coded. Administrative is white. Environmental is yellow. Chemistry is pink or red and toxicology is blue. You will help us sort through the questions at lunch if you follow that scheme.
We will try to get to those questions in the afternoon. There will be questions and answers for each of the speakers speaking about guidance, also, so there should be plenty of time for discussion and feedback.
Just to go through the agenda. The morning we will spend talking about mostly administrative procedures and processes of the program followed by discussion of the guidance on each of the technical areas of chemistry, toxicology, and environmental.
There will be a morning break at 10:30, an afternoon break at 2:45 and a lunch break from 12:15 to 1:30.
In the afternoon session, we will have three workshops, one on environmental, one on chemistry matters and one on toxicology matters that will involve discussion of some more detailed topics including exposure estimation, development of environmental assessments and some new information on structure activity analysis in our toxicology review. Then we will end sometime before 5:00 with wrap-up questions.
I believe that is all I wanted to say at the beginning here so I will turn the podium over to Dr. Alan Rulis, the Director of the Office of Food Additive Safety for a few introductory remarks.
Thank you.
Statement from the Director
RULIS: Thank you, Mitch. Good morning. I am Alan Rulis. I am the Director of the Office of Food Additive Safety in the Center for Food Safety and Applied Nutrition at FDA. I would like to extend a warm welcome to everyone present including notifiers, possible notifiers, representatives of notifiers, consumer group reps and others in the room as well as FDAers who are here.
When we look back to 1997, when Congress passed the Food and Drug Administration Modernization Act, that was really a landmark period of time for us. It established, in statute, a new process for dealing with food-contact substances. In fact, it defined them as an entity and put in place a procedure for premarket notification of the use of those materials.
Of course, that statutory provision did not become active until Congress appropriated funds, which it did for Fiscal Year 2000. So, on October 1 of 1999, we had available earmarked funds for executing the program. As a result of that, we were able to start in January of 2000, January 18 of 2000, to receive, for the first time, food-contact notifications. Since then, we have been processing them.
Most recently, of course, you are aware that we have published a final rule--it became effective in June of this year--of governing the processes, the food-contact notification process, the submission-and-review process, and, as well, as final administrative guidance. Prior to that, at toxicology and chemistry guidance has been available.
So there is a lot of documentation out there. Of course, we all know that, in its pristine form, those documents can be helpful but not necessarily answer all of your questions. So this workshop is intended to provide additional guidance and help to everyone.
Over the past couple of years, since January 18 of 2000, we have converted a number of pending food-additive petitions and accepted a number of notifications and seen them go to closure such that now we have almost 300 in almost three years. Actually, when you think about that, from the perspective of somebody who saw food-additive petitions for food-contact substances going through the process years ago, and how arduous that was in many cases, that is a remarkable change and a lot of credit goes to both the industry and the government sides on this because there were advocates on both sides who worked very hard to bring into place the statutory provisions that enabled this work to go on.
As a matter of fact, I think it might not be a bad idea--there are many FDAers in this room who are, at the moment, contributing to the success of this process. We often think of our government regulators with some cynicism over the years. You hear cynical comments, but this is a group of people who are making the process work and work very efficiently for the benefit of all.
It is working efficiently for industry and it is protecting public health at the same time. I think it would be, hopefully not embarrassing too much to the FDAers in the room--to ask you all to who are in here to just raise your hands so that folks in the room can see who is available.
You see the number of FDAers in the room. These are folks in the Division of Food Contact Substance Notification Review and elsewhere in the Office of Food Additive Safety who are contributing to the success of this process. So thank you all for the work you have done and the work you will continue to do.
Even though this process has been successful, this workshop is being held in recognition of the fact that there is always improvement that can be made. We, on the FDA side, want to make the process work as efficiently as possible. We know there are gains to be made. There are ways to improve the way we do our job.
At the same time, we are aware that industry submitters of notifications can improve those notifications. There are ways to avoid mistakes, but they have to be identified and you have to be provided guidance. So the notion of this workshop, then, was born to try to bring both sides together to make the process work better.
In addition to that, I think we are open to the idea that we need to push back the boundaries of science and administration such that new ways of doing business can be seriously considered. So you are going to hear discussions today, in addition to the traditional kinds of submission of information and review of information, scientific information that we have always done over the years, you are going to hear some discussions about some of the scientific barriers that we are trying to overcome.
We will be discussing a little bit about structure activity analysis so that we can do a more efficient job of evaluating these notifications. We are open, obviously, to examining modern methods of migration testing and modeling migration in food, and even applying new and sort of barrier-breaking toxicological evaluation methodologies to this process. So, with all of that, we hope that, as time goes on, the process will become ever more efficient.
One other thing I just want to mention is that, since September, we have had an assignment--as you know, over the last year, we have reorganized the Office of Food Additive Safety. Just in the past month, we have assigned permanent directors to two of the divisions in that office and, as it turns out, we haven't made it publicly very noteworthy. We haven't made a splash in the press about it but it turns out that Mitch Cheeseman, who was up here a moment ago, is now the permanent Director of the Division of Food Contact Substance Notification Review and Dr. Francis Lin is the Deputy Director of that Division.
Those of you who follow this area and who work in this area know those two have been champions of this process and are very well suited to be senior managers in the Division. They will continue to carry the torch, so to speak, and I commend you to them and their senior management skills.
So, with that, I wish you good luck today in the workshop. It is my sincere wish that everyone finds this session helpful and, ultimately, will bring in even better notifications for us to evaluate and tune our process up so that we can more efficiently evaluate them.
With that, I will turn the microphone back to Mitch Cheeseman and send you forward. I will probably have to leave about mid-morning, but if you have any questions of me, I would be happy to try to answer them either now or before I leave.
Thank you.
CHEESEMAN: Maybe I should yield for any questions for Dr. Rulis. If not, I will go on to the purpose of the meeting.
[Presentation slides for Dr. Cheeseman are not available]Purpose and Question/Answer
CHEESEMAN: Good morning.
[Slide.]
Welcome to FDA's 2002 Food Contact Notification Stakeholder's Workshop. In honor of the season, my talk is entitled Food Contact Notification Review Process, Trick or Treat.
[Slide.]
The first thing I want to do is to give credit for a lot of the work that went into this workshop where it is due. As many of you know, I just returned a month ago to the Office of Food Additive Safety from a temporary assignment so most of the hard work of organizing this meeting was done in my absence.
In addition to all the excellent speakers that you are going to hear today, the organizational work has been done by a few individuals that I would like to recognize specifically. Among those, are Bill Trotter, Anna Shanklin and Carolyn Young who are here today. Also, I would like to recognize Sandra Varner who is the past Acting Division Director of the Division. Under her leadership, this meeting was developed and planned for the most part.
Last, but not least, I would like to recognize two of the Division support staff, Sylvia Dodson and Julie Mayer, who were helping out with registration this morning.
[Slide.]
Next, following up on Alan's mention of the reorganization and assignment of new folks, I wanted to give you a snapshot of what the Division looks like today. Francis and I are respectively the Deputy Director and Director. We have a small support staff and a vacant, at the moment, senior special assistant position under the Division Director's staff.
The remainder of the Division is broken into six teams. There are two each of regulatory teams which do primarily CSO duty, chemistry review teams that do chemistry review, and toxicology review teams. The supervisors of those teams are Arthur Lipman for the CSO team, and we do have one vacant supervisory position in that section. Some of you may have dealt with Andrew Zajak who was a supervisor in this Division up until September 22. Andy transferred, at that point, over to the Division of Petition Review and so we have listed and hope to fill shortly his previous position.
Dr. Michael Adams and Alan Bailey are the supervisors in chemistry review teams. Dr. Chingju Sheu is the current supervisor of one of the toxicology teams. Dr. Lin's promotion created a vacancy of a second supervisory position. We have, again, listed that position and hope to fill it shortly.
[Slide.]
I am going to talk a little bit about our goal today, and our goal overall. The mission of this Division is to protect the public health by effective regulation of food-contact materials. We expect to accomplish that through a couple of avenues, through informed regulation, which requires us to stay engaged with you, the industry that we regulate, as well as the public whom we serve.
Through the current and complete knowledge of the food-contact materials in the industry that we regulate, we are able to accomplish the most efficient use of the limited resources that we have.
I have mentioned before in talks, and I will mention again, that, in the absence of complete knowledge, regulatory agencies tend to make conservative assumptions or conservative decisions. So the process of staying in touch with you, the regulators, and all our other customers, ultimately pays benefits for all of us by permitting us to make more realistic estimates of consumer risk and better decisions regarding consumer protection.
Moreover, knowledgeable regulators breed confidence amongst the public in the decisions those regulators make. In addition to informed regulation, we also seek to achieve efficient review of food-contact submissions, whether they be food-contact notifications, inquiries, or prenotification consultations. We hope to make our review processes more efficient by producing better guidance, by striving to make presubmission interactions more fruitful, by continuing interactions such as this one today and by focusing our review efforts at a level that is commensurate with that likely risks of the consumer.
[Slide.]
With that goal in mind, our theme today is one of the importance of telling a complete story. Much of what we will discuss today are simple but important aspects of the food-contact notification process which, if ignored, create much more work for both you and us.
Implementation of our advice for you to tell a complete story requires each of us to try and think like the other. In many cases, where information is lacking in your submissions, we can formulate the most logical answer to our questions. However, we cannot act or make final decisions on such educated guesses so we must ask for additional information.
Being a bureaucracy, documenting and making those requests can be time-consuming, as you well know. So, in this way, providing complete information helps us to help you because we don't ask the questions that we can easily find the answers to. However, I don't want to suggest that we are offering to relieve you of your responsibility to document your safety decisions regarding notified food-contact substances. This requires a complete consideration of all migrants. Such consideration should be proportional to the likely risk and need not be exhaustive. However, it must be complete. If a substance is expected to result in an immeasurably low exposure, then often a brief, reasonable explanation of why is all we are looking for.
If the toxicity data recommendations are to supply a literature search, then the discussion of the parameters of that search, in addition to the report of no hits, is useful in determining that your safety assessment is adequate.
These are just a couple of the examples and you will hear more about that during the more specific discussions later on today.
[Slide.]
Following the advice of telling a complete story helps us get to end product that we all want and that is FDA helps you comply with the law and notify the substances that need notification and also not submit unnecessary submissions to the agency.
One of the end products is greater consumer confidence because we have a more knowledgeable regulatory agency and greater public-health assurance and, also, ultimately what you, the industry, want, greater ease in bringing innovative products to the marketplace.
[Slide.]
Today's task will be to present our guidance in an updated manner, to discuss some of the common shortcomings of food-contact notifications in relation to that guidance, to explain how we deal with different types of data such as genetic toxicity data, end-test data, things of that nature, but also, just as important, we are here to listen to your questions and to your feedback.
We held a stakeholder meeting prior to the beginning of the FCN program in March of 1999. Those of you who participated in that meeting, are aware that we listened at that meeting, that we made some changes to the program and that meeting resulted in a better program and I have great hopes for this meeting resulting in a continuing improvement of the program.
It is our hope, of course, to leave today with new ideas to improve the FCN process for both of us.
[Slide.]
Finally, I want to answer a few of your questions that have already been submitted. In our notice announcing the meeting published last month, we did offer the possibility of submitting questions in advance. We will attempt to answer those throughout the presentations this morning and in the early afternoon as appropriate.
I want to address a few of them that are purely administrative and policy-related this morning. First of all, let me assure you that the input that we have received regarding suggested revisions to Form 3480 and the administrative guidance will be seriously considered and we will act on those in conformance with FDA's good guidance practices and in conformance with the Paperwork Reduction Act.
