 Okay, I'd like to reconvene the chap and as a first order of business I think we need to discuss Our calendars and when we're gonna have the next Chat meeting so might could you? Take over on that. I don't know about you burn, but my schedule for the fall I'm gonna be teaching, but I'm pretty flexible. What is that the same for you? I'm pretty flexible too. Yeah, so I shouldn't be a limiting factor. I'm gonna have this So what we need to do is talk to the other members of the committee and see There are specific Dates that they cannot meet. I think we're talking about probably October November Late November would be all right with me. That's I mean the fourth week or in November is a third week, okay? Fourth week would be better Yep, well, yeah 15th work would work the week of the 15th no, I Could do the week starting with 22nd of November, right? How about the next week? Yeah, possible Outlook just broke down The first week in well 29th 30th and December 1st I'm praying Front end of the week is okay Russ, how's that for you? The week of the 6th this out for me, but I could do one two three That's that inside no problem over So the next decision is do we want to schedule a two-day or three-day meeting? To do we plan to invite other guests? Have you talked about that? We have not talked about that yet I think it would be good to renew the invitation to Tom Berg but other than that. I think I don't think we That I don't think there's a need to invite anyone else at this stage I would like to invite somebody who might help us to interpret the enhanced data because the deeper I get into enhanced data and extrapolating from the biomonitoring data to the dose the problem is That and hence data is generated after fasting Though I would have like to have somebody who can model out the fasting period and what does it mean in terms of exposure? Because we know many of the delights are mainly foot-borne and if you have fasting period of 12 14 hours that's a major influence of As a major influence on on the metabolite excretion and then of course in back calculating to the dose Chris, do you think you can handle that? Because that has to do something with with kinetics and because I think this is going to be a major point Those calculation of anyone in mind Not yet It's open for discussion. I mean, I'm I'm sure Antonia would be willing to come up But you know her She does the analytical part The other things I'm not sure. She's the right person, but she might know who is I read some Publications from I think it's Rick Stollard It's some calculations based on including the fasting period For the modeling, he's more of a statistician Pickable. Yeah, one is the date a Question of whether it's a two-day meeting or other than that and that question of what the agenda is Got to nail one of those down before we get more things on the table. I Would suggest we have a two-day meeting and Explore the agenda and then if it needs if it can be one fine if it needs to be three fine But let's start as a default for a two-day meeting. Okay Mike, where did you arrive in terms of dates? Add the options of November Somewhere between November 29th Get it and December 3rd with the I think flying the caveat that the 29th Not a good day the 28th is not a good travel day. I think was it the Tuesday was the 30th The first is the first day Hanukkah Which is it's not a religious holiday, but just young children Just for me And I could Why why don't we say second and third then but that means flying on the first Okay, I Guess Monica starts on the evening of the first Does this mean chaos for us international travelers? Or are we the second to third? Well, we're together with calendars should we explore an alternate to that in case we need one we're getting closer to the end of the year which is Not a good time 13th would be possible as a foldback, but I would prefer the date we agreed on first That would be the first choice, but I'm just looking for a backup in case we need it Sure We can week of the 13th 14th as a foldback 1314 13th and 14th is not going to work for everyone Well, I think going the next week we're getting too close to the Holiday, so let's go into January Yeah Andreas is not available And January is pretty open for me except for the 24th and 25th and other veterans age and orange and California So that week wouldn't be good for me the 24th about the week of the 10th fine Wins, okay, because we wouldn't have the building 18th ogre Chris January 18th 19th Yeah, well, I think that's this it's the 17th. I think so January are you gonna go to that? Yeah, I don't well, I didn't know that they had set a date. Okay, that's good It's SVOC's So it includes phthalates and also flame retardants and other volatile comp Bounds that you find in house dust and window film So it may be informative Okay, so we've got Dates December Two through three as a primary and January 18th and 19th as a has an alternative December dates don't work then Mike you're going to Work with the EPA in terms of their fall workshop on yeah, and now It was January 18 to 19th as the backup. Yes, okay, I will Coordinate with the PA listening so our possible dates and we do want to fight back Tom Burke possibly for another agenda item Information that we didn't get yesterday Since we continue to Struggle with this question of where does it come from in food and we didn't have the food center with us yesterday Would seem as though we should either Maybe first choice is to ask them to provide a written summary table for us that would be easily understood about what the levels are and what FDA assumes is the source of Phthalates in those foods where it's measurable Second choice be to have somebody come and talk to us next time If they could get those data to us now, it would be helpful to us to think through what We want rather than respond to it for the first time in December Think you know the answer is that what they if they have data. It's probably not very recent It would be helpful to know also what are their plans for gathering more data, right? And also there was a question raised the offer was raised yesterday whether we want to know anything more specific about drugs right by by class by agent composition by thali by age of Patient and that was mostly for diethyl valet Diabutyl to That will die most of their data or diethyl. I mean, I think they said they have Last Diabutyl And then the supplements and nutrition, I mean, that's that's a different Part of the FDA I guess a different part of the government. Is there any reason why it would be because Compounding of the pill. I think Holger you you have German data, right? I could provide for the next meeting the data from Germany in which medications Diabutyl and Di-Evil of the late are I don't have any data on this food supplements but Possibly it's possible that They're used there, too So I think we should really pinpoint it to Description drugs over the counter drugs and food supplements and in the light of the fact that the data from and Haynes is from the 2003 and 2004 I would be interested in delayed containing Pills at that time too because we might need this Information for interpreting the data because there are a couple of publications Linking high diabutyl for the exposes to the use of medication Yeah, and we had published on using the end Haynes data using the urinary levels and the self-report of medication use and It was Must I think it was 2003 2004, you know and in Haynes it was two to three or all I'll check but From the fourth report is two three to two two oh four That's the three to four, but I'll but I'll check and are we ready to tell Abbey in Stephen Exactly how what form we want the data like age groups or whatever or do we want it we could Continue to Think about that Was it the sense from the rest of you that what they had to do was generate these data or is a matter of what they send I think it's a database and they could summarize it in any Different ways So the honest I had a look into this database some of the data it didn't help me much, but Yeah, I but I think they have More info they may have more information than is in the public database and so they could You know class things by type of drug or something like that. I think that's the I think that's the difference I think without seeing something of what they have it's hard to know what to ask for Based from my perspective, so I mean I could take a take a stab at Now if we ask them to stratify it by age and by gender or Something like that. Yeah, just so we get to see what they have. Yeah, are we assuming that they might give us Urine data as well as blood data We're talking about in Haines. Oh The FDA Yeah, or the drugs Drugs we're talking about what's in the formulation. Oh, so it's just exposure, right, right exposure. It would be the sort of Scenario-based exposure and Haines. We're talking about it's it's essentially I think it's all Yeah, and I'm not well anyway, I'm not sure I don't know for certain that FDA can go back to 2003, but they probably can age gender And a year something like that Okay, so we've is that everything that we think we need for the next meeting Well, I will ask about pesticides although It there may not be I Think like a lot of things everything's being reformulated But I will ask That part of EPA Holger did you have some other? I Was it was a separate topic, but about the alternatives to get more information on those Jazz I mean Dinch if there's more information Well, I think I Mean I think we we have what there is the Versailles report and The Nick there is a Nick Nass report Which I'll make sure if I didn't send it to you I will Make sure you get it and then back to Holger suggestion about Rick Stahlut. I mean Rick Could at least present the data from his paper. I mean he could do it relatively quickly I would think in 20 minutes But in terms of you know someone in the area of pharmacokinetics Like I can't think of someone within the area of phthalates. I mean there's a lot of people You know that that have done this with dioxins or Pesticides other chemicals I would think that it's the same principles that they could apply I have a good working relationship with metal over from us ebay. He's living around the corner He has experience on satellites and I think he could give us a little introduction to the problem I think it's it's the problem with enhance with the fasting with the data generated after fasting is a major issue We have to talk about what is the impact of fasting on Exposure to non-persistent chemicals, which are mainly football and especially for DEHP and the and the high molecular weight delights So are they routinely take the samples after fasting? Requirement they're asked to fast. I think it's overnight and those seen in the afternoon. I think it's six hours at least Variable that describes how long they fasted But it's it's given in the questionnaire and that is I mean is that because they're collecting lots of other things like cholesterol and Yeah, so that you know could on well underestimate the contribution from food, which is Significant Holger in your paper. You've got some nice graphs showing Dalit levels dropping With 48 hour fasting, right? So I mean can't they considerably drop after 12 hours of fasting But I'm not the expert to interpret interpret this data for the whole enhanced population But the graphs that you've got in your paper could be useful in You can use all the pharmacokinetic graphs the elimination kinetics from the from the oral dosing experiments and the fasting graphs are the same So there is the data is out that we just need somebody with With pharmacokinetic toxicokinetic background to model this into the enhance population The names that come up to my mind. It seems to me that's a That's a research project. I wouldn't make it that complicated. Do you think it is that complicated? It can be but I don't think it needs to be okay could find I like think simple potentially, you know, whether the levels are 20% lower than you would expect because of fasting or 50% I mean more of a range I would think so yeah I mean you're talking about correcting for them or just assessing the impact you have to correct for it Well, if you're in a fasting window of 12 to 24 hours, it's a dramatic correction. Yeah, and actually six is In a way, it's worse because it's somewhere in between But the slope is probably steep I think this is a major issue that has generally to be discussed regarding and hence data and Probably most data because I know most studies probably don't collect that information You know when was the last time you ate something With the spot urine samples You know it from the german environmental survey. There is no fasting period That's the major difference between the german data from the environmental survey and from enhance Could we approach it sort of in a two in a tiered level one being a kind of a simplified Approach where we just do some