 So Chris could you just on that slide? Could you just explain what the different headings mean the upper bound since so on? This is the high high intake estimate so The second cop. Oh, it should say points of departures. They're my fault We've changed from reference doses to points of departures. It's still in micrograms per kilogram for body weight per day and Units there because that would match the the exposure data So the third column is the the high intake estimates as Calculated here except Is it only above a certain level? So the last three the last three values are just means they don't reflect the 95th or the high-end values Okay, okay And the fourth column are the biomonitoring so those are from the in Haines 2005 and 6 they are the population average I mean population Estimates for the 99th percentile That's using the population weights the sampling weights in in Haines. I had a question. Is that for women for pregnant women? Yeah, it's remarkably close And then the last two columns are simply the ratios of What should be the points of departure there in the second column over the corresponding exposure columns? The suggestion was to get rid of what I was trying to do with the folds higher and lower What you see there is actually the calculation But I think you should recognize that those numbers are too many I don't think we should emphasize that many, you know significant digits. We're not we're trying to de-emphasize significant digits here But at least it is the actual Ratio so I think Andre if you want to pick up on what yeah, yeah So normally you would demand since you are here these these comparisons are direct Comparisons between what what was given in these animal studies to the animals and what human exposures are so for you you would expect a margin of exposure to be Between hundred anything between hundred and thousand maybe depending on the uncertainties behind it the Severity of the endpoint etc. etc. So what what this shows is, you know one one thing sticks out That's the DHP that there's a This is a margin of exposure of around 10 That is definitely not good news And so on you know you can read the data yourself The rest of them seem You're not concerned about the other ones above that Pee-pee which one D. B. P. I would say even the D. E. P. It's actually interesting to me because I've been thinking That we know the exposure there is so high Another that estimate for a point of departure is very Rough that was based on what was that for Phil But it looks it's interesting that the three band chemicals D. B. P. B. B. P. and D. E. H. P. Have the lower ones And it's like another order of magnitude up for the Interim bands well, I don't know about the last three. I shouldn't look at those numbers But the DI so those are actually based on they haven't Calculated the high-intake estimate so those On the media Well on the on the modeling column right the last column But look at that. Yes, the dinp looks you know, that's kind of That region where we might be worried What's your worry factor? I mean factor of 10 versus factor of thousand versus facts of 10,000 I'm not sure. I mean factor of 10. Yeah, I can see where's a worry factor factor of thousand Andreas help me Yeah, that's that's sort of a matter for for consideration I mean we can't do this in detail now. It would be we would need more material for that, but I'd say Women, yeah, that would be one that would be that would be the gray area So if we have worry non worry, just the great that you'd call that the gray area Well, what what sticks out here is as Chris said that the Permanently banter thala it's there seems to be Seems to be a failure a system failure which shines through here very clearly Very much so yeah, I am he looks and falls into that as well, which one the I am P That's the one we don't have looking at the last column That's where we're only looking at the biomonitoring intake of the other okay What I think it's going to be very curious is Nop or mean is to the high-end biomonitor you'll be curious to see what that comes up with Because that's means either very narrow distribution or there is a very large number sitting out there 95th percentile The other table if you want to look at I don't know if it's interesting as the median Estimates But with this now you can do Considerations along the following lines for example Holger, please correct me if I'm wrong D. I am P is proposed to substitute DHP right, so Could that be the case you can't expect the experts for D. I am P to go up Probably I don't know I'm that's speculation But the concern would be that they then reach Reach the zone where you would be come concerned about too small a margin of exposure Whereas for example that it these numbers would indicate that that's that's little Concern with the IDP at the moment Let's talk about the median too because this is very curious because only basically shows there's only one If you go by Andreas's initial Differentiation it's HP which is Shows up as being a concern and There's a very big difference between Well, let's put this way. There is there are much greater differences in terms of the margin of exposure between the modeling and the bio monitoring median which could probably be due to the fact that again How representative our median is of the total reality of what's out there, or is that still biased because we have to use exposure factors and We have to there's a little bit more uncertainty in those values No, we should probably That's probably a point for for our report to say that so maybe a call for the other competent authorities in the US Looking at DEP to say well Something should be done. I mean, this is something that I guess is beyond the competency of CPSC Or the jurisdiction of CPS. Yes The HP HP this is this a number here for DHP is more troubling in the high-end numbers for any other yeah, even even with media and exposures the margin of Exposure is insufficient. Yeah, in fact, I would I would say that for the median a number of less than 10,000 is a worry number Going with the median value HP is really an issue thousand is your worry number then But that was for the high-end 95th percentile. We're now talking about the means I mean I'm still there then BVP gets close. Oh, no, that's 147. No It's it's DHP, which is a which is an issue and rightly so Andreas is saying that this is total exposure which Requires some other agencies to start thinking about what the heck to do That's the the the three permanently banned. We see the numbers here We now need to consider the interim band INP is For the three band we're still not going to change the recommendation. It's poker to you What do you? The one that recommended the INP go up onto the band Category do you still feel that way feel that way? Doesn't seem to support it. I just brought it up for discussion. Maybe we can switch to the 95th percentile again Let's go back. Well, we we don't we don't know about our calculate about values What you're dealing here was with NHANES at this point. I'll explain it to you on the upper-margin slide right now for DINP we have Margin of exposure looking at the bio monitoring data of 1,000 850 so that's one of the intermediate worries It's in a meeting for us, but if we assume that DHP is totally replaced by DINP We would assume that the exposure to DINP will rise significantly because you would have to Zero out 375 and put it down to a line for DINP this of course would make the margin of Social consider the smaller for DINP then if you're seeing one-to-one equivalence exactly replacement But that's what we have to assume unless somebody says that doing something else These are these are the issues we have to take into account. Yeah, I didn't I agree. I agree So DINP is still in the woods Or play or still in the playing field to for two reasons in the morning. We again discussed Concerning the hazard right yesterday study clearly showed that DINP has to be regarded as ripped up with toxic and and the prime disruptor. So hazard is clear and Unlike here where we have a factor of 10 in potency between DHP and DINP The other studies or all studies suggest that there's only a factor of 2.5 to 3.8 in potency So we have to be aware that these Point of departures are not the conservative ones Want to have a table with both? Do we want to select the more conservative ones? Can I suggest we use Bernie's criteria to consider DINP and go through it one by one Adversity let's show we start with adversity We have three well the the reason why DINP was put into into the interim ban I think well at least speaking from a European perspective at that time There were very few data available for DINP. That has changed substantially. We have three well conducted Animal studies for DINP two of them offer caliber Normally required for for regulatory purposes because the numbers of animals for those group are sufficiently high