One comment inquired into the reliability of information given by the Division during the prenotification consultation process. In particular, one question suggests that FDA has a history of, perhaps, reversing its decisions or changing its mind.
I have to say, without specifics, it is difficult respond to such questions. However, I can say that acting on specific information of this nature is an important part of my job, and of Dr. Lin's job, to insure that the guidance we give and our review practices are consistent.
I can also say from experience that, on many occasions, seemingly insignificant changes in identity, manufacturing details, and use are made by you after consultation with us. In these cases, we may have to modify our previous guidance so, again, let me go back to our theme of "tell a complete story" and add that you also need to tell us the same story each time.
Some of you have registered complaints regarding late-acknowledgment letters. I know that we have, in fact, sent out late-acknowledgment letters. You have also complained about short deadlines for submitting information to FDA.
It is difficult to deal with a general complaint like this again. I can only offer that, if you have specific problems, I hope that you will bring it to me or bring it to Francis Lin as quickly as possible so that we can act to correct the situation.
There may be some mitigating circumstances in many of these situations that drive the issuance of these letters to a later date or that require us to ask for information quicker than we might normally ask for it.
One of the comments has suggested that we incorporate into our administrative guidance a time frame of ten working days for response to requests for information in FCNs. We will be considering that change, among others, that were suggested for the administrative guidance but I believe that we can make the suggested change and I will say so today.
There was one final comment, and I am going to ask your leave to actually read it because I don't want to get it wrong, and I didn't really want to type it up into a slide for you.
"During FDA's review of FCNs, the agency frequently requests additional information. FDA sometimes accepts supplemental information and considers the date of the submission to be the date the initial information was received; i.e., the start of the 120-day review period.
"In other situations, however, FDA considers the date of receipt to be when the supplemental information was received as per 21 CFR 170.104(b)(1). Both the final rule and the administrative guidance specify that FDA will refuse to accept an FCN only if a component or element required by Section 170.101 is missing.
"We recommend that submissions of additional information in response to an FDA request should establish a new date of receipt only if the information is so significant as to render a required element of the FCN under Section 170.101 missing for purposes of Section 170.104. An element should be considered missing only when the information requested by FDA is sufficiently significant that its absence would support an objection to the FCN becoming effective or would preclude evaluation of environmental impact."
We certainly agree that, if environmental information is missing or insufficient, then that is grounds for not accepting the food-contact notification. In fact, I have spoken before in discussions of the program and stated pretty clearly that the reason for the issue of acceptance/non-acceptance was primarily the environmental portion of the food-contact notification and the fact that the environmental information was not a basis for objection. That still stands.
With regard to the interpretation of what is missing and when FDA issues a nonacceptance letter, in general, we are concerned about the date of receipt of the food-contact notification when the absent information hinders the process of the review. So, even a small deficiency in one part of the notification, if left unrectified for a period of time, will ultimately hinder the review process at some point.
What we are trying to correct in regard to resetting the receipt date is to provide us with a fair amount of time to review the food-contact notification as provided under the statute.
So, we won't totally agree with this particular interpretation. However, with regard to missing information being equivalent to information that FDA would object to, we will stick to the practice of only resetting the receipt date when the information that we are missing tends to hinder the review process from progressing.
Of course, our goal, once you tell a complete story and we give complete guidance, should be that the FCN review is a treat and not a trick.
With that, I will introduce the next speaker on our agenda, Dr. Anna Shanklin who is a consumer safety officer in the Division. She will be speaking on administrative guidance.
[See presentation slides for Dr. Shanklin]Administrative Guidance and Regulations
(FCN Background, Common Deficiencies,
Form 3480 and SOPs)
SHANKLIN: Good morning. Thanks, Mitch, for that introduction.
[Slide.]
I am Anna Shanklin. Today I will be speaking on FDA's Food Contact Notification Program, administrative guidance and regulations.
[Slide.]
In today's talk, we will have a brief introduction and look at the FCN Program from an historical and current point. Mitch and Dr. Rulis have already covered several of my points, so I will sort of run through this. We will also talk about the scope of the FCN Program. We will talk about the FCN vocabulary and review the standard operating procedures for FCNs.
We will cover a few of the administrative deficiencies that we have seen and, finally, a conclusion.
[Slide.]
Since we are part of the information age, I would like to begin by noting that OFAS has a new look on the website. This is our new web address. On this site, we have useful links and general guidance for our approval and notification programs of food ingredients and packaging.
Now, many of us wouldn't be here today if we didn't have a genuine fondness of interest in food additives, but let's begin by reviewing what a food additive is. According to Section 201(s) of the Food and Drug Cosmetic Act, the Act, the term food additive means any substance the intended use of which results or may reasonably be expected to result directly or indirectly in its becoming a component or otherwise affecting the characteristics of any food.
This includes any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting or holding of foods if such substance is not generally recognized as safe.
As you can note from the definition, we have two informal classes of food additives, direct or indirect, and a lot of our indirect additives will be our subject for today.
[Slide.]
Since FDA's mission, pure and simple, is to promote and protect the public health by bringing safe and effective products to the market and monitoring those products while they are still on the market, let's take a closer look at how FDA regulates food additives.
[Slide.]
The 1958 Amendment to the Federal Food and Drug Cosmetic Act, in addition to providing us with a definition for food additives also requires FDA approval of food additives prior to their inclusion in food, thus the term "premarket."
It also establishes the standard of review, the standard of safety and also gave us formal rulemaking procedures. As Dr. Rulis has already mentioned, in 1997, the Food and Drug Administration Modernization Act also defined the food-contact substance and established the Premarket Notification Program for food-contact substance and this is the primary method for authorizing new uses of food additives that are food-contact substances.
[Slide.]
What is a food-contact substance? Just briefly, it is any substance intended for us as a component of materials used in manufacturing, packing, packaging, transporting or holding food if such use is not intended to have any technical effect in the food.
[Slide.]
So here are examples of several types of food packaging and food-contact substances in direct food additives: coatings, and those are paper and metal; plastics, including both polymers as well as their monomeric components; paper; adhesives; and ingredients used in packaging such as colorants, antioxidants, antimicrobials.
[Slide.]
Here are some more specific examples of food-contact substances: they are substances that are used in the manufacturing of foods such as boiler-water additives for steam or ion-exchange resins commonly known as your secondary directs; constituents of food additives are also considered to be food-contact substances such as the monomers of the polymeric material; and also GRAS and prior-sanctioned substances that meet the statutory definition of a food-contact substance such as sodium sulfate and pulp used in making paper.
[Slide.]
Dr. Rulis has already covered but I will briefly run through some key events in the FCN Program. On October 22, 1999, the FCN started and we had several food-additive petitions and threshold regulations that were converted.
On November 12, 1999, FDA announced the availability of draft chemistry and Draft Chemistry and Toxicology Guidance Documents. On January 18, 2000, FDA began celebrating my birthday, as I told you, as SPI nine months prior to my arrival and that, on this day, we began accepting new notifications.
[Slide.]
Also, on July 13, of 2000, FDA published this Proposed Rule. On May 21 of this year, three documents were published in the Federal Register. They were the Final Rule, the Notice of Availability and Advanced Notice of Proposed Rulemaking.
[Slide.]
Now, as of October 7, 2002, we have approximately 291 FCNs to date. Eighty-three were converted for petitions and threshold regulations. We have 206 FCNs that are effective and 206 are also posted on our website. We have only had 48 that were withdrawn after Phase 1 review and, really only three that were withdrawn after Phase 2 review. Only one FCN was not accepted and we are currently reviewing 36 FCNs. So we are busy.
[Slide.]
Throughout this morning's talk, you will hear from all of the technical disciplines. That will give general requirements. They will also discuss some of the concerns we have, our lack of information that we have seen in our FCNs. We would like to keep in mind that guidance is available on the OFAS website.
[Slide.]
So, since our mission is not only to bring beneficial products but safe products, let's look at what a notification must contain. A notification must contain the identity of the food-contact substance, the manufacturing process and intended conditions of use, data and information that forms the basis of the notifier safety determination, environmental considerations and Form 3480.
All these criteria make for, hopefully, an acceptable FCN.
[Slide.]
This is Form 3480. The address is located on the front of the form and this is the mechanism of submission. I will briefly run through the parts of Form 3480.
[Slide.]
Part I contains general information where the person submitting as well as their representative is listed. We would like to pay special attention, if you have had a prenotification consultation, if you could list that number, we would appreciate it. Also, if you have previously submitted and FCN for this food-contact substance, we would like to see that also indicated.
Also, if there is a place on our website in the listing of effective notifications where this substance is listed maybe for another intended use, we would like to see this. Again, this is a part of our search that we do regardless, but it helps if this information is readily available.
[Slide.]
Part II is the Chemistry Section.
[Slide.]
Part III is the Toxicology Information where your safety narrative and comprehensive toxicology profile is mentioned.
[Slide.]
With that, I would like to say that one of the most essential components of the FCN is the toxicology part. The burden for demonstrating safety lies with the notifier. It is the notifier's determination that is essential here.
Actually, there was some sound that was supposed to go "boom" so that you could really feel that this is an essential component for the notifier.
[Slide.]
Also, the National Environmental Policy Act, which you will hear about later today, requires that FDA considers the environmental impact of all its actions, so Part IV contains our Environmental Section.
[Slide.]
Part V is the Certification Section. It just says that all the statements are accurate and complete that are placed in the notification. So we would like to see that sign.
[Slide.]
Attachments are in Part VI. One of the points I would like to bring out is that the attachment name, along with the page number, is clearly indicated. That also helps facilitate our review process.
[Slide.]
So, now that we have looked at Form 3480 and some of the historical aspects, let's take a closer look at the scope of the FCN Program, the whos, the whats and the whys.
[Slide.]
When should a notification be submitted? FCNs are required only for new uses of food-contact substances that are indirect food additives or substances used in the manufacture of food such as the boiler-water additives we talked about earlier.
FCNs can be used to notify FDA of new uses of food-contact substances that are not considered food additives in the definition such as constituents of food additives, GRAS and prior sanctioned substances, that these are not a requirement whereas these are a requirement.
[Slide.]
The same safety standard applies in evaluating food additives under the food-additive petition process as with the food-contact notification process. There are two cases in which FDA would warrant a food-additive petition and that is when the new use of the food-contact substance will increase the cumulative estimated daily intake of the food-contact substance to greater than or equal to 1 part per million or 3 milligrams per person per day or, in the case of a biocide, if the level is 200 parts per billion or 0.6 milligrams per person per day.
I would like to pause at this moment and stress, as is stressed in our administrative guidance, that prior to the submission of a food-additive petition, even if you meet these two cases, to please contact FDA because an FCN may be warranted under those cases, also.
[Slide.]
Who should notify? A manufacturer or a supplier of a food-contact substance may submit to FDA a notification for a new use of a food-contact substance. Now, what does supplier mean? The supplier means any person supplying the food-contact substance including the company supplying the food-contact substance to themselves for manufacture of the food-contact material.
[Slide.]
Who may rely on effective notifications? The manufacturer of the food-contact substance and anyone that can demonstrate that the food-contact substance being marketed has been manufactured or supplied by the manufacturer identified in the FCN and that it is being used under those exact intended conditions of use that are the subject of the FCN. This is important.
[Slide.]