corrections based on the data that you've got in your paper and then and then get maybe somebody more Of an expertise in pharmacokinetics that can Evaluate, you know, how Close or far off that simple My point with that might be a project Was simply I can rephrase this and ask do you think that say if we confront matt lober with that That he can do it As part of a presentation to us I would think that would be possible maybe together with Rick's experience or with the experience he made Right. Yeah, I I would think you could pair it with rick stahlhardt. Yeah I think it would be a great idea That's something that Could be accomplished before our next meeting Accomplished and then presented at the next meeting or yeah, I think so We would need to approach these two Entry searches so we would want both You know matt lober and rick stahlhardt It's stahlhardt. I don't know Yeah, where's rick? You a university of Rochester with shana Holger to help me explain to them What it is we want or maybe just have you do it They they both of them perfectly know the issue They will know what you're talking about But we're asking is how to adjust or At least to explain the issue I think rick would be able to explain the issue And then matt in terms of how to adjust or what kind of Magnitude of the differences may make I like andreas's point if we could get them to actually do it and not just talk about it. Yeah And present us Yeah Actually, I I would love to have a compilation as russ mentioned it of which of the studies In our focus are based after are collected after fasting and which not And it's very difficult to to find this in the materials method materials description So regarding in hains, it just came to my mind a couple to my attention a couple of months ago As I think it slipped the attention of most of the researchers in this field and as you mentioned it Mike many of the studies are initiated to get clinical parameters and they are No, you get them after fasting. I mean we do uh Kent Carlson my colleague here is Uh trying to keep track of the different studies and I don't know if he knows that but maybe he could find out what the Procedures are in the different studies around the world. Um, I mean, you know what what the german study is doing, but I'll ask him if he knows about anything about this um, because I think once these things start they tend to Sort of follow method methodology wise. They tend to follow one another a broader issue I think we need to discuss Are we going to do a risk assessment? What kind of risk assessment are we going to do are we going to do it? as a committee Are we going to ask someone? outside to do that and provide it to us Because I'm I'm a little bit unclear as to What our path is to completing our charge I mean if you're talking about how the the chap operates The ideas for the the panel to do it although it may be possible to get Help with some certain things Certain steps or something as long as it's done to your specifications That's allowed, but in general it's going to be the panels it should be the panel's risk assessment now As far as operationally what to do and what to include I mean that's up for discussion I think You know the nuts and bolts of doing it, but I think the expectation I mean it is the chap's risk assessment Again, this not being my area. I'm I may be asking some Well, no this is this is um, you know, uh, other committees May I mean, I don't know exactly how they work, but I know they contract out a lot of material a lot of the work and That's A little bit different. That's not how the chaps have been done in the past, but Of course the given the size of the the task will Get As much help as we can Well, let me try and make my questions a little bit more specific EPA is going to have a workshop where they're going to be looking at phthalates And they are going to do a cumulative risk assessment eventually eventually I think this risk asset or this workshop is going to be Just to hear to discuss and to hear from like we did yesterday How to go about it What are the end points and all of the the same stuff we talked about yesterday the things that we Learned a lot yesterday, but I think the We have to sit down and say, you know, this is in this is out. We're going to do it this way not that way Um, but my point is that eventually they're they're going to do what what we I think are being asked to do well what they're what the epa iris program is going to do is um Well, they're sort of in in um new territory Because normally iris does they do the hazard id in the dose response assessment Um, and of course we're doing the whole thing That's the difference between us and iris at epa someone else, you know, they do that And then other people take the iris and in their iris report might be applied to many different risk assessments But but can I assume correctly that Given that epa has contracted Uh and an a s panel to Tell them, you know, how to conduct cumulative risk assessment in 2010 That's been published. Yep that that's what eventually they will do. I think, uh, most likely. I mean Why I mean, I think it's a it's a very good report. Yes, and pretty clear, uh I mean not that I understand all the subtleties, but It's it's it's pretty clear what the direction is. Yes um So my question is if if that's what they're going to do is that what we should do in other words Is that the state of the art? Um, well, I think that report is It's the state of the art for the Valley syndrome effects Can I just uh, I think it would help at this stage to if we turn again to the charge in the law? Yeah 26 and 27 of the unofficial compilation Yeah um What what it says there in my well, it's probably open to discussion But I would say that what we are charged with under b examination does not necessarily mean that we have to do A risk assessment in the sense of a risk characterization according to the silver book Right What it says is, um We're supposed to examine all the potential health effects Now, I think it's a little open to interpretation but precisely that mean but I read into this that this is not necessarily A full blown risk assessment in the sense of risk characterization where where you First consider exposures and then map it against Assumed safe levels and then come to a decision Are we now in the zone where the red light begins to flicker or not? Well, I see what I mean I agree. It's a I think it's a decision point The chap has to make as to whether to focus on those, you know, phthalate syndrome or to actually go the Um The distance on all all of those other or other end points beyond that. No, no, no, I think we misunderstand each other Yeah, what I'm saying is uh I think definitely what we are supposed to do how I interpret these uh under b what is listed in the law We definitely have to do what I would call and what's commonly called a hazard assessment right right But not necessarily a risk assessment right and and that's what I'm trying to say. I think that Well the keyword it's not necessarily and I think the chap has to to decide whether You do the quantitative on multiple end points or just the one. I mean, that's your decision Not even even if say we decided on a critical endpoint, let's say hypothetically the phthalate syndrome. Yeah, I What I read here, I don't necessarily understand To mean that for even for the phthalate syndrome We have to do a full risk characterization in the sense of a risk assessment in other words Considering exposure first then considering hazards and then come to a conclusion about risks Well, we have to be clear about the language here Some people understand different things by risk assessment and risk characterization But I think that's my personal interpretation priest correct me and maybe we have to come to agreement here now I read this to mean Something with an emphasis on hazard assessment definitely. Yeah, we also have to look at exposure. There is a number What was it? Yes, number number three consider the levels likely in children etc etc. Yeah, but I think I would ask the panel to consider Whether they whether you think Whether you interpret anything written down here to mean a risk assessment or a risk characterization where you compare Quantitative levels dosages exposures associated with certain hazards and then make the comparisons with exposures And that's why I brought up this discussion because I don't think we've resolved at least I haven't in my mind How we're going to go on this And it seems to me that we that's a critical decision we need to make up front because If we go and we say we have to do a quantitative cumulative risk assessment Then do we have the expertise to do that? It's the next question. So I think we need to resolve what it is we are going to do and also Have a justification for that So because it seems to me the state of the art I may be wrong because it's not my area Yeah, that's overbook In terms of how to how to do the kinds of things that where they're really more like the I think the blue green book Nrc the or that with all each one. Yeah Um, can I just ask a point of clarification? So andreas are you saying I'm thinking back to the courting camp fowl's paper that you presented to us at our last meeting Where are you relative to what that approach that you have in that paper? Are you saying that's the approach you don't think we need to do? I'm not sure I know what yeah. Yeah, that's what I'm saying Yeah, yeah, no What what we did there in the courting camp fowl's paper is a it's a very crude first approach at Some kind of risk assessment cumulative risk assessment what this paper does more than anything is highlight the the knowledge gaps And probably maps out a possible modest operandi very crude. There are alternatives. It needs to be refined but I I see nothing in these Under be examination here that would suggest That we should Carry out something similar. I think the emphasis that that's my interpretation is more on hazard On hazard assessment What do you mean by hazard assessment? Well, it's the usual the usual Triple jump in risk assessment. You look at exposure You look at hazards of chemicals and then you put it together and carry out what's called a risk assessment or risk characterization By comparing by asking the question having say established a level quantitatively of a chemical where we think It is not safe anymore. And then you ask the question. Do current exposures exceed that or come near it? Yes, or no, and that's called risk assessment I don't think we have to do that last step I'm not sure, but I think we should discuss that Well, I think I think it's implied. It doesn't doesn't say it explicitly, but I think it's implied And treas how about number four under there considered the cumulative effect of total exposure I mean, how how would you do that otherwise? Yes, I think that's That's a point Well, but it says consider well Yeah, of course we can consider but Yeah, I think Russ. Well, yes, we we need to come to an agreement there I think it is open to interpretation Our consideration there would be a recommendation And encouragement that EPA would proceed with a cumulative risk assessment of the phthalates but that might Be responsive to that just simply to say that without the need for us to do it ourselves I would like to continue what Andreas has Stimulated us to think about because I think that is something that we have to have this discussion Or we will continue to gather information and not know what we're going to do with it With the possibility that we will end up collecting information that we don't absolutely need to answer the specific questions And we won't have the information that it does take to answer the questions So my thought was to step forward And look specifically at what cpsc has asked us to address and in addition to this there was a request For us to have some advice On what to do with these phthalates that have already been banned temporarily and should that be extended or should it be dropped What about other Phthalates and what about alternatives should there be something else banned should there be some restrictions that we would suggest as opposed to banning So I would use that as a very specific request The cpsc has made to us and if we don't answer that and we answer a lot of other stuff They may feel that they didn't get from us what they really asked us for so Looking if we can agree to the interpretation of Specifically what mike has told us about these banned and unbanned phthalates I think that That leads to a discussion of what do we need to have in hand to be able to answer that specific question And if cumulative risk assessment is needed to be able to do that which I don't think it is Then we would have to do that or we would defer to epa Since they're probably going to do it anyhow But the risk of two of us doing it is that they will not agree That would be bad For regulators. Well, I think We don't have to agree And