 Mike we begin I'm all set. Okay So based on our discussion at the end of the day yesterday Where we talked about DMP and DEP Burnett I put together I think most of our comments in The format of I want to say Yeah, the outline that that Burnett put together and talked to us about yesterday, so Here is What we came up with last night for DMP and we'll go through DEP as well So the the six Characteristics that we would like to have as a template for each of the phthalates as we go through our Adverse effects and under that we have animal human Relevance to humans weight of evidence risk to humans and Underweight of evidence experimental and replication risk to humans exposure and hazard and Then five is our recommendation six with this recommendation if implemented effect exposure of children to in this case DMP and We Asked is this a format that we could use to Nicely and precisely summarize our thoughts for each phthalate and Precisely come to a recommendation in this case We say no action for DMP. So let's go through this so adverse effects Yes my expectation is that these Recommendations this page of recommendations is something that will be copied and Quoted and whatnot and the last thing we would want is to have a miss Interpretation of what chemical we were talking about So I would recommend that this is not the place for abbreviations Alone that we would use the full name of the chemical and the common abbreviation that we use throughout our report And then perhaps the cast number but is the cast number internationally recognized identifier so My suggestion would be that we should have the cast number on these pages for each one of the chemicals so that if somebody is More used to going by cast number than an abbreviation We have that as another backup for proper identification of the chemical that we're talking about I'm not going to take us much more time To put that on these reports Okay, so under adverse effects animal studies Reproductive no studies available Developmental there's the gray at all two thousand single dose study 750 milligrams per kilogram per day Found no alteration in sexual differentiation or male reproductive tract development. So that's a concise Summary of what was found be human no studies available And again, please correct me if anything I say we've said here is not correct or needs to be amended So that's the yes Just a question which has an impact on Well, sometimes there are Effects observed in in experimental studies where whether they are judged Adverse or not is it's a matter for debate And should we I mean with most of the endpoints we're discussing here this debate is rather philosophical but Should we maybe in the annex have somewhere a Section where we reflect on on the adversity of various effects that that we consider for example, just to illustrate this Years ago. There was a debate about among Toxicologists not very familiar with endocrine disruption whether something like change in a no gentle index would be classed as adverse Now the understanding of that has progressed and we now know that this is a biomarker for Insufficient under an action in the rat in fetal life. So With everything that hangs on it. So in this context AGD is now judged in a in a fairly clear way, but that hasn't been so always so therefore I Don't think it the right place for this is now in these recommendations, but we would need a Section somewhere where this is clearly explained what what we class as adverse agree and agree and that is in the 30-page document that Right, okay, I will have to write for developmental talks and burn for repertox and maybe we'll have to have that a combined section We have to sort that out later, but you're absolutely right but I think we shouldn't confuse no-wells with no-ails and We have tried to standardize that what we're reporting from the studies is that was what the authors and us would agree is a no-ale But there are times where the scientific community changes its mind and we have to be tuned into those But for use with the hazard index approach, I'm assuming that we would always be using the no-ale Not a no-ale But we're where we need to explain this we we need to okay The second point relevance to humans Here because we have no human studies, we just have animal studies minimal We would I think go to the default position and say animal studies assume to be relevant They seem to be semantic But I think it's good for us to document what our choices are in some of these categories to achieve consistency from one to another and In my experience with this in dealing with other kinds of Reports there are three three Choices when you talk about relevance is either assumed to be relevant or it's known to be relevant or known to be irrelevant Well, I would encourage that we not invent further categories unless we absolutely need to But we then to be consistent from one to the other we should use that Yeah, and those those would need to be defined up front in that 30 page Document somewhere and then the third point is weight of evidence so there under a is experimental design and Again, we would have to find this upfront as well Here we have a single-dose study which is not suitable for risk assessment and be replication is another Issue and no, we do not have replication. It's one study under point four risk to humans under a Exposure is low and then we would refer C table in Under hazard index in there in the report or some such reference Be hazard Unknown minimal data do not demonstrate hazard. Please jump in if you wish to make a comment or So yes, could could I suggest to call this heading? risk assessment considerations Rather than risk to human risk to human sounds frighteningly focused often week This assessment consideration sounds a bit more flexible risk assessment considerations or something like that He's always misbehaving