We will briefly review some of the FCN vocabulary, receipt dates, starting the clock, withdrawal, nonacceptance and objection. The receipt date is the date indicating receipt of a complete notification. That is very important. Starting the clock. This is when the receipt date is set which indicates when the 120-day FCN review period begins. Then the clock starts. So, thus, a started clock equals complete submission received by FDA. We have had some language, resetting, starting the clock. But the clock does not officially start until we have accepted the notification.
Withdrawal; a notifier may withdraw without prejudice to a future submission at any time prior to our completion of review of their FCN.
[Slide.]
Nonacceptance; as Mitch mentioned, nonacceptance is when components are missing under 21 CFR 170.101 and, thus, it gives us incomplete submission and the notifier chooses not to withdraw the submission, then it is a nonacceptance status.
Objection; FDA recommends, due to noncompliance with general criteria for the FCN, failure to demonstrate safety under the intended conditions of use, or when 120 days of the receipt of the FCN occurs within a fiscal year when the program is inoperative.
[Slide.]
Who are our key players in the FCN process? We have the notifiers who prepare our notifications. We have our notification control assistant who is busy at work here. [Slide.]
Our review team is very essential. It consists of a toxicologist, and environmental review scientist, a chemist and a consumer-safety officer.
[Slide.]
What happens when you submit your FCN to FDA? As a notifier, when you submit your FCN, the notification control assistant receives it and she set a receipt date, the date that we received it and also 120-day target date is set. Then the notification is distributed to all the review teams, a CSO environmentalist, chemist and toxicologist.
Within three weeks, we hold what we call a Phase 1 review meeting to note whether the FCN is considered acceptable, which gives us Case A, or not acceptable, which gives us Case B. Let's review Case A first since those are the types of FCNs we like to see the most.
[Slide.]
If your notification is accepted, you will receive an acknowledgment letter and Phase 2 review will continue. If all goes well, your FCN will become effective. A final letter will be issued and a listing will be published on our website in the Inventory of Effective Notification.
However, in Phase 2 review, if we have safety concerns, the notifier has the option to withdraw or receive an objection letter. So those are the case for Case A.
[Slide.]
In Case B, if we don't accept the notification or find it unacceptable in Phase 1, the notifier receives a deficiency letter. The notifier has two choices at this point. They can either respond to the deficiencies or they can choose to withdraw. If they choose to withdraw to the deficiencies, they have up to two weeks or ten working days for us to receive the information.
If it takes more than two weeks, FDA considers the information not forthcoming. It is missing. The notification is incomplete. Thus, you receive an nonacceptance letter. However, if we do receive the information within the time frame and we don't accept it, you still have an option to withdraw or receive an nonacceptance letter.
However, if, within the two weeks, we do accept it, a new 120-day date is set if the information is substantive and it remains the same if it is not substantive and we have Case A, and you follow your notification through to listing on the website.
[Slide.]
These are just a few administrative concerns that we have seen to date. We have seen some incomplete Form 3480s, so we have to sort of look for the information which runs over or ties into organizations of the FCN. Some of the information is there, but it is not as well organized so we have to spend time looking, and someone may say, "Hey; I actually saw that information on Page 210 when maybe it should have been on Page 20."
We have seen illegible and faint copies of documents, especially or chromatograms. Timeliness of submission of additional information; we would like to see it within the ten working days. That would really help us out a lot because we don't if there has been a mailing error or if you are planning not to submit the additional information, so that would help.
Also, we have seen where we don't get sufficient copies of additional information. We get five copies of the FCN but, when you send the additional information, it is also distributed to our review team so we need extra copies for those, also.
[Slide.]
So how do we avoid some of these deficiencies? FDA wants you to come in and talk to us. We have prenotification consultations. They are interactions with you, the industry, and our office prior to your submission of an FCN. We would like to see those and they can arrive via e-mail, fax or letter.
[Slide.]
What types of prenotification consultations have we seen? We have meetings to discuss the requirements that will make for an acceptable FCN submission. Sometimes, we receive prenotification consultation information concerning the CEDI and ADI for your food-contact substance if it is not already available on our web.
I would just like to say that this website is updated every couple of months. Also, information concerning the eligibility of your substance prior it being considered for an FCN. We are here and we are willing and able to help.
[Slide.]
Now, I would like to say that we are accepting electronic submissions. However, they must meet the requirements in 21 CFR Part 11 and we also need a paper copy. They must be submitted on CD ROM or IBM-compatible disc and we are currently developing guidelines for these electronic submissions that will better aid you. But, for now, Part 21 CFR Part 11 is your bible.
[Slide.]
The Freedom of Information Act requires that all federal agencies make their information publicly available. But, for FCNs, let's take a look at what is releasable and what is not releasable. We will not release any information until the 120-day effective date has been reached. However, the notifier must remember that FDA's conclusion is made publicly available on our website in the Inventory of Effective Notifications.
What is releasable? General information, safety and functionality data and also information incorporated by reference. What is not releasable? Trade-secret and confidential commercial information is not releasable and information in withdrawn FCNs we do not release. So your withdrawn FCNs are safe with us.
[Slide.]
If you are looking for us on a Wednesday morning and we are in our Phase 1 review and you need some FCN guidance, how do you find us on the web? If you go to www.cfsan.fda.gov under Program Areas, Food Ingredients and Packaging--
[Slide.]
--if you click to us, you will come to our Approval and Notification Page. Also, if you look under Notification Programs for Food Ingredients and Packaging, you will see Food Contact Substances.
[Slide.]
This is our website. Our Inventory of Effective Notifications, you can get to there. Also, we have guidance that is available here. The CEDI/ADI database is available from this website and also some of the documents that were published in the Federal Register are also available on our website.
[Slide.]
So Form 3480 is also available and can be retrieved on our website. We are currently revising Form 3480. However, if you would like to print out the form and fill it in via typing, we recommend that you print out the PDF format. Also, we have received several of your suggestions concerning modifications that can be made to Form 3480. As Mitch stated, we are considering those. Just keep in mind that all forms have to go through OMB for approval so we are working on your suggestions.
[Slide.]
In conclusion, I would just like to briefly run over what is needed in the FCN. The comprehensive summary, which deals with our safety. The chemical identity, intended conditions of use, the intended technical effects. [Slide.]
We need to have the estimation of intake, exposure to the food-contact substance, toxicity information, environmental information and FDA form 3480 completed and signs. These are points to remember.
[Slide.]
We would also like to have five copies of the FCN and all FCNs should be submitted to the notifications control assistant at this address. Again, the address is available on the front of Form 3480.
[Slide.]
So, take-home points. Notifications for food-contact substance must contain sufficient scientific information to demonstrate that the substance of the notification is safe for the intended use for both human and environmental safety and also FDA encourages you to please come in for prenotification consultations to facilitate development of a complete FCN.
Are there any questions at this point?
CAMENISCH: Steve Camenisch with Englehard. One question around the ten-day. One of the problems that I have run into is actually getting the notice to you through Federal Express or mail. Are you all addressing that at all?
SHANKLIN: As far as safety or security, someone may want to comment, but what I have done with you in the past, and others, if I know that a Fed Ex copy is coming, I will let that serve as my hard copy, but I have accepted a fax. But, again, Mitch or Dr. Rulis may want to comment on that.
CHEESEMAN: I think accepting a fax is fine. If you are sending it via a carrier like Federal Express or UPS, you can also give us a tracking number and we can track it over the web, I think, also, if I am not mistaken.
SHANKLIN: Yes; you can track on the web. That's fine.
Yes?
BOWER: Does the ten days start when you send it or when I receive it?
SHANKLIN: It starts on the date that I send it which, again, I am not in management to make that call but usually the day that I send it is when the ten days start, because usually we send it via e-mail or fax where you readily get it. We never really send it through mail. We may send a copy of the deficiency letter through the mail, but I always make sure that, on that date, someone receives it via fax or e-mail.
CHEESEMAN: I just wanted to mention that folks should identify themselves and their affiliation when they ask a question for purposes of the transcript.
BOWER: I am David Bower from R.T. Vanderbilt Company.
SHANKLIN: Did we answer your question? The ten days start the day that I send it which usually is the day that you receive it because I am sending it through electronic media.
BOWER: Do you attach a receipt to your electronic mail so that you can document that I got it?
SHANKLIN: The notifiers, again, that I have worked with, I have always followed up to make sure that they have received the deficiencies. So we probably have to make that a part of making sure that the notifier has received the deficiencies. I do. I'm sure more CSOs do also.
Yes, sir?
SIMMONS: Ralph Simmons from Keller and Heckman. If we are filing electronically, how many paper copies do you want?
SHANKLIN: One.
SIMMONS: Just one?
SHANKLIN: One paper copy.
SIMMONS: The other; just a comment. We have, on occasion, received requests for additional information by mail only which can reach us pretty close to the ten-day period. So I guess we would just ask that there be a consistent policy of sending those by e-mail or fax.
SHANKLIN: Okay. We will make sure of that.
SIMMONS: Thanks.
SHANKLIN: Yes; Naeem?
MADY: Naeem Mady from Ciba Specialty Chemicals. In the electronic submissions, the toxicology will accept tox studies without signature electronically, if we are submitting the whole submission electronically, not just the form?
SHANKLIN: Tox doesn't really like to receive electronically. So, in those cases, I have seen where we let the ten days vary a little. Usually, if you Fed Ex it, then we sort of let the ten days vary. Whatever comes on fax, we would like to receive--we will receive it, but we would still like the hard copy especially for toxicology information.
MADY: I am just talking about not the ten days. I am talking in the original submission, if you are submitting, accepting electronically, the form, we can submit the whole submission electronically.
SHANKLIN: Yes.
MADY: Including the tox studies.
SHANKLIN: Yes.
MADY: However, there are electronic signatures because these are GLP studies. I am not sure if you would accept those electronically--what is the signature? Is it important to the agency at all?
CHEESEMAN: I am not sure we have dealt with that specific question.
SHANKLIN: JoAnn is back there for electronic signature.
CHEESEMAN: I will let JoAnn add something to this but I would suspect that Part 11 would apply to any sort of required signatures in electronic submissions.
MADY: Can I ask another question?
ZIYAD: In terms of electronic signatures, we are working on that module and we hope to have it ready by the end of October, 2003--hopefully, before that time. But, as soon as we are ready, we will let you know.
MADY: Thank you.
SHANKLIN: Just one paper copy, also, with that electronic copy, just to reiterate that.
MADY: I just have another question. I think Dr. Cheeseman mentioned that before. When we receive the final notification letter which it is not really that important as long as we know that the time came in and we did not receive a letter--it usually comes in, like, a month later, or twenty days later. However, Dr. Cheeseman mentioned that before, but I am not sure what the answer was.
When we eventually receive that letter, if there are changes from the original acceptance letter, then it causes a problem. So what I am saying is we don't mind receiving the letter on time, the final notification letter. However, it should not change, if it doesn't come on time, from the original acceptance letter.
SHANKLIN: Do you mean the final letter that you receive at the end? We are not bound to send those out, as you know, but we sort of do that as a courtesy.
MADY: I understand. But if I receive a letter twenty days after, or a month after, I submit the final-version submission and they accepted everything there, then I am already marketing the product after the 120 days because I didn't hear from the agency. Now, I am marketing the product for a month and then I get another letter saying, "We are changing the name and we are changing the CS number. That is not correct." It is an issue.
SHANKLIN: Okay. We will definitely take that under consideration. I hope that doesn't happen often, but we will take that under consideration.
CHEESEMAN: Again, I am going to have to say that bring specific problems like this to our attention. There are certainly situations where information does get changed after the acknowledgment letter. That is, in fact, the purpose of the acknowledgement letter, to work out any changes that are necessary.