and that's the bullback study from Denmark and what Rebecca Cluel presented us yesterday Then the third one is the Hanna et al. But I think that's a smaller smaller studies Yeah but in in all these studies we we do see an effect on on AGD and the Cluel study at post-natal day 14 There's no doubt the effects of DINP are Well DINP is not as potent as some of the other phthalates nevertheless With that with that's a common thread to throughout all these three studies at sufficiently high doses you see an effect on landmarks of male sexual differentiation That indicative of undivided insufficiency in fetal life Well what what you see in the the bulber study is increased multi-nucleid gonocytes and Nipple retention at 600 milligrams per kilogram and above Yeah, and increased testicular testosterone content AGD at 900 milligrams per kilogram and in the Hanna study It's decreased fetal testosterone at 500 milligrams per kilogram per day and then affects on gene expression And as I remember in the cluel study, which was presented yesterday It was decreased testosterone Expression, but I don't think they saw Yeah It was decreased Well, they measured testosterone levels. Yes, go back and I'll measure testosterone production, which is a which is the difference Yeah But there was two hours after in the cluel study. There was also an effect Well, we can say that's my number So they thought they saw no effect on AGD No in the in the shorter time point no effect on AGD, but at post-natal day 14 there was That is slide number my reading glasses That's like number 25 How are you? 7400 ppm Okay, okay the the the all of these studies especially cluel and and bullback are Extremely well conducted very high standards the outcome Of both of them is comparable Considering that one used the wisdom right the other one spragtoli They're talking about effects That indicate clear adversity so Well, we've already covered also the sort of the Quality Standards that are of good quality. We have the other criteria and is fulfill fulfill these effects were seen Independently in several studies conducted in different laboratories But these criteria are fulfilled Adversity relevance to the human well in the absence of anything To the contrary The default position is always to assume relevance for the human which in this case we should do We have three sets of these criteria fulfilled So adversity relevance to the human and their high quality and now we're Moving into the area of risk Assessment and and I think what we see here from these numbers that ask exposure stand currently in the US Margin of exposure considerations would suggest that the INP is currently not in the zone where the umberlight begins to flicker However Following what Holger said I also would have the concern that since this is slated as a replacement for DEHP The concern is then that this will change exposure will go up and we're consequently will have a reduced margin of exposure So for my in my mind that would be justification enough to say let's make the INP Permanent Clearly exposure could go up two orders of magnitude The product guys and are on your side are they what would the product guys say I don't know Well, I mean there's there's a general trend DEHP is going down Productions going up and it's reflected at least in the German expo biomonitoring data Whether it's a one-to-one. I mean they're both general-purpose plasticizers I'm sure the use is Overlap might not be a hundred percent. I don't know if it's a one-to-one plus things are always changing. I mean The INP, you know, there's also DP HP and DI DP Might well DP HP. I know is going up, too. So It's a complicated picture If you say it can go up one to two orders of magnitude if it goes up one order of magnitude our margin of exposure Now is already less than three orders of magnitude true That's those are the kinds of broad Swipes we're trying to do at this stage, right Andreas, would you be willing to write up a Summary of what you just said about the INP That's what we're certainly do. When do you want it now? Tomorrow be fine. I think it might be important for us to make some kind of a declaration in there whether our concern is Strictly limited to the possibility that it will increase if something else is decreased Or another way of saying that is I think we have an obligation to say how close we are to Concern right now Nothing changes and then we become even more concerned if the levels go up because of more widespread use I Think it's important to find that information out because I'd hate to put something out and find out You know, we're off base because of a new direction being taken by industry We would be kind of embarrassing moment But even so I mean the discussion about a margin of exposure of three orders of magnitude Talking about pregnant women. I'm I don't think we should be down in a margin of exposure or one or two orders of magnitude I think three So we're there now We're in the we're in the gray region now We're in from what from taking Andreas's criteria. We're in the gray area right now we're not in the The area of ultimate concern. It's the gray area. We got to be really careful We should clearly say that and this like like Bernie said, I totally agree with what Bernie said Did we should say it stayed very clearly that the concern is for this movement this change in exposure should should this be a replacement for for DEHP Well that raises the question would we recommend banning if we knew for sure the level was going to increase If it's going to increase by first back, let's say we let's make the the ultimate assumption and use Hover's point That increase goes to be equivalent to 375 that pushes it over into What Andrea says is the region of great concern? correct The right concern. I do not know would be qualified like that. Well, it would be in the area of An exposure factor around 10 9 or 10 would that raise your antennas up very high That would raise my antennas up very high is that it would be in the DEHP Right range where we are concerned, right? So therefore it depends upon whether or not this is truly Again, we need that other information to help us make it make a wise The other thing Russ today this morning We were talking and you said something about you are aware of some of the chemicals that there are some really high levels based on medication use of whatever so it might be interesting also for you to take a peek at the High exposure estimates here relative to what you know About extreme values because those extreme values may not be represented in the population study Yes, far as I know the extreme values would be for the for the butyl Primarily there are Examples through medications where people have a thousand-fold higher exposures Butyl dibutyl phthalate for din p.m. I don't think it's used in that circumstance. Holder may know better But I don't think it is DEP DEP in medication isn't how about in in medical products? Are they substituting din p for dhp to soften Plastics no, no, but it doesn't matter medical products are a totally different issue because the risk-benefit issue is highly significant you know, I don't want a metal pipe put down my stomach when I when I have a Also used for other purposes, but what I'm saying though and even if you're in dialysis I mean you're under credit critical care at that particular. I think I think there is But the risk-benefit issue is but to the person is getting it. Yeah, I Think the risk-benefit issues come into play when you're dealing with medical products And we have to keep that out of the conversation for the time being But what about just a more general conversation about? Knowledge of things that more are more extreme than what's here give me an example by a monitoring population study if we are aware of Studies that had whether it's medication or other sources. I Think we ought to take that into account here. Just as But I wouldn't want to make a decision on dinp based upon medical uses It's not it's not part of the I think the equation at this point in time different risk different risk issues Another thing about what I think we should consider with each one of these reviews that we do and The recommendation that's within it is to make a statement of whether or not this regulatory Action if followed would change the exposure of children then we're directly responsive to the charge This would I think we should make the statement that we would expect this would have a Significant decrease in risked children because of a decrease in exposure to this valley that a fair statement We want to use then the biomonitoring estimates for infants Those kinds of statements. This is now these are values for pregnant women The infants ends up being higher in some cases. I first thought Chris would be Know that information we can have that back in the in the text where we describe the information But if we begin to put