 Any issues you want to raise before we start? Um, I just wanted to welcome everyone and Remind everyone that this is a public meeting and it's being webcast And will be recorded. Thank you We're gonna start a this morning's meeting and This morning what we hope to accomplish is a discussion relating to criteria that We hope to use in making our recommendations to CPSC in terms of various phthalates and phthalate substitutes in terms of whether they should be banned put on interim banned or no action taken and to begin that discussion Holger wishes to Review a couple of slides to start the discussion. So so the the first two slides refer to the presentations of Dr. Euclid and Richard sharp and they are About the Xenograph Testus red implant and I had I have some thoughts on the on the Applicability of the model In terms of Toxicity estimations I asked both Dr. Birkelheider and Richard sharp what they regarded as most relevant for their model and it was Can be like who said it's the area under the curve So the active metabolite of the phthalates in his case It was the mono butyl phthalate. I have here data on the active metabolite of DHP We recorded blood levels of the active metabolite plus other oxidative metabolites of DHP way back in 2005 and published this in archives of toxicology You can see that in serum or in blood me HP is the main metabolite So the active metabolite is the main metabolite in serum So what intrigued me then is is there any possibility to compare The active dose that is the serum concentrations of the active metabolites in the different species when other words What is the C max and the area under the curve after a certain dose in? Reds in marmosets in pigs and in the human and As you can see from this slide Here we found that the area under the curve for the active metabolite MEHP is Normalized to the dose much higher in humans than it is in rats by a factor of Would say 10 to 20 So in other words giving Humans the same dose as rats. We would assume that the serum levels of the active metabolite over time is considerably higher in humans than in rats and This concentration being the driving force for the experiments in the in the red test is implants I think that these red scenographs give us a good idea on possible mechanistic issues but they Certainly have problems Evaluating the level of toxicity because We have to assume that we implant the human test is Into the red metabolism and the red metabolism produces less active metabolite over time Than the human metabolism. So it's no surprise to me that when implanting the Human test is into the red metabolism. It is less sensitive Because the area under the curve is going to be seen here Is higher in the humans for the active metabolite compared to rats? so these are just some thoughts on the Red Scenograph models and I think there's Much more behind that model to be investigated so that brings me to the third slide and to Dr. Kluhl's presentation christen me we use the simple formula risk is Exposure times has it and I will show to you that we can Provide a reliable and good measure of exposure with the human biomonitoring data we have The question of course is how to relate this exposure to the hazard was hazard times exposure makes the risk So we need reliable toxicity data for the delights and or the substitutes in question and We all agreed that we would focus on the Reproductive toxicity data order and the crime disrupting potency of the tellades So I think for the Three fillets listed here. These are the three fillets under Permanent ban We have reliable Data to believe that these are endocrine disruptors DHP DNB P and butyl pencil fillet for the fillets on the Preliminary ban we have heard yesterday that We definitely have to regard the INP also as a reproductive toxicant having both effects on testicular testosterone levels and Effects on the germ cells. So for the INP we in the meantime have three Results from three work groups. That's the all-grade group. That's the Boba publication and now the Hamner Institute public presentation which Provide us with reliable data to assume that the INP definitely is an endocrine disruptor and a reproductive toxicant You also have reliable data for the IPP Which is not on the banned list To regard it as an endocrine disruptor and the reproductive toxicant So these are the five fillets we have hard and reliable information to perform this quantitative risk assessment Multiplying exposure data with the hazard data Regarding with the latest the IDP and DNOP We are I would say on a rather data poor side. So we have problems fixing a number to the hazard and We have to decide here. I think Do we regard them as hazardous or not? That's the issue and On the other side of the Backbone scale we have DEP which Seems from animal data to be non-active, but from epi data to be active. So there's ambiguous data there and As we heard also yesterday. We cannot be sure that the animal model with the backbone activity between three and six carbons in the backbone might be of That relevance to humans. So this is how we are standing now And these are all the points we have to take into account when performing our hazard index approach So I think we first have to talk about the hazard Can we quantify the hazard? Do we need to quantify it in certain aspects? To then later be able to calculate our hazard index Which takes account of the cumulative exposure to all of these tellings That was the introduction I want to make. Thank you, Hager any response comments To Hagers Andreas Just a little I found the Data with every undercarve you showed very very interesting. Could you show those again? just for the the birth came Bockelheide and Richard sharp used grafted Tissues on the mouse if I understand correctly so But you don't have other data every under the curve in the mouse That's what I asked him because I think it is It is it is mandatory to have information on metabolism if you Transplant human tissue in this in this species because the level of the active compound is The driving force and therefore you have to know something about the metabolism. That's why I always ask them. What do they know about? the metabolism in Mice or it's comparable to humans Compared to humans and we see that there might be considerable