these Tell me that in school Oh, yes risk assessment considerations no wonder we get along better risk assessment considerations. Yes, okay Yes, it's better So going then to five recommendation. We said no action again, we would define upfront what our Choices are in terms of recommendations and six with this recommendation if Implemented effect exposure of children to DMP and we said no like the way that And that we we took that verbatim from what someone said yesterday because we're willing to because there may be others where Well, how are you going to define effect exposure? You know Ten that would determine you see again. We're back to the issue of total exposure versus from toys, which is our charge Would this change affect? Exposure maybe Not for this particular one there could be considerations for others like, you know total exposure could affect children Bozier in toys may not affect children if it's a much less less than 1% So we could we could qualify that right here. Okay. That's what I'm saying is that we have to Categories in that because that gets back to the point. I think we're not and I talked about yesterday before we left We got to remember the charge, but we got to also remember other situations Actually, the word no here is not enough because no is not answering the question Because there is no action. So I think it would be more clear just to say it no action was recommended so the question of whether it's going to To result in a reduction of exposure of children is a moot point because there was no action recommended that would affect it Not applicable And burn you just use the word reduction and exposure. I mean, would you want to make that more specific and say would this reduce? Might we recommend some actions that would result in greater exposure? Good theoretically For example, there's the other example we'll look at the recommendation was to do more research to gather more information That by itself Won't result in a reduction of exposure But it could eventually So I'm not sure what question we're answering here, but I guess the term effect exposure We would need to define that Give it a direction. Well direction and and also I mean if One percent change in effect is You know it it would almost be like in Epidemiology if you say is there an association you ignore any statistical testing or confidence limits if it's 1.01 The answer is yes. It's not 1.00 the null There's an effect whether it's meaningful or Important is a different question, right? I mean because that's basically asking the question is Is the effect different than zero? Right when you say Does it affect exposure that we're guessing? Well, yeah, that's the plan. I think we're guessing so we're gonna qualify any of these Answers to that question, but we could say with this recommendation if if implemented be expected to reduce exposure of children to DMP I can't guarantee that it will but do we expect that it would that's the reason we're taking this action I think we could say Would this recommendation if implemented be expected to reduce exposure of children to this phthalate Does that get it be expected to be expected to that's more specific? Turns out that it doesn't I mean we also don't know what is it how much reduction does there have to be before it becomes significant or important or I Think we could go on record of saying that we expect that this action will reduce exposure Otherwise, why would we take it? Again, there's gonna be the issue of taken action on Charge meaning the toys would we expect it to reduce exposure? relative to the total exposure which is have to address I mean you It's it's very complicated because you know Haven't got the result yet back from the kids, but some of the results we've already seen in And I think for it's really important Paul that in your section in the 30 page that you discuss this in detail I will yeah that you lay out those issues There are significant issues. Yeah, I mean it's like saying, you know, you know, we have toxins and everything arsenic and drinking water Arsenic always order in New Jersey Do I ban kids from drinking? pregnant women from drinking arson to water with arsenic in it Only if it's above a certain level But he's getting rid of it. It's almost impossible. It's a natural compound There these are really complicated issues because there are toxins everywhere Chemical world, but would this be a good time? I've prepared something to open this box weight of evidence a little Yeah, it's fine They're great job guys. I Would have another question Regarding for a exposure we focus most of our discussion yesterday based on the MOE or MOS model and this is not implemented here with a C-table and has it index report The hazard index itself is more designed to be the cumulative exposure part while yesterday We focused our discussions on the margins of exposure or margins of safety and we also Talked about current exposures and expected exposures. I think that's why I favored Sorry this weighing up Has to go has to go in there. I mean in the case I agree with what burnt and Phil have done in the case of DMP these considerations are fairly straightforward, but they've become more complicated with other phthalates So we would have to fall back on the MOE's and Take into account Anticipated changes in exposure patterns, etc. etc. All this comes It's also a question for debate what kind of margins of exposure one would Expect minimally to say okay negligible risk But at least it gives us a box that we have to fill that in Could I ask Andres to say a bit more about what you mean by changes in exposure pattern? I mean this is that this is the issue I've been thinking about is my concern is is that when we make action on one chemical others are gonna come up That we don't know as much about Do we need to have that kind of consideration in what we're