that up Very them within this recommendation and people are going to look to compare those numbers from one Decision to another and we're going to be held accountable for very small differences And in fact, they may be less important than something else that is driving our recommendation So my first thought But leave up to others Ma'am I spoke it looks like BVP is the one that has a higher infant value The others are sort of about sort of comfortable. I would I would say Holger are you comfortable that the biomonitoring? data captures the DINP in terms of the metabolites that were measured and In the studies Chris and me looked at I am pretty confident that By a monitoring data captures the exposure to DINP because Exposure estimates were based on oxidized DINP metabolites Not the monoyster, but I think this data is reliable Also, it is based on only one metabolite in Germany on Europe we use three different oxidized metabolites, but it pretty much confirms the data Have we finished discussion of DINP? Where are we with it? Well, we have Andreas writing up a summary For us which you know, we will revisit It's the is this in broad outline acceptable to the committee Yeah, so the the in broad outline is this acceptable to the committee this Consideration accordingly to the criteria so the recommendation in For the INP would be to make it partly to to suggest a permanent ban. Is that consensus? I have one question for Mike Mike you you did the DINP Evaluation a couple of years ago. Did you and you modeled Oral exposure by sucking on the on on toys or something The biomonitoring or daily intake we calculated here Is it in the same region that you calculated in your model or did you calculate higher daily in high Intakes because in contrast to the time you studied the INP we now have a point of departure Yeah, well we estimated I think Forteithers and toys on the order of a few micrograms per kilogram per day just from mouth Of course At the time there wasn't any bio Well the bio monitoring data was were negative So but it was probably and it was inadequate as well so You know so the you know modeling levels of microgram per kilogram per day that probably I mean, I think we were definitely below 27 Unless you're looking at you know upper bounds or something Okay, oh if that's the 95th. It's a median It's a median on the modeling Okay, and the 95th on the biomonitoring well that that would fit in with what we had for the children for just mouthing Mouthing teethers and toys Okay For which age group? Well for I mean we did up to 36 months, you know by year But that you know roughly 200 order magnitude without looking it up It was you know a few micrograms per kilogram per day in the upper bounds, you know, I Just might be around 27 something like that I will know more when Confirm it Versa sees the oral route or that the Incheson route as the major root of uptake to DINP Well, have the right is it right? Let me confirm that There will be soil dust Cosmetics as as in lipsticks. I can't see it right. Could you go back? Yeah, DINP the bottom Indirect And food in the model because you had unlimited data or is it There because you had negative data No, these are the numbers where we looked at The ones that did not we did not include concentrations in this Yeah, yeah, but actually I can maybe go back to the spreadsheets. It might be I think what we should do is keep these Concentration numbers, okay, so let's look at ingestion Food and we can look at DINP. Don't have DINP here Don't have data Therefore it falls out of the equation Therefore it is an Unknown factor if we assume that the IDP replaces DHP We would have to assume that something would add up on the direct ingestion route That is food stuff point that out Okay, I would assume based I think based on on on you on the Versa data I would expect that they compared to the biomonitoring data under estimate the exposure Because you don't have any data on DINP in food stuff I agree. Well, let's see what happens But I would I would expect an underestimation for DINP. What was the reason again? Because we know from fasting studies for example human biomonitoring data that the DINP Major source of exposure is contaminated food stuff like for example with DHP No, I mean the food data that we have or is is old and it might not have DINP There's no food data. Yeah, yeah Which is one of one of the things we need to consider in the modeling is I mean I made a matrix of you know These are the scenarios and these are the phthalates where there's data and you know If you don't see DINP in food you have to say, you know ask These are older studies where they even looking for it, and they probably weren't Yeah, but I think we're gonna use in our analysis. We have to put an asterisk next to it and say Void of this data Yeah, well, that's is is is not Available for true comparison with the biomonitoring data and so therefore if it's low It can be artificially low if it's high Well, then is even a different story saying there is another there are other routes of exposure there Where there is data that one is considered to be concerned about well, yeah, it's it's exactly why I did that I was looking for where you know, is it low because it's lower is it low because there's a gap in the data Yeah, I think it might be a appropriate time to comment on what we're doing or what it sounds like we're doing There's some of us in the room and some listeners may decide that Chap decided this afternoon to recommend banning DINP and I don't think that would be the right conclusion We are discussing data on example chemicals But we're also shaking down the system We may decide after three or four of these that we want to take a slightly different approach in which case we we help we helped ourselves by Exploring the system that we're about to use with live examples so to speak but I would sure not want to see in the newspaper that chap decided to recommend that The INP should be banned Because we're not voting. No, we're going through an exercise And we're seeing how well this system fits that we've been working on for some months. Is that fair Mike? Absolutely, and I wouldn't want anyone to in the audience to to get the Impression that this is the final answer and You know I would in the last chap There were certain issues like is this mechanism relevant to humans and that that they would have these like straw They kept voting and if they kept coming back and voting again And you know would it change up and down and you know, it's not final till it's final I think it's more fundamental than that. I think that That's right We're discussing the framework for coming up to decision and looking at the variables and the information We have available us to make the decision and also some of the variables that we want to consider in making the decision so the discussion to today is purely you know a group of Scientists others Sitting around trying to decide how we were going to approach finalization of the problem rather than even Deliberating about an individual chemical For the time. Yeah, but I still want to emphasize that I think is important Andreas that you capture Yes, you know this in in writing so that when we come back again We don't go back to square one that we say this is what we talked about and Do we have agreement on that or not? Do we want to modify it or not because eventually and sooner rather than later? We are going to have to vote Up or down so Can I add to this I totally agree with everything that's been said Before the problem. I think we are facing is this That we have to probably for the first time on this topic have to develop and come up with a set of criteria that is that is plausible and transparent and This has not been done before in the way that's been handled in Europe and so far here in the US as well Was on the basis of criteria that well to put it politely were opaque So we are now for the very first time a group that that has to face up to this and Develop first of all a set of plausible criteria and then apply them and that's what we are Wholeheartedly agree that is what we are Tentatively trying to do this afternoon and this is by no means a final decision, but we are playing we are trying out a Set of criteria that Bernie has developed and and see how where that gets us No more, but no less and along those lines the issue of the different routes the different sources are still up for grabs because we still need to consider more calculations and The fact that we have not dealt with the transfer between The mother and the child issue either I think effectively. We're just looking out at the mother We're gonna be looking at the children. There's gonna be a crossover at some point where some of the Valates could go from in utero from mother to child and Even after the child's born and we have to consider all those things too so we have a lot of work in terms