But there shouldn't be any surprises in the final letter. If there are surprises in the final letter, then please bring it to our attention immediately and we will work to correct that problem.
SHANKLIN: Yes, sir?
DOWNES: My name is Jim Downs with Solutia. I have a follow-up question on your slide, when should you provide a food-contact notification? In there, you stated that, for example, if you have a GRAS substance, do you still require a food-contact notification for a new use for that?
SHANKLIN: It is not a requirement. It is just that some notifiers wish to notify us that they are using that food-contact notification that is GRAS, they are using that for that use. But it is not a requirement. You don't have to do that.
DOWNES: Thank you.
SHANKLIN: Are there any more questions?
ETTINGER: David Ettinger of Keller and Heckman. One of your slides addresses the issue of information that is disclosed by the agency. Typically, notifiers will sometimes mark portions of the notification that they deem to be confidential. If the agency disagrees with that, is it the agency's practice to notify the notifier and give them an opportunity to respond before the information is disclosed?
SHANKLIN: I have only been here two years and I have seen both cases. Sometimes, I do receive FCNs and they also have what we call redacted versions with the FCNs. Sometimes I have and sometimes I have not contacted. Some people make it a standard practice. I am quite sure we will have an administrative meeting and decide if we will make that a part of our practice.
We are not, under law, bound to do that.
CHEESEMAN: I believe that there are some exceptions to the procedure you are referring to and one of those exceptions is where there are some specific regulations describing the releasable information. That is the case, actually, for food-additive petitions, for color-additive petitions and for food-contact notifications.
So we are actually not required to discuss that in advance although, if we think that there is likely to be an issue, if we are talking about information that may be in a grey area, we sometimes do seek to discuss it.
SHANKLIN: Do you want to continue?
ETTINGER: I guess it is just a concern for most people. I am just wondering if there could be something that could be taken maybe a little more consistently and more seriously, that a phone call or a fax be sent to the notifier if that information is deemed to be disposable and the notifier claims it to be confidential.
SHANKLIN: Okay. We will definitely take that into consideration. That is one of our points and it has come up in our hallway meetings.
Are there any more questions?
[Slide.]
If not, I would like to close with some acknowledgements. I would like to acknowledge the Division of Food Contact Substance and Notification Review; also Blondell Anderson who is one of our consumer-safety officers; Art Lipman, who is my current supervisor who keeps me busy with interesting projects; Sandra Varner, who is also a great repository of information; and also Mitchell Cheeseman, who was my first supervisor when I came to FDA who actually had my first notification assigned to me even before I reached yje post.
So I would like to thank all of these.
[Slide.]
I have the pleasure of introducing our next member on the review team. If you remember our slide, we have toxicologists, environmentalists, consumer-safety officers, and we have our chemists.
[Slide.]
Our chemist will give us some guidance and take us on a little journey. Who is one of our premier chemists that will be taking us on this journey?
[Slide.]
None other than Mr. Kirk Arvidson. So, Kirk, take it away.
[See presentation slides for Dr. Arvidson]Chemistry Guidance
ARVIDSON: Good morning. Thank you for the introduction.
[Slide.]
As Anna indicated, I will be going over one of our guidance documents, the chemistry recommendations.
[Slide.]
Basically, what I am going to try to provide today is a brief overview of our chemistry recommendations. I will be covering these topics including what we recommend providing for the identity of a food-contact substance, its use, use level, and also some information on migration testing and analytical methods. I will also touch briefly on how to calculate consumer exposure to food-contact substances.
At this time, I would like to remind everybody that this afternoon we will be conducting a workshop where Dr. VanDerveer, one of my colleagues in the Chemistry Section, will be able to answer any very detailed questions about calculating exposures and any other scenarios that are of interest to you.
[Slide.]
As Anna mentioned, our guidance documents can be found by accessing the CFSAN web page. I have provided a screen shot of the CFSAN web page here. This is what you will actually see when you get to our web page.
[Slide.]
You can find our guidance documents by clicking on Food Ingredients and Packaging hyperlink, which will bring you to our OFAS web page. Down here, on the right-hand side, are our guidance documents. All three guidance documents, chemistry, administrative and toxicology are located here.
[Slide.]
As I indicated, the first topic I want to discuss today is the identity of your food-contact substance. I have arranged my talk to mirror the information provided in our guidance document and I have also included on each slide the actual section number where you will find this information in the guidance document.
As we discussed previously, you need to provide a name for your food-contact substance and we recommend providing the CAS name or a systematic name for your material. You can also provide trade names and common names for the material and other synonyms, but we do recommend that these names are not the only forms of identification. The CAS name is the best option.
We also recommend providing a CAS registry number for the food-contact substance. This serves as a verification of not only the name of the food-contact substance but also the structure that you provided in your notification. Not only do the chemists use the CAS registry number but the toxicologists also use this number to perform a variety of searches for additional information on your food-contact substance.
[Slide.]
Continuing with identity, we recommend providing the identities of all potential migrants contained in your food-contact substance and also their amounts found in your food-contact substance. These potential migrants may include any residual monomers, impurities and breakdown products that you may have from, say, quenching a catalyst in your reaction.
We also recommend providing CAS registry numbers for all of these materials. Again, we can use these numbers to verify structures, names and also search for additional information in our toxicology databases and any additional chemistry information that we may need.
We recommend providing a full description of the manufacturing information. As Anna mentioned, we do keep this material confidential. We like to see the identity of all your reagents, including catalysts. We realize these might be trade secrets. But we do like to see the identity of the catalyst and the solvents and the amounts of these materials that are charged to the reactors.
Include times and temperatures for your reactions and also any purification steps or purification aids that you use in the production of your materials.
All of this information is important. For example, we can use this information to verify your list of potential migrants. We can also use the information to estimate consumer exposure or to refine an exposure estimate that you have provided to us in your notification.
Finally, I would also like to mention that we recommend providing chemical equations for the production of your food-contact substance and any known byproducts that are in your food-contact substance.
[Slide.]
We also recommend providing some sort of spectroscopic data to identify your food-contact substance. Typically, people incorporate infrared spectra but we will accept other information such as proton, carbon-13 NMR spectra, other NMR active nuclei, and mass spectra. I believe we even accepted some Mossbauer data in a notification. But I would like to emphasize that you should make sure, when you send these spectra in, that you assign the peaks in your spectra and label them identifying what type of a spectra it is. I'll mention briefly here, please provide the structure of the food-contact substance and any of the impurities that are in your material.
[Slide.]
We also recommend providing the physical and chemical specifications for your food-contact substance. For example, if your food contact notification is for an adjuvant, you may want to include the density, boiling point, melting point, and the solubility of the adjuvant in the food simulants that you will be using.
This is not an exhaustive list, obviously, but this is just giving you the idea of the information that you may want to include in your notification.
For polymeric materials we recommend including residual levels of the monomers that are present in your food-contact substance and also any information on the molecular weight, number-average molecular weight, weight-average molecular weight. If you don't have that information, you can provide some viscosity data, inherent or relative viscosity information.
Also you should identify whether the food-contact substance is a random or a block copolymer, the tacticity of your material, crystallinity, if it is crystalline, and the percentage. Also, you should provide the glass-transition temperature for the polymer.
You may also want to consider providing a thermal gravimetric analysis of your material. There is a section in Form 3480 that you have to attest to the stability of your material under the conditions of use and TGA could be used to support your determination.
Also, we would like to see the analysis methods used to determine impurity levels in your food-contact substance and also the analysis method used to determine the concentration of the food-contact substance in a currently authorized material, if applicable. Remember to provide supporting data for these analyses
[Slide.]
Now that we have thoroughly identified your material, what is the material going to be used in, its use and use level. We recommend providing a full description of the use and the typical and maximum use levels of your food-contact substance. Also try to include any limitations that you may have for your material.
Some examples I have here are: an antioxidant that is intended to be used at 0.1 weight percent in a very specific resin or maybe you have a polymeric material that is going to have a specific use. For example, the polymer could be a coating on the inside of a can or just specifically used for production of soft-drink bottles.
We also recommend providing the maximum thickness of the food-contact article that will contain your food-contact substance and also information on whether this material is for single or repeat use. All of this information can be use to either estimate a consumer exposure or refine an exposure estimate that you have provided.
Also, we recommend providing the types of foods that your food-contact substance will come into contact with. Typically, people reference Table 1 in 21 CFR 176.170. This table gives some generic raw and processed-food types. In our guidance document, in Section II.D.1.c, we do provide a cross-reference table, which correlates those particular food categories with our recommended food simulants.
[Slide.]
We also recommend providing the conditions of use of your material. Normally, people reference Table 2 of the same regulation here. These are our standard conditions of use A. through H. I have reproduced all of them here for your reading enjoyment.
[Slide.]
Now that we know what your material is going to be used for, we recommend providing data to support that the food-contact substance actually achieves the intended technical effect that you stated the material is going to exert. We also recommend providing data to support that the use level of your food-contact substance is actually the minimum amount required to achieve your intended technical effect. This is a very important point.
[Slide.]
The next topic I would like to talk about is migration testing and analytical methods. I'll briefly describe the different types of migration cells that you could use. These descriptions are located in Section II.D.1.a of our guidance document. If you have a specific use, perhaps your resin is going to be used in soft-drink bottles you can actually formulate your soft-drink bottle and actually do the migration tests with the soft-drink bottle (i.e. place the appropriate type and amount of food simulant in the bottles and subject the bottles to the appropriate migration protocol).
Alternatively, if you have broader uses for your material, you can use a two-sided migration cell. We recommend one by Snyder and Breder. This cell is described in a reference listed in Appendix V of our guidance document.
Although this cell may not be universally applicable to every scenario, we do recommend that if you use a cell of your own design that you keep a couple of points in mind. We do recommend that the solvent should always flow freely around the plaques in your test cell. We also recommend that you minimize any headspace and also maintain an air-tight and solvent-tight seal. You don't want to lose your solvent over the extended test periods. Also, we recommend that you agitate your cell periodically.
Finally, sometimes you may need to use a single-sided migration cell. This is most often used when you are dealing with multilayer laminants. A reference for these migration cells can be found in Appendix V of the guidance document.
[Slide.]
The next thing you will want to consider is what kind of a test sample do you want to test in your migration cells. I am going to briefly talk about the formulation of the test sample and what types of information about the test sample we recommend providing in a notification. If your notification is for an adjuvant, you will want to formulate your test sample using the maximum-use level of your food-contact substance.
We recommend providing the characteristics of your test sample. For example, provide the concentrations of other adjuvants in the test sample such as plasticizers. These can affect migration. Provide the chemical composition and physical properties of the test sample. Is the test sample a homopolymer or is it a copolymer? If it is a copolymer, what is the comonomer content of the material? Again, provide molecular-weight data such as number-average and weight-average molecular weight and the density of the material that you are working with. If you are working with a paper sample, please provide the basis weight of your paper sample.
[Slide.]
We recommend providing the dimensions of the material; not only thickness but also length and width so we can calculate or verify the surface area of your test plaques.
I just want to make a note here; if you use a sample that is 20 mils thick and also not more than 25 percent of your food-contact substance migrates out of the test plaque, you can actually consider the migration of these materials to be independent from either side of the plaque and you can use both sides of the test plaque in your consumer exposure calculations.
Just a quick look at some of the polymer properties that you may want to consider when you formulate your test sample. If you are putting an adjuvant into an already notified or regulated material, we recommend testing a polymer with the lowest molecular weight and the characteristics of the currently regulated material as described in 21 CFR 177.