talking about here? I mean it may be that we don't know we have no idea what what the next Vocal up to that would be but I Don't like the idea of falling off the abyss, you know, you don't we make one action and there's Something's gonna happen Yeah, we had this this yesterday looking at the example of the IBP Where? It's not widely used apparently bards the the exposure increases and we are already in the The gray zone with the margin of exposure so yeah such considerations would then have to kick in You had the same considerations regarding the INP. I didn't want to mention it just now So does that mean we need to add another component to this sort of framework that says you know What's the impact what's the behavior pattern or what's the exposure changes that's anticipated or do we know anything about what's anticipated? Yeah, I think we should handle this flexibly as and when it arises. I mean that this frame work I think it's good enough to allow us this flexibility. I mean this has to be done on a case-by-case basis Wouldn't ask it as a final question no because we may not know the answers And I think that's important to say in these cases we might anticipate this in other cases. We don't know So you could be it's it's it's not just the risk side of it. It's a risk-benefit side I mean are we better off staying where we are in a case where it's the margins are wide Compared to what we don't know that's the question. I that's an interesting question most people don't ask Benefit considerations don't enter this at all But let's be very clear about that. That's beyond our area of expertise. We're not doing risk-benefit considerations What are we doing Michael? Risk assessment, no, I'm asking Michael about I know what you said and But it needs a context as to what we can and cannot do Well, I think it's so the point of risk benefit was just raised and I think it needs an airing Well, I don't think we're doing What the we would normally do risk benefit which is you know costs right basically But I think to consider You know substitutes. I mean I think that's one of the Part of the the charge is to consider substitutes and if you take away a phthalate and replace it with something else Well or that just ask the question if you take away this phthalate, what's it going to be replaced with is it's going to be better or worse? I think in that sense That's I think that's so that's within the charge because I was wondering from the standpoint of of The three placements since we had really discussed it and that is a consideration and that's I think Why that provision is in the in the charge? Okay, I miss about calling it risk benefit. I agree with that right right. Yeah We're like unintended consequences Okay, that's fine Mike because the CPSC is the primary customer of our report if we follow this template For the rest of the chemicals Will CPSC consider us to have been responsive? Charge Yes, apps apps Absolutely, I mean you're going to go through this for the list of phthalates and the list of substitutes. So I mean Yes, absolutely to Yes You I think this will work from there our computers great That fantastic, okay, this is very very briefly There are There are a number of weight of evidence approaches and in this area there's no no general consensus about what to do and The complicating thing is also that the term weight of evidence is used with different meanings in different fields of study so but What what is most useful to us is to look at epidemiological criteria of causal inference, but with qualifications and quality criteria for toxicological studies So I take this in turn the most famous Criteria for causal inference and epidemiology are the Bradford Hill criteria And this this arises out of a out of a fireside conversation between Bradford Hill and doll they were musing about When when can we claim on the basis of epidemiological evidence that something is causally Linked with certain disease outcomes and that is because the term causality in epidemiology is very complicated Normally epidemiologists studies at associations, which is different So they they came up with these criteria or Bradford Hill did These are the ones we can briefly go through strength of the association that that's a that's a measure of the relative risk estimate Consistency is this consistent across Geographical social or temporal scales for our purposes. This means has it been reproduced The specificity is this a specific association between exposure and disease Temporality evidence that exposure precedes disease Or not all of these are totally applicable to us here, but I'll go to Biological gradient. That's a that's a word for do we have any information about? those responses Relationships plausibility is what we're looking at plausible from a biological point of view Coherence with natural history and biology of the disease What happens if if you can do an experiment where exposure is Interrupted or seized totally will then do we have a recovery effect? And then lastly analogy the consideration of the known effects of similar factor So is there anything out there already? Similar to the exposure we're looking at where we know that something adverse happens I mean these are these are the original Bradford Hill criteria in practice. They are not all used To to judge the strengths of epidemiological evidence. There are some variations some criteria are left out and some are really not applicable and they have only very Rare cases where the full set has actually been been looked at or can be looked at That's a that's a guide for us. I think to To look at epidemiological evidence It has been used for example by the WHO in their global assessment of Endocrine disruptors, which probably is the most useful application for us because we're we're looking at Thale and there I mean the the original number of of these