Intro:
You might not realize it, but we are exposed to dozens of hazards every day. Can any of these hazards negatively impact your health?

Dr. Alex Le Beau:
Definitely.

Intro:
This is the Exposure Scientist podcast. My name is Alex Labo and here we answer your questions and concerns on what you may be exposed to every day. Welcome to the Exposure Scientist podcast. The views expressed in this podcast may not be those of the host or management. This podcast is for informational purposes only and should not be considered health advice. It is recommended that you consult an exposure scientist to discuss the particulars of your exposure scenario.

Dr. Alex Le Beau:
I'd like to welcome you to today's episode of the Exposure Scientist podcast. A timely topic I'd like to discuss is food, the safety of food, and the safety of what we consume on a daily basis. To discuss that, I have brought in Amy Mazingo. Amy is the vice president for us nutrigulatory sciences for grass Associates. She holds a BS degree in biology, an MS degree in environmental resource management, and has her certificate in preventative controlled qualified individual status. She has over 20 years of experience in food and dietary supplement regulatory science for the US food market and has expertise in development of safety data for food and dietary supplement ingredients. She also has experience in claim substantiation, labeling, and current good manufacturing requirements for dietary supplements. Amy, welcome to the Exposure Scientist podcast.

Dr. Alex Le Beau:
Amy, thank you so much for joining us on today's episode of the Exposure Scientist podcast.

Amy Mozingo:
Thank you. It's a pleasure to be here. Alex, thanks for inviting me.

Dr. Alex Le Beau:
Of course. So one of the reasons why I wanted to invite you here is the food intake has caught a lot of people's attention. These days. There's been discussion of food and food safety. Last year there was the determination by IARC that aspartame was a human carcinogenic hazard, a class two or group two b hazard. There's been other issues or other thoughts on food safety. So I brought you here, I wanted to have a discussion with you on. There's a lot of, I'll say, blogs and misinformation out there on food safety and thinking that there's not a lot of scientific rigor that goes into it.

Dr. Alex Le Beau:
So I brought you here today to kind of discuss the scientific evaluations that do go into food safety. So if you could, generally, food and food ingredients are viewed for intake purposes from FDA standpoint. So if you gave us a broad overview of different types of, I'll just say food safety evaluations, or I almost say registrations, because as we get into it, we're not going to see everything has to be registered, but the different kind of categories of food safety determinations as identified by FDA?

Amy Mozingo:
Sure. Well, a new food ingredient must be safe and it must follow an appropriate regulatory framework before it can be lawfully added into the US food supply. So which framework pathway to take? That depends on a lot of variables, but just to give a little bit of history, today, many ingredients enter into the food supply through the grass process. Okay. Grass means generally recognized as safe. And to give a little bit of history on that, in the 1958 Food Additive amendment to the federal Food, Drug and Cosmetic act established that any substance added to food is a food additive and subject to pre market approval by FDA unless the use of the substance is generally recognized as safe or otherwise exempted from the food additive definition. So some exemptions would be it's a color additive or it's prior sanctioned ingredient. So in essence, grass is an alternative to the food additive petition process first, just to establish that.

Amy Mozingo:
And a lot of ingredients do enter the food supply via the grass process. So may we talk a little bit about the grass process?

Dr. Alex Le Beau:
Sure.

Intro:
Yeah.

Dr. Alex Le Beau:
No, please. I'd love you to elaborate on the grass process and kind of discuss what it is, because I know people have heard of grass and they hear this generally recognized as safe. But I think some of the question is who's making these determinations? Or how are people coming to the conclusion that it is safe and what are the safety data that's, I want to say, required for it, but is used to support that finding?

Amy Mozingo:
That's a great question. First, for substance to be grasped, there must be general recognition of safety. And this requires recognition throughout the expert scientific community that's knowledgeable about the safety of substances that are added directly or indirectly to food. Okay, so the safety criteria for grass is that there is a reasonable certainty that the substance is not harmful under the conditions of its intended use. So a finding of grass requires the same quantity and quality of evidence that would be required for the food additive petition process. Except there's one big difference. For the grass process, the information that's pivotal to supporting safety must be publicly available. Okay, so that means that the safety data supporting a grass conclusion can't be proprietary data that nobody else but FDA sees.