differences in in metabolism Which might have an effect on the interpretation of the data? But if I understood correctly there was also another difference Kim Bockelheide to dosed with Dbp and Richard sharp also had experiments where he dosed with mbp didn't he? But yes Metabolite in other words But your point is that the the unknown toxicokinetic factor in the mouse in these xenograft models might have Obscured some effects or at least it's sort of another black box whose content we have to guess What this data is suggesting here is that? At same exposure levels the level of the active metabolite In blood over time might be higher in humans than in in the animal models Which also goes to show by the way the heart why why in the animal you have to use higher doses all the time Not many people understand this Another point you mentioned in your last slide that DEP that there are that there's epidemiological evidence of some effects There there isn't that there's only indirect Some indirect evidence no one knows what what DEP really does then in epidemiological studies It's only there's only one hint. That's what I mentioned yesterday. That's why I feel compelled to At this here. There's one epidemiological study from United Kingdom Ormond as first author Carried out by Imperial College London where they found associations in the male babies from hairdressers with Workplace exposures and cryptocritism Hubspedia from if I remember correctly, but the the DHP is a little on the spot and Very indirectly because we know we don't know precisely what the exposures are at these workplaces There's also exposure to other things No one has measured them and it's terribly complicated to measure them, but by inference had dresses use more I mean if you look at the profile of phthalates that make up the exposures of these workplaces You will come to a conclusion very quickly that DEP will dominate and not not any of the other Because of all the sprays and that's Russ any comment Agree, I guess in terms of the discussion about DEP I mean there was the paper Andreas mentioned but Also the associations that were seen in the swan study with reduced AGD MEP was was one of the metabolites. I think it's Important to consider as we go forward that the data in humans is is sparse, but there's some there so But that's exactly the issue we we are facing now with our hazard index approach Putting a quantitative number to the Quantify the risk. So the first question we have to answer is do we regard? All of these substances as hazardous If yes, we might include them in the model, but we cannot give numbers to it. So we cannot Take account of these I would argue that the the charge Asks us to to perform some some risk assessment we We can only do this with to the standards described by the state of the art in this area. We've heard yesterday some Exploratory studies very interesting that throw a certain light on things But we have to bear in mind number one that these haven't been published yet. They're not peer reviewed There are some questions. There are question marks about their usefulness well, they're definitely not useful for for risk assessment because therefore they weren't intended to to Make a risk assessment and that would clearly fall behind the standard of studies which you require for for hazard and risk assessment But I think it is very helpful interesting Information to to keep in mind about the usefulness of some of the animal models, but I mean we are we have two choices either on this basis of the evidence we heard yesterday. We conclude The hazards and risks therefore are not quantifiable which that's one option or we say we proceed Within the state of the art in the field My personal opinion would be to say it is a little it would be I think a bit of an overreaction to Conclude on the basis of the information from yesterday that these things are not quantifiable The exploratory studies are not even published. So But that's just my personal opinion and just to remind you again both presenters were reluctant to Advise us to change the TDIs or the reference doses we used and they were reluctant to clear These delays of the suspicion that they might be in the crime disrupting agents well, and the other important thing I take home from this is the the the the relevance of neonatal exposures which Wasn't emphasized so much previously again by by undisclosed undescribed Mechanisms, but clearly neonatal exposures in these models seem to have effects Which is I think very relevant to the charge we have we have to work with Okay, I think that the slide that's up right now is a nice lead-in to Our overall charge I think it's Clear that we have data That's relevant to some of the phthalates That we are charged to evaluate but there are a lot of others that probably are very data poor yet We have to evaluate and come to a recommendation. So I think it we need to have criteria that we use that are transparent for all of the others so Burn put together a list of criteria That I'd like to have him lead a discussion on and we've got some slides That we can use and hopefully with those and the discussion that ensues We can come to some other criteria that we can use in our discussions and used to judge those other phthalates and phthalate substitutes and so Holger, would you give me the mouse, please? Thank you. Thank you Phil Holger for setting the stage because I think you've done that well Regardless of this state of information that we have and Regardless of the research activities that are going on that might be helpful down the road at some point we are faced with making a decision with what we have in hand and Now we're coming close enough to the end of this process that we kind of stop the merry-go-round and we make the decision based on The best we can with what we have in front of us. So I Actually a couple of months ago sorted out in my own mind What did I think were the criteria that would be useful for distinguishing a decision to make a band versus an interim band versus? No action With the thought that maybe someday we would have used for that in this committee and maybe today's the day but I Have on this first slide some criteria that could be considered for making a ban first of all these are just my opinions and Is