criteria has been reduced somewhat But it's but it's still useful and there's also Further examples in the literature where people have tried to apply this to to various hypotheses and questions Which we could look at but without going into further detail now Very relevant to us is to judge the quality of toxicological studies and here the most important bit are these so-called Clemish scores This comes from a paper by Clemish and colleagues published in 1997 I've put the reference down here So they have Four criteria where they this is all about judging toxicological studies in the context of usefulness for for for making Regulatory decisions So the best is reliable without restriction and that generally applies to studies that conform to GLP or some other set of quality Criteria now we need to dwell on this a little that there is a problem because Blanket application of the GLP criterion will kick out a lot of studies. We are dealing with because normally scientists do not Apply GLP criteria, which is not to say that their studies are somewhat worse, but the way Academic institutions are run is is is not amenable to implementing GLP Now the problem is that many regulators would but disregard any scientific studies and kick them out I don't think we can be we can be that restrictive The other complicating factor is that Guidelines studies that that's also that's also a criterion to demand that the Studies we are looking at have to conform to guidelines I think I also think that's a bit dangerous in our case and too restrictive Right the next one is reliable with restriction that applies to studies generally well documented and scientifically acceptable But surely falling short of GLP in some measure I think that would be a lot of the studies. We're dealing with falling into that box here These are just the original clearmish scores. I'm just You know telling you about we can think about whether we take them as read or whether we modify them Not reliable means method used to either Unsufficiently documented or unacceptable and they're not assignable where the documentation isn't sufficient for risk assessment Of in many in some situations only an abstract is available. I don't think that really applies to us But that so this we could use as a guide or But the next one is I think we also need to reflect and Yes, yeah, you go back to the to the slide before that Cleemish and co-workers they Of course probably see these scores more from the industry perspective Well, yes, and We know with the data. It's for example that Many studies performed were thoroughly Following GLP, but the guideline they were Let me put it this way talk studies that follow the classical guidelines on for satellites We're not dosing in the right exposure window. So from from from looking at this the GLP side, they were fully Compatible but we know that the study approach Was looking at the wrong exposure window or the wrong timing. Yeah So this is just For Let's say the GLP compliance Nothing more I Totally agree with you. That's why I say we have to take the Cleemish scores with a pinch of salt You're quite right and that is the problem. You can have the most wonderful GLP study which will give totally inconclusive results But we have to exercise judgment there and and bear this in mind and also You know often okay Guidelines as you can adhere to certain guidelines, but from our knowledge about the toxicological context We have would have to conclude these guidelines studies or these guidelines are inappropriate to show the effects We we want to see so we have to bear that's what I meant We have to bear all this in mind, but nevertheless Broadly speaking, I think the Cleemish scores are useful or we could should keep them in mind or modify them probably for our purposes But we also talked yesterday about having reproducible study, you know studies with reproducible outcomes Yeah, and which is also the evaluation of quality that may not follow these guidelines But it is something that we sort of talked about. So yeah, it seems that regulators look at this in a slightly different way They they they put more emphasis it seems to me on the quality of one study So it is quite possible to make risk assessment Decisions on the basis of one study only, but if it's wonderful and well conducted well documented, etc Etc. There's no problem with this. So the demand for having having the effect under consideration reproduced independently is Somewhat handled flexibly May prefer that Well, if you can say that has been reproduced in several laps that will strengthen The case of course and if it if that's the case we should mention that, yeah, oh The quality here the quality criteria here apply it not for the study design, but the performance of the study No, the documentation. Yes performance as well. Yeah Not the study design The design to a degree as well Here look Scientifically acceptable What you're saying is that it may be Studies may be reliable They may GLP be GLP, but they may actually mean they may not address the right questions. That's right. Yes, we have Yeah, yeah, we have concrete examples for this in the past there have been and we have Seen some of these studies presented to us by industry representatives here where they were wonderful beautiful But sadly Exposure didn't take place in the period now recognized to be the vulnerable period and therefore the results are totally inconclusive for our purposes So if it were if I I want to take if I want to take this father Considering we have data gaps in many different arenas That one of the recommendations could be that you know GLP is not enough you need GLP plus and not enough Plus you have to have your study design focus on the particular Question or gap that we're trying to fill. Yeah, and that's right I think that would be a more than in fact, I think that would be