Amy Mozingo:
It has to be publicly available, and that's generally accepted to mean that it must be published in a peer reviewed journal. So any ingredient, so the graph process, you can go two different ways. You can grasp a substance by scientific procedures or history of use. Now, history of use must rely on use in food prior to 1968 and honestly today, most grass conclusions are based on scientific procedures. So, a graph to describe it a little bit better. A graph dossier is specific to the manufacturing, the identity specifications and the intended use of the ingredient. The manufacturing information includes information such as details on the manufacturing process that are detailed enough to show that controls are in place throughout the manufacturing process. And the methods used to confirm the identity and the purity of the ingredient are adequate.

Amy Mozingo:
Specifications are set that are acceptable, and contaminants are present at the lowest feasible amount. And that is something that's a very big deal now for FDA, because recently they did announce their closer to zero initiative, which there's a heavy emphasis on heavy metals, but that it covers all contaminants. They want to see contaminants in food ingredients to be as low as technologically feasible.

Dr. Alex Le Beau:
No. And that makes sense, which is, I think, has always been the goal of that process. So, please, I appreciate it. Continue.

Amy Mozingo:
So, one thing I'd like to talk about is what intended use means. Intended use.

Dr. Alex Le Beau:
Sure.

Amy Mozingo:
For grass. Grass is not a blanket approval that you can use that ingredient in any food. At any level. A grass is very specific. It includes the food categories that you're going to put the ingredient in and designates what the maximum use levels in those food categories will be. Now, these are key points, because this information is needed in order for us to do what we call an intake analysis or exposure assessment. And in the majority of cases, the exposure assessment, we perform that using data from the National Health and Nutrition Examination Survey, or in Haynes is the acronym that everyone uses. So, based on the survey data of what people in America eat, the selected foods that the ingredient will be added into, and the level of use of the ingredient going into the foods, we generate through a program, an estimated daily intake.

Amy Mozingo:
Okay, so we then take that estimated daily intake, we look at the mean and the nintieth percentile consumer intake on a per day basis, an amount per day basis, and also on an amount milligram per kilogram body weight per day basis, and using the survey data, we can actually get the actual body weights of the participants of the survey. So it is an estimate, but we're using the real data, the real body weights of the individuals consuming these foods. So this information, this output, is compared to the safety data. And what the goal is, is to ensure that the estimated daily intake at the nintieth percentile, which is the high consumer, is within the acceptable daily intake that's established by the safety data.

Dr. Alex Le Beau:
And it's important to emphasize that the information that we're using for establishing the safety of it and going through these processes. We're basing this on FDA data. We're looking and following the procedures for scientific procedure, evaluation of the safety of that material and using nhanes. And I'm familiar with nhanes. NHanes is from a national survey. It includes sampling of people all across the United States. So that's how we can use that data for determination of what the typical exposures would be in an average of nintieth percentile. One thing I'd like you to differentiate, and I think you did it.

Dr. Alex Le Beau:
I want to expand on a little more, is the difference between grass and a food additive petition. Is a food additive is typically included in, I'll just say, publications from the code of Federal Register or whatever saying FDA approves of its use. They have a review and everything. So if you could expand upon that a little more, just the difference between the food additive and the grass.

Amy Mozingo:
Sure. Well, the food additive petition process is rulemaking process. So what that means is that you submit the food additive petition to FDA. They do a review. The information can be proprietary, the data on safety can be proprietary, and you can protect pretty much all of your data that you submit on the ingredient for the process. Then once FDA reviews it, they issue a draft proposed rule in the Federal register. There is a comment period. FDA has to address the comments and make any modifications.

Amy Mozingo:
And then they publish the final rule in the Federal register. And following that, they promulgate the regulation in 21 CFR, which is the title that covers food and drugs of the code of Federal regulations.