that I present this only for discussion not that this is The menu that we need to reach agreement on or to follow But these were these were some considerations that We would be looking at hazard. We will be looking at risk. We will be looking at exposure and The fact that there are replacements Potentially available in the wings out there that could be brought in is not a consideration for whether or not something could Be banned. This isn't like a life-saving drug Where if there are problems with it you have to decide what's the consequence of withdrawing that from the market because it's saving the lives of people Well, that's not a factor for us here. I think we look at face value at the risk to people. Oh These were meant to be criteria that should characterize a chemical that we agree should be banned and the hazard index Could be equal to or greater than one that would be one criterion that the responses in key toxicity studies that are considered the responses in the key toxicity studies are considered to be relevant for humans and We're struggling with that But the default has to be that or should be that we would consider them to be relevant for humans when we don't know otherwise Thus concern for human safety is plausible The health effects expected are seen in humans are serious adverse health effects So I it raises the question of you know If you had a material that caused a rash in the skin from dermal exposure Would you ban that chemical and my suggestion is no we want the consequences of leaving this in Commerce to involve potentially serious adverse health effects The key toxicology studies are replicated with similar results from multiple laboratories So we would be more reluctant to make a decision if there was one study from one lab And it had never been replicated Because that that's not a good basis for making a serious regulatory decision Identity of the toxic agent in animal studies and in human in the human environment is confirmed with analytical methods of sufficient sensitivity specificity and limited detection in multiple laboratories It's kind of the same idea of having one study from one lab there. There needs to be Analytical chemical confirmation that what we're worried about is actually what we think it is And we can find it in a variety of media whether it's air water food cosmetics Toys, whatever it might be But that we have we're not going to be discredited six months down the road when some other analytical chemist says Oh, they banned something and didn't even know what it was Because that we couldn't confirm it across laboratories or across media So we have to be firm that the chemistry supports a decision and that we're not going to be undermined by making a decision a decision based on toxicity When in fact we were uncertain about the chemistry that supports what actually was there causing the problem And also the levels of human exposure are sufficiently high To cause adverse Effects again, that's part of the plausibility not only do the animal studies predict something that we think could be relevant for humans But the human exposure is such That it gives us concern that maybe that maybe there is a relationship between exposure and an effect so I'm suggesting that if we review chemicals and We don't have this pattern of information. We probably don't have a sufficient basis for making a decision about banning it That that's setting a fairly high standard but Let me then talk about how different are the criteria for an interim ban and I didn't back away very far I think the same Criteria need to be considered But maybe not all of the criteria for banning have been met and It's reasonable to expect that with more effort in the laboratory or in the field that results would be available Could be available to determine if the substance shooter should not be banned or should be restricted so We haven't come up against a wall that says we would never be able to analyze this to determine biomonitoring That the possibilities are out there the effort hasn't been made yet or the data haven't been collected Maybe they're in sight, but we don't have them in a peer-reviewed mode Or we don't have them replicated in another laboratory yet But somebody's doing it those kinds of considerations so I I see a relatively small distinction between banning an interim ban and It's mostly a shortage of some data that perhaps could be collected if if we were either waiting for it or we went after it and the Another factor here would be that additional survey samples to obtain to further determine human exposure might be needed and can be obtained in a timely manner and How distant are we from those that we leave on a on a list where there Is no action, and I think we're fairly distant The distance between an interim ban and no action is much greater than the distinction between an interim ban and a ban and in fact What I have on this one isn't quite correct because the the criteria for no action is probably based on the lack of availability of data Talks data or exposure data So then a hazard index couldn't be calculated because we wouldn't have no else And the data are insufficient to characterize hazard and to evaluate risk Exposure data may or may not be available So there's a long list of chemicals out there that fall into this category if we don't have enough data to make a decision But as Chris said yesterday, and I say frequently the absence of data is not the absence of risk So it makes us nervous to have chemicals where there is human exposure, and we have no no data But in the world of chemicals, that's a long list of tens of thousands of chemicals So it isn't unique to the ones that are in front of us But nonetheless when we're trying to put these phthalates or the substitutes in one of three bins either to ban or to Interim ban or to take no action Is discomforting to know that there are a lot of them out there that if we just have the data We don't know which bin they'd be in but it's not a given that they would remain in the no action bin Maybe someplace in between no action and ones that you Think of from time to time as do we really are we just waiting for a human effect to become observable in epi studies? Or are we confident that we could live it in this no action category and