of assembling information to do not the fact that we're at a point where we don't know pretty much where we're heading but Coming up with the different routes of exposure is going to be an interesting process of elimination Because even though we have inhalation we have dermal whatever we still don't have that transfer between mother and fetus or mother and child Which I think is going to be an interesting set of discussions keep in mind that You know this report needs to be finalized in very short order. So We're going to take into account What you just said You need to have that finalized fairly soon And that's why I said it because I don't want us to do any more analysis on adults Besides pregnant women and childbearing areas if we're going to do any additional analysis, it will be I assume on the transfer of phthalates between Mother and fetus in utero or mother and child After gestation meaning breastfeeding and things of that sort. That's where I think we should spend our time Because I think that's the only place we're going to get any real new information that can help make a decision I could just maybe you guys don't want to talk about this at this point But I'm sitting here thinking about sort of the approach that we're talking about here I mean, this isn't the only approach we're going to use we're going to look at other things as well like the hazard index and Things like that but in terms of the points of departures They're largely based on no elves They are based on no elves if I had my choice I'd much rather see the points of departures being lower confidence intervals on benchmark dose Willing to assume that lower confidence interval in a benchmark dose could be an order of magnitude Lower no, well, I mean that the no elves are not not the The best way of having a point of departure it is what we have here So if we're starting to add up things like How many orders of magnitude or you know or important pregnancy? Congratulations, I would even want to include something about Variation in the estimate of the points of departure. So I think we could easily get to three orders of magnitude that would be Other pieces there that should add another order I would I would agree with you I mean these numbers important at this stage are the principles not not the precise numbers And I would you know considering the harsh critique that is leveled that at no else I would also prefer benchmarks lower confidence. Yeah, sure as fast we as As far as that is possible, but this is a detail. I mean important other principles now For both of you Does it matter which one you use will the relative differences be the same? No, the the benchmark procedure has a has an advantage with no elves poor data quality is Reboarded by having a higher noel with benchmark lower confidence Limit poor data qualities Give gives you a lower estimate. So that's that's why the advocates of the benchmark approach Emphasize that and there are very various other problems with no else Okay, so there to depend on the experimental design that really not fixed numbers So they're always treated as if they were et cetera et cetera So I mean we do have part of our criterion that you're writing about as far as quality of the studies and things So it hopefully though, you know, we would have a quality study so that the very it the variability would be But it's still the choice of the doses may not have been done based on trying to find a point of departure Yeah, I don't I don't think any of the studies that that I reviewed were done in a way that Designed to develop To come up with a benchmark dose No Only one for DHP It's possibly I don't know. I mean that leads to farm for this afternoon. I mean, this is a detail We need to look at it If possible, we should use it. If not, then the reason I think it was no elves I agree. It's it's my new ship But the reason I was thinking about that one thing and how many orders of magnitude really should we be comparing? Should it be two three four? Then it made me think about well, I think there ought to be at least an order of magnitude because of that distinction Other factors that may Okay, yeah, let's go back up to the the top the top to DMP and DEP The no wells for those both of those the Developmental talk studies are there isn't much information. What's there? They weren't really designed To determine no well, but the studies showed no effects basically But didn't determine a no well we took the the dose 750 milligrams per kilogram We plugged in as a no well arbitrarily But at that dose for both of those there basically isn't any effect now DEP Given the exposure has a much different margin of exposure number than does DMP Would say the the quality of this point of departure that's gone into that is also rather poor for poor What what just to remind us what were the endpoints that's based on there weren't any There were no effects I'd say roll over So But again, what what do we do with the DEP where there's it's a high exposure? Phthalate in humans. I think there's some correlations E in the swan paper Mm-hmm the cat kind of situation where we need more data And so if we put it in a situation where we're trying to push those kinds of studies to come around It is a high exposure data important to have that point of departure nailed down They'd be very conservative and again the Animal data You don't really know Russ, how would you interpret the epidemiology there the Ornament papers very difficult to say what was going on there what had us as I exposed to precisely we don't know It's probably a mixture of DBP and DEP. I guess I have no idea We have the the swan data where the DEP metabolites were very high in the urine and She aggregated by simply adding up and then found associations with a GD index And with MEP alone, so MEP alone as well as the aggregate Exposure, okay But that's you know, it's it's um, you know single study about a hundred infants with prenatal Exposures measured in the mother's here and the Occupational studies you're referring to are You know I've included them, but they don't have specific biomarkers of exposure plus there's confounding by co exposures That's right. That's right. And the follow-up studies one at how Which one the the we're talking about in 2005 studies one at all and then 2008 the follow-up. Yeah, they were they were consistent, you know, basically, I think the 2005 I can look at I think 85 infants in 2008 had a Hundred maybe 105 so it wasn't tremendously larger And and remind us what's the relation precisely between the original study and the follow-up where the follow-up new Individuals included. Yeah, they added additional in Individ infants So would you therefore think the same cohort same exposure metric same timing of exposure same Way in which they measured outcome. So I guess this doesn't really fully qualify as a as a new Independently reproduced study, but what you how would you say how far I described it as basically a second analysis from the same study, right? It's not completely independent is what you're getting at. Yeah And Russ how much Well, okay. I mean, I know I read your your text. I Think there's no doubt that stuff like that needs to be reproduced, but how much weight can we Put on it now I'd say some Some weight I don't How much further to Okay, then so we apply our systematic criteria and see how it plays out Well, I wouldn't ignore it basically so I would give it some weight Yeah, but I agree with Andrea We should see how it fits with the criteria if it if it's got some weight does a little weight Medium or high weight that you have to have some degree of Confidence that means your confidence though medium or high medium The worst possible As a true epidemiology need more studies Burn you had a comment just to fill out the three sides here for MP regarding reproductive data In humans and animals there were no studies available for review on DMP in humans and For animal data, there were no single or multiple generation reproductive studies in animals that were available for review So essentially there were no studies DMP and for DEP there are Well-designed at least one well-designed reproductive study. There are some studies in humans But there was an NTP continuous breeding study in Nice in which the dose levels were Different from males to females but about five hundred twenty five hundred and forty five hundred milligrams per kilogram per day and the noel for females was 4,800 milligrams per kilogram per day there were adverse effects reproductive effects but not resembling these Valley syndrome and the Noel And the weanlings was about 250 to 270 milligrams per kilogram per day primarily a body weight effect and Low at the noel for adult female rats in that reproductive study about 250 to 270 milligrams per kilogram per day No male reproductive effects there were there was a decrease in sperm count and sperm Quality Is it