a very important recommendation Yes, we do some out of waste of money and time and effort trying to describe and Convince people about the adequacy of a study that doesn't answer the question. Yeah, I agree This is I think sorry is also relevant. I mean that comment to epidemiologic studies I mean there are studies that have been done in let's say an occupational setting looking at an exposure and development of cancer and you Have five or ten years of follow-up and it's you know a tumor that takes two decades to develop the study could be adequately powered Designed but you know the follow-up period is not adequate We're the exposure window, so it which is not really included in the Bradford criteria. That's right That's right. That's lead me leads me to the next slide. I think both Bradford Hill Criteria and Clemish scores alone are not sufficient For what what we need to do. We have to judge the technical quality of So I try to encapsulate this here But only for experimental talk study something similar would have to be done for epidemiology I didn't have the time to do this so consider I try to Express this in terms of requirements for deriving P. O. D.'s We already have a knowledge various studies where that are not where a not designed to derive a point of departure nor What these what would this mean meet the quality criteria required for that but these are so You can define this in terms of a minimum number of animals per dose group So I think OECD guidance says around 20 It has to be defined in terms of the number of dose groups So single doses is a bit of a problem. You would want several And it has to be defined in terms of control groups and how big they are and how well designed often You want to see a negative and a positive control So there's more in OECD guidance about about this But I think that would be helpful for us and something equivalent for epidemiology would have to be drawn up, but I've reached the end of my my competence there Maybe Russ can step in and that's the end of this Thanks And I think in my section of developmental talks I Developed criteria for how I selected studies that were acceptable for developing The well so and I think that needs to be expanded Yeah, okay, so going on to DEP For DEP under the heading of adverse effects. There are more data on this chemical First of all they were regarding animal repro studies there were Two multi-generation reproductive studies one in mice was a continuous breeding study Protocol that showed an increased prostate weight decreased sperm concentration increased rates of abnormal sperm and Decreased number of live pups per litter at 4,500 milligrams per kilogram per day And this is a study of lamb at all 1987 and then a two-generation reproductive study in rats reported by Fiji 2005 Where rats were given one or 1.4 grams per kilogram per day. There were no effects on fertility or fecundity But there were dose-related decreases in uterine weight in the number of gestation days We're both of those were affected and reported with a no whale of 255 milligrams per kilogram per day in the Reproductive in the developmental area A study by gray and all 2000 single a single dose study of 750 milligrams per kilogram per day Found no alteration in sexual differentiation or male reproductive tract development This is an example where a single dose study that might generally Make you think that well, this is a non contribution because it's a single dose But in the case of Earl Gray's lab, this is in the context of a large number of studies that he's done and he has Zeroed in on 750 as a meaningful starting point. And if you don't see anything then there's no need to waste resources On something that's not going to be productive. So There are times when a single dose study is Contributing information and other times when it isn't but this one I Think is appropriate to bring to the frontier, but it is the only observation that there is on DEP and the human and Bill and I talked about what is a GI and it isn't clear to me, but maybe some of the rest of you can explain What a GI In a general index so so basically what Swan did in the in the 2005 paper Is since the infants were of different age and of course body size You need to adjust for their weight in In some sense and so she did that Different that she calculated in a general index which took that into account and use that as her outcome rather than the straight AGD in the 2008 slightly larger Analysis of the same cohort She used AGD, but she calculated weight percentiles and then adjusted for that as a covariate really rather than So that basically the the outcome measure was a regional distance and a GI versus the 2008 analysis was just a different way of counting for body size Okay, so then they what what we wanted to capture from that pair of studies was that Relevant endpoint was affected in both of these studies decreased AG I associated with the urinary tract concentrations of MEP in The 05 study and then the decreased AGD that's adjusted for weight percentiles Assorted with a higher urinary concentration of MEP in the 08 study You may want to just add in higher maternal urinary concentrations just so it's clear That it's not the incense any maternal urinary concentrations of MEP then the weight of relevance humans This is another case where the animal studies are assumed to be relevant Studies that we cited do not Provide proof that it's relevant, but it's assumed to be relevant Weight of evidence experimental design the Two reproductive toxicity studies that I mentioned are both suitable for risk assessment single-dose Developmental talk study was not suitable for risk assessment Then we left the question for you to flesh out for the epidemiology studies are they suitable for risk assessment? I would I would say yeah, I would say yeah. Yeah, I think so. So I think we