that we wouldn't Wish we had not done that some place down the line anyhow, those are some thoughts about How an interest this is addressing your highly relevant question of yesterday that before we begin Discussions of what what can we ban what should we recommend to ban? What should we make no statement about I think we we need to have some understanding and agreement between us some on these criteria or other criteria I Just put these up for discussion I've already talked Maybe more than I should have but Hope for discussion Andreas Before we go any further with discussing the details of your criteria, which I think are very helpful We some time ago decided to go on a hunt to find out why the three Salates in the text of the law have been banned permanently and why an intermediate ban has been put under three others, but is there any result what criteria were used then to Make these decisions and I'm asking this because well if there are some We could probably borrow from them, but if these decisions have been made in the total absence of any Rational criteria, then that's something worth noting and emphasizing as well. I guess So the question I don't know where were we that some Have we found out something what led to the decisions then in the text of the law? Like can you share with us your field? Well, yeah, I don't have a lot there's not a lot in the record on that and It parallels the The European ban the the six chemicals parallel the European ban. I think the General Reasoning was that there is good data for the three permanently banned ones At least hazard data for the other the interim banned ones. There is a suspicion of Hazard, but the data were less convincing. I think that's probably the best Explanation one can give Okay, then well, I think that that matches with my with my my own Record and research of this topic, but do we have any information what led the Europeans to And those or put those salads in the frame so that's the next that would be the follow-on question So if the criteria in here in the US that motivated motivated the inclusion of these salads Was to say okay the Europeans have done it like that. We're doing it like the Europeans do The next question is what motivated the Europeans is that any information on that? Well, yeah, all I have on that is the In the regulation itself It says something to the effect of what I just said is that the the three d idp dinp dnop The data we're not convincing, but they chose a precautionary approach in the Face of incomplete data and I believe that was the the logic Mike another follow-on Question to that are we constrained by the decisions that have already been made in the past? well Well, it's clear that That the purpose of the I mean they did the interim ban and said the chap will recommend on whether to make that permanent or not That much is it's clear if you mean Are you bound by any previous Decisions by CPSC or previous chaps. No, absolutely not. We're certainly not bound by the European ban the only Thing is the I think the permanent ban if if I understand correctly is permanent. I'm not sure Changing that would be an option Mike. Do you know the date of that? The date is was August of own was it August or September of 09 It was the bill was signed that the US Band was signed by the president then in late 09 It seems interesting that perhaps to have two of the chemicals on the interim ban, but then there's still no more data Certainly not not a lot more There might be a little I mean there's just one paper that just came out that has a dnop And dnop that might be helpful. I haven't seen much on d idp No, P with that enough to have a reference dose I you know, I haven't read the paper I did email it to the chap probably last week or so Add some are we supposed to be discussing burns? Is that the is that what's on the agenda? Or did you want to do that more I? Guess one one point I might want to add but I think you the way you've outlined is very helpful, but one point I might want to add is The hazard index is gonna it's gonna change based on exposures, which evidently is going to change over time Now I'm thinking we really probably should think about the fact that the ban took place in 2009 Which really should have changed exposures in the biomonitoring? We're evaluating 2005 and 6 data. I Think largely I'm not sure how much 2007 and 8 but I don't think the more recent data are available That's something to think about I mean I that's the that's the the issue of this that's that's so Not just black and white. It's not like there's a dump site and we're saying here's the chemicals there And this is what we're gonna make a decision on I mean these are things that are gonna be changing and could I think it's changed very drastically Based on decisions that have been made As exposures go up the hazard index, you know some go up some go down. It's yeah Just to clarify what it was 08 August 08 when the CPSIA was passed and the Valley bands were enacted what we don't know. It's what industry expected to happen and if there were changes, you know prior to that or Well, I you know, it's It's a narrow at that time. It's a narrow range You know we're talking about toys and childcare articles. So the CPSIA would only have affected those products and You know, I think the industry was gradually changing anyway even in Was it 2002 or whenever we last looked I mean there weren't that there less than half of the toys had DINP anyway as far as the other products. I mean, I don't know but I think there's you know for things like Cosmetics, there's been a gradual decrease in phthalate use but other products in general I It's hard to say as far as I know, I mean there have been changes in Which phthalates are being produced? Over time that has changed how that translates into exposure. I mean you'd expect to see a change eventually I don't know what so what years. I mean have you looked at sets and Haynes data from different years So far, it's just the 0506 I think we talked about going further, but I haven't had the time to do it Yeah, yeah, we possibly could try to do that Yeah, well, yeah, I don't know. What's the latest but those are the latest data anyway 778 or the 09010 I mean I think it's the same We're I mean they've been publishing data from 778 I