clear in any way by what mechanism or is this totally in term Determinant right that wasn't part of this study. Okay, but okay, then if we apply those criteria Adversity first, I mean these effect you're describing would we cluster must adverse Doing both of these chemicals at same time or one at a time. I think the MP is falling by the way side Let's shall we focus on DEP? May I suggest that we focus on DEP but they come back to DMP with the idea of the World Health Organization saying At first here we can make some kind of assumptions about a reference dose even You know to get us As I would suggest that we take DMP to completion Okay, so that it forces us with the system to deal with the chemical for which there are no data and Decide what statement we're going to make when there are no data to determine risk We should I think we should try to come up with a conservative estimate for reference dose Well, that's what we did. I mean we I don't know if that's conservative, but we we chose the Are there similarities between DEP That would connect us to say whatever DEP has DMP. We would there as a filler Yeah Structurally though, are there can compare you put them together? I think it's important to to keep in mind to the Biomonitoring data between the two. I mean there's extremely large difference Human exposure so apart from the hazard side Usually, you know very little fairly not detectable Right. I mean generally D or M MP the fact that DEP and DMP Lowest molecular weight ballades. Would you expect there to be a similar? reason to group them Backbone thing that you guys toxicity the backbone thing I Would think so, but I don't I've never seen Data suggesting that the same way that's been done with the C4 to C6 I Don't it's that any data that would give give Reason for concern any hints. I can't detect anything From what I hear we are saying there is no well just that DEP causes reproductive effects in adult mice No, sorry. We're talking DMP DMP. Don't don't have any day. So no you're saying that both based on the Rfd or pointed departure and the exposure No, I think we need to separate this out the RFD as it is guesswork But first we need to see is there any evidence quite independent from Quantitating potency in terms of an RFD or whatever. Is there any hint any evidence in the literature that would Make us getting slightly concerned about DMP. I Can't detect anything no developmental talks No, mainly because it was tested. Is that correct? Well was tested, but it found no effects Okay, then. No, that's that's that's different. Yeah So the first criterion adversity is clearly not fulfilled Wouldn't you say? That has an impact on the second criterion human relevance. Well No case to answer. Yeah, it doesn't apply Elevance is that there is minor exposure Yeah, so no further no further action flows from this My my concern about this way of thinking though is then it seems like that these are the kinds of situations that that sort of push Will not to continue to study some of these chemicals I think I'd rather have it the other way around where the burden is on In this case, I'm not so worried because the exposure is so low But if the exposure jumped up to levels of DEP But there is some some data, right? I mean, but it's didn't show any effect Johnny It's not like there's zero. Yeah, then the next question would be according to Chris I'm just following on from what you said a couple of minutes ago The next question then would be okay if we have poor data or very little data and I don't show much Is there anything in the chemical structure? That would make us conclude. Aha It looks slightly similar to one where we have more data and we where we are concerned But I can't see that Fulfilled either Holger would you agree? No, I wouldn't what a statement of this kind for a chemical where we have One study But it's an adequate study That generally falls below the threshold for making a risk decision because generally You like to see at least the teratology studies the developmental talk studies in a rodent and a non-roding tradition since the 1950s So I would call this a marginal database that does not throw any hazard But acknowledges that there are data But it's it's marginal being only one study not replicated anyplace else Well, that's better than no data Couldn't discredit that but it's Still a little below the threshold for being able to say with more confidence that it's been Studied in more than one species perhaps more than one site and the results are negative That's the case here One dose One study worse One dose. Yeah, maybe easy to pick one dose of anything and show that you control fluid amide is okay No picking one low dose. No, but it is a dose that with other phthalates It's clearly toxic Would you would you want to say on the basis of that we need more data for DMP? The reason to say more testing required We can't say that because we don't have any authority to require anything but we could say that More data would be needed to follow to more fully characterized the hazard this Might represent. Yes But that's different from saying for example, there are hints where there are Marginal concerns and it would be good to have more data You see my point. We're not in this ballpark with the MP Wouldn't use my word marginal to relate Anything other than the the data that are available The amount of data available to determine hazard is below the threshold Is in this case if you exposed rats to DHHP Dbp bbp dinp to the dose that they exposed DMP you would have had The full effect that rat phthalate syndrome. So in that case Your your concern is is diminished It shows it's not a DEHP and it was done in a in a study in which they also exposed rats to DHHP at 750 milligrams per kilogram per day Yes, well it was a reasonable screen, but it's not a definitive study, right? But my concern would not be particularly high So the tentative conclusion for DMP would therefore be no further No further proposals Not in not an interim ban nothing do you agree tentatively no action at this time My concern is that then that means when there's no data then that's the good thing In this case there there are data Limited data, I mean You know Well, but there's limited data in the context But I think we should keep keep in mind what what Bernie said in that this is an exercise and we're not Yeah voting or making a final decision yet. So when we get to some of the other Chemicals for which it really is no data To kind of see how we handle that and then we may come back and revisit Ethel or not, but this isn't isn't our final It's more of a kind of an exercise to see Just because there's no data and it doesn't let people off the hook and burn and I'll put together a Recommendation for this one and DEP as well for further consideration Question is what can you recommend with no data? Well, I'm going I'm trying to get to the I think the thrust of Chris's argument is that no data is better Well, this Is an opportunity for us to make a statement about the absence of data Even though we're not going to recommend interim ban or ban. Mm-hmm. It isn't I Really do hate to give the message that it's it's okay. It's probably a good choice to not have data because they don't say anything I agree with Chris fully that we shouldn't pass up the opportunity to make a statement that risk can't be judged With the small amount of data available on this count. What do we recommend because it's got to be you know Otherwise, you know, it's pie and sky. It's like godmother and apple pie. Yeah What are you gonna say? It's still a damning statement to point out that there aren't enough data to make a risk judgment Or do you even know what the hazard is? it's a criticism of the people who own this chemical it's a criticism, but I don't know if it's okay It's criticism of of the sponsor of this chemical or it's a criticism of the system requiring. Yes, I would say it's more of a criticism of Those you know, we're going back to Tosca then you know look at industrial chemicals. Yeah chemicals being used in consumer products Which is the black hole? By nanoparticles is such a mess I think the phthalate Industry in general would be well served If more of the chemicals to which people were exposed had data behind them I agree and this is an opportunity for them to Leave a message saying that yeah So we can do that one by one or we can make it in a more general statement Every time one of these is identified as enough of a concern that it's banned. It's a signal To the world that somebody didn't do their homework They should have anticipated that absence of an adequate database to protect human health and they could have done something about it So they haven't The issue becomes this then that the absence of data doesn't make you valve yourself of the issue, but Question becomes is when is the sufficient amount of data to say no further action? It's