If it is a new polymer, you would want to test the polymer that is going to give you the highest migration results. This will tend to be the copolymers, also the materials with the lowest molecular weight, crystallinity and cross-linking density.
[Slide.]
As I briefly mentioned before, we do have a variety of recommended food simulants. The food simulants that we recommend are shown here. For aqueous and acidic foods, we do recommend 10 percent ethanol. If 10 percent ethanol is causing a problem, either with your analysis or if it is reacting with your migrant, you can do separate extractions in water and 3 percent acidic acid.
Alcoholic foods; if it is below 15 percent ethyl alcohol, such as beer and wine, 10 percent ethanol is recommended. If it is above 15 percent ethanol, we recommend 50 percent ethanol as a food simulant.
Fatty food simulants; we recommend the use of food oils such as corn oil. Alternatively, you can use Miglyol 812 or HB307.
I did want to stop here a moment. We have talked about the food simulants in our sample cells, but how much food simulant do you actually want to put into your sample cell and have in contact with your test sample. Typically, we recommend maintaining a realistic ratio of food-simulant volume to surface area of your test plaque.
A lot of times, we will accept 10 mL per square inch. If you us use less than 10 mL per square inch, we do recommend providing a justification for why you went below this particular level and also show that you haven't reached the partition limit for your system.
[Slide.]
We do have alternative fatty food simulants. Obviously, corn oil is not the most easily dealt with in an analytical situation. For polyolefins (complying with 21 CFR 177.1520) and poly(vinylacetate)copolymers (complying with 21 CFR 177.1350), we recommend 95 percent ethanol or absolute ethanol. Although, this solvent can exaggerate migration from other polymers so it is not universally applicable.
We recommend for PVC, polystyrene, rubber-modified polystyrene and PET that you use 50 percent ethanol as a fatty food simulant. You may, in your own experience, have come up with an acceptable food simulant but we do ask that you contact us first before you go ahead and do full-blown migration studies and submit a notification with the alternative food simulant.
[Slide.]
Times and temperatures of migration tests are discussed in Section II.D.1.d of the guidance document. The generic migration protocols that we recommend are located in Appendix II of our guidance document. These protocols correspond to the Conditions of Use A through H that I mentioned a few slides back. Again, you should give careful consideration to all potential uses that your food-contact substance may have, to ensure that you test under the conditions that are most severe.
Typically, our migration protocols recommend testing for ten days and that you sample your migration solutions at four different time intervals.
I want to make a couple of notes here. Polymers that are used below their glass-transition temperature, such as polystyrene and PET, we do recommend that you extrapolate your ten-day studies to thirty days. You can, to avoid any uncertainties in your extrapolation, actually test your materials for thirty days.
Another point I would like to make at this time, and there have been a number of incidences of this, concerns the use of end tests in place of migration tests. End tests are often found in the CFR for a variety of different polymeric materials. These end tests are meant for producers to use to make sure the materials that they are producing meet the specifications listed in the Code of Federal Regulations. These tests cannot be used as a substitute for migration testing.
[Slide.]
As mentioned, the recommended migration protocols are located in Appendix II of the guidance document. Regarding these general protocols, which correspond to the conditions of us A through H, I just want to provide some caveats for these particular recommendations. For example, Test Condition C, hot-filled or pasteurized above 66 degrees Celsius. This protocol supports Conditions of Use C through G only. It does not support Condition of Use H.
I would also like to point out that the Conditions of Use A through H do not cover cooking above 121 degrees Celsius. We do have a protocol that we recommend for food-contact substances that will be used in a cooking scenario above 121 degrees Celsius.
[Slide.]
Along with our general migration protocols, we do have a variety of specific protocols. I believe, if you look in our guidance document, there are roughly fourteen different scenarios. I have just listed a few of them out here. Unfortunately, I don't have time to go into depth on some of these.
If you are interested in submitting a food contact notification or testing adjuvants for polyolefins, we do have guidance on how to test these materials. For example, we have protocols that cover the use of an adjuvant in just one particular polyolefin or its use in all polyolefins. We also have protocols that would cover the use of the adjuvant in all polymers.
As I mentioned, we have protocols for high-temperature uses such as dual-ovenable trays, and microwave susceptors. Dry foods with no surface fats or oils, at this point in time; we don't recommend any testing for this scenario. We have a scenario for articles that are intended for repeat use. These are conveyor belts, rubber gaskets, O-rings that are used in the production of food. We also have a scenario for additives used in the manufacture of paper, and paperboard.
Finally, I want to bring to your attention a new addition to our guidance document. If you are interested in submitting a food-contact notification for materials, either a new polymer or an additive for a polymer, that will be used during the irradiation of prepackaged foods we can supply you with specific guidance tailored to your needs through the PNC process. We don't have any guidance document typed up at this point in time, but if you come to us, we will be more than happy to sit down with you and go over your ideas and provide you with some guidance on the types of studies that we recommend.
[Slide.]
Now that we have discussed your migration studies, what about characterization and data reporting. We do recommend triplicate migration studies. As I mentioned previously, we do recommend analyzing your samples at four different time intervals. We also recommend that you test blanks or control samples. The control samples serve as a baseline for your migration tests and they can also be used in the validation of your analytical method.
If you are submitting a food-contact notification for a new polymer, it is beneficial to you to actually analyze the migration solution for residual monomers instead of relying on their residual level in the polymer to estimate exposure. The magnitude of the exposure that you calculate in your notification will determine the amount of toxicology information that you will need to supply for your food-contact notification.
We recommend identifying and quantifying the total non-volatile extractives (TNE). These are all of the materials that migrate out of your test plaques including monomers, oligomers, antioxidants, whatever else might come out.
We recommend identifying those materials for the same reason that we recommend analyzing for the monomers. Again, you need to supply a certain quantity of toxicology information for these materials.
You don't, necessarily, have to identify every single material in the TNEs. You can classify them into different classes. Perhaps, you have fatty acids in the TNEs. You can classify the fatty acids as C8 through C18 fatty acids. You don't have to identify each specific one in there.
For polymer adjuvants, you will want to analyze the migration solutions for the adjuvant itself. Again, you will want to test for impurities and decomposition products of your adjuvant. For example, antioxidants decompose into different compounds when they exert their intended technical effect. You will want to test for these compounds for the same reason that you wanted to analyze for your residual monomers. Again, keep in mind that the amount of toxicology data that you will have to supply for this material is tied to exposure.
We do recommend reporting your results in somewhat strange units, milligrams per square inch. This facilitates conversion to the concentration of the additive in food.
[Slide.]
The next topic I would like to talk about is your analytical methods. This slide is somewhat deceiving since this is the bulk of your chemistry section in your notification. But we do recommend supplying a full description of your analytical method. Not only how you handled your samples, from concentrations to the different dilution factors that you may have used, but also providing the analysis method, and the type of instrument you used. Did you use GC; if so, what kind of a column did you use, what was the temperature program for your GC, and what type of detector was used?
We recommend providing detailed information on how you prepared your standards; what did you use as the standard, concentrations, et cetera. We recommend including calibration curves and also the raw data used to generate the curves. A lot of times, we send out deficiencies for lack of raw data. What I mean by raw data is the actual instrument response that you get with each of your analyses.
For example, for GC it will be area. If it is a UV/Vis, it will be an absorbance. But we do recommend providing all raw data for each of your analyses and also for the analysis of your standard solutions.
We recommend providing example spectra or chromatograms for your analyses. You don't have to submit every single one of them. We recommend including example calculations showing how you converted all of your raw data to the actual concentration of your food-contact substance in food.
Keep in mind when you are putting this notification together that the chemist's job is to verify all of your data and results. We are going to verify your calibration curves. We are going to verify the equations that you used and all of your calculations that you performed in support of your food-contact notification. So the more information you can give us, the more easily we can verify your data and results.
[Slide.]
As I mentioned a little while ago, you need to validate your analytical method. Typically, this is done by the fortification of your migration solutions; in other words, spike and recovery analysis. You are going to essentially report your precision and the accuracy of your analytical method.
We recommend performing triplicate analyses of migration solutions spiked at levels equivalent to the 0.5, 1.0 and 2.0 times the level of the food-contact substance found in the food simulant. If you don't detect your material in the food simulant, you should determine the detection limit and, again, for all of this information, you want to provide your supporting data, all your raw data, example spectra, example calculations need to verify this information.
[Slide.]
Finally, leading up to our consumer exposure. There are a variety of ways that you can calculate consumer exposure. One of them is 100 percent migration. As I mentioned in the beginning of my talk we recommend that you provide residual levels of the monomers in your food-contact substance, if it is a polymer. You can use these residual levels to estimate exposure to the monomers by assume that 100 percent of the residual monomers migrate to food.
For example, you have provided the residual level of the monomer in the food package, the package thickness, and the density of material, so we can calculate the quantity of your food-contact substance (residual monomer) per given volume of the food package. We than assume 100 percent of that material migrates into food.
Again, keep in mind the magnitude of exposure is going to determine the amount of toxicology data that you need. So you may want to try 100% migration calculations first but then you may want to actually refine this down by doing migration studies.
As I mentioned just a few slides ago, your migration results can be used to calculate exposure by combining the concentration of the migrant in the various food simulants (Mx) with food-type distribution factors and consumption factors. The food-type distribution factors and consumption factors are located in Appendix IV of our guidance document.
I have placed the equations that we use to calculate the concentration of a migrant in food <M>, dietary concentration (DC) and estimated daily intake (EDI) on this slide. The concentration of a migrant in food, <M>, is calculated using the first equation. In the second equation, the concentration <M>, usually provided in micrograms or milligrams per kilogram of food, and a consumption factor (CF) are used to calculate the dietary concentration of the migrant.
The DC is then used to calculate an estimated daily intake (EDI)or micrograms of your food-contact substance consumed per person per day.
[Slide.]
There are other methods of estimating consumer exposure such as migration modeling. This is based on Fickian diffusion of a migrant through your polymeric test material or your food-contact packaging. I am not the expert in this. If you have any questions on this, Dr. VanDerveer would be a better source of information concerning migration modeling.
We do have a variety of specialty scenarios. For example, repeat-use items. Perhaps, you have a new additive that you want to put into some O-rings. This is essentially a variation of the 100 percent migration calculation. We just divide the result by the total quantity of food that the O-ring, seal or conveyor belt will touch during its service life.
We also have a scenario for lubricants and their additives. We even have a scenario for calculating consumer exposure to rinse aids on plates and silverware.
[Slide.]
Finally, as Anna mentioned before, we have the cumulative estimated daily intake (CEDI). This is essentially the sum of all the different estimated daily intakes for the different uses of your food-contact substance. We have a database of these numbers located, again, at our OFAS web page.
If you can't find the CEDI in our database, you can request a CEDI through the PNC process and we can calculate one for you.
[Slide.]
As I mentioned, you can get to the CEDI/ADI database by going to our OFAS web page, which is shown here. At the bottom left corner of the OFAS web page you will see the hyperlink to the CEDI/ADI database.
[Slide.]
I have talked about a majority of the appendices that are located in our guidance document. The only one that I haven't really discussed is Appendix III, which contains examples of how to validate your analytical methods. I recommend that everybody takes a look at that appendix. It does give a couple of good examples of how to validate your data.
[Slide.]
In summary, I would like to remind everybody, to provide all of the details for your manufacturing process. Again, we can use this information to refine exposure estimates. Please provide the details of your analytical methods and your validation experiments. This will allow us to verify the results of your migration studies and the consumer exposure that you have calculated.