Dr. Alex Le Beau:
Sure. And again, that difference, that makes a difference between that and grass is grass. You don't have to notify FDA on. They do have a process for it.

Amy Mozingo:
Yes. And we can go a little bit. It's actually kind of a pretty interesting history there on what they've done. So I mentioned earlier the 1958 food additive amendment. Following that, a list was published in the Federal register that same very year that became to be called a grass list. So over the years, additional grass substances were added and regulations were promulgated in title 21 of the CFR. And those are in parts 182, 184, and 186. Now, these include substances that FDA has affirmed as grass, now affirmed grass substances.

Amy Mozingo:
These are substances that the FDA reviewed based on a graph affirmation petition from industry. So keep in mind, this was not pre market approval. A request that FDA affirm as grass was a voluntary exercise. Okay, so let's fast forward to 1997. FDA issued a proposed rule that would eliminate this grass affirmation process and replace it with a notification procedure. The proposed rule invited parties that had determined use of a substance as graph to notify SDA under this interim timeframe, which the interim timeframe is between the draft rule and the final rule. Okay, so this proposed rule would replace one voluntary program with another voluntary program. The voluntary grass notification program operated under this interim period for 19 years before they issued the final rule, which was issued in August of 2016.

Amy Mozingo:
And what the final rule did was it formalized the notification procedure and established regulations for the notification process. So FDA reviews grass submissions, and the agency response is to issue one of three types of close out letters. The letter that you want to get is one that says FDA has no questions about the notifier's conclusion of graphs at this time doesn't mean that it is set in stone as new science comes available that it may change. The other type of letter that no one wants to get is a bad day letter in which FDA says the notice does not provide a basis for conclusion of graph staff. And then there's a third type of letter, which is a letter that notifies that at the notifier's request, FDA has ceased evaluation of the notice.

Dr. Alex Le Beau:
Go ahead. No, please continue.

Amy Mozingo:
I was going to say, just to note, the graph notice inventory is available online. It includes access to all of the graphs, cas, their amendments, and the FDA close out letter. So it's very transparent. And currently, there's over 1100 notifications in the inventory.

Dr. Alex Le Beau:
Important again, as you said earlier, it's public information, so the information has to be publicly available. And we'll get into this in a few minutes. Is the safety studies that go into making the determination of grass. Those are published in the peer reviewed literature that's publicly available for everyone to see. So even if they have the safety dossiers and they say, well, I'd like more information, they can go get the references from where it's published and when they did the studies as well. One thing I'd like to have you kind of discuss a little more is the concept of self determination of grass by manufacturers. Can you give us just. And some people may say, okay, well, I've heard grass.

Dr. Alex Le Beau:
I hear what you're saying. Can you just give us some examples of what grass ingredients or things that have been identified as grass ingredients so people can understand? This is stuff that we deal with every day.

Amy Mozingo:
Oh, sure. There's different fibers that have grass notifications. There are many human milk oligosaccharides that are in the grass notice inventory. And there's so many, likely because many of them have intended use of infant formula. And FDA really wants to see those notified. That's one of the unwritten rules that if you're going to put it into infant formula or USDA regulated food, you need to notify it. Otherwise you're going to have issues. But again, there's one pecan shell fiber, right? You don't eat the pecan shell, so it had to be grass because that's not something that was normally consumed by people.

Amy Mozingo:
So you have to look at it from this perspective. Also, you may have something that you have isolated the protein component from a food. Well, because you have substantially changed that ingredient, that food. You have to show that the manufacturing process and the specifications, the intended use, that's all safe. So even if it's something that may be common, that has been slightly modified, then that drives the need for grass dossier and graph occlusion.

Dr. Alex Le Beau:
No, and I think that's a very important thing to point out is, as you said, it could be a protein. It could be a protein in something you eat every day. But because the process has changed the manufacturing process to isolate that material, and I'll just say, concentrate it in a certain way, it's not only the ingredients, the safety of it, as you said, it's the process of it as well. It's setting the specifications, as you said before, for that one particular thing. Just because you may have ingested it some other place doesn't mean that you're ingesting it in the same way. And I think it's important for people to understand that it's all about what your exposure is. You may focus on something that has a higher fat content or a higher protein or higher carbohydrate. Is it higher fiber? Whatever it may be, it's understanding the safety of it in that particular exposure scenario.