and it also depends on what the disagreements are and why and certainly Uh, but I think you know you made the point the other day uh The bottom line is We're asking the chap a Shall read Blah blah blah Make recommendations to the commission regarding any phthalates or combinations in addition to those identified in subsection a Or phthalate alternatives that should be declared banned hazardous substances in other words Shouldn't be allowed in in in some of these same Children's products, uh, and then uh a little farther down. I think based on That the staff also has to decide whether to make the interim ban permanent Um, if we can work from Those specific questions and back away a little bit and reach agreement on what data do we need to answer those specific questions Then we at least are being responsive To the fairly narrow question that they have asked of us And then if we want to address things that are Out on the edge of that that have to do with phthalates in general or other phthalate related issues that Are perhaps adjacent to the specific ones that cpsc has asked us to address We can do that if we want and if we have time If we have the information but My suggestion is that we can I like the hazard assessment approach perhaps because that's what I have done in my career as opposed to the more specific Modeling and I'm not against modeling if that's the way to go But I think we can perhaps answer these questions through a hazard assessment approach And perhaps the data I mean we've done this we've done hazard assessments with less data than are available on phthalates So I think it's doable And I think if we can reach agreement starting from the endpoint and working back a little bit We will be More efficient in being able to get this done if we just focus on the the phthalates that are currently banned I mean is it safe to assume and I don't know this area that those were not banned on the basis of a cumulative risk assessment Right It was they were banned on the hazard assessment process that you're Talking about Is that correct? I think that's pretty much it. I mean I there was no cumulative risk assessment per se I think they were concerned about cumulative effects I would ask if we could be a little more specific. I think you guys are using terms and I'm not sure the distinction If I'm sorry, I apologize No, I'm in the same boat when you say risk assessment as opposed to hazard assessment I don't I don't know exactly what you're saying if someone if either burn or Andres could be more specific. It would help me a lot What are the steps that we would take and go and decide that the three that are banned stay banned So and in particular, I'd like to hear relative to what I understand andres in the andres Sorry in the courting camp fast paper relative to that what's on the table or off the table from that exactly Can I Yeah, I totally agree with what what burnt just said we I I I think that's the bottom line. We let's work backwards and ask the question What kind of information do we need in answer to fulfill the charges? And what would be a very helpful and you said it already would be to Get information about what criteria were used in order to Um come to the decision to ban the three ones in the law Is that documented somewhere? What criteria were used? Um, I I don't think it is that well documented. Uh, uh I think that's the problem. I I think that the european ban Is uh, there is a little explanation in the in the um documents, but In ours, there isn't the law itself doesn't really have a justification In there's as far as I know not much of a Of a written history of of how and why things were done. Okay, if that's not the case then I think we should A first step would be for us to reflect on criteria that would Support a decision to ban something But I don't know what they are, but I think we should be clear about them and secondly in answer to your points chris, um I'm also aware the terminology and the use of phrases in this area is sometimes a little confusing and I would strongly Recommend since we are operating in the usa to follow The terminology used by nrc and starting with the red book ending with a silver book Yeah Shall we agree on that and these terms are very Clearly defined In the silver book. I mean we can take the silver book It goes back and explains the the whole history of how they Develop this visc assessment framework and the terms they use shall we agree on that for simplicity? Certainly agree with that I think for my enlightenment and and perhaps chris as well if if one of you could Outline in general terms what the process is That would be helpful to me okay, the I will have to pass over to some of my colleagues here because but generally the the um And that is terribly important and often neglected and I think that's what we should apply ourselves here to the the process starts with a state of problem formulation and defining the context and I think we're about To do that and we are very near to that point So that that step is so important It then as burnt has outlined already That helps us to decide what kind of information do we actually need So we need to define the context and the problem I don't think that should be very difficult and then the core of risk assessment or risk characterization begins with exposure assessment and Holger for example is an expert there It asks the question what are what are likely exposures to the chemical considered this will vary According to population subgroups age, etc. Etc. But it basically asks that question in parallel A process goes on which is commonly referred to as hazard assessment. It asks the question What information do we have first of all qualitatively on the effect profile Produced by the chemical in question Yeah, we've already also considered it partly, you know counts Da da da all the end points what is happening? And secondly it asks the question is there quantitative dose response information available for any of these endpoints and if yes Um, it then if possible concludes with a process whereby Risks associated with certain exposures or dosages are quantified So that's that box. So exposure assessment has an assessment goes on in parallel Then the final step of risk assessment or risk characterization Is to unite these two steps by asking the question Are the levels that we've established as likely to occur through exposure assessment Are they reaching a zone which the hazard assessment tells us is associated with risk? Except all this has to be done in terms of a mixture not a single chemical Yes, that's an additional issue, but there are there are ways of Doing these approaches have been mapped out how to do that. I mean in a sense Um If you're going to do mixtures you kind of could start all over I mean Do a hazard ID for the individuals, but then for the mixtures Um in dose response for the individuals and then for the mixtures. So it's It complicates it that much more So andres you would not support us using a hazard index approach Well, hazard index or whatever is far too specific an approach. I mean, that's just one way of of Doing a cumulative risk assessment. There are others But let's not get too hung up about a hazard index approach or not At this stage I'm sorry to keep pushing you, but I'm Why not? I it helps me if I can think through those kinds of steps. What are we gonna when we're talking about data? What are we going to do with the data? We keep talking about biomonitoring studies Trying to and I I was thinking of blending down biomonitoring data into No, I think I agree with burnt what burnt says if We have to be clear what what we What we're aiming for and my feeling is that In order to reach reach decisions about continuation of of prohibitions and bans Um, I'm not sure we need to get quantitative or let alone Get very complicated with with mixtures risk assessment or cumulative risk assessment. That's my opinion, but We we should consider that first and to in order to simplify because Otherwise as burnt said we end up in a situation of having assembled facts Which then we realize at a later stage. We don't need at all Am I correct then in in this approach you've outlined if if holger were to convince us that Cumulatively we were being exposed to One milligram per kilogram per day of phthalates and we know from Animal data that Three milligrams per day per kilogram per day causes an adverse effect Then we would apply some Factor to say that that's close enough to The animal data that tells us it's adverse that we're going to say this is a problem in humans Yeah, that is one way, but I would say That is already very quantitative and potentially Complicated. I mean in my mind mixtures risk assessment or cumulative risk assessment would first of all start asking questions like such as What is the evidence that co-exposure to several phthalates in fact? Qualitatively exacerbates risk. You don't have to be too Quantitative you ask questions in what direction Would this likely Move a dose response curve for an individual phthalate questions like this Without having to be too quantitative at this stage Or similarly What is the likely anticipated effect of co-exposure to other anti-androgen? Etc. But isn't that sort of approach Important or maybe potentially the most important When it's the when you're in the process of trying to gather data So if you don't have to go out and get the quantitative data Then you can start asking qualitative questions and then along the way decide Yes, we need to go further or no, we don't need to go further But I think we're in a position where we've seen a lot of data And we have it at our fingertips already So yeah, I I would propose that we go ahead and think about more of a quantitative approach No, I think steady steady because Why would you why would you need quantitative data on something very complicated cumulative risk assessment if the question is To decide whether we want to Whether we are of the opinion that the existing ban on certain phthalates should be continued or not in my mind You don't need this information in my mind what you need In order to answer these questions is a is a hazard assessment I guess the problem gets back to what do you mean by that? by hazard assessment Because I don't quite follow how you would do that in a qualitative sense only Come to the conclusion that something is bad because to me That almost implies that there has to be some quantitative aspect of that. Am I wrong? I mean, well, I see it that way. Of course, that's what I do, but Hazard assessment has quantitative aspects dose response analysis Well, once you do dose response, then you're moving beyond The just the hazard assessment, but I think Ah, okay. That's a terminology issue According to the silver book you don't maybe we should look at that and yeah but uh if Suppose we did a the most simple minded kind of a quantitative assessment Not worry too much about, uh, you know advancing the state of the art Using the principles applying the principles in the the NRC report on phthalates Maybe even limiting it only to the phthalate syndrome effects for starters at least Is is that doable? Of course, of course But here's a thought which Which I'd like to put to you for discussion Maybe that makes it clear In my opinion, it is very problematic to Support the decision for or against a ban by doing a full-blown risk characterization risk assessment. The problem is this Holger has has very eloquently informed us about those substitution processes, so Um Experts to phthalates are they're they're like moving goalposts. That's already we are fully aware of this a substitution process going on because Decisions are made by industry to Limit the use of certain phthalates which they regard as Problematic or for whatever reason and there's a move towards others. So for example hypothetically a Due to this process a risk assessment for the EHP may conclude that Because the current exposure levels have gone down That the risk attributable to DHP is now I'm making up an example negligible Right, right, then if you want to use that outcome of a risk characterization risk assessment process That would be typical If you want to use that to now As a criterion to decide on a ban or not you may end up in a very absurd situation You then decide okay currently nothing to fear from the EHP Yeah, the reaction to that And so then hypothetically you would argue No need to ban the EHP if this happens Then there will be a substitution process going on in the other direction. We will see more exposure to DHP And then in the future you might might find yourself confronted with a situation Aha now exposures to DHP are so high They're getting us into the zone of attributable risks hypothetically Right, and I think so I conclude from that that a full blown risk assessment Is unsuitable as a basis to decide for or against a ban It has to be based on a hazard assessment That makes sense, but couldn't