guess up until 2010 I think we should wait with this this discussion until we have the information from the external exposure estimates What might be the significance of putting out the phthalates in certain products and leaving them in others? So I Think with with our approach Honestly taking it out from toys and Child care articles. I probably think we wouldn't see much and what is currently known about the roots of exposure Of the roots of exposure In the end Haynes's children over six, so But the pregnant women is what we were Right, but but still with childcare articles. You wouldn't right But the whole point about the hazard index, you know using that I think the hazard index could be a guide I'm I'm like it to say if the hazard index, I mean we're thinking of a distribution of Piteria for no action, you know if the if the hazard quotient for a set of chemicals are small But with the with the idea that there could be substitutions for others that go in and out I think we need to think of it as a snapshot that can change And that's that's I think very difficult part of this How do you look at things that could be changing and I I agree with Mike's interpretation of of the charge that with the Permanently banned thalates there's I Interpret this text here such that That's probably no option. There's no option for us to say are They can be reopened or Permanent ban will stay So in other words, that means we have to focus our efforts on the thalates that are Covered by the interim ban and we have to focus our efforts on those That aren't mentioned at all So I guess the first question would be which of those Covered by the interim ban in our opinion would qualify Upgraded into a permanent ban and by what criteria are we doing? I mean that I'm saying that so we can focus the discussion. We don't need to discuss much the permanently banned anymore. Yep Everyone agreed on that? Yeah And in Holger's slide the last slide In a good case for the three permanently banned ones the data are there I'll agree that that's case He also made the case that DNI NP should go from interim ban to Band is that's I think where we should start a discussion That what criteria are we going to use to support that if that's the Proposal like to open that discussion In doing so, can I can I make a couple of suggestions to group for the the criteria which which Bernie has? As a laborator can we perhaps turn to slide number one? baby, I Think this is this extremely helpful the first criteria and is is basically a risk assessment The second one is the question of relevance Adversity and Then there are a couple of criteria which relate to the quality of of the studies the quality of the evidence and So on can I suggest to lump all this together under the umbrella of? Weight of evidence Our weight of evidence in chemical risk assessment is not a uniform and unified approach The epidemiologists are dealing with this in slightly different ways, but these are Weight of evidence can mean judge the quality of the toxicological studies by various criteria There are there are established ways of doing that Can I can I suggest we we we follow these these well Concepts that I worked out other It's it's just for We don't have to change it now, but with levels of human exposure being the weight of evidence separate Various ways of evidence approaches one way of saying so is for example in epidemiology you You know before before you state, okay There's there's probably evidence of of adverse effects in humans based on epidemiology You would you know some people demand at least to independently conducted epidemiological studies There are quality criteria to judge these epidemiological studies, etc. Yeah, and it's similarly in with experimental Toxicity studies. There are also fairly well described quality criteria for judging those I Pick them up after somewhere in my computer So criteria for example would be simply first of all the number of animals used Was this a GLP type study either GLP or similar Quality of the end points technical quality, etc. And then questions such as Is this just one study? Is it a yeah? What do we do? For example, is there's only one study although well conducted? It will require evidence from two independently conducted Questions like this Why don't we do you want to make up a new? Yeah, but it would be yeah, I can My computer and knock something up. Okay Don't need to do that now, but okay so All I'm suggesting for for the time being that we separate out these Criteria, let's call them operationally weight of evidence from the question, you know, is this an Adverse effects or adversity is clearly an important criterion for us to to judge the the evidence from experimental studies and The other important criterion is Various animal models are they actually relevant to what we're concerned about in the human so adversity and relevance are Absolutely important criteria Yes exposure is is right. It's how we characterize it because the question of risk collection of the probability of some harm and that's a function of toxicity and exposure So the exposure does get plugged in and If we decided there was no hazard, I mean the hazard is not very Compelling from the animal studies and the risk is not very of much concern because of the lack of exposure We wouldn't be considering a ban I don't know how openly we want to identify How clearly do we have to say or want to say that exposure is a driving force when it's already captured in risk? We have to make sure that it is captured in risk Not trying to minimize the importance of Exposure, it's just a character How we characterize it? I guess what what what we have to concern ourselves is Situations where some but not all of these criteria are fulfilled. For example, if there's good evidence to think The effects in question are adverse and if there's good evidence to think that they're relevant for the human and say good quality studies but question marks with with Quantification or quantifiability of risk. What do we do then and for adversity the Outcome in a human study could be actually a surrogate for Something else so for instance AGD. I mean that's Probably be difficult to argue in and of itself without any other effect That's a serious adverse. It's an anatomical change, but it's