Dr. Alex Le Beau:
That grass process is important for establishing the safety of.

Amy Mozingo:
Yeah, a good example of that is the psychosol, better known as alulose. There have been several grass notices for alulose, and the use level for alulose is reaching that top level where you're not going to see probably many grass notifications get any more significant additional intended use. Because once something, you have to also look at the background. So it might not be just your intended use, but what are other products on the market, what's their intended use? So you have to look at the total potential intake, including background. So that's something that can sometimes be a little bit tricky, especially when all grass notices aren't notified. How do you know how to assess background intake so that is one area. It can get a little bit tricky. But for the graphs, the notified graphs, you can take a look at those and you have to account for that background intake from other uses of a very similar, substantially equivalent ingredient.

Dr. Alex Le Beau:
Now, one question I have is, and I've heard this before, as you said, you can go on the grass notification website. I'm not asking you speak for them, but I'm also say a general manufacturer that says, I want to make this same thing. The process may not be the same, the specification may not be the same, but they say it's already grassed. What would be the scenario there that that manufacturer that wanted to sell the ingredient would be facing?

Amy Mozingo:
Well, they need their own graphs. They really do. The nice thing, if someone has come before you and they have notified, is that you have access to that information and you can, for lack of a better word, piggyback off of data that someone else generated. So if you can show that your material is substantially equivalent and accounts for any differences, then you can bridge to use the data for that other ingredient. And that is one reason why some companies don't like to notify FDA of their grass. Conclusion because if they are first and they notify FDA, that becomes publicly available. It makes it easier for competitors to piggyback.

Dr. Alex Le Beau:
I was going to say, as you said, but that manufacturer still needs their own grass determination whether or not they're piggybacking or not. They have to do their own. And one important aspect, and we're going to get into this now, are the safety studies that I performed. You may be selling an ingredient that you're not using the same manufacturing process to make that ingredient for the use, and the safety study that was done for generation of that grass. So that's a whole new grass and potentially a whole new safety study that you may have to do or get back to for making that determination. So the safety studies that go into the substantiation of the grass or support of the grass, I kind of like to discuss those safety data requirements for you. And of course, it all depends on the use condition for that material. But can you kind of discuss the kind of safety data that goes into supporting the grass? The types of studies that are done, the things that you may know FDA would typically look at for this kind of safety study based on what we know about the manufacturing process or the ingredient.

Amy Mozingo:
Sure, you made a good comment about the contaminants. That is one thing that you have to look at. If you're using some solvents in your process or physical chemical synthesis and you may have some leftover chemicals, you really do need to dive into the exposure to those contaminants. And specifications should be set. And so in order to look at a worst case scenario, you have to take that top limit of the spec to determine what the potential intake would be of those contaminants based on the intended use. So that is one thing that you do have to tease out. Now, when it comes to the safety studies that are required to support grass, it is dependent on the type of ingredient. But in general, for a novel ingredient, there are a standard suite, if you will, of studies that's expected.

Amy Mozingo:
You have genotoxicity, which there's an Ames test, and we typically recommend an NVtro micronucleus to start. If that comes out clean, then that's great. You don't go any further. And then you also have a repeat dose oral toxicity study for novel ingredients that is really expected. And so that typically is a 90 day in rats. And you have to do a range finding study first to make sure that you get your doses right, because these studies do take time and they are expensive. So you have to make sure that you get the doses right. So you can establish a no observed adverse effect level.