necessary and it's chemical because it's not going to be a significant health concern Those those are issues we have to grapple with on all counts because bans interim bans and no further action should be our three criteria Yeah, three are three recommendations you mean yeah, I'm sorry three I agree. Sorry Phil for me the threshold is To Maritology studies to developmental talks studies Preferably in two different species a rodent and a non rodent and both well-designed was adequate statistical power to be able to the effect to detect an effect and to not have Confounders that would mask an effect. So that's that's my threshold. Okay, that's fair. It's good I guess I could put that in the commentary on my piece for the report Fit with Andreas's I couldn't agree more Guys are the experts in this and I But I just comment, but I just made a comment on my threshold for Phil's part There's all for the reproductive studies is different You never ask for reproductive study in an and a non rodent yet But so the first there is a threshold in each area just like there's a threshold in the epidemiology area And maybe that's something that we need to comment on in each of our three sections Yeah, and it's it's a it's an issue that I grappled with in my section because there's a lot of a lot of studies Relating to phthalates and in utero exposures, but many of them were not designed To do to provide data that that burn would consider adequate They simply weren't so if we want to generate the kind of data that Chris needs You know many times we just wouldn't have it if we Use burns criteria so Let me throw it into my Bullpark as well as Holger's bullpark What do we consider as de minimis exposures? That beyond which There's no reason to think about in terms of either biomonitoring numbers or in terms of calculated values Or any one or a number of roots of entry into the body Clearly this question can't be answered without any information about the potency of the chemical in question Well, actually sure it has to have both those parts to it if it doesn't then it's a it's a it's a futile exercise But I think both of them have to be put together This is an extremely low exposure. Is it a de minimis risk is what the issue? Yeah, without any information about put into you don't yeah, I agree totally great EP yeah, well that burn and I will put together a recommendation for DEP and DMP and then another next Session we will discuss those and Modify change, but have we discussed the EP to the end? No, we can we can we can do that So DEP is as I said in the same same boat Same group did the same study one dose one study no effects But but in Contrast to DMP we have now although imperfect, but some hints indications from epidemiology That really distinguishes DEP from the MP Yes, and and the exposure I'd say to yeah and the exposure differences thousandfold difference So the human evidence would raise concerns about adversity Would you agree would raise concerns it does not prove adversity, but it raises some concerns Yes, and and not just I mean the the endpoint was AGD But in the reporter or maybe in that smaller front section It's the recent studies in the last year showing associations between AGD and semen quality and adult men in Fertility and hypospatias, you know, it wasn't in the swan study, but basically supporting Potentially that AGD is a surrogate for other Developmental effects in the reproductive tract or fertility measures later in life. So though there are three studies That were you know, they're done on a different population. They were just looking at do chip to boys with hypospatias have shorter AGD Yes Do men in an infertility clinic or men with infertility have shorter AGD than men with proven fertility. Yes, and Is your relationship with semen quality and yes So I think that that adds more to it than just this is an anatomical marker That that it is associated with with function and development But then clearly the looking at the weight of evidence data quality of studies etc. Etc. We're here We have also short faults. It's only only one one or two observations and I think According to Bernie's criteria this morning that would fall short of a recommendation for a permanent ban, but the question is Would it qualify for recommending an interim ban until further data are available that prove Margin of exposures just about three orders of magnitude. I have a problem with this one because I I'm on the fence And there's only one just there's only one human study, right? So how I just can't Well, it's it's something we need to yeah, I think ourselves into you know We're playing here with where we're thinking a lot more. I agree. I'm also unsure about it I don't know So based on Red studies and the delayed syndrome in reds and Backbone chain length paradigm in reds that says Backbone chain lengths from three carbons That's the eyes a beautiful delate to six carbons. That's the DHP Now I would say it could go from a three to seven including the INP We have the hotspot of activity so from these studies Rethinking here, we would expect that the EP If at all would be very very very weak Other hand, of course, if we see that the exposure is very very high That would kind of level it out we have no real proven tox data to to Wait the closure in terms of Risk or related to the hazard you have the human data and We have some indication that at Very high doses. We might see some effects that remind us of the effects that Can be observed in a delated syndrome I'm just citing from What you wrote down from the NTP report Hi, those is the EP F1 parental males had 32% increased prostate rate 30% decreased sperm concentration increased rates of normal sperms so at Very high concentrations We might expect to see some effects indicating into this direction We put again which would again fit into the picture of well, we are on the tail end of the Potency of the phthalates and we heard yesterday that Maybe the backbone paradigm might not be Applicable in total to the humans that's a question. Yeah, it's a question again meaning me more and more toward not Wanting action discipline. I couldn't stand Weight of evidence and I don't think there's enough weight to the end again. This is all we're all speculating at this point But this is good. This is good conversation because There's going to be others which is obvious Give you a little more information on the reproductive studies because there is a second study beyond the NTP study And it's one reported by a few G It's a two-generation reproductive study in rats given Amounts to provide one over 1,000 and 1,400 milligrams per kilogram per day and they saw nothing so study by the NTP those late dose levels ranging from 250 to 5 4500 milligrams per kilogram per day where they saw the things that are consistent with what were reported in humans That was in mice and then Study in rats Reasonably well-designed. It's a 2005 study. It's not a 1946 study So nothing there. They're highest toast in reach. No, that's right. So it's lower. I mean, yeah It's with Holger's argument So that should we change our lack of information on that? Be a point of departure from the NTP study at M's per kilogram per day. No, well That would be lower than that We can talk about Identifying a point of departure for that. Oh Well, we're telling me going back to the criteria. I'm very uncomfortable trying to Yes, we don't have enough data to make a decision Yes, Paul what I'm not at that question yet I'm still back at the question is it is for reproductive effects. There's there a threshold of data here and Because there are two multi-generation reproductive studies in two different species There probably is a threshold of reproductive data here, but that doesn't answer the question of the phthalate syndrome Right and the developmental talk study And the existence of the human data and the very high exposure And I also might point out that in the Fuji study they say they observed decreased serum testosterone levels and increased Taylor's burns But they did did not consider it as significant. So again, this is just free thinking allowed a hint that we might be at the lower end of the Activity, I hope that you know if we write this up we take the information from Russ's Part we take information from Chris and hold your part on terms of exposure and we take part from the repro to Developmental and put it together into a document that we can share with everyone and then we go over this again Then I think we have it all in front of us and we can say okay. There's this is what we have What are we going to do with it? It's helpful to me to have something in black and white in front of me to Rather than just hearing tidbits from different people that I can't assimilate and keep my weak brain Well for DMP we can write the complete paragraph But for DEP I think we need to figure out where do we where do we come down