can Regarding the replication end of this the reproductive studies. Yes, they were there were two different studies to different labs Developmental talks. No, it's not replicated. It's one One laboratory one experiment And the epi there are two different times Is that considered replication of the same effect or is it it the documentation of the two analyses from the same? cohort with a slightly larger data set, so I wouldn't consider them independent because in the Second analysis that I think there were 105 in fence the first 85 But the 85 from the first analysis were part of the 105. So no and not Not really replic the replication or independent So then because leave it as it is regarding risk considerations there There's high exposure to this Valid so the answer is yes from the stamp from the exposure standpoint. Yes, there is a high exposure and What exactly to reference here was not clear But the we need to reach agreement on what are the best exposure data that we want to cite in all of these cases so is it the Is it diverse our data or is it biomonitoring data both? We need them both. I wouldn't call it and hence data. I would call it by a monitoring Because it's not only in hence data. We're basically our based on biomonitoring data and Aerial exposure modeling External exposure modeling, right? Okay, so that's terminology we should capture and use again Mm-hmm Modeling External exposure modeling. Well, that's not quite true because we got an internal. We give an internal value It's not You you mount model the external to achieve the internal That so we were using the external modeling to achieve an internal value pain Micrograms per kilogram per day you you model external exposure roots and Thorses So that you come up with an aggregate or accumulative exposure that you can translate to a dose to the body It's it's external modeling. I mean it's exposure modeling compared to biomonitoring Yeah, but the externals where they get you know, just say exposure modeling if you do exposure modeling to achieve Number of micrograms real great to per kilogram per day, then I think that's a simple way of explaining it Which one was it was high for D? This is D. Right? Pardon me EEP right Then on the second half of the risk considerations being the Hazard information that we've gathered. It's it's unknown for developmental effects in animals because there's just that one single dose Study, so it's on it's uncharacterized or unknown in animals However, there is the decreased a GD observed in humans But the effects and in addition the effects observed in the reproductive studies are minimal Have to characterize the two categories of animal data and the human response Once can't be ignored Once is unexplained by mechanism So you don't know what the association that's real Mechanism of action You're saying because in Rats MEP is not biologically active or that it's a different because AGD is is a Anti-androgenic response, which is what you would expect Yeah But you wouldn't expect it from DDP Right it could be that the human the human data you're looking at could be a mixed exposure Well, it is so therefore you can't you can't You can't tie it exactly to DEP you can tie it to phthalate, but no they measured the specific Metabolites and then they put each one into the model Looked at the association. They do the aggregate. Yes And aggregate didn't come up with the no the aggregate came up that it was stronger when you basically combine exposure to multiple phthalates Which is what I thought you said yesterday, so that I want but by stronger. I don't mean that the AGD was Much shorter and these are odds ratios are looking at so stronger in magnitude odds ratio, right? Yeah But in terms of mechanism, you know based on the the animal data DEP is Is not thought to act as an anti-anxious just isn't interesting I'm trying to discuss this this goes back to my Point about total exposure, but not only total exposure based upon source But based upon total exposure to a variety of phthalates what some of which have a much higher Potency than others But this this can be easily dealt with Within the framework of the Bradford Hill criteria. That's this one biological plausibility So so we could argue that in this case. It's it's not really fulfilled, right? No, again, this has to be always judged in in context, you know, there are If if biological plausibility is not fulfilled, that's not necessarily a decisive criterion because in the past There have been many examples for example one from from your area of expertise Paul with particulate matter Where these associations between particulate matter and cardiovascular disease were discovered but at a time where? There was no biological plausibility for that, right, but this has emerged later, right? So you always have to be judging this very carefully. I'm not I'm not discounting it What I'm trying to do is just like you are we have to put these things in the context of where we are in terms of Evaluations when we make our decisions We're using the best available evidence knowing that in some cases that well, maybe it's so You know, it's fuzzy too fuzzy for us to make a decision now, but more work is needed And I think that's what we're what we'll cover in the Get to this part here Don't we need them the something about the margin of exposure before we get to the The risk assessment considerations could we have a part C that does our best in terms of an estimate for a point of departure and an estimate for Exposure high-level exposures or whatever and I agree and you know actually this is one case where once we get the data from the availability of Exposures and children You know if it's very very low then this even is more of an issue in terms of what we have as our charge as to being something That is not consequential at this time because there is a higher exposure