Amy Mozingo:
And that no observed adverse effect level is what is used to help determine what the acceptable daily intake is based on applying uncertainty factors. So usually you take a look at the safety uncertainty factor of 100 and then you take that to determine the acceptable daily intake based on study data. If there's anything in the literature or any indication in the sub chronic study, the 90 day that there might be some issues with repro and development, then that may drive further studies required. Because for grass, the ingredient is supposed to be safe for the general population. A dietary supplement can label out pregnant and breastfeeding women. Foods aren't supposed to do that. Foods are supposed to be safe for everyone.

Intro:
Exposure science covers a broad subject area, including toxicology, industrial hygiene and risk assessment from occupational community or environmental exposure. Exposure scientists apply scientific methodologies to understand exposure risks and apply controls when necessary. We at exposure assessment consulting have this expertise. Please reach out to us at info@exposureconsulting.com for a free 15 minutes consultation to discuss the specifics of your exposure scenario.

Dr. Alex Le Beau:
Right. And I think that's important. I'll tease out a little more what you had discussed, but I think the important emphasis here for what the information that Amy supplied is. There's a lot of safety data or safety evaluation that goes into determining the safety or genuinely recognized safe status of a food ingredient. You're talking about, as Amy mentioned, genotoxicity studies. You're talking about sub chronic studies in rats 90 days, feeding them the same type of ingredient in different dosing groups for a certain amount of time to see if, as you said, any adverse effects develop in them. So one thing I want to discuss first, you mentioned the genotoxicity tests. Those are mechanistic type tests to, I'll say, screen for the potential, under the conditions of the study, for there to be the potential for it to be identified as a carcinogenic type substance.

Dr. Alex Le Beau:
So can you discuss that a little more on what is the implication of the genotoxicity tests and how, as far as the grass or the ingredient safety status of those types of products viewed for looking at the genotoxicity?

Amy Mozingo:
Sure. Well, we typically recommend, if clients have the time that they stage the studies, they do the genotoxicity first, and they don't proceed on the in vivo studies until they have the results of the genotoxicity studies. If they get positive results in those genotoxicity studies, there's really not much need to go any further because you're not going to be able to grasp the substance if you have positive results in an Ames and a micronucleus test, there may be, depending on circumstances, the toxicologist may recommend doing an in vivo micronucleus study. However, again, that's a case by case basis, of course, and it really depends. But that's why if clients have scheduled enough time in their product development plan, we always recommend doing the genotoxicity first.

Dr. Alex Le Beau:
Jordan, I think that's important to everyone, and I've run into this before, everyone wants to rush to the end, but it's important to understand that there are different stages, and there's a reason why we do different stages, because you don't want to be in the middle of doing your genotoxicity tests while you're concurrently running your 90 day sub chronic or chronic rodent assay, and you get something that pops up positive there, and what do you do then? So, as you said, the project planning is important, and I think it's important for people to understand that there's not a fast process. It takes time. There are steps that you have to go through for it.

Amy Mozingo:
Absolutely. And the other consideration, too, is you don't want to use live animals if you don't have to. Unfortunately, we still have to for establishing safety of food ingredients. But staging it in a way that you don't proceed with that step if you don't have to, is a good way to go.

Dr. Alex Le Beau:
No, I completely agree. And not only for the live animals, but obviously the whole effort, understanding, even doing your, I'll just say, homework before you get to the testing stages. Understand if anything's ever been done like this before, any safety studies in this arenas, and review those articles to see if there is anything that you may anticipate popping up on some kind of safety study.

Amy Mozingo:
Absolutely. We always recommend to do a preliminary assessment, feasibility and gap analysis first, before someone dives straight into placing studies, because as I mentioned, they can be quite expensive and going about it in a very methodical way saves time and money in the long run.

Dr. Alex Le Beau:
I was going to say, I know we're talking about food, but that advice has applicability beyond just the food arena. When you're looking at chemicals or pesticides or what have you, is understanding that it's not a fast process. There are safety studies and steps that you have to go in through. Like you said, a feasibility or a gap analysis to understand what you know and what you don't know is important for whatever you're doing in these arenas, as far as a regulatory process or understanding or establishing the safety of it, because there may be a lot of unknowns involved in it. So I think knowing what those unknowns are is just as important as understanding what is currently out there.