it's indicating that there was decreased androgen Signaling during development and may have implications for Product-attract development that's unseen Seeming quality later in life, etc. So just just in terms of how we define some of the end points that may be Relevant or important to consider that the end point in and of itself May be a surrogate for something else And dresses these sort of capture Yes, I would separate out adversity from hazard risk Because there may be a situation where you where you see where you can say that clearly from say the experimental evidence That you have to conclude the effecting questions are adverse But still The risk assessment might say Doesn't quite reach the exposure doesn't quite reach the levels of Doses where we would be concerned So I would make that a separate criterion risk assessment As a new hazard or risk assessment as a new like like you have now, okay And and exposure following what Bernie said exposure is already part of hazard risk Assessment so can be can be deleted. So are there ours ours are there ores between these are ands between That is the question I'm feed into each other. I mean I could almost see I mean thinking from an epidemiologic perspective you would start off with outcome Where adversity is, you know, what is the outcome? Is it a adverse outcome? Is it serious? You know visitors surrogate for something else and then Exposure, you know, what are the levels of exposure? How well, you know, just speaking about it human studies How well is exposure measured is it measured at the relevant time point our levels high enough, etc that you would expect to see an association and then you put the exposure and the outcome together to look at Association a relative risk, etc, which would be comparable in this case almost You know not strictly speaking, but you know hazard of what you're trying to to do So I think from an epidemiologic perspective, you know You could think that you know you have your outcome your exposure And then your association which in this case is kind of equivalent in a way analogy to a hazard risk where you're bringing both Exposure and outcome because in a human study for instance if you have an adverse outcome and you've measured exposure at the wrong time Or you've measured the wrong metabolite of the wrong exposure Obviously you're not going to see an association and in this case you're not going to Conclude there's a risk because you've oh, I mean it's just a different perspective But I think what I'm trying to say and maybe I'm not saying very well It seems to me that the hazard risk may be the highest bar if we're thinking about a hazard index there I'm thinking about the risk side of that I guess Recognizing that that exposures change as patterns change as behavior change whatever You know if would we meet the the band criteria if we had adverse outcome evidence of exposure Development problem the quality of the studies was good Maybe the hazard index risk evaluation doesn't quite How high does it have to be because I don't think again I think the data can change so much with substitutions that we how do we Evaluate that we have a snapshot that may be dominant by some one or more chemicals and others at a particular case may be very low, but as some go out some go up and We have to do it with what we have right now closure levels you're saying yeah, I mean we can you know indicate in our narrative that Things may and probably will change and that you know that may change our interpretation, but that's Beyond our control in terms of our recommendation that we have to make Now and paper you're saying kind of is if you calculate your hazard index or your risk and your numerator and denominator You can change either one or or neither or both and If you calculate it and it comes out to you know point eight point two, you know whatever and Then it goes into you know no action category, etc. Then if the exposure Then comes up right and then the new calculation will be it's At one or exceeding one right? I mean that's right and that's the thing that's bothering me is because you know We haven't looked at our chapter yet, but you know there are band chemicals that have very low hazard quotients Current data set that doesn't mean it's permanent Yeah, one could argue that's the effect of the band. It was before the band 2005 and six data You know Bansal or which is I mean is it one of the three? Yeah I think there's also Another question and maybe this is adjacent to yours Chris there's a question of how wide we look for hazard as we Consider making any recommendations and the example that I would give we have focused largely on the phthalate syndrome in the rat but there are some of these chemicals that Cause an effect when adult males are exposed and it affects sperm quality Which isn't part of the phthalate syndrome? Because the exposure is out of the window that we've been talking about so you've got adult men working in a plant exposed as High levels of some phthalate they end up with decreased sperm quality Are we going is that in our window? Would we've been a chemical because of that? If it met all of the other criteria or are we narrowly focused on the phthalate syndrome and We're only concerned about the fetal exposure And the consequences in the neonate Reference doses have been chosen for the latter in the latter case for the phthalate syndrome Then we argued that that would be a conservative value for infants So we use this and my point is that I mean we felt comfortable saying the band chemicals are banned without even looking at the hazard index so It met in our mind some kind of a cutoff that Agree with that. So I'm not even thinking of this in the context of one of the three that's banned I'm thinking of other chemicals where we would be forced to make a decision of changing it from interim to full or Making a decision on something that isn't banned at all at this point But what it would look like if we left a chemical out of regulatory recommendations outside of the scope of any recommendations that caused infertility and Adult men adult males But it didn't cause the phthalate syndrome So we took it off. We we put it aside and said we're not going to make a decision about that When in fact men are still exposed in the