In addition, not only do we recommend providing a dietary concentration and EDI for your food-contact substance but we also recommend providing them for any of your impurities such as residual monomers or catalysts in your food-contact substance.
That's it. If you have any questions, I will try to answer them now. I would just like to remind everybody, we do have a workshop this afternoon that you can ask more detailed questions.
Dr. Lickly?
LICKLY: Tim Lickly with Dow Chemical. You ask for all the raw data.
ARVIDSON: Yes.
LICKLY: I guess my problem with supplying you with all the raw data is, as you know, we do different food simulants. We do multiple-day analyses. There is a different calibration curve for each one and modern analytical equipment nowadays processes that and takes that down to micrograms per ml of solvent or something like that.
Isn't it more appropriate to just give you an example of raw data, again, a consistent package where you give a linearity curve, give a response. You give an area for that response so you can see the typical analysis of a given then and then give you a process data, because the raw data would be meaningless without all the other data. That would get voluminous to review.
ARVIDSON: Well, yes. You can give us a typical chromatogram, a typical calibration curve. Typically, people--Anna and I are fairly new people here; typically, I have seen the majority of the data, or all of the data, provided for the analyses for your food-contact substance. There will be a stack of information. We like to get I guess what I would call the raw data, micrograms per square inch or micrograms per milliliter and peak areas so we can go through your equations and see how you calculate everything and double check.
Granted, we may not be able to double-check all of your calculations, but we do need to go through and make sure there are no error in your equations and calculations. We do run into mistakes and things like that. But, if you can provide as much information as possible--the more information, the better.
HECKMAN: My name is Jerry Heckman. I am with Keller and Heckman. This is not really a question. You may well want to say that this should be taken up with the General Counsel's Office or something, in which case we will be glad to do that.
But, in your paper, on Page 4 and in the Form 3480, both, you tend to indicate that people have an obligation to supply you with extensive data about intended technical effect and the amounts necessary to accomplish the effect, et cetera, et cetera.
The statute doesn't support that. Under the statute, you are not required to prove efficacy with food additives, not even direct additives much less indirect. That fiction has been carried forward in FDA for reasons that are not clear to me, other than that maybe some people got transferred from the drug side, for a long time.
So anytime I see it, I have sort of an obsession about trying to straighten that out. You are entitled to information to indicate that the substance will accomplish some effect and you have a right to deny the application if it will work a fraud or deception on consumers, but you don't have a right to inquire any further than that with regard to intended technical effect, in my opinion.
We have written a couple of papers on that, one of which is on our website, a copy of which I can give you today if you would like to have it. But I think it is time for FDA to stop perpetuating that myth.
In 1958, we fought long and hard after it was proposed that you be required to prove efficacy to convince Congress that that was neither necessary nor proper. So, every time I see it, I am going to say something about it, as you may have just gathered.
CHEESEMAN: Let me thank Jerry for that input and also you don't have to send us any copies of the paper. I actually have several copies in my office that you gave us the last time we had you at a meeting. So we appreciate that input.
ARVIDSON: Are there any other questions?
McCOURT: Chuck McCourt from Dow Corning. You mentioned that there are special calculations for repeated use and for lubricants.
ARVIDSON: Yes.
McCOURT: In the guidance documents, I haven't seen a whole lot of special calculations. Are those somewhere else?
ARVIDSON: Like I mentioned, the rinse aids, we have come up with scenarios. Often, they are not included in the guidance document but we have scenarios that we have on hand.
McCOURT: So, if I contact you, I could get that information?
ARVIDSON: Yes; you can contact us through a PNC and we can write something up for you and get you a copy of those particular recommendations that you are interested in.
McCOURT: Okay.
ARVIDSON: Yes, sir; in the back?
PACE: Gregory Pace, Sun Chemical Corporation. On Page 7, you are talking about the analytical method and chromatograms and raw data. You say to label all spectra and chromatograms. If we have groups, functional groups, like you said, food acids, can they be labeled that way or does each individual peak need to be labeled?
ARVIDSON: I would think you would be able to provide us with some general indication like peaks, with retention times 5 through 17 are fatty acids between this molecular weight and that molecular weight or C8 through C16. I don't think, in that scenario, you would have to identify every single one as long as we know that it is a generic category and which peaks are assigned to that category.
There could be something in the middle that maybe some other substance that you would want to bring to our attention, "This is some other compound." But you could, I believe, do that; yes.
REED: Peter Reed of Ondewo Nalco. I would like some clarification on the confidential aspect of the information we give you; for example, it may be nice for us to send our manufacturing procedure, our catalyst information. You indicated that would be confidential. However, in the previous question and answer session, there was a discussion about the requirement for you do that. Apparently, there is nothing preventing you from releasing that publicly.
I would like some clarification on that if I misunderstood anything because, obviously, we don't want to send you information that would compromise our ability to make a profit.
ARVIDSON: That is completely understandable. Mitch, I am sure, can address that better than I.
CHEESEMAN: Since I created the confusion, I should try to clear it up. What I was speaking to of not having an obligation was not necessarily having an obligation of coming back to notifiers about information about information that is marked confidential that we do not necessarily agree is confidential.
There has never been any question, I don't believe, that manufacturing, specific manufacturing information, catalyst information, is confidential, commercial or trade-secret information and is not subject to release under FOI.
SIMMONS: Ralph Simmons from Keller and Heckman. It is not really a question. It is a comment but it relates to that last comment from Dr. Cheeseman. Our position is that you do have an obligation to contact notifiers before releasing confidential information. We do not agree that you are exempt from that regulation.
We can get into the details of that at another time, but, beyond that, we have run into at least one occasion recently where the failure to make that contact resulted in the release of confidential manufacturing information, specifically impurity information.
Fortunately, we caught that before it went someplace other than our office. But, nevertheless, that did happen and it resulted from the failure to contact us before the information was made public.
ARVIDSON: Any other questions?
SHANKLIN: I would just like to say that there is an administrative workshop set up for this afternoon, so I will be available along with other CSOs for questions that you have targeted for administration and maybe clarify some of the things regarding confidentiality of information.
ARVIDSON: I guess we are scheduled for a break at this point in time? Is that right, Mitch?
CHEESEMAN: Yes. Why don't we go ahead and start that.
[Break.]
[See presentation slides for Dr. Young]
Toxicology Guidance
YOUNG: Welcome back. Thank you for being here.
[Slide.]
I am Carolyn Young. I am a toxicologist and I will be presenting information this morning on toxicology and the Toxicology Guidance Document that became final in April of 2002. I will also present information on the deficiencies that we have seen.
[Slide.]
This afternoon, we will have presentations on the Form 3480, the Tox portion of that form. We will have speakers talk about genetic toxicology, structure-activity relationships and the integration of that genetic toxicity information in SAR and risk assessment.
[Slide.]
So, welcome to my portion which is Toxicology Guidance 101.
[Slide.]
As you have heard before, we have webpages to assist you in locating these documents. The first address up there, as you know, is pretty long. FDA has a new webpage which you may find helpful. This is a little bit easier, at least for me, to remember so, in the next few slides, I will take you through the steps to get down to the guidance document itself.
[Slide.]
This new page has so much information, I just want to make you aware that it exists.
[Slide.]
You have seen some of those pages before.
[Slide.]
When you get to this page, you do have to scroll down considerably--
[Slide.]
--to get down to the individual guidance documents. Again, there is one for administrative, chemistry and for toxicology.
[Slide.]
The Toxicology Guidance Document is divided into twelve separate sections. I am going to be focussing on these six sections. The first one is an introductory section.
[Slide.]
Moving right along into the topic here, exposure estimates for the food-contact substance and constituents. I am going to bring the point up right here that we do need information on the constituents. This is a little bit different than what has been the practice with indirect-additive petitions. So you will see repeatedly, in these slides, reference to constituents as well as the food-contact substance.
[Slide.]
As mentioned here, the exposure estimates are important because we use these as a guideline for the level of safety testing that we recommend that you submit to us.
[Slide.]
We have already heard the definition of a food-contact substance, so I don't need to go through this again.
[Slide.]
But, for a constituent, it is a nonfunctional and unavoidable chemical entity associated with a food-contact substance. Examples of this are impurities, unreactive monomers or ligomers, processing aids, side-reaction products during synthesis and decomposition products. These do need to be considered in developing your tox information that you will submit in with your notification.
[Slide.]
We do ask that the test substance that you use in toxicity studies represent what you expect to migrate into the food. So this would be either the food-contact substance, itself. When the food-contact substance has been a polymer, sometimes, then, the best material would be low-molecular-weight oligomers. Again, the constituents. We do recommend that you use a single batch when you are doing your toxicity studies instead of using multiple batches or to use similar batches that are comparable.
[Slide.]
We also want to know exactly what the test compound is, the name, the structural formula, some of the components and constituents of the test material and, as mentioned earlier, the CAS number is very helpful for us in being able to do our literature searches and carry out our review.
[Slide.]
The safety-testing recommendations that we have in our guidance document are a tiered structure. That means that, based on the exposure in the daily diet, the lower the exposure, the less testing that we recommend.
There are basically three separate levels in this scheme. The first group is the lowest exposure which is anything that is less than or equal to 0.5 parts per billion. For this level of exposure, we are not recommending that you provide or conduct toxicity studies. However, we do need to make sure that any potential carcinogenicity issues regarding those compounds is addressed.
One way to do that is to make sure that you conduct a thorough literature search of published and unpublished studies and then provide to us summaries of the these studies. If it is a pivotal decision that you are making, sometimes we will even ask for the actual studies, themselves. But, at this level of exposure, you can see that we are not asking for you to go out and conduct studies.
I have listed this information on the bottom half of the screen in a lighter yellow color. The reason I have done that is that this same information in this lighter yellow color will show up on the next several slides as we go through these three different levels. So it is easier for you to know that this information repeats at every level.
[Slide.]
As I mentioned before, we need to know about any carcinogenic potential that is brought about by migration of the material into the diet.
[Slide.]
The second level is for exposures that are greater than 0.5 ppb but less than 50 ppb. At this level, we have genetic toxicity studies that are recommended. We recommend gene mutations in bacteria and we also recommend an in vitro study. Chingju Sheu will be talking about these studies in more detail during the workshop section this afternoon.
[Slide.]
As I mentioned before, this is that lighter yellow color. It is the same information requested for the lower exposure is, again, requested at this exposure level.
[Slide.]
Again, the carcinogenic constituents need to be addressed.
[Slide.]
The third level is anything that is greater than 50 ppb but less than 1 ppm. At this level of exposure, the recommendation is for two subchronic oral toxicity studies, one in rodents and one in nonrodents. These studies should be able to provide an adequate basis for determining the ADI, the acceptable daily intake.
[Slide.]
Once again, you see genetic toxicity studies. This time, in addition to the first two where you have a choice, either one of the in vitro studies, a gene-mutation study in bacteria. This time, the third study is an in vivo test for chromosomal damage using rodent hematopoietic cells. So that is something new that gets added at that third level.
[Slide.]
Once again, the potential carcinogenicity needs to be discussed and this information carries through including the carcinogenic constituents.
[Slide.]
Anything greater in exposure than 1 ppm, the testing significantly increases. At that point, we ask for comprehensive studies including bioassays. But, as mentioned earlier, I would like to remind you that the recommendation to either go with an FCN or a petition, FDA would really appreciate it if you would contact us before submitting a notification or a petition so that we can help you make that appropriate decision as to where that notification or petition should be; should it be a petition or a notification.
[Slide.]