a Risk assessment and form a hazard assessment in other words. I understand what you're saying There's a moving target in terms of the exposure levels of these chemicals And we probably could even study that and enhance if we had had the opportunity to look from year to year to year, right Um, but but we could we could also You know make up I shouldn't say make up but consider scenarios where we say, okay now if DHP actually did increase by 20% Then here's where you are if it decrease, you know, we could we could consider it in a lot of different ways Right or one one thing I've done is if you you know turn back the clock to a certain date and say well You know when this whole business started Uh, you're darn right. You wouldn't you would definitely ban this chemical And you wouldn't want to replace it. I mean there's there's ways to deal with the moving target issue um, I think that's Compared to the other issues, uh, not not uh insurmount insurmountable, but um I know I know but it helps us Answer the question according to band which which burn burn and burnt us as brought up What kind of information do you need if for example? We reflect on this a little more than immediately becomes clear That for these discussions, we don't need exposure data Well, there are other there are other points here in the charge Where we do need exposure data, but in order to argue for or against a ban of certain satellites, we don't need exposure data Well, we need to have the hazard profile But when you say exposure data, do you mean like biomonitoring data or do you mean hypothetically like for example, we have data showing migration from the products and so you could Say, uh, you know given the Uh, known toxicity characteristics and this amount of exposure It would be below any level of concern or above and um Assessed the alternatives that way, um, so You know If a particular alternative say didn't migrate Um It could have a higher toxicity if it migrated a lot it would have to have a much lower toxicity but I mean you're you you raise, uh Good good points, uh, and it's um, but You're right. We I think we need to sort of think through What are the steps? That we want to do to answer these different questions And what do we need to do? What do we um Want to do or and what can we do? Yeah, and and I'm just wondering andreus sort of to get us off of Starting gate here I'm a very visual learner. So I have to see things To really analyze and digest Would it help us if you were to use the process you've been talking about? With relationship to the three that have been banned And go through your process And show us, you know, what that would lead us to That way we could say that's Okay, we should go or I'm being put on the spot here. I don't know I can I don't know I can I can do this But that's why I asked is that it's a documentation of the decision-making process What criteria were used to arrive at the decision to ban the three satellites and the law? Yeah, and I I don't think there's a lot um Well, phil that go ahead anything we can attain that's useful And clausen with latheman walkins um in 2005 There was legislation in the eu Which looked very much the same it put a pretty much permanent Well, not on any of them wasn't permanent, but it was a a fuller ban on the three lower molecular weight and then a interim tight ban on the Higher molecular weight phthalates it did provide for a reassessment of that which is happening right now With regard to the higher molecular weight particularly dinp and didp They had also done risk assessments that showed no risk But they decided to go ahead with the legislation and explicitly stated that was on the basis of the precautionary principle After that was passed california past legislation that was explicitly modeled on the eu And the legislature did no kind of hazard assessment. They just picked up on what the eu had done when the cps cps ia Was being promulgated Senator feinstein from california Wanted that phthalates added to the cps ia on the same basis that it was in california So again, it was added to the legislation Really as a political process with no kind of hazard assessment explicitly done by the legislators And it's thank you. Uh, I mean that's my understanding of the process. I don't know that there's a Written record that we could refer to um, it's it's For me at least it's second hand information third hand fourth whatever um But that's my understanding of the process, but there wasn't a uh Um You know, it's not like a formal rule making where you do a risk assessment and so on there were risk assessments done in the in the eu and it's debatable They don't necessarily They didn't necessarily support the ban the eu ban I think the eu ban was more of a precautionary print as as they call it in the eu If you're not sure ban it Kind of approach And I I think anything after that Simply mirrored what was in the european or more or less mirrored what was in the european ban and the As part of this um, that They said oh well, we'll have a chap And the chap is to was kind of a A multi-purpose it's to look at The the alternatives And also to do the actual risk on the um The three interim banned ones or weigh in on the three interim ban ones and to do the risk assessment. I mean I I don't think anyone Would argue with the the three permanently banned ones They're well There's no risk assessment in part because they weren't really being used I think that in the eu ban they said we we did the Put the three permanently banned ones in not so much because they were being used But because we didn't want them to become substitutes It was a preemptive Act You know the other three the interim banned ones. It's you know, they're not It's not so clear You know dinp is May fit in the um the phthalate syndrome category, but it is weaker the other two I i'm not so sure Uh, you know, I don't think there's any strong evidence That they caused the phthalate phthalate syndrome things. So you know those they're in sort of a An in-between category So for us they ended up as a as an interim ban and they talk about this a little bit in the the european document which is on Your cd, but i'll make sure you can Find it if you want to read what's there but but that's that I mean the The I guess the answer to all of the some of the questions, you know, why are you doing it this way? Why is congress doing it this way? I mean the chap is to answer some of these questions Yes, thank you very much for these explanations Um, but I think it would be a little unfair to summarize the precautionary principle as applied in the eq by saying if you're unsure ban it It doesn't work like that If we did it if we did it this way, uh, we would have no cat chemicals. Well, we'll instruct the jury to ignore that remark but Having said that If we find that the criteria, you know, if we find that the criteria used are shall we say A little obscure then I would think it would be one of our key tasks to Reflect a little on these criteria to be absolutely Transparent and a good way to start would be to consider the three data banned already and reflect Reflect on criteria and arguments which We think would support and justify that with the aim of applying it to the others and then see where we end up Is that a workable way forward? I think I think we will we will have to be transparent and clear with criteria Is and you had a comment Yes, my my assumption that when a decision is made under the precautionary principle There's an expectation that when data are available it'll be analyzed And it isn't a matter of second guessing how somebody else made a decision that decision wasn't fully based on data It is based on on a composite of of things that were true at the time One of which was there wasn't enough data to really make a firm decision Or we're going to make one anyhow So we're not we're not at risk of second guessing somebody because now we have data And that's how the process should work But make a question of view regarding what the options are we've only talked about banning or not banning Isn't it possible that something could be restricted in its content in products? Without banning it and it would still therefore be useful in products But we have restricted the level in it so that what migrates out into children's mouths or skin someplace or in the diet Is restricted down to a level where it represents an acceptable risk Now maybe that level would have to be at a Concentration where the product no longer is flexible and therefore the addition of a plasticizer is a moot point because you it wouldn't work at that level But it kind of keeps us out of the mentality of saying that it either has to be banned or not and That's a good point. I you know I The term banned hazardous substance it I think that it literally means something that doesn't comply with our regulations. So It's unfortunate to have the word ban in there, but it really means well the other The six phthalates are limited to point one percent. So in effect, it's a it's really a performance standard You could say or something like that. It's a regulation not so much as a ban We don't we can avoid using that word and say regulate or limit It already does what you what you just said it Regulates it to a certain level right and we don't you know, I think it's okay to Think outside the box a little bit. We it doesn't necessarily have to be a thumbs up thumbs down it's a It could be uh some other uh None of the above if that's what you want to say Managing it. I mean the the step that wasn't added here is risk management And if the risk can be managed by lowering the level to an extent where the exposure Is not high enough to be of concern relative to the toxicity Then it is successfully managed We haven't talked about for what part of the population is it for everybody or just a subset or for just those who are insensitive Those are other issues that we need to deal with as we Talk about are we comfortable or not with a certain level of exposure? but it make by By managing it to a certain level makes it more of a quantitative process and not just an all or none process I I guess certainly that thought process Is would would be a criterion to to support this decision making that's one way But there are others but that's certainly one way I think all i'm saying is we have to be clear about about this And and also let me add I don't think that's solvable In a wednesday afternoon it requires careful condition and maybe that's one of the pieces of homework We should agree on for next time That was my question is how can we proceed so that when we meet again in In december or january we have something that we can discuss and and then make the next step forward In you know quantitative risk assessment is a is a way to solve To make these decisions And it's not the only way You know it's it's not a bad way either Just kind of an aside Wouldn't there be precedent for other? Chemicals or metals I mean in terms of you know lead and Products or cadmium or you know You know phthalates are just one out of a universe right and there's been other Fans and there's been other You know percentage of you know a metal or a chemical loud. I mean in terms of Well in the precedent lead for instance the way our regulations Um At least before the cpsia the way the the rationale was Let's naturally occurring for one thing and it's a It tends to be ubiquitous, but it's a contaminant Um And so we would assume a certain background level of exposure and take that into account in the in the risk calculations Um And that's how they would arrive at you know going back calculating a level of exposure that's allowed For other things Like phthalates we might consider well are these things that can be regulated by other agencies, you know Uh if it's intentionally added to drugs or whatever Um, you know, we might say nor well, you know, this is not a normal Risk assessment process we're talking about but normally we would say well if it can be If most of the exposure is from Something under fda or epa jurisdiction will will say we'll let them deal with it But in in this case where You know, you have a lot of stuff that's in food and in the environment and it's not Clear whether it's something that is Uh can be addressed, you know, we It's coming from so many sources and you know, some of them are clearly in somebody's jurisdiction But others like how it gets into food Uh Maybe not, you know, um, maybe that's just because it ends up with the environment I I'm I'm kind of Thinking out loud here, but uh Um, but lead is very similar to that, you know, if you go back And even now it's it's purposely added to products. Yeah And it's in the environment from gasoline. It's probably in our you know, our food supplies or dust Yeah, and decisions from I was just wondering if there's You know, rather than trying to reinvent the lead, we would assume that there's a certain background Level that is always