plant and are having low sperm counts or a low quality of sperm And we didn't do anything about it. Are you saying that if in the case? It's almost like the band but the having these band chemicals as sort of case cases to look at I mean if we don't find evidence that Maybe in the the risk evaluation the distribution of the hazard index being high enough that Met this criterion of you know around one that then we would go look at other out Outcomes that could potentially be part of this So because what I'm saying is if we've done that for the band chemicals Then that wouldn't that set the same stage for what we do for the ones that we haven't looked at yet? my comment now might sound contrary to what I just said a minute ago, but this to some extent the scope of the field has already been narrowed for us because the concern is what is What phthalates are present in? Plastic products to which infants are exposed Oh, does that give us? Licensed to ignore the possibility that exposure of adults may cause a change in sperm quality because it's out of the scope of exposure of children to Plastic plastic products that have phthalates. I mean the children's products is the bottom line But it all you know that the charge says you have to consider cumulative exposure From all phthalates all sources and from you know pregnant women and other Sensitive groups, I guess is the word didn't specify what who they were but You know, I don't think it's off the table to consider that on the other hand I Think before yesterday You know, I thought it was a A similar mode of action now, I don't know or I'm not so sure And Chris I'm not suggesting that if if we make our first cut on the phthalate syndrome consequences of exposure that We then have to open the door up again and say is there anything else out there As we have already In the writings that we've done we've kind of said that you know, there are other toxic effects of phthalates that involve carcinogenic response that we're worried about in rodents and Hepatotoxicity and some effect on the kidney potentially. I'm not saying that we should go back and now do another Committee activity reviewing anything some toxicities other than Phthalate syndrome. I don't think we're I think we've already put that aside exposure during the relevant window but outcomes that are Unclear whether it's part of the phthalate syndrome for instance the neurodevelopmental outcomes in children. So those are prenatal exposure during appropriate window and also early life exposure But you know, they're in the epi studies, you know, the six or so let's say that have looked at the neurodevelopmental outcomes It's epi. So they're not looking at mechanism. It's an association. So it's unclear. Is it through? Reduce androgens during fetal development affecting, you know, brain Development programming etc. Or not. I mean that's not even approached in those studies, but it's the relevant window If for now come so I think we would be remiss if we didn't make some kind of a statement that there are potential consequences of exposure during that critical time That are outside the phthalate syndrome and they shouldn't be ignored Reflection of our state of knowledge today Focusing on the phthalate syndrome because that's that's where the data is and where it's thought to be the most sensitive response But recognizing that there are other outcomes responses No, but I mean just just putting it down clearly why That was chosen and it's not that there's nothing else to look at but why I mean I think that gets to the point of you know, we were looking at DVP and saying well, it may have you know Currently or 2005 and six data But we didn't feel comfortable about saying oh, that's a good chemical. Let's keep it There's something in our heads that's saying There are other things about that other than just this risk evaluation My point is whatever we did there. That's what we can also do in other cases I understand what you're saying Chris that the the hazard index analysis is The results are driven in large part by DHP, right? But that's not to say that EBP and butylbenzol phthalate are not playing Any role in that? It's just Montefy that I mean it depends on which case you look at These two values for the reference doses the 75th percentile of butylbenzol was 0.015 023 the maximum values 0.12 and 0.20 has a quotient for those compared to DHP which had a 75th percentile of 0.13, but a maximum value of 7.5 on terms of ratios of DHP to DBP for example, what would they be? ratio of the maximum Hazard quotient That 10 10 to 1 100 to 1 More than 10. I'm trying to get a handle on how how we would use The DHP which I think Does come out as is something that we we would ban beach based solely on the hazard index evaluation. Yeah, okay So using that How would we then use it to Evaluate DBP and say yes still we would be That would still be of concern 10-fold less or whatever it is Chris what you're what you're also getting at two is these three are Permanently banned and you have a Number mathematical hazard quotient that is Less than the criteria that we be using for the other three, right? So it it doesn't seem Have to be consistent consistent right well, but if I look back at the exposure table the DEHP is there is ten times the exposure levels at the median Then BBP So if exposure for BBP got to that same place as DEHP you're gonna have the same problem And that's the that's the point. I don't you know This is a very static static analysis that is trying to represent something that's very dynamic You're making two points the one with the exposure Being dynamic and changing and then I think the other is I mean just hypothetically if there were only two permanently banned and Diabutal Abutal Benzel was in the interim ban based on those numbers What would the recommendation be? Right Because the hazard quotient would in most cases are clearly be below one Right. I mean is that kind of right? And so we're applying that criteria to the others Is that fair or consistent right coming back Why we started this discussion an hour ago Awesome criteria for making a decision and I think Honduras your suggestion is is helpful to Back us away from for example an automatic decision that if it if the hi is less than one then it's not banned