Amy Mozingo:
Absolutely. And also understanding what you can leverage. Right. What's similar enough that you can leverage it. An interesting example, a CDL glycosides, for example. People don't do testing on CDL glycosides as a general rule anymore because there's so much information out there and so many are notified to FDA. And one reason for that is because of an import alert for detention without physical examination, because way back when there was a lot of acidity leaves and crude extracts coming in. And so an import alert got issued for that.

Amy Mozingo:
And so the best way around that is to have your grass notice that you can point to on import to avoid any issues. But that's a good example of, in most cases, looking at a lot of the CBL glycosides. There's so much information out there that it is very rare that you have to do an excessive amount of testing.

Dr. Alex Le Beau:
So one thing also on the rodent side is that we talked about the average daily intake, and typically when you're doing rodent studies, you set up different doses because you want to know what the, I'll say, maximum dose is and looking where adverse events may occur. It may be where you have, as a manufacturer, have an idea where you want your average daily intake dose to be, but the rodent study tells you something otherwise. Have you encountered that previously?

Amy Mozingo:
Yes, sometimes people are disappointed, but you have to take what the science says and the grass has to be reflective of what is safe. So that has occurred, and I'm sure it will occur in future. That's just part of the scientific process of determining what a safe level for use in food for human consumption is.

Dr. Alex Le Beau:
Right. And I think it's important to. It's a scientific process, and I want to remind everybody, whether it's manufacturers who are listening or the general public, if the science says that we can't ingest something over a certain amount based on the animal study, then that's it. The manufacturer may go, well, I want it to be more, well, this is what the data is showing us. It can't be more than what the safety study is establishing for us to use. Again, based on the safety factors that we know, we're going to incorporate the types of uses that you're going to use this ingredient in. It's not just a quick, I'll just say checking a box kind of thing. There's a lot of process and thought that goes into establishing the safety of food ingredients for general consumption in the human population.

Amy Mozingo:
Absolutely. And just of note, in some cases, for example, if it's a macronutrient, say it's a fiber source, you may be limited as to how much you can give a rat. Right. And so in those cases, there are some different things that you can do because to support higher levels of use. But that may be a bit longer of a process than your first grasp, right?

Dr. Alex Le Beau:
No, it's also important to remember the process of doing this is important for the manufacturer, because if you start selling something where you haven't established the safety of it and it gets back to you, you're going to be looking at a lot of eyes from regulators or attorneys or whomever. This is your safety data to show anyone that has any questions. There's grass panels that go into it. It's not just one individual. There's lots of people looking and agreeing that this substance is safe. And it's an important process to go through that I don't think should be skipped. You sometimes hear about people who are selling products that didn't go through safety assessment. They're not often, but sometimes you'll see people either making claims or what have you that they didn't go through the proper process and they're paying for it on the other end.

Dr. Alex Le Beau:
So this is important, a process to go through, and it's a tedious process. Sometimes people think it's going to be over in three months, where sometimes I've heard people, including, I'll say, grasp, even food adaptations take three years. That's probably too long for a grasp. But when the regulator is going to fall for food adaptations, it's not fast. So people just have to understand that patience is sometimes needed.

Amy Mozingo:
Absolutely. It's not a quick process. Just because it's grass doesn't mean that, especially if you have to generate safety data, that's when you will have some delays. It's more than just a few months for sure. Right.

Dr. Alex Le Beau:
Working with those CROs, coordinating with them, managing them. You have to get on their schedules, too. They're just not waiting around, especially, and this is, again, beyond grasp. But during the times of COVID when people are wanting to register antimicrobials, you call up a lab and say, I don't have availability to get that in my door for like six to nine months. So you have to understand what the laboratory's scheduling is like as well. There's lots of stuff that goes into these processes that I think that it'd be more beneficial for the public to be aware of, as well as manufacturers.

Amy Mozingo:
That is very true.