going to be there In that it can't be regulated by, you know, epa taking it out of gasoline, you know, there's there's some um Background level left that we have to accept so we sort of subtract that out of what we say you can be exposed to Um for phthalates, uh, I guess we could just Look at total it. I mean if there were a way because this came up with the dinp if there were a way Uh To do it I would have said gee you have this much total exposure Um, you know, how much sort of room does that leave? Uh In other words, well if if dinp is adding to that risk Um, we would have explicitly taken that into account in in at least in my risk assessment I would have done it that way. I would have said, um You know There's this much risk from the dinp, which is not bad But if you add in the background and it puts you over Um, the level of concern then, you know, it is a problem So that You know, maybe that's one approach we can take is you know, you have total exposure Depending on on what The risk from that is because i'm not sure what it is if it's You know over or below that sort of level of concern, whatever you want to call it, but um If that's really that high then You know, uh adding to that I suppose does make a difference Even small amounts But I you know, that's one way to look at it is whatever total exposure is and then say do these toys Um, you know put you over a certain level Well, am I wrong andres that what you were saying that you you don't want to go that way you don't want to Say there is some level That if we go above that we have a problem You want to say they're qualitative if it if it shifts No, no, no, no, I don't I can't I don't want to be prescriptive at this stage But I think we we have to enter a process whereby we map out options What what you've just said is definitely one But there are others we have to map them out Be clear about it and then look at it and make a decision and work from there and then answer the question What if we agree on a certain option or a modus operandi, then the next question is what data do we really need? Yeah, yeah I didn't try to be prescriptive. It's just How do we define the options and and move forward? But one option definitely is the one mapped out by bernard Where you consider exposures. This is the the that would lead us into a full-blown risk characterization risk assessment project and then ask the question Can the exposures resulting from toys? Can this be managed by reducing the levels of phthalates in these toys if that's not possible for technical reasons? For example, that's one possible outline of argumentation then There is a good case for a ban. That's one one way of doing it But I think there are other options as well and these need to be mapped out one other option is one I I mentioned I haven't made up my mind at all Which would be go the way of hazard characterization In in by hazard you mean not Going you mean going as far as a dose response? Yes dose response. Yes and okay it went But but to what end if we're not doing exposure For example, that's a good question. Do we really need a quality a quantitative hazard assessment or? And questions along the lines of how likely is it that this and that chemical induces the phthalate syndrome, etc, etc I'm not absolutely clear about this at this stage, but We need to reflect on questions of that nature What would clarification come by? again applying whatever process you wish To the three that are banned or and or the three that are interim banned and Let us as a committee see What the different options tell us and Yes, definitely. Yes. I think a good way of doing it would be to see what the europeans have done The thought process there Not that we might want to model ourselves on europeans totally. We're in america here, but Just keep an eye. Well, I think what what they did the the scientists the The programs did risk assessments of individual phthalates, although they were aware of the possibility of cumulative risks and You know and then somehow the the led the legislature the uh Voted, you know as we did in the u.s. It was a legislation that Did the ban? so there wasn't necessarily a direct link between the science and the um In the in the regulation In fact, we had some file after the dust settled We had some follow-up conversations with the scientists there and are we you know someone said well, how come They banned it and you didn't and At that level risk assessor or risk assessor We were pretty much in agreement on on things But the decision to ban it was Based on precaution Maybe it would be productive for us to bear in mind that this process can be carried out totally without Um Totally or let's say independent of this classic Risk assessment we're we're all used to I mean someone mentioned it. It could be based on a decision To say we don't want substitution to go in the To go in favor of a certain phthalate if we don't ban it this will happen. We don't want that and therefore we ban it simplified argumentation, but in no if if you Consider this thought process you will notice that Well, you will have to ask the question answer the question. Why do you not want to go substitution to go That way so what health hazards are you concerned about and then you have a health hazard assessment step in there But this doesn't necessarily have to be quantitative That makes makes a lot of sense. Yeah Um Hypothetically that would be one option to go. Yeah semi I mean you want to it's quantitative in the sense. You don't want to go to something. That's more toxic But you also have to be mindful of the Exposure potential I think for most of these the The actual exposure migration seems to be about the same but in case it's not you would have to consider that as well But it would be kind of a semi quantitative approach Yeah For my taste we are leading a too much hypothetically discussion right now Because I think we are still in the stage of data collection And I think no weather no no matter which way the the discussion may lead us We need to face the fact that we have to sort out the basic data As you said we need a discussion about the endpoints We need to harmonize all the delights in terms of the endpoints plus the substitution products We need to collect the data there. We need to have a look what toxicity data for the delights is there in regard to the endpoint the most sensitive We have to check if this data is present for the substitution products And we need this data for the substitution products, too So I think it's a perfect discussion we led right now, but this is going to be a discussion for the next or the Meeting in in in the half years time Yes, that that is true, but it is a very important one because Well in the silver book that would fall under problem definition context definition It is very important to do this because we may find Because whatever decision we take at that stage will then drive What data we need? But let me come back to To the text the charge I think the legislator had something in mind when they and here I agree with you Olga when they Listed certain things we also have to examine for example The likely levels in children, etc, etc Maybe the legislator had in mind that Our deliberation should follow a certain structure. So there are definitely data We need to look at and analyze because it's listed here And no doubt this will help in This thought process to decide in favor or against the ban of certain chemicals Olga I I agree with you at one level, but another level. I'm a little bit unclear If you just take the The problem of which phthalates are we talking about or which alternatives we we haven't even come close to Talking about that. How are we going to decide? of The universe of phthalates and alternatives the ones that we're going to be Concerned with is it going to be all of those and if it is I mean then you're saying to me that we have to have a matrix Down this side all of the phthalates and all the alternatives and then over here in different columns exposure data In different children and in the fetus and pregnant women Whatever Is that what you're suggesting that we need and if that's the case and we agree on that How are we going to get that put together that matrix? I think The core data is on the six phthalates here And it definitely says we need information about exposure and exposure. I mean as mike said it both based on biomonitoring data, but also on usage data Migration experiments and so on And as andreas pointed out we have to be aware as soon as we restrict one phthalate It's likely that other phthalates or substitution products Come into the market With the same amount of production volume. So we need information on these possible likely substitution products I think we just cast some of these substitution products It is just cast dinge Where all did it to we discussed dphp And there are possibly other substitution products, but we have to keep these products in mind right now Use the word likely and and if you look at the one of the epa documents that we received There's a whole list there of alternatives that Either are being used or likely to be used Um, are we going to go through that list one by one and say this is one we're going to be Talking about and this one we're not interested in And if so then what criteria are we going to use so this leads to you know, this is not a simple matter No, but a decision on the acceptability of an alternative is a decision of the future We we can't decide whether or not to make Some recommendation on a phthalate based on what we think the risk is of An alternative that we think the industry might go to or will never make a decision on on the phthalates The decision of whether or not an alternative is acceptable Is in the hands of the regulators We can't really make a judgment now That will preclude the possibility that Some company will make will approach epa or cpsc or fda With their choice and the agency says absolutely not We we don't want another chemical like that as an alternative to the one that we are looking at from the standpoint of managing So I think it's important for us to know that there are alternatives, but I don't think we can make a decision On a phthalate based on what we fear might be an alternative until it happens but but number two b Seven says explicitly we should consider the alternatives Well says we have some alternative. Well consider possible similar health effects. Yeah I mean some of them are already being used so Uh, you know the hypothetically Uh, you know, there's a an infinite universe of things that could be used I think we have to take our best shot and start with the ones that we know are being used and um If it if there's something that looks like it's going to be used we can add it but it's Uh, we can't hope to Have everything cover every put possible alternative It's back to if if we need this matrix that hogar is arguing for Then we've got to make some decisions I'm specific phthalates and alternatives And I would assume we have to have a rationale for why we select one and not another I think Paul and Earl yesterday Pointed the way Because we are focusing on the phthalate syndrome So looking structure-wise At the chemicals which might be the replacement products. We might have to look if these similar products Replacement products might have similar effects. I don't think we've made that decision yet. No, we didn't make any Great. I mean regard to the phthalate syndrome as their endpoint. I don't think we've made that decision I mean what would it help to? Write some of these things down like write a list of things decisions You need to make Uh, maybe write down some possible approaches like a qualitative and a quantitative Uh approach That's what just listening to this I was going to suggest because it seems like We're talking about two or three different things. Yeah kind of at the same time and I think At least in terms of processes thinking about The different approaches that are available and then what's needed for the different approaches What we have available And then we can make a much more informed decision, you know, we have these you know, whatever three or four possible approaches What's needed what's available and then How do we go forward and then of course picking one of the approaches because there's a You know just listening, you know different You know the discussion is not completely meshing and we're I think we're also Talking on different levels. I think you know, I think this is the highest level What's the the bottom line when we're all done? um How to do it is is another level and then some of the Nitty gritty details is yet another so Yeah, and again the point I try to make is how do we going to get there? How do we move forward? Are we going to do it here? We're going to try to hash out what you just said that we need to do Or are we going to ask? Yes, see to do that and Give it back to us and we we've digested and