It's one of the things that we would consider And we consider hazard we consider risk and we consider the adversity severity All of these other characteristics, but there isn't any one of those that would force us into a decision About banning status. It's the composite of that and that's Why this exercise was relegated to it a group of experts as opposed to somebody who would just Calculate some numbers and take a slip of paper to the Commission and say here's what it is I Think we are here because this is it's it's more than gut feel But it's also a composite of information that it distinguishes above and below a threshold of activity And so it gets to the point where the toxicity information for maybe the band chemicals are somewhat similar I mean in our case, too. We we set them the same, right? so I Mean, I'm no exposure expert, but it seems to me With the toxicity values that are about the same high-quality. I mean those three chemicals have been studied a lot There's a lot of data there to suggest toxic toxicity so you know with a with a Exposure values that are within tenfold of what could be a problem that I Don't know. I mean it's it's I know it's different than just looking at the hazard index That's the easy part, but it's do we do we try to say something from the exposure studies that have you know That's exposure modeling. I think that's what's so key about why we we're so interested in the exposure aspect Because that's the other part of the equation if if there's a lot of exposure then that Influences the risk obviously and so what we're going to talk about this afternoon is is going to be important part of this discussion Sort of the informant maybe the point. I'm trying to get to is the information about how they would substitute for each other I don't I don't have a sense of that Would dbp ever substitute for de HP or bbp for de? I'm I have looked into The the origin of the of the European way of handling this so there was Just like with the permanent ban here the three So that's were banned in children's toys and Children's care products and then those that Have an interim ban here are banned in the European Union But only if the toys in toys, but only if they can be taken directly into the mouth But that's is not What's happening here in the US that does instead an interim ban Well, but it the interim ban only applies to Child care articles in toys that can fit in a child's mouth. Okay, fine. So that's a That's an analogy there These these Recommendation of this kind of action in Europe was based on various risk assessment reports by various EU scientific committees and What I'm Now trying to find out is what they mean by risk assessment nicely and whether Whether that really means a quantitative risk assessment in the sense of what what we've just discussed a couple of minutes ago Or you know risk assessment can mean all sorts of things Doesn't necessarily mean you you require that a that a hazard quotient is Smaller than what So I'm trying to find out so there's evidence that there's exposure. There's a evidence good toxicology data on chemicals Across something that could be the phthalate syndrome and it could be even broader than that. I mean that all leads to discomfort in Continuing or dropping the ban, right? Which is not based on a number of the hazard index The ban was not based on a risk assessment. I mean, this is the risk assessment. I think That's what they why they part of the reason why they told us to convene a chap but looking I was also looking at the the origins of the EU ban and one of the things they mentioned. Well, if you take You know if you allow You take one away and allow the others in I mean if you were to say well Maybe the exposure from one of the band ones is low, but if you Okay, you can use it because the risk is low and then you know, what's the risk if they begin to use it? There's a different scenario then Maybe chemicals like DEP that have high exposures And maybe we don't have enough evidence yet on the toxicity of it, but it sounds like DEP is not as toxic as these If we had I'd rather maybe that's what we would prefer At least it Rats it's less toxic another point it isn't essentially one of these criteria, but a A lot of Concern that has arisen several times as we've discussed the impact of a regulatory decision Is that it may take some of the bad actors off the scene and replace them with chemicals of unknown behavior? And on known toxicity on known exposure except that they would probably have an exposure similar to the ones that are being taken out by a regulatory action and I'm pretty sure that CPSC doesn't Have the authority to demand that certain types of toxicity studies be done before a chemical replacement is is decided upon by industry So we can't make that a wreck we can't make that a recommendation as such with the expectation that it's going to happen But we may choose to be on the record of recommending That alternates Be selected only on the basis of known toxicity profile that would make them of less concern than the ones they're replacing And I think simply from the public health standpoint that's an important message to give Rather than take a replacement and do the experiment in humans to find out if it's better or worse than the one that we're replacing So I don't know how that's going to play out in the report, but I'm just putting a marker there that I would like to have us Go on the record of making some recommendation of that kind in the report and another another recommendation in my mind would be just to Sort of have some some pressure for the agencies to work across You know have the EPA the FDA the CPSC work together. I know But I mean because it really in terms of public health It's not just one product at a time or one cosmetic at a time. It needs to be thought of together And I know that's difficult, but my my thinking is we're doing more of a public health risk assessment not just based on toys And I mean, I it's an excellent idea. I mean just for the record. We are Have a lot of interactions cooperation and sharing going on with the EPA FDA Health Canada NTP, I mean there is a lot of crosstalk But there's always, you know opportunities to do more than that. Yeah, I think it's time for a break We convene about Order to 11