issue here, but it may not be the source may not be Toys I'm trying to bring all the stuff in because we're going to have to explain this crap Unfortunately is a lot of confusion that can result if we don't we're not careful how we explain these things And we're trying to use this as a logical weight of evidence in a logical way in which this discuss, you know our decisions Now I'm beginning to see how we can do this a little bit more strategically. I Mean if what you just said is true. I mean you could then right here put a however Exposure from children's toys is low in consequential or inconsequential whatever you want to use I mean you can modify and then that helps us make our decisions better This will work for you I agree that it would be helpful to have to have the POD information and the MOE information in there But these are kinds of terms of art among us And I think in order for us to use them as a basis for our recommendations We need to have a very good explanation of what is the point of departure? What does it mean? What are the criteria that are required to be able to select a point of departure as something that's meaningful as a basis for? Yeah, whatever we're going to use it for and the same thing with the they are Margin of exposure But that's the previous discussion could actually each of the toxicology part of the epidemiology part whatever Was your part could each end by saying with this information our you know, we're in our consideration for a reasonable point of departure as With some evaluation of the quality of that I agree well I'm saying is that for readers who don't use part of departure thoughts every day We have to have an explanation someplace in the report for what is the part of what is what are we departing from? What are we taking with us at this departure, but even with the point of departure the actual data we have from mechanistic studies actual quantitative exposures that occur the evidence from epidemiologists to epidemiological studies all will Support the ends what will happen how you might say reduce my angst in terms of the uncertainty around a point of departure Because if these other things line up, let's say high high high well, you know It doesn't matter the point is it's it's there It's real or low low low or and then the only only place we will get into trouble all the time is when we have this confusion somewhere in the middle and That will help us those data real data or at least estimates will help us resolve some of those problems Agree, and I'm just saying that when we use no oil we define what it is. Yeah, if we use POD and MOE we need to define what they are or Benefit of and that could be in the original strategy part of that inner of the introduction that we're right That's part of the 30 pages. Okay on number five with the recommendation itself My guess is that there's an inverse relationship between the clearness of the recommendation and the length of it This is a longer one It's not a yes or no answer the things to consider I love that the high levels of exposure together with the decreased age GD measure and Humans raises concerns However the epidemiology study was not replicated and adequate developmental toxicity studies in animals have not been done What's not said there is that therefore there is no recommendation for banning, right? What we say instead is that therefore recommend the recommendation is for further studies To help determine the risk of DEP to humans Well six I think covers the point you were just going to make that no regulatory action It says there that there's no regulatory action, and I think that's that's a fine answer very minor Point in terms of wording when you when you say because it could be Misinterpreted when you say the epidemiologic Epidemiologic study was not replicated Someone could interpret that to mean another study was done It didn't replicate this study. So I would just write. I mean someone could interpret it that way Because when you say something's not replicated it means However There is only one Epidemiologic study where the data consists. Can I ask a question of rust? You made we just discussed the issue that Was a total exposure issue Not just DEP Which let is there some place to put in that number five or somewhere in the epidemiology Leading up to it the point that you know this is a this was a mixed exposure in the epidemiological study Well in all of them it'll it'll be a mixed exposure So they'll measure you know six or eight or ten of the metabolites, and then they'll explore each one independently To try to see if there's an association, but you're correct that Not only is MEP in the urine, but MVP MHP the oxidative et cetera plus other other exposures I mean the concern always in Epidemiologic studies is you know even though you can statistically model it. So you just have your MEP predicting your outcome It could potentially be a surrogate for another exposure that you either measured or didn't measure you know maybe In this case pregnant women that use more cosmetics personal care products also do something else different and have a different exposure Then number six the wording would be changed to what we agreed to earlier Would this recommendation if implemented be expected to reduce the exposure of children? And the answer is no regulatory action was was recommended. I really like this approach that you guys It really it for a person who's not a toxicologist. It frames the questions better for me How we proceed I think this is really well done Thank you for your help yesterday and arriving at a template because I think these will be looked at independently People aren't going to necessarily read through every one of these They're going to look at the one the most importance to them. So it has to be a freestanding piece of information just for that the talk studies