comment and make changes or No, no, I think that's that's a task. We shouldn't and can't delegate. I think we have to do that ourselves But we can't do it in the re in the remainder during the remainder of this day. So and nor should we rush My suggestion would be We could all independently Think about this And each of us perhaps prepare What can we call it a kind of submission or discussion paper for next time? This could be circulated well in advance and refined and That's then for next time the first discussion topic in I I was going to suggest that We each jot down what we're on paper a flowchart or bullets or something And And then get do it well before the next meeting so that the next meeting we can See what we agree on I was going to actually suggest that as well, but you know potentially since our next meetings not till December At the earliest, you know, maybe a conference call where we can You know spend A few hours in october november Talking about some of the approaches because I think if we do come together in December january we You know, it would be nice to have a decision in terms of approaches and needs Before then and agree upon at that time Like in terms that these are From the standpoint that these are public meetings. Can we have a conference call? Yeah, we we have had conference calls in the past and and you know, this is a Kind of a nuts and bolts kind of thing and it's it's just a really to prepare us for the For the real meeting Okay, so I think that would be okay, then the plan would be for us individually as committee members to Come up with a document That we will circulate among the other committee members Yeah, and then we will have a conference call Where we can discuss what each of us has proposed and then hopefully come to a A consensus that will drive the meeting in December Can you be more specific of what we should have in that document so that we don't end up with apples and oranges and nuts I was actually thinking kind of this the same thing because there are you know different pieces and each of us have different expertise So maybe you know, I don't know Mike or a way of framing the main points and then each of us could Continue to outline it or fill it in because for certain aspects I know I won't have the expertise and for other aspects. I will But it would help, you know frame, you know exactly What Is needed in in this document and one of some of the Questions it would be helpful if we had a sense of what different people are going to address. I mean Based on your expertise Although you wouldn't be limited to that it would make sure we cover all of these things. Um, I'm not sure if if we would we start with the framework or I guess Or get the submission some submissions first. I think we I guess it would make sense to have some sort of a framework You know very general in terms of the questions to answer the approaches that are available The data needs Decisions, I mean, you know more of a you know very general outline that we can pick pieces to fill in Okay, could it might could it be based on the various elements of our charge? That's I think that's part of it and then sub Sections that deal with each of those. What do we need to do this and Yeah Also come back to comes back to where we were yesterday which phthalates What age group? What metabolites These are all factors that we would have to take into account So that we begin to segregate that small number of phthalates that are of highest priority versus those that are out on the margins Those that are of highest toxicity versus those that are out in the margins and those are the things that would Allow a meet to be able to say well the fourth allites that I think we really need to focus on and these two endpoints That's where the meat of this is and the other things we will have less certainty Toxic there's less exposure or whatever the factors might be So I would hope that as a group we can begin to narrow down those kinds of As well to give us focus on where to spend our energy And it would also help if we could get sooner than later Paul's and Earl's Slides from yesterday copies of those. I don't think we've got those shots Yes I think in answer to Bernadette's point So I think there can be no discussion That the six phthalates mentioned in in the legislation are the ones that that's the minimum And I would say in terms of substitution or proposed substitution products, it's dinge dhph at the very least Yeah Possibly more but so we're eight already Well, there's a handful that are actually in use dphp. We have I don't think we've seen yet But it's a it's a potential Mike is that something that that your office could put together for us? Very a framework. Well, yeah that and and also in terms of Bern's point of Identifying the phthalates if if those could be just enumerated and You know why we wouldn't consider some of the alternatives that they're they're not in production or Yeah, there's no data Uh, yeah, and and we're sort of working on that and I'm actually going to try to get in touch with some of the industry people to To get more information on that list about the chemicals on that list, you know, which ones are really Used and so on um, I don't think we need to Go too far down that list I think, you know start with the six, you know, there's a few everybody has like the isobutals not on there There's everyone has a few Uh, or uh, that they might add to that list and well we could certainly do that um I notice the epa document had eight Right, right in part of that. I mean the the pentel is there not because it's used but because of its Activity in that assay. So it's it's almost like a model compound You know some of those like the Up to and hexel I someone told me that, you know and hexel no one really uses anymore But it's because it's active in that assay it it's something we might consider at least for One part the hazard ID part or something like that um And I could also, you know conceive of you know because we have so many chemicals Um, whatever the final process is all of the chemicals don't necessarily have to make it all the way through And vision the document that we put together would have something as simple as the table of all the phthalates and alternatives and and then a short discussion of of why we Chose some and not others to really in if anyone used or thought about using a substitute that You know wasn't high on our list It wouldn't be that hard for either them or us. We would have a framework to go through. Yes One other thing that we haven't talked about and that is the role of judgment In this process of us being able to make recommendations. I don't think any of the approaches that we've talked about lead you down To a final line in the evaluation that says yes or no It's a matter of our judgment on when you get Down where you've got all the things on a page that are important to make a decision The decision isn't there the decision comes from us And it's a matter of judgment of whether the differential between exposure and toxicity Is sufficient that I would accept that this is an acceptable risk And what you would accept might be different from what I would accept But nonetheless That this there there isn't a recipe for taking this Divinitively to a yes or no answer And I think we have to be Prepared to have a discussion when we arrive at our interpretation of what's available to make a decision Then there's another step ahead of us to make a judgment of what it means And does it translate into a recommendation to restrict? or not We haven't talked about that but that's another task. It's not easy I mean along the same lines. I mean uncertainty is something we need to Think of I mean whatever every step of the way We might as well Do it as as we go along is these are what the uncertainties are because Have to be able to document well what that judgment is Because the the themes by which we make the judgment is often more important than the decision Is that shows the strength of your conviction? And if we end up looking at individual phthalates But recognize that it's part of a family of phthalates out there and in exposure That becomes part of the judgment if we don't have a quantitative way of adjusting A level Of something to take into account that it's a cumulative effect We at least have to have that as one of the judgments that we have introduced an additional factor based on the exposure to multiple phthalates And that's perhaps why we are as conservative as we are in this judgment because of that nature of the exposure I need to have a break I suspect others may as well. So let's uh reconvene 15 20 minutes Okay, let's uh reconvene Is there any more discussion about the issue that we were talking about before we broke for lunch or can we consider that Complete at this stage Mike is going to put together a framework And then individually we're going to build on that And share our contributions by Before our conference call Okay, hearing no Further discussion on that I'd like to move on in in the Brief time that we have two of the members have to leave Shortly after lunch. So I thought we would take what time we have available to discuss a couple of other issues and One of the issues that I we need to discuss Is what are the end points that we are going to Use in our assessments, whatever they may be Is it going to be the the phthalate syndrome? Are we going to be more inclusive than that? I'd like to open up that discussion at this point Any comments What do we agree that the the majority of the data at least from the animal studies is going to be phthalate syndrome Maybe human data we have more variety of end points It seems like the phthalate syndrome would be the default Because it is the one that seems to appear at the lowest dose level the one that has consistency across phthalates Doesn't have consistency across species, but there are so many studies now that have explored this in rats That it has that internal consistency that it's been repeated So I I think with those And there are parts of the syndrome that resemble the situation in humans and In terms of end points So I think it would be hard to come up with other end points that Have characteristics A pattern like that that would drive us to another one But maybe we could if we think about the phthalate syndrome as maybe the Place we put a initial focus and then come back and ask If we had chosen is there any evidence that other end points could have been affected at lower levels than what we might find Phthalate syndrome. Yeah, I would agree. I mean, I think the animal data and and the phthalate syndrome is Where most of the data is the most sensitive in humans, of course, you know, there's other end points neuro development growth body composition, but there's there's not much Comparison data in the animals And then on the other side, there's not a lot of human data on the Pysico there's genesis syndrome apart from shana swan's agd paper There's not a lot So then do I understand from that that going down to our second question that we're going to Focus not restrict but focus our attention on prenatal exposures it it raises the question that paul talked about a little bit and It's prenatal in the rat Well, what is the time of exposure in the human that corresponds? ontologically To that prenatal period in the rat I think paul had mentioned and specifically give A definitive answer, but I think he said from about eight weeks to 15 weeks or so Or even maybe as early as six weeks But I think we need to have that footmark in there that that that time isn't the same in rats as it is in humans But what we're focusing on is when the time of exposure during that ontological period is what we are really concerned about Correct Over Plus there might be more than one testosterone modulated Windows of susceptibility in the human Even after birth That's that's the question I want us to discuss. So do so we are pretty confident to compare the air the the the gestational day 16 to 17 in the rat with the End of the first trimester in humans, but we have other windows of susceptibility Possibly in the human free and both birth The mini puberty at three to six months and then of course pubertal development But at least from the the rat data they suggest that the fetal window Is more sensitive even though they do see effects during pubertal exposure So maybe comparable in humans There's a recent new experimental evidence from ritter chops lab to show that Continuation of exposures in the neonatal period will make sure that the effects persist So that is quite important as well. I think These are dated in rodents in rats Okay, so we're we're going to expand the time frame of our consideration to the neonatal period as well Oh, is it with human puberty? Is it regulated by testosterone? Yes in boys so In the other When you think about life stages the other part of it the exposures obviously the neonatal's exposure pathways are