Dr. Alex Le Beau:
So one area I want to shift over to. I know we talked about grass. I'd like to have you also, you talked about new tie interior ingredients. I'd like you to kind of discuss NDIs and their significance and their use. Not only the use for consumers, but from the regulatory standpoint as well. Please.

Amy Mozingo:
Sure. Well, the new dietary ingredient notification process is mandatory unless the ingredient is grass and in the food supply. And that same ingredient is used as a dietary ingredient and a dietary supplement in an unchanged state. Right. That means you can't do anything different as the exact same ingredient that has been grass, and it's in the food supply. So that is one way that a new dietary ingredient can avoid the new dietary ingredient notification requirement. Now, the benefit of the new dietary ingredient notification regulatory pathway is that the information that supports the safety does not have to be publicly available. It can be proprietary.

Amy Mozingo:
And the submission process for the NDIN is 75 days. That group has to evaluate the notification and close it out after it's submitted. Now that's a double edged sword, right? Because it's quick and that's great. The process goes quickly. But if there's any doubt, you're not going to have time to generate any data that they say there are gaps. The. And the NDIN process, it allows you to redact all of that proprietary information, so you protect your investment of the studies. No one else can use that data to support their filing.

Amy Mozingo:
So it's a great regulatory pathway if you qualify. But the challenge sometimes is, especially for, say, let's use an example, live microbials or what people call probiotics. A lot of times they don't qualify under the definition of a new dietary ingredient because the source of isolation is not in food. And if the source of isolation is not food, you can't say that it's in the food supply, and therefore it's a dietary substance that people want to get more of. And then you have to go down the grass pathway in order and put it into food before you can put it into dietary supplements without the notification needs. Sometimes it's a winding path, deciding what regulatory approach is best. But yes, the new dietary ingredient notification process is a lot quicker, but it's not without its unique challenges.

Dr. Alex Le Beau:
And again, I think that, as you said, it'd be a case by case basis on whether someone wants to go down that pathway or not. I think not only, as you said, the availability in the food supply, but their manufacturing process or what safety data they may have for the information. So what challenges have you run into? I'll say, for the NDIN process that.

Amy Mozingo:
You'Re able to share, I would say that sometimes. Well, with the new documentary ingredient notification process, any cited reference must be supplied in your submission, and that's going to be difficult if you have old data that you can't get the full copy of. But that has been secondary citations. Right. You can't use a secondary citation. It has to be the primary. So that can pose some challenges. The other challenge, as I mentioned, is that if the FDA has questions, usually they give you three business days to respond.

Amy Mozingo:
You can ask for a bit of an extension, but you're not going to get a huge extension, whereas the grass group gives you a bit more time. And remember, they have 180 days after they've accepted it for filing for a grass notice, they have 180 days, compared to 75 that the NdIn group has. So there is a bit more sense of urgency. And as I say, if in doubt, they throw it out.

Dr. Alex Le Beau:
Yeah. No, I mean, that makes sense. And I think that the information you're giving us, the 180 days for grants versus f 75, I think this is why it's critical to go to the people who have the experience, like you do, for identifying the best pathway, because saying, listen, the manufacturer may have an idea of, this is what we want to do, this is the pathway we want to take. And when you present all the options to them or all the pitfalls, but the potential pitfalls, it may change their dynamic. They may have something already planned out in their mind where when you approach them with this information, they say, well, that changes my plan on my end. So I think it's important to, before you head down this road, grass or ndins is consult with the people who know and have experience in that area, even for safety stuff, because I've seen people that think they know what they're doing. I don't know if you've seen it, you may have experience with it or not, but they come to you and they say, I already have had a safety study done on this particular ingredient. And you look at it and you say, okay, that's great.

Dr. Alex Le Beau:
It's not what we need. We have to do it again, or we have to do it the way that will support our grass.

Amy Mozingo:
And the pivotal information that's going to support it. The studies need to be done under GLP and according to the OECD guidelines, if they're not, then they're not going to be considered with the same weight as a GlpoECD guideline. It may not be adequate support. Safety.