We also have provided, in the guidance document, a statement that when the test material is a biocide that the previously discussed testing recommendations, those three levels that I previously mentioned, are the same, however, at one-fifth the value of CEDI. So, in your handout, you will see that this information is provided for you. I just took one-fifth of the values that I previously mentioned.
[Slide.]
Some of the information about the safety-testing protocols; I would like to mention that, originally, in 1982, the toxicological principles for the safety assessment of direct food additives and color additives, better known as the Redbook, was published. In 1992, there was a second draft of this. Beginning in 2000, we have started putting the final edited chapters of the Redbook available on the web. The address is provided here.
Not all of the chapters are available yet. We work on those on a continual basis. So, if you don't find the chapter that you are interested in right now up on the web, then refer back to Redbook II or back to the original Redbook I.
Of course, whenever you are planning to conduct toxicity studies, if the recommendations that we have provided in the Redbook are different from what you plan on doing, please contact us so that we can offer our opinion and our suggestions so that when the study is eventually submitted to us, we don't have to go back to you and say, "Oh; if you had only come and talked to us, we could have told you that we needed it done this way or we needed an extra piece of information."
[Slide.]
For the organizational structure of the information that we would like to have in any food-contact notification, the safety summary is the first part and then there is a second part, the safety-data package.
The primary component of the safety summary, from my point of view, is a safety narrative. After that, there is a listing of toxicity studies for the food-contact substance and the constituents and a description of other relevant studies. All of this part of the safety summary is found in Form 3480, Part III.
The Safety Data Package forms part of the rest of your submission. The major component of that, in my opinion, is the comprehensive tox profile. The comprehensive tox profile is a summary of the different studies. I will provide more information in just a few minutes on that.
We would also like to have you submit the original study reports, a complete published study. If it is a published paper, don't send us just the top page and say, "Here it is." Please provide us with an entire study.
Appendices; underneath the appendices, I have included literature searches. The documentation for searches is included in this section.
[Slide.]
The safety narrative is a concise summary of the scientific basis for a decision of safety for the food-contact substance and its constituents. So the safety narrative is a combination of all the information that you have put together to form that basis of safety.
It should include an estimate of human consumption, the EDI that Kirk previously mentioned. It should discuss all the potential toxicity and to include any information and decisions about mutagenicity and carcinogenicity including the worst-case upper-bound lifetime risk levels for carcinogenic constituents.
[Slide.]
In the guidance document, it mentions the ADI, the acceptable daily intake and a way to arrive at the ADI using the no-effect level. We remind you to use the most relevant studies and the most relevant endpoints when you are doing your calculation to come up with the ADI.
The document also provides the general safety factors that are used in the calculation with the NOELs. I have provided this table for your use. Once again, we do have our database, the CEDI/ADI database. As you have heard before, we do appreciate when you contact us ahead of time and request information on the CEDI or the ADI so that we can assist you before you actually submit your notification and have all that information in the notification when it comes in.
[Slide.]
So the take-home message is, for the safety narrative, have one for notification. It is part of the safety summary and it is located in Part III of the Form 3480.
[Slide.]
As you heard Mitch mention earlier, we like to have a story--not that we really need to have all story stories, but we do like a complete picture of what you are trying to present to us. Make sure that the safety narrative and the information includes a concise summary for decisions of safety for the food-contact substance and the constituents. Include in that, your ADI, your NOELS, your ADIs and discuss the main points that lead you to make that decision of safety.
[Slide.]
The comprehensive tox profile is a little bit different. It is a summary and critical evaluation of all the available toxicological information pertinent to the safety evaluation of the food-contact substance and its constituents. So, in a notification where you have one safety narrative, you may have five, six, two CTPs. You should have one CTP for each compound, whether it is a food-contact substance or constituents that are migrating in at levels that would cause us to think about how much is there, what toxicity testing do we need to substantiate that decision of safety for each one of those.
As I have indicated here, we ask that you do literature searches so that the information and your discussion to us, your story to us, is up to date. Based on the information that you have found out about the food-contact substance and/or the constituents, we ask that you provide us with summaries of that information.
Sometimes, that summary is going to be really short. "We conducted a literature search and there wasn't any information available." Other times, there will be a lot of studies and you will be submitting the actual study reports to us and we ask, in the comprehensive tox profile, to give us a synopsis of the study and then, as indicated earlier in the safety data package slide, to make sure that you give us a complete study submitted in the food-contact notification.
Use the information from the available studies in your determination of your NOEL and ADI. We recognize that the NOEL, usually we have studies that are a minimum of 90 days in duration that we use in order to use that NOEL and calculate an ADI. Again, risk assessments for carcinogenic constituents. Then there is a bibliography.
[Slide.]
So the take-home message here is that there is one CTP for the food-contact substance and one CTP for each migrating constituent. This information is located in the safety data package which is part of the body of the notification.
[Slide.]
Once again, tell us a story with the CTP. Again, you can have multiple CTPs in a notification. Tell us a story. Link all the pieces together. It is like anything you would like to read where all the pieces fit. We like to see that as well.
[Slide.]
This concludes the portion on the Tox Guidance document.
[Slide.]
You have heard a lot about the stories you want you to tell us. This is my opportunity to tell you the story of food-contact notification, some of the things that we have seen, some of the deficiencies that we have experienced and how we have dealt with them.
[Slide.]
These are two of the characters in the stories. As you can see here, "We sure have seen a lot of variety of deficiencies in the food-contact notifications that we have received." As, is my hope, that the stakeholders meeting that we are having today helps you in the future when you are putting together a notification and I hope it helps everybody so that these notifications are submitted without any deficiencies and that everybody can take care of what they need to easily and efficiently.
[Slide.]
Deficiencies can be grouped by the prenotification consultations, exposure estimates, the safety narrative, safety assessment of the food-contact substance and of the constituent. A special case; a low-molecular-weight oligomers and the organization of that safety information.
[Slide.]
All too often, we have seen this scenario where we look at the notification when it comes in and we say, "That is not what they asked when they came in. They came in and they talked to us. We thought we knew what was going on". Sometimes, it is a different contact substance. Sometimes, the use is different and I am sure it is frustrating for all of you in the industry as well as for us.
[Slide.]
Our recommendation is to provide sufficient background and use information so that when you submit the request for information that we can provide to you exactly what will serve best in the long run.
[Slide.]
For exposure estimates to the food-contact substance and constituents, we have noticed that some notifications do not take into consideration the cumulative exposure. They have not actually calculated exposures. Oftentimes, I have seen this in relationship to constituents. We need all of this information to be addressed or it becomes a deficient submission and then you hear about it from us.
Our recommendation is to submit appropriate chemical-identity information and exposure estimates for the food-contact substance and the constituents.
[Slide.]
For the exposure estimates, a deficiency is the notification does not include the scientific basis for a decision of safety for the food-contact substance, and, again, the constituents. Sometimes, we see the narratives and they have really done a great job talking about the food-contact substance but there is absolutely nothing about any of the constituents.
So, please, when you submit the notification, go back and read your safety narrative and make sure that it is a complete story for us.
[Slide.]
We need adequate information to support that decision of safety. Sometimes, we encounter inadequate or missing toxicity studies. Sometimes, this means that, in our literature search, we have identified studies that have been conducted but you have not mentioned them. Sometimes, we have only gotten parts of toxicity studies. Sometimes, there are pages missing.
So we ask for a complete submission of toxicity studies, especially when they are the pivotal studies for that decision of safety.
[Slide.]
Another big thing is the missing or inadequate literature search. I have presented here what a literature search should include; the names of the databases that are searched, the period of years that are searched, the specific search terms that are used, documentation of the search, justification and relevance of the search, and review and the summary of the individual references and how they are pivotal to that safety decision.
It is very frustrating, from my point of view, to open up an FCN and see 150 pages of literature search but you can't tell what the search terms were, how it relates to the FCN. You just sit there and look at it, and "How does this fit?" So, my personal preference is, "Tell us a full story when you submit your literature searches." It would make our job a lot easier and it would avoid that call back to you saying, "I'm sorry, but your FCN is deficient."
[Slide.]
In the safety assessment of the food-contact substance, we have an inadequate assessment of toxicity. Sometimes the studies that were used for the basis of safety or for determination of an ADI was an old study and there could be newer studies that are out there.
Again, make sure you do a comprehensive literature search and that you are aware of the information and then look at the studies carefully, make that you are understanding the basis for the NOEL, that it is the most relevant endpoint and that the study that you are using has the most relevant endpoints and that is most applicable.
[Slide.]
So a reminder to use the lowest ADI, the NOEL from the most relevant study and from the most sensitive endpoint, use the appropriate safety factors and also use the CEDI/ADI database as a reference.
[Slide.]
"Well, they submitted a pretty good FCN except for constituent information." Her response is, "I agree, but it is still a deficient FCN."
I, unfortunately, deleted my gold star. I really want to compliment a lot of people who have submitted FCNs and have done a fantastic job, not only on that safety narrative but they have been very good at including that constituent information.
[Slide.]
Some special notes about constituents. Exposure is generally low relative to that of the food-contact substance. Safety evaluation should usually focus on the potential mutagenicity and carcinogenicity and the quantitative risk assessment required for carcinogenic constituents. We need all of that information.
To make sure that when there is a carcinogen of concern, that concern is based on more than one piece of information. It is based on the weight of evidence that we have from toxicological studies, the exposure estimate and we oftentimes will rely on the structure-activity relationship information.
[Slide.]
As I have indicated before, the safety assessment also applies to the constituents. We want to make sure that we have adequate information for that decision of safety and, once again, what we have experienced as inadequate or missing toxicity studies and missing literature searches. So, please make sure you include that information.
[Slide.]
As we have seen with the food-contact substance, itself, we want to make sure that you are using the most up-to-date information possible and the most relevant studies for the NOELs and the calculation of ADIs.
[Slide.]
We have also noticed, with the constituents, that there has oftentimes been a lack of quantitative risk assessment or an inaccurate calculation of the extreme case upper-bound lifetime risk to humans from exposure to carcinogenic constituents. So our recommendation is make sure you present convincing scientific evidence to justify any alternative approach to estimating risk.
So, if you are planning to develop an argument, look at the Tox Guidance. If your plan is different from what ours is for justifying and supporting food safety, talk to us about it. Lay it out in your story and your narrative so that we know that you have really considered it and we can also evaluate it and look at it through your eyes, and then make a reasonable decision.
[Slide.]
We have a special case, low-molecular-weight oligomers. We have seen where notifications did not include exposure estimates, assessment of safety including toxicity studies. I have an asterisk here as a reminder that sometimes the oligomers may be chemically synthesized for animal tests. We don't expect you to go out and spend exorbitant amounts of money and time to get enough test material when it is just not feasible to do that.
This is where the chemically synthesized oligomers may be the way to go. Again, we want you to discuss these low-molecular-weight oligomers in the safety narrative and also in a separate CTP.
[Slide.]
Generally speaking, the organization of the safety information; we really appreciate it and we give gold stars to all of you who have taken the time and effort to organize this information in a way that is easy for us, when we pick up that notification, that we can easily find the information.
Again, the safety narrative, the comprehensive tox profile and the literature-search information are things that I look for right off the bat when I get a notification. It is very nice when we have tables and it says, "The literature-search information is located here in this notification," and that there is that little table of contents that many of you provide for us. That is extremely helpful.
[Slide.]
The grand take-home message; make sure that your notification provides adequate qualitative and quantitative information regarding what migrates into the diet; food-contact substance, low-molecular-weight oligomers and the constituents
[Slide.]