going to be different than the um, you know infants and toddlers and so on my hearing then that we're going to go all the way through the pubertal period of Exposure for our consideration Okay, where does that take us in terms of time frame? Human development eight weeks prenatal to per puberty And is it complete in the mail? Probably with say, uh Well definitely by 1718, but generally 1617 It varies, of course Yeah, you're by about the time you can call be called into the army in the u.s. But still not allowed to have a drink of beer Earl url suggested that the Brain doesn't mature till much later That's another issue. I think url should speak for himself Okay, um I was just looking at our list of critical issues and I think we've We've discussed the third one which phthalates are essential. We've we've Discussed that to haven't come to conclusion yet. We're going to determine that And then the issue about Building on the Yes, I think we should stick with this point with point three Because okay if we Take the long and winding road through a cumulative risk assessment. We need common endpoints So I think we should discuss on which of the Phthalates or substitution products we focus And if we have the needed information on the respective endpoints But I thought mike was going to get that together for us I missed that Well, I'm I'm certainly going to try to get more information about the the uses and potential exposures of that Long list of phthalates I think we should keep it a bit pragmatic here. We We can elaborate this but I think for the good starting point. We should just throw these the latest substitution products in the round And in a couple of minutes discuss if we have the relevant endpoints and data on these endpoints present Okay, let's won't you start Yeah So I think for for most of the phthalates in question. We have the relevant data but If my recollection is correct For some of the substitution products, we don't have the relevant data So I would say that the relevant endpoint is the phthalate syndrome with the most sensitive Parameter being the testicular testosterone level And the hgd for example So my question now is do we have this data exam for example for the dphp, do we have it for tinge? well for in earls talk yesterday for the His assay on a testosterone production Bevo he had one experiment on dinge, which was negative kind of a screening dphp Was on his list, but has not been done yet as well as di dp, which is of course one of the interim band ones He hasn't gotten to that either And I think that would be very useful information As far as the range of substitutes, you know, we have Among other things We have the versa report which Lists potential substitutes and we also have our own report where we measured What was actually in the toys? by a year ago and You know, there were five or whatever five or so very common ones probably dinge In you know the usual the ones you would expect citrates and adipates and So on deht Was common of those. I know deht I pretty sure was negative in in At least paul fosters experiments from the last century Some of the others You know deha, maybe they should be maybe, you know, maybe we couldn't suggest to earl and paul that they Look at some of the others citrates Because I'm not so sure if we have those data Yesterday when we discussed this earl pointed out our great pointed out that dinge he tested But it was a screening experiment with I think three dumps were dosed And he Um, he admitted that had he he he said he cannot exclude To have probably seen an effect had he done a dose escalation study so it is pleasing to hear from him that there was no observer would be effect, but He himself was not absolutely certain that Uh with a dose escalation such an effect would not appear From the robust summary which we have in front of us from basf concerning hexamol dinge Um, I think what we can glean here is that in the study according to ocd test guidelines which they carried out They used a far High-powered experiment 25 dumps or something But I cannot detect From that robust summary whether or not There are the relevant data to us relevant data gathered whether Reduction in testosterone was measured. I assume it wasn't So I conclude that Concerning dinge the relevant data are not available really to us either to us or not available at all Yeah, I mean the actual studies Are not available right now and that's it That's an issue. That's an important issue What other uh, either Phthalate or or alternative should you wish to discuss? What do we know about that Well, I I suggested to uh, Earl and paul that they sit test dphp because it's Three propyl heptyl. It has you know the branching Not Similar to dhp. So I definitely wanted that test did and even though it's It's not I don't think it's being used in toys yet Um And basf says they wouldn't necessarily Recommend it for that use but still it's such an obvious To me it's an obvious potential substitute. Someone's probably going to use it. So That was high on my list To nominate for them, but again, that's in the same category. There are data that we don't have access to the original studies Industry data we don't have right I think andreus's point is that when we have such data instead of just having at a screening level if we could have more Right, right, right with 25 dams in a group or whatever. I mean that whatever the standard is right and that's of course We can't do it or tell them to do it. We could ask them to do it. We could dominate it to ntp or or you know We can try to get it done that I think that comes under the Number five Are there any critical studies? We can certainly ask for them You know, is it reasonable it with the lack of data to make Conservative assumptions about the potential risk for such chemicals where we don't have data and Yeah, I'm not sure we I'm not sure we can I'm not sure we can yeah I guess that's a question of judgment Precautionary principle. I mean it's one of those, you know one of the potential steps is to We do have reviews of these chemicals and to just quickly go through and say What do they have and is that going to be adequate? Or or not But lack of information doesn't mean safety. No, no, I think we need to be careful about we need to be. Oh, absolutely. Absolutely. I mean it We can say, you know, maybe we can't evaluate it. That doesn't make it safe Um Or you know prove that there's no hazard or no risk And we need to be clearer about that Mike you know the CPSC does not have the regulatory authority to ask for certain kinds of data on Any new product coming in? Well, we can't that's absolutely right. We don't have the authority to well, we can't Demand that it be done our options are to Nominate it to NTP well ask the company nominate to NTP or Work through the EPA's interagency testing committee and see if they can Uh get the companies to do it. Um I mean those are our options we can't Uh demand that someone do it and we can't uh We don't have the The labs anymore to to do it ourselves Any other alternatives? We want to discuss apart from the alternatives we Although the animal data is not indicative. We might have to evaluate methyl and esophilate also because of the Well suggestive human data We're definitely for The diethyl phthalate Oh, you mean what are the end points? No, what is it use? What is it? Why are you saying for humans? Oh because there's human data showing associations between monoethyl phthalate and It's used in personal care products, but yeah So that would be a phthalate. We want to add to our list not an alternative Yeah, so DEP so we're DEHP bbp and And dbp are the ones that are quote Band we'll look at those dinp ddp dnlp the interim we'll look at DEP the i bp isobutyl phthalate Any others for the decal and the um octal. There's not a lot of animal data. I don't think 10 well, yeah, but for the matter of completeness the the We should include this one too and also the p7 potential prop of delays The linears, yeah I wish we had url's slide I remember the slide that he had the list of all of the chemicals that he looked at I don't I don't remember what was on that and what was on which Um, do we do we think that all of the chemicals we've listed are on that page? Whether or not they've been evaluated? um probably well Yeah for the phthalate a lot of The high a lot of them And have we asked him if we can have the data? Uh, not yet, but we'll And I think the date the underlying data On those slides. I think are published. It's just that I was having trouble Tracking it all down and recreating So we'll we'll get what we can from him Well, the new stuff that they're doing that this the new results where they're doing the testosterone production. That's that's not Published I don't think but will we have this at least have the slides We'll make sure whatever they do publish we'll make sure we get it we're on their list of uh To get copies of it when it is published or get an alert Any other nominations to our universe of? I just wanted to to clarify the D. E. P It's a cell essentially yourself and it's not going to be in in the toys. It's Probably not going to be in that what we call child care products although unless although The cosmetic child care products it could be in but the it's it's a different exposure source Yeah, but put potentially up a high exposure Well, it is a high exposure It falls under roman 3 which we examine likely exposure of children pregnant women Pregnant women are very likely to express it to be exposed. Absolutely. Yeah, no further comments nominations numbers, yeah A point number four. I don't know whether we need to Discuss that any further I think we agree that we're not going to Wow new ground with in the ignore what's been summarized very nicely in in the nrc documents But is there any any comment and number five? We've touched on i'm not sure we've we've Express definitively that we want something done, but are there Are there critical gaps essentially that that some study Given the lifetime of this committee could be done that would help us in our Achieving our charge. I'm sure there are critical gaps I think what was on my mind when we talked about this earlier Was the possibility that there are some gaps that if we proceeded without information we would regret it As opposed to just nice to have additional information And it doesn't seem like we have identified gaps that if we don't fill them before we proceed we will be Remiss It isn't clear that there Are studies that would keep us from proceeding That would have to be done if he nominates for studies to the ntp. It'll be a couple of years before you see the results If we ask industry it'll take Time if you nominate to the ntp it prompts industry to do their own studies and I don't remember what other alternatives you have for filling data gaps We can go to oral or to others. Yeah, that might be the quickest. Yeah But there isn't any one of these that Would generate information Before the next or even the subsequent meeting to be of that much help to us I can't envision studies being done before we're done Certainly true for for human studies as well. Sure unlikely that anything Become available in the time frame that we have. Well, I think Shana said she'd have Some some data not so much on the phthalates, but I think the agd in relation to Other endpoints Well, one thing, you know, we tried to do yesterday is find out What's almost done And I I think we've Discussed six Quite substantially this morning. Oh, we can we can look at seven and talk about that We may not do a cumulative risk assessment, which makes if that's the case that makes this one mute, but I think the concept of of Are we going to include other anti androgens in our? The evaluation should be discussed Well, again, I think the distinction is Quantitative cumulative risk assessment or in terms of You know, you can consider whether or not co-exposure to certain substances Will for example shift those responses for phthalates and I think we can On the basis of Evidence presented to us yesterday about our grade. We there are some chemicals where we can make such statements albeit not In a in a quantifying way. I think that's premature, but in my mind What is asked of us explicitly in the charge Would mean that we have to consider such factors I mean what I didn't get from yesterday was a sense of You know, this is one that we're all exposed to and you have to include this I think I haven't Or I keep asking people what are the ones that are You know Where there's lots of exposure universal exposure that have to be included in this And I haven't gotten an answer yet Well, I thought I'll try pointed out tc dd Okay. Yeah. Yeah. Well, that's definitely universal In Dde power power dde. Oh, okay. I'll let it be to you Which was shown to be anti-antigenic kelch There's also a question mark concerning certain anti-antigenic pesticides And but I don't know what the situation is here in the