Dr. Alex Le Beau:
Right. So I think the process of consulting the people who are in the know who can work as your representatives with CROs or with the FDA are the important people to assist in this process. Even setting know. And I know we're kind of talking general terms here, but even understanding, they may come to you and say, these are our specifications. And you may say they need to be tighter. You need an upper bound here. You just can't say, just have one number. You need to have something that says you're showing, you're working to establish, maintain the safety and the consistency as well.

Amy Mozingo:
That is so true. And that's something that I would say that more than 95% of the projects that we work on, we do have to have some discussions about specifications. As I mentioned earlier, the closer to zero policy. A lot of clients say, well, my heavy metals are set because that's what FCC has. And it's, you know, let's look at your results, because if your results are much lower, FDA and the expert panel are going to want to see a lower spec on those heavy metals. And for botanicals, it's so common to see a specification where a company has a standardization of greater than x percent of this botanical constituent and said, well, you have to have another upper limit, or we're going to have to use 100% for all of our assessments on safety based on the safety data for that constituent. So there's a lot of considerations, and it really impacts the way the grass dossier or the NDIm is written because you are using those specifications to do the assessment on the contaminants and the components of the ingredient.

Dr. Alex Le Beau:
Right. I think that's absolutely critical. What you want to do is minimize the potential, say, for any contaminants. If you're doing any of the animal or safety bioassays, you want to be able to say, we studied the ingredient that we are interested in. If anything was seen, you don't want to say, well, it could be the contaminant, it could be this. You want to minimize and specify, we are focusing on the ingredient. We're not considering those contaminants because they're just so minimal. We have minimal levels set.

Dr. Alex Le Beau:
So I think that's also critical. So hopefully, using the information that Amy has supplied today, again, I said this podcast is for the general population and manufacturers alike is understanding that there is a lot of safety that goes into evaluating the ingredients that we eat on a daily basis. There's lots of information that's out there, and you can probably look at it. It goes up and down on what's available in the news for, I'll say, food safety in general, but there's a lot that goes into this. And as Amy said, you can go look it up on FDA's website about the notification process for grass and see what grasses have been notified and find a list there. It is not a check the box kind of thing. There is a lot of safety that goes into determining what your exposures are, the safety limits, who can ingest, like we said, for new dietary ingredients, what the use conditions are. So I think that the information that Amy has presented today is very useful in just making people think that there is more to what they eat than just the thought that somebody just quickly looked at this.

Dr. Alex Le Beau:
Everyone says that, oh, well, the food supply is different than what it was before. This is why we do these continual assessments, because there are changes in the supply and we're assessing the safety of those changes that go on or new ingredients that we identify. Amy, do you have any last thoughts for anyone who is listening for the information that we have supplied so far? And again, I appreciate the information you've given.

Amy Mozingo:
I would just like to say, know the grass process is a robust process. If people follow the criteria that have been established for grass. So it is a robust process and based on the public availability requirement, that's where the generally comes in. The generally recognized comes in. It's a very robust process. And even though there has been some criticism that all graphs conclusions are not notified to SBA, there are a lot of really great companies out there doing very good work, and that is the majority of and not the minority.

Dr. Alex Le Beau:
No, I agree. As you said, they will have that grass determination in case anyone comes knocking on their door. You say, here it is. It's a robust study. It's a robust assessment that was looked at by toxicologists, safety people alike. And here's the information I'd like you to find where you think it is not safe based on everything. And a lot of times, like I said, if it's with companies who have the experience and have the robust studies done, it's going to be very hard for someone to say that there are any safety issues with what was done based on the experience of those companies. So, Amy, thank you again so much for joining us for today's episode of the Exposure Scientist podcast.

Dr. Alex Le Beau:
The information you have provided has been, I think, going to be very helpful to those who are listening as, again, as I said, the general population and manufacturers alike who may not even know where to go for getting this information. So I'll supply your information within the show notes. And we appreciate you joining us today.

Amy Mozingo:
Well, thanks for having me, Alex. It was a pleasure speaking with you today.

Dr. Alex Le Beau:
Sure. Thank you.

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