Tell me a story. Make it comprehensive, concise and make it a summary of all the information that you use to form a decision of safety. Also, make sure in your safety data package that you include these comprehensive tox profiles and that you include literature searches, the documentation of those searches, for the food-contact substance and the constituents.
[Slide.]
Provide a detailed review and fair interpretation of the pivotal toxicity data and determination of the NOEL, or NOELs, as the case may be, and the ADI or ADIs, as the case may be.
[Slide.]
Be sure, when there are carcinogenic constituents to calculate the acceptable lifetime cancer risk.
[Slide.]
As our characters in our twisted tales remind us, "I think that we have covered most of the main points related to the tox portion of the food-contact notification," and, "I guess this wraps it up for us." I hope everybody remembers that--
[Slide.] --when you are standing there and you are pulling your hair out, this could be for those submitting the notifications. Keep your hair attached to your head. Turn around. Consult the Tox Guidance Document. Consult with FDA by phone or by e-mail. Let's keep your hair attached to your head.
It also keeps us from looking like that as well.
[Slide.]
So, if we look into the future a little bit, this is my hope for the future, at this time next year that we can say, or your supervisors or your bosses can say, "Congratulations. During this year, all of your FCN submissions have been complete and no deficiencies."
As we have had our little characters throughout the second portion of my presentation, here we can see them in the Year 2020. "It has been great working with you on all these FCNs all these years." Her response is, "It seems like it was just yesterday that we started with FCNs and had that stakeholder's meeting."
[Slide.]
His response is, "That meeting sure did make a big difference in the FCNs that we received." Hers is, "As I recall, the percentage of deficient FCNs significantly decreased immediately after that meeting."
So that is my hope and my intention was to present the information and hopefully keep everybody's hair attached to their head rather than pulling their hair out.
So I appreciate your attention. I will take any questions that you have and hope that I can answer at this time.
DOWNES: My name is Jim Downes with Solutia. Has the agency had any experience at accepting HPV dossiers such as the Euclid format for comprehensive tox profiles?
YOUNG: I didn't understand. Let me say back to you what I did hear, that there is some other information that you want to know whether we would accept as being equivalent to the information that I presented?
DOWNES: Yes. In the High Production Volume Chemicals Program that USEPA has along with the OECD, industry is doing a lot of pretty comprehensive tox profiles under a Euclid format which is a European format. My question is are those profiles acceptable in food-contact notifications to FDA?
YOUNG: I am not personally familiar with those documents so I can't answer the question. But we can find out an answer and get back to you and let you know.
DOWNES: It may be a unique subset of chemicals that are going to be notified because they are chemicals which are in commerce at greater than 1 million pounds a year. But those documents are generally available and would be a much smoother operation than starting from scratch to prepare a new one.
YOUNG: Thank you.
Any other questions? Yes?
CAMENISCH: Steve Camenisch with Englehard. What information would you require for constituents that are previously FDA-approved? If you have a constituent that is FDA-approved, are there any differences?
YOUNG: My understanding is if the constituent is already previously approved and there is no increase in exposure, remembering that our recommendation is based, to a large extent, on exposure. So, if you have an increase in exposure to a constituent and it is not covered by a regulation that is already there, then we would recommend that you provide us with the additional studies.
Does that answer the question for you?
Yes?
ITZKOFF: Mark Itzkoff, Olsson, Frank and Weeda. For constituents that are present at less than half a part per billion, how much information do you need in terms of identifying that constituent if it is a minor constituent that is hard to identify? Is it sufficient to say that it is present at, say, 0.05 ppb, that you can't identify it to do the tox profile?
YOUNG: When we have an exposure that is very, very low, we do ask that if there is a potential that it is carcinogenic, that you have done a literature search, sometimes there is not going go be any information there. Sometimes, we recognize that it is very difficult to positively identify exactly what that constituent may be because of limit of detections.
In those cases, you can always submit a PNC and ask ahead of time whether there is anything else. But I think that, if in your summary, in your CTP and the safety narrative, that you mention exactly the parameters that you do know and the exposure, and you discuss it, that that, a lot of times, will be adequate. But make sure that if there is any likelihood of mutagenicity, carcinogenicity, that that is adequately discussed.
ITZKOFF: Thank you.
YOUNG: Yes?
LICKLY: Tim Lickly with Dow Chemical. In the case of oligomeric material where we come up with, say, a new monomer or a new comonomer in a polymer, and we are really replacing an existing material such as, say, a new alphaolefin in a polyethylene or something, it is very hard, again, to do the mutagenicity studies and stuff for low-molecular-weight materials and where it is a replacement for a similar constituent, again, methyl acrylate versus ethyl acrylate.
Maybe methyl-acrylate polymers are already regulated and you want to use ethyl acrylate. Would that be acceptable to just identify it as a replacement and identify the amount of oligomeric fraction in the diet rather than trying to generate the mutagenicity studies?
YOUNG: We recognize that there are those times when this type of situation occurs. But we also know that a different substance can be a different substance and then the tox profile would be significantly different.
We do look for information that would correlate the information, supportive documentation of similarity, similarity in structure, what might be known about the compound that you have previously brought to our attention and this new compound.
This would be another time when that prenotification consultation could be very helpful. Based on the similarity and what information is known and what the exposure is, then we would make some sort of determination that would tell you specifically whether or not you would need to go the route of actually conducting the studies.
If there are any other questions, I encourage you to use our question box and our three-by-five cards over here--they are color-coded--to help us in sorting through the questions and getting them to the right discipline during lunchtime. We hope to answer those questions for you during the afternoon portion of our presentation.
This concludes my portion. I introduce Paul DeLeo.
[See presentation slides for Dr. DeLeo]
Environmental Guidance
DeLEO: Thank you, Carolyn.
Good morning.
[Slide.]
I'm Paul DeLeo. I am an environmental scientist in the Division of Chemistry, Research and Environmental Review. That is not to be confused with the Division of Food Contact Substance Notification Review. Our environmental review team supports activities in the Office of Food Additive Safety both in that division and the Division of Petition Review and we also support the Center for Food Safety and Applied Nutrition in other areas where they need to meet their environmental requirements. So we are in a separate division.
This morning, I am going to be discussing environmental requirements for food-contact notifications.
[Slide.]
As part of my talk, I will discuss some of the background of the National Environmental Policy Act, what we call NEPA. I will talk about why food-contact substances and notifications are the subject of NEPA. Then I will go into the specific requirements that you need to be aware of in your notifications including environmental assessments or categorical exclusions from the need to prepare an environmental assessment and how you can fill out the Form 3480.
[Slide.]
The National Environmental Policy Act was passed by Congress in 1969. It requires each federal agency, including FDA, to take environmental considerations into account in their final agency actions. The requirements of NEPA supplement FDA's authority under the Federal Food Drug and Cosmetic Act and other public-health statutes.
NEPA does not supersede the authority of these statutes. In fact, NEPA does not require the agency to favor environmental protection over other considerations such as human health in its decision-making, just that environmental impacts be considered during the decision-making process.
FDA's NEPA regulations are found in 21 CFR Part 25.
[Slide.]
In addition, NEPA is a full-disclosure act. It requires that interested parties in the affected public are informed of the environmental analysis including the decision-making process for major agency actions. The complete environmental record is open to the public and public participation is encouraged.
NEPA is also a broad statute. It requires consideration of all aspects of actions which may have an impact on man's environment including impacts on natural resources and energy use. In addition, it applies to actions which may have impacts abroad.
[Slide.]
NEPA states that all agencies of the federal government shall include an environmental impact statement with every major federal action significantly affecting the quality of the human environment. Environmental impact statements are extremely resource-intensive documents to prepare. Therefore, environmental assessments are prepared to help determine if an action will significantly affect the quality of the human environment and thus require an EIS.
[Slide.]
At this time, I am going to move on to why FCNs are subject to the National Environmental Policy Act.
[Slide.]
I am going to be summarizing a discussion of this analysis that was published in the Federal Register, the May 11, 2000 edition of the Federal Register. This was part of FDA's Direct Final Rule expanding NEPA regulations to cover food-contact notifications. So, again, this is a summary of a legal argument or a policy decision. I just want you to be aware of that because there is some detailed legal analysis in here.
[Slide.]
NEPA requires agencies to consider environmental impacts for actions that are major and final. So I am going to go into these issues of finality and major actions.
[Slide.]
Regulations implementing NEPA define major actions as those which include circumstances where the responsible official fails to act and that failure is reviewable by the courts under the Administrative Procedure Act. This definition is in the NEPA regulations which are under EPA's regulations at 1508.18.
The obvious example here is that failure to object to a notification falls under this definition of failure to act.
[Slide.]
The agency's decision not to object also meets the finality requirement under the Administrative Procedure Act as was recently articulated by the Supreme Court. It marks the consummation of the agency's decision-making process; that is, by not objecting, the agency can be considered to have reached a conclusion about the safety of a food-contact substance and rights or obligations are determined; that is, authorization for marketing is a direct and appreciable legal consequence of the agency's decision not to object.
[Slide.]
Subsequently, the agency's decision not to object is a major and final action and therefore the requirements of NEPA apply to the food-contact-notification process.
[Slide.]
I am going to go into those requirements now.
[Slide.]
Every food-contact notification must contain either an environmental assessment or a claim of categorical exclusion from the need to prepare an environmental assessment. If an FCN does not contain an EA or claim of categorical exclusion, the agency does not consider the notification to be complete and will not accept it for review.
Similarly, if an EA or categorical exclusion is submitted with an FCN but a component of that is deficient, your FCN may not be accepted for review. That is a possibility.
[Slide.]
I am going to talk now about environmental assessments and categorical exclusions but I am going to actually do them in reverse. I am going to talk about the categorical exclusions first.
To begin with, what is a categorical exclusion? Well, a categorical exclusion is a category of action that the agency has determined do not individually or cumulative affect the quality of human environment. Ordinarily, when an action meets the criteria of a categorical exclusion, neither an environmental assessment nor an environmental impact statement is required.
You will recall that EAs are prepared to determine whether an action has significant impacts to the environment and would require an environmental impact statement.
Also, you should be aware that there is a provision in NEPA that requires an EA to be prepared even when an action meets the criteria of a categorical exclusion but when extraordinary circumstances exist. I am going to be speaking about extraordinary circumstances a little bit later.
[Slide.]
FDA expects most food-contact notifications will be the subject of a categorical exclusion. In fact, to date, about 80 percent of effective notifications have a warranted claim of categorical exclusion. Anna Shanklin previously provided some statistical information about the notification program. The categorical exclusions have only been able to be used later in the process so that is why only 112 effective notifications are considered here. Of that number, 89 were excluded from the need to prepare an environmental assessment.
You also need to keep in mind that you make the claim of categorical exclusion but it is the agency that determines whether that exclusion is warranted.
[Slide.]
If FDA determines that, for a given claim of categorical exclusion is not warranted or extraordinary circumstances exist, then you would have to prepare an EA. The categorical exclusions which pertain to FDA's Center for Food Safety and Applied Nutrition in general are located in the CFR under 21 CFR 25.32.
[Slide.]
The exclusions which we feel are specific to food-contact notifications are 25.32(i), (j), (k), (q) and (r.) But, in reality, we have seen notifications using mostly 25.32(i) and (j) and there is one instance where 25.34 (q) was used and there is an effective notification using that. So I am going to just go into what the criteria for those three exclusions are, (i), (j) and (q), very briefly.
[Slide.]
If you look in the regulations, 21 CFR 25.32(i) is a categorical exclusion for a food-contact substance tha