on this as a Is that this is worse than no data because we have a lot of exposure and we have a Report we have information in animals and humans But it's the question is is enough to recommend a regulatory action, right other than leave it alone and Identify that this this one is a close call and this is one where we may need more data and more sophisticated studies Yeah, my feeling is right now. It's leading to me to say we need more sophisticated studies to Truly reduce the uncertainty and maybe find Hulgur's point of you know The toxicity does start we can make a statement of that kind. I Think that's a reasonable way to think about it. This this one's very interesting So DIBP BVP DHP DIBP is on the interim, right? Oh No Or is it? Europe isn't is it? Yes It's included, right? No, it's not included, but it is labeled a Reproducts HN category 2 and therefore it is forbidden in cosmetics, but it's not on the interim then It's through because it's an isoform Which was not taken to account. They've made a statement about its hazard, but they haven't officially labeled 2000 since 2009 so the DVP and BVP and DHP were finished, right probably the band ones were finished. Yeah So the interim band I NLP next Yeah, we unfortunately can't we don't have the high exposure modeling intake yet For the last three how soon is Monday help us today We're trying to figure out what we can do yet this afternoon or tomorrow morning Otherwise, we won't be together again for another month. What about noon tomorrow? Okay? I'll try to have something by tomorrow morning Okay, all right That's that's true for all the last three correct. Yeah, the last three are in the same category. We have the median Estimates, but we don't have the high exposure modeling estimates, correct? Yes, the only one remaining than this D. I BP DIBP That one has no exposure where there's very low exposure and In the swan study there was an association with shortened AGD With MIBP That's metabolite. They measure it in the urine. So it's the DIBP. It's the intermediate. So it's the DIBP. Okay. Yeah All these new all these acronyms get me a little confused after a while DD is the same swan paper that the MEP So should we start with the hazard for the IP? What are the experimental data like the IDP? The IDP DIBP, right? Oh the third. Oh, sorry Yeah, okay, cuz DIBP there are two studies by Salin fate One in 2006 was a really big study exposed in gestation day 6 to 20 and And They saw Increase in male fetuses with undecended testes at 500 milligrams per kilogram per day another study in 2008 Somewhat smaller study reduced male AGD and prosnatal day one increased nipple retention Those are at 250 milligrams per kilogram per day Also delayed onset of puberty and increased hypospatialist Undecended testes and that was at 500 milligrams per kilogram per day So those were the two studies that really were of sufficient magnitude to determine a a no well and Based on the more conservative of the two studies DIBP A no well was chosen of 125 milligrams per kilogram per day And they were you know, there were other studies that that weren't of What we would call sufficient? Magnitude but found basically the same effects at the same similar concentration or doses I feel pretty confident in that no well is in the is in the ballpark for the developmental talks So we have good quality studies or reasonable quality reasonable quality. Yes adversity Concerned yes relevance to human criteria Reproductive studies on DIBP There are no animal studies that are multi that either are single generation or multi generation reproductive studies So there are non-generational studies where animals Looked at histologically for adverse effects on the testis, but no no reproductive no generation data Do we had a study looking for testicular effects in male adolescent rats given DIBP for up to seven days at those levels ranging from 100 to 1,000 milligrams per kilogram per day and And there was a significant increase in testis weights increase in that appetite apoptotic Matagenic cells disorganization or reduced by mentum filaments in sertoli cells at those levels of 500 and higher Well, there no effect level here would be 300 milligrams per kilogram per day in This non reproductive study Then there was another and that's the study that's reported in 2010 The other study was one reported by Hodge in 1954 And it was the effects of DIBP in a four-month sub chronic study in rats And the dose levels were 67 738 or 509 5,960 milligrams per kilogram per day Absolute and relative testis weights were significantly decreased at the high dose level. So the noel was 738 milligrams per kilogram per day Testis weight fluctuates with changes in body weight so it's very in a study that 1954 rats were not very homogeneous very difficult to say to rule out that a Chemical that's given in high dose volume dose amounts toxicity generally like decreased weight gain in a four-month study that Couldn't be uncommon to find a change in Intestis weight that was not reflected in it would not be reflected in a Like it is nothing in a reproductive study It it's a signal it's data on the right organ, but it's not very definitive information Study by zoo would be more definitive. So I think the answer here is there are there are no reproductive studies There are two other studies where authors looked at the testis as part of another study The swan paper Plus we have the harness at all study 2011 from a grace group Terminating the relative potency factors for several relates on fetal testis endpoints Including testosterone reduction and testicular gene expression and they found that The IPP reduced fetal testicular testosterone production with a similar potency to DHP and And they found that The IPP was even slightly more potent than the EP Reducing star and CIP 11-18 expression levels April was that and as Well great I mean that this point of departure could be five thousand Which is why in case two we use different point of departures Also, this study is not Cannot be used to derive a novel or a point of departure. It can be used to compare the relative potencies so with that Justify altering that point of departure there Okay, so that's the point so we originally said we were going to work through this exercise using our case three Estimates for reference doses which turn into points of departures to consider other cases Like other rationale for coming up with a value One of those where you really feel comfortable doing that Archer that we have Too high or based upon the real the data that we've just looked at and which summarize This is why in case two we decided to have a point of departure comparable to DHP. I Feel comfortable uncomfortable with this point of departure here, but we have In case three here with this point of departures a different approach We base it on studies On literature data and we have to be aware that these are all studies from possibly different groups different authors Different years and different study designs. Okay, then let me let me cut to the chase straight away So if we have Point of departure similar to DHP from a study well suggested in a study. That's really not set up for deriving point of departure then you require a higher margin of Safety of around thousand. Maybe you can I don't know but we are getting with that one into the gray zone here Although the experts are low Your pointed departure becomes Oh Where what's the how does the value change is reduced by factor 10? Well, if you if you 20 or 100 5,000. Yeah 50 it's factor 50 right so factor 50 So we're in you're right. We're in the gray zone. Absolutely Gray zone So to summarize adversity relevance to human satellite syndrome Risk assessment Gives borderline. So what do we do with that quite a lot of criteria fulfilled? Let me start it off. Is there anything on this in this base of evidence that? Would lead us to argue it's false a little short of proposing a permanent ban So which would then consequently lead us to propose an interim ban Is there anything quite a bit of discrepancy between what the point of departure is so again if that could be studied a little further to where you could really come down on a point of departure that would make it a clearer picture Just thing is interim If you had to make a decision now You're leaning because it's in the gray area, but with the fact that there is uncertain But that's some of the studies have been moving toward meeting the crate the criteria that Andreas But you have to remember to you have the human data so with I mean if we kind of think about Keeping the bar consistent as we go through these If with DEP we didn't have the animal data and we had that same swan study And we were Approaching a gray zone With the IBP we have the same swan study plus we have some animal data Plus, you know, we have the exposure data. So The the bar is moving I think as we're going from