US But in Europe, you would definitely say, you know, that's that's exposure to those as well But we would know which chemicals to look at there One pesticide would be a Winclo solene but we At least in the US do not have biomonitoring data regarding this pesticide There's no data in and Haynes We know there's exposure to Winclo solene or it's metabolites in Europe After consuming certain types of red wine The the all azole pesticides basically are Need to be looked at Whether that's possible in a quantitative way, whether the data are there here for the US is a second matter but Probably that will be one thing that Will more or less be self-limiting but they they might be More like a qualitative exercise I mean going going back to number six. I thought from Earl slides That there is hope for having, you know common end points and common dose response Shapes and so on so that might not be so bad it I suppose it may be a problem if you include other pesticides and other non phthalate compounds it might be an issue We're dealing with diethyl but as far as the phthalate syndrome goes Well the animal data it looks pretty good I think we've talked about eight That kind of corresponds to the populations Exactly I guess But we could consider But what are the sources of We've talked a lot about that I don't think we're overlooking A lot of any major sources. I mean I'll try to see what I can find out about the pesticides but I don't think we're We're missing too much Other than the From foods. Yeah, I mean well We're aware. I think we're aware of the major sources. Yeah, uh, whether we have the data, um, right Because we don't I mean even if we had data on levels and foods in the us it would still be Of a very difficult task to estimate exposures older I think a point that has to be made clear is also what Is the distribution of the exposures we are interested in are we interested in median exposures Are we interested in the 95th percentile of exposures? Are we interested in 99th percentile? Or in maximum values This is a question of importance for interpreting the biomonitoring data But also of interest for interpreting the model data from Mouthing experiments and so on I'm pointing that out because on monday most of the data presented by certain presenters had been focused on median exposures And I think this does not help us at all I mean, it's and it's you know It's one thing to have Percentile exposures to the individual phthalates, but how do you combine that the person who's in the 95th percentile for dinp maybe in the fifth percentile for something else I think that's pretty simple. We have the individual data on the lanes We know what the person a has its exposure He's our exposure to phthalate a phthalate b phthalate c and the question is do we want to stick to the conservative approach and add the exposure of each individual or do we kind of want to make a Certain worst case projection and adding up the 95th percentiles For each value and put assume that in the worst case approach There might be individuals taking up all of the phthalates in the higher percentiles. So in the I think in the Migration approach you do use this worst case case assumption. So in my In my feeling there is no argument against Doing this also in the bio monitoring data, but I think this is the point we might discuss I think that that I mean that would be a very conservative approach There probably are statistical methods to estimate 99th percentile of the multidimensional set of chemicals I don't think that's a simple task I can certainly look into that but I I You know because it depends on it's going to depend on what else is there. You can say you're on the boundary of some cloud But in which direction? I mean we could try to investigate that a little further and see If you're still on that percentile, you know, what's the worst case of that percentile in terms of risk or something? Be helpful if you could Think about that and include that in your contribution Yeah, and I mean it's It's fine to be conservative and you know add the 95th percentiles, especially as a first cut But if you do that and then you say the risk is too high Then the question is do you want to refine that? Also in if you do with the individual data, I mean do you would you wait the different phthalates differently? Due to potency differences or or how would you do that my recollection is there are no potency differences Except maybe dinp. I mean the others are are pretty close enough But okay, I'm just Wondering about that But I would agree with holger, you know in terms of using the 95th percentile for multiple phthalates because You know, it's not unreasonable. You know, maybe in the n. Haynes. It's whatever 1500 people But which sounds like a lot, but it's not unreasonable to think that People will have multiple exposures To these phthalates because they're from different sources and one doesn't preclude the other so you could potentially Have an exposure to dehp bibutal phthalate etc that are In the upper range and then there's of course the special circumstances where you know, you have Whether it's from medications medical devices etc. You can have exposures that are 100 or a thousand times higher Any other comments? Yeah It's it's on to me yesterday like the distinction between epa and fda is fairly clear And maybe a topic of ongoing discussion As time as needed But that the distinction between the regulatory realm for epa and cpsc isn't as well defined True well in the sense. I mean epa has what five different activities Going on right now involving Valates so they're definitely active that's for certain and there is Significant overlap between our purview and in toska the oppt and You know, we're we're used to working with them. I mean not that we don't work with Fda, but we're certainly Probably work with oppt more than Then a lot of other agencies Guess what I was looking for rather than activity was just the question if you have consumers Who become Alarm because of an exposure and perhaps a response and they say what who regulates this who do I go to? Do they end up hearing from epa? No, we don't do that cpsc does and cpsc says no, we don't that's epa's That are there gaps of that? um, I think usually Uh, it's more of an overlap than a gap But in terms of exposure, I mean, I don't know that I have a strong sense this actually happens But you know if the epa ended up doing regulatory making regulatory decisions based on exposure only to pesticides But then we knew there was exposure You know, well, the science needs to be Yeah, well epa and f I mean Fda or almost like Five different agents, you know um And of course, we really are a different agency and that makes it hard to do Things like this, but we are you know, we're looking for ways to work together. Someone suggested that exposure because It is the thing to do because we have no one started that yet um You know and there is a potential with the iris activity in their workshop coming up There's a potential that we can if not work together at least Share information and make our jobs relative respective jobs easier um but uh I mean, it's not unprecedented for To have an interagency activity. Well, we did it a long time ago for dioxin where uh Fda the different parts of fda and epa and cpsc contributed to a Then it was a multimedia Risk assessment was the term that they used um, and then we've collaborated on other activities um as well So, you know, it's it's a possibility the trick is to line up our uh Not just our You know Program needs but also the timing Hey, it's close to the new break for lunch Given that we're going to lose two of the members of the committee before we reconvene do Is there any other business that the rest of us want to Discuss between the end of lunch and in 2 p.m When the rest of us have to leave or should we Adjourn the meeting at this point. Okay, can I If if if we decide to adjourn um Do I think it are there are there any little? business things um the The books have two cds everyone should have two cds one that I prepared that's essentially what's in the book But add plus a few extras that were too big to put in the book uh The other cd is is from xon mobile and that has Not only their presentations, but there's a lot of data in there. In fact, there is a database in there that Dr. Clark talked about yesterday when she was talking about exposure There's a whole database in there. So There's a lot of information published papers unpublished reports and so on Anyway, there's a lot of you should have two of those at least when you leave we could if you're on an airplane We can mail you the the book itself if you like, but You might want to take those cds. I also have some Hard copies of some of the of dr. Godwin slides from yesterday That you are can take with you if you like because we didn't have have them in advance. Yeah And might you make sure that we get Uh information from the presenters that I'll make I'll track them down and get everything. Um, I will also I'll go through my notes in in Lat as I did last time Summarize any To do list of to-do things Oh, do we want to make a a date firm when we will each of us on the committee have our Whatever it is we put together Do to the committee We're going to meet presumably in december Can we not Can we not make the date firm the dates we agreed on and Assume that it's going to go ahead then and until We have otherwise well the the meeting date. I think firm is firm. Yeah, uh a date for Submitting uh all of your search Distributing all of your thoughts on how to proceed Will you want to do that? Uh, we want before the meeting or we want andreus's cumulative risk assessment Yeah to us A draft will be okay. Yeah, a draft is fine Um, no more than a hundred pages Yeah, and um, you know two or three significant digits will suffice Um, but do we want to get those uh things a month before Month two months before and then talk about them a month before So do the first week in november when Uh, should we pick a date for a conference call? which I'm not sure we I guess we'd have to do it late in the day Here or early Early in the morning u.s. Time. Oh, yeah. Yeah, I I got it backwards Which means it's really really early on the west coast The hardest went we had one Where we had europe, canada, australia, and I don't know if we had japan but I mean it was It was kind of difficult so five a.m portland time is nine hours difference from germany I think we're in the graveyard after lunch then I mean five my time would be four your time in the afternoon But if we say work backwards, uh four o'clock Germany no five o'clock in germany is four o'clock in britain And that is nine o'clock here and Six o'clock It's okay for you It's okay for you. I don't want to As long as I have my coffee In the question is would would uh, you two rather do it At the end of the day from work or At night from home. I mean it's an option end of end of day From work would be fine. We don't necessarily stop at five at british universities Okay, so six o'clock, but they are in the pub at that point Well, that's two o'clock so that'll be Or is it seven a that would be seven a.m on the east coast Nine a.m east coast. Oh nine a.m east coast six west coast four p.m the hours between new york and London We can do it. We can do it at five or six p.m. german time So really that's okay. I mean is German and germany an hour behind Yeah, for a head. We are ahead. We are ahead of of of andreas You know germany is always ahead in terms of time So britain is an hour behind Journey so when it's five o'clock in germany, it's four o'clock in britain. So let's make it six o'clock german time five o'clock london time so that would be ten o'clock noon in new york and After breakfast in That that that works for me. I I can usually get be to work by noon Oh and not a day yet, but we were like Well, if we have the if we get the stuff by november 1st, when would you like to How long do you need? Do you want to read it? Uh a week a week to digest I'm doing a NIH review the 8th and 9th of november. So if we could do it after that About friday the 12th. Not good for you. Okay. Well friday's not good period I don't go I may be in horton Look me up if you are okay Looking at the week of uh november 8th How's the 18th 18th and november Not teaching that day so I can do that Holger that good for you 18th and november not good 15th or 16th 16 I think that's the day I teach, but that's okay. I can do that But not going to teach until the afternoon so Say we turn that the 15th then 15th of november work for every day the 15th Order yep, that's fine Okay, that's it November 15th the other business Mike, um, I think that's it Uh, some of them a couple a couple of you need to see lisa before you go Okay, if if so, that's monday november 15th At 6 p.m. Germany or i p.m. England or 5 p.m. Is that uh, Greenwich meantime GMT yeah And it's okay the second meeting of the chap is adjourned