so Adequate developmental talk studies and animals have not been done. So I mean in talking to toxicologists in the field they would they would say that DEP is not anti-antrigenic But do you feel that? Because when you're saying adequate developmental you're saying you you can't determine yes or no if it's behaving through that mechanism or do you think that there's enough data to say that It's not anti-antrigenic Guess what I would say is adequate based upon the criteria that we will have in the 30-page document as to what constitutes adequate developmental toxicity data in other words a Study that has more than 20 animals for dose group More than three doses or three or more doses replicated in multiple labs Was to ask you directly. Do you think based on the tox data DEP is? Not anti-antrigenic in the same way that The other phthalates are or do you just think that we don't have enough data yet to say whether it is or isn't I think Because I know there are some toxicologists that would have A different interpretation I think the fact that they came from Earl Gray's data I mean you kind of said earlier if we do have that the comparison to other phthalates Yeah, at least we could say it if it is anti-antrigenic. It's not as potent as others. Yeah, and that may be an important part I think that was what Paul Ger kept referring back to you yesterday with respect to the talks Think where it's the approach that was taken was justifiable But there is still some uncertainty Would 800 milligrams per kilogram per day have caused an effect? We don't know If he have repeated this study at 750 in the same strain of rats would we have gotten the same exactly the same answer? We don't know so there It's a pretty good pilot study or Saying how should I spend my resources and my animals, but it's not the definitive answer on Under challenge was this chemical and anti-antrigen? We're not making a statement on that I don't think we can To two things for comment number one Okay, the focus on anti-antrigenicity is important, but in my opinion can't be the only one that potentially other effects by mechanisms Not related to anti-antrigenicity which also give rise to developmental or reproductive toxicity Which we need to take into consideration So the focus on an anti-antrigenic mode of action is a little too narrow in my opinion So we have to bear that in mind second which leads me on to a to a consideration what we could do is Include An additional criteria on which which simply is called mode of action But I I hesitated to suggest that yesterday, and I'm still hesitant, but I still sort of put it up for for debate here it would Give us the opportunity to reflect on on this anti-antrigenicity Put considerations of biological plausibility in there, which would answer some of the points we discussed this morning It may be useful on the other hand I Feel at the moment that the framework as set out by by you too will work and It can live without this additional criterion of mode of action You know you're suggesting for example considering effects on gene expression in the absence of Productive more to the point for for many of the thalets We're looking at the question would then indeed focus on on anti-antrigenicity or on endocrine disrupting mode of action, but I think Well for obvious reasons that's an important consideration for our purposes, but in my opinion can't be the only one There are pros and cons so if we included this in our framework as an additional criteria and it would give us the opportunity to Consider biological plausibility, etc. You know the points Paul raised a couple of minutes ago in a nice place on the other hand I think it can live It can live as it is I don't know just an idea. Well for example the observation in the human studies of In alteration, you know genital distance if we just said there was a reproductive a male reproductive effect I think we would be remiss Because there's a special trigger value to saying AGD is Something that was caused by this thalete So I think we can bring it in in that way because that what we're observing is Related to a mode of action I think we need to have a place in the report where we talk about Motive action as it relates to this group of phthalates and It becomes in a criterion or Deciding which of these phthalates have this Motive action Comment to them and which do not appear to trigger this mode of action. I'm not sure that we should Have a section to comment on it With each phthalate individually That's why I Hesitated yesterday to to include it and I didn't suggest it because it's it would on the one hand be a nice way a nice box to put various relevant considerations, but if mode of action is say if we you make the demand the mode of action has to be endocrine That's nonsensical in our context and if that criterion is not fulfilled then nothing There's no consequence. So therefore I didn't mention it yesterday, but I say yeah on reflection I've answered my own question. I think we should leave it out Sorry about this So we just got a brief Picture into the internal mechanism mechanism of you deciding yes or no Yes, you had a look and into the abyss Okay, so have we finished the discussion of DEP Hearing no further comments Andreas are you prepared to do dinp? Yes, I am Do you have that on a PowerPoint? No, no, no I haven't the choice was either to do the weight of evidence or the dinp But in a in a break I can quickly do that for later So it's time for a break. Oh, yeah, all right This is a point of intersection. Could we go over? the the new chart for That added the three other Dalits last night sure today because I think we should do that before we leave You have that on the PowerPoint We have everyone everyone has it now I don't have a verse of the verse or data to For those last three compounds and someone put that on PowerPoint. Yeah