Chemical from DEP to in this case the IBP Because we have more information I Didn't say that I would say either an interim ban or a ban I Would want to review especially the tox data more to have more on that But I would say at a minimum the interim ban just given that Where the bar was for DEP? And that single human study and the lack really of animal studies Whereas here we have more Difference between here is Holger and Chris's comes in Holger in terms of DEP We're talking about low toxicity and every every word we're constantly coming up with that number We're coming down with Chris's point was that We're talking about uncertainty with respect to what the point of departure is But there is yeah with diabetes. So so Even though it's you know, it's moving me more toward the interim ban and Finalize it once you get a better point of departure, you know, it's it's definitely moved me in that direction, too Plus looking at enhanced data we have to be aware that the Body burdens nearly tripled in the last eight years Yes, we have to assume that it's coming on to the market as a replacement for Diane BP So the numbers show that exposures rose from geometric means of two point five four to seven point two two And that's overall percentiles That's in micrograms as a replacement of what for what flight for dye and beautiful delayed And be DINP That's a process that already took place in Europe. It was the 1.9 here is is that reflecting the Increase over time or no no, I would assume that data from today would be higher How did this So how did Europe handle this? I mean they replaced a with being in reach didn't reach into the issue I'm sure I understand you're placing one with another and No testing had been done prior to the replacement Now in Europe the IVP is labeled but until 2009 we saw the process in in the biomonitoring Data that the replacement process at the place because the MVP was labeled in 2004 I also want to make some comments about How we derived the the no well so we set the bar which will be described in in my section of the 30 page document about how we chose the study that Defined the no well, which I've just given you the study But there are other studies if And as I think hold your just referred to if if you were to go to the Hanna study, and if you were to choose the effect that They showed that sip 11a expression was decreased significantly at a hundred milligrams per kilogram per day Then the no well would be 50. They're different But that study was not designed to develop a no well By my criteria So meaning if properly tested we would with that endpoint probably get a no well. That's even lower. Yes. Yeah Had they done it? Yeah, which pushes us with the margin of exposure Considuation into the great zone here. We have quite a lot of criteria fulfilled why I mean In my mind now this is between interim ban and permanent somewhere if not And and you know we I could write that up as you know If we if we set these standards for for choosing the study that's going to determine the well This is close to it what we're going to get if we go to other studies and use other criteria This is what we're going to have and now we're in a different area In terms of our recommendation What do we feel do these criteria make sense? This seems what do you what do you think I? Think they're fruitful. No, very fruitful. I mean if you if you believe that you know the rat valate syndrome starts with changes in gene expression and testosterone Synthesis decrease and that then funnels down to all the other changes then you know sip 11a is a very important Initial change and there's no reason why you can't select that To determine your no well Visas criteria, and I'm happy with our discussion. I think we've made nice sort of The thing that I think we haven't really addressed yet is we haven't thought of them as a set We've we're thinking of them where we thought of them as a set is in terms of the hazard but then go from this to Hazard index or do we try to accumulate something here? Well, I think we have to do both and it's not mutually exclusive, but we have to do this exercise here first then derive additional information additional criteria from consideration of cumulative And also It also leans toward the idea of doing more Complex mixture studies if you're gonna do this aggregation that you're suggesting and I agree with You know, it's it's better to look at the Groups in total When you're thinking about how you doing to regular. Yeah It makes more sense because that's what we're gonna be living with each day So based on our criteria, I would propose to propose DIPP for a permanent then I would agree with that Who would like to write that one up for our subsequent discussion? DIPP P. Yeah, the one we just discussed The write-ups for for the I mean they're gonna contain Different components, right? So you'll probably want a few lines or someone's gonna have to go Human study exactly lines on the talks a few lines on the Exposure something that we can all look at and then say that's that's it or modify it At this stage it can be pretty rough. Yes, something. Yeah But I would recommend that every one of our reviews has the same elements So that we we agree on the format The template for this and we'll use exactly the same template even if in some cases it's it's either the relevance might be assumed or it's known or We may have some blanks here But if we all use the same template then we're not creating new words and new concepts from one chemical to another Do have one issue though We're doing this right now total absence of information about The levels that lead to exposures in kids toys Based upon chemical structure and based upon toxicology based upon studies But it's not addressing the fundamental question of the kids toys again. We have to Somewhere in that have to factor it in I mean it's it's it's the issue that we have to grab with although We can rate them and make recommendations about Other agencies dealing with the total exposure issues We still have this other burning issue that we will eventually fill in the gap But I don't want to lose that thought at this point in time But I'm just trying to get us one step closer. Yeah, I agree having Recommendations we can modify these add to them. Well the question I have is we say we're going to a permanent band Based for what you know just for toys for the chemical self. I'm not sure where I'm Again, I'm a little bit in confusion about what you mean Well, we can't we can't ignore the charge here that our remit You know, we can't pontificate about a general ban. Of course, it has to be in Caprax and toys as defined by the act. That's because we're making recommendation to CPSC And that's that's the only thing I want to remind ourselves that we have to Constantly go back to that throwback to that question See as we see the levels of that may be a qualitative statement. These are bad effects, you know Closure may be very minor to children's toys Bad chemicals and children's toys, but the CPSC is only can deal with factor x y or z not a b c d e f g I would suggest Again trying to achieve consistency and what we're going to write down that there would be six pieces to this One in addition to the name of the chemical but Nature of the adverse effects Second would be the relevance to humans third would be the weight of evidence fourth would be risk to a risk consideration That would be the recommendation itself and the sixth one would be would this recommendation affect the exposure of children Phthalates to this specific phthalate So that we have that answer every time even today's discussion We I wrote it down on the first one, but I don't have an answer to that on the last three I I didn't ask myself or the rest of you that question and that that will come as The analyses that you're close to finishing up and getting to us because I think the main thing to get to us or This analysis eventually will be the differentiation either as percent of exposure or the aggregate of exposure that Right from kids toys versus other roots And by root of entry to it could be kids toys by incident on that gestion. It could be done by a Direct ingestion through sucking it could be a whole host of issues We have to figure out the body burden Phthalates that's due to the kids toys But we have to be aware that probably also for the IPP. There's a lack of data On the exposure side because the IPP I Think has only been regularly measured as an isoform not in a sum with MVP for a couple of years So we have to be aware that probably the data is very Older would you tackle the DIBP take late? I'll get your arms around it right up a paragraph. I think we'll break for today and tomorrow we'll come back and Tackle the remaining phthalates and phthalate substitutes. Thank you all So tomorrow we're gonna meet at nine Mike Let's meet at 8 30 tomorrow. Okay, so we're gonna meet at 8 30