 Folks went back and updated the modeling exposure. Are you looking, is that the, yeah, that's the high intake one. A couple with mine seeing. Versaurs data is the third column. So those are from the biomonitoring data. Those are the 99th percentiles. Versaurs data is the third column. And then it's just the ratio. So what we did remember yesterday, the points of departures are based on no ALs from the discussion. Some of those we've, you know, put in just sort of force numbers in. So some have better quality than others. But it's just the ratio of the point of departure to the corresponding high estimates from the two different approaches. And so you see those in the last two columns. And much to my surprise, there was a vast difference. In this case, then it's the only case in which the modeling was significantly lower than the biomonitoring data. It could mean that we're missing roots of exposure. It means there's not enough data out there to make an estimate in that. What we're looking at here is that for now, the different roots of exposure are going to have to catch up in terms of concentration data to see whether or not, how to account for this difference. Well, I'm curious too, because these numbers are actually smaller than what the medians were yesterday. So I'm not sure what he's done that's different. He took out some, remember he had those two columns where, you know, he had the ones where he had real data and he had, you know, fractional data. I think what he did is took out all the fractional data for these two, and that's why I am. There was once, there were a couple studies in which there was not enough data points to make an estimate. So he made some adjustments. Basically it shows there's no data. That's what this is showing. But the DNOP dropped like five orders of magnitude from yesterday. That's right. I think the DNOP and DINP and IDP are relatively, I think they're more data poor. And so if he took out a couple of, you know, studies where the data were outliers, that would make a big difference. Right. I think that's what he did, because he realized it's just not an update. Another hint that especially DINP might be data poor is that the exposure profile, the pie chart for DEHP looks totally different than for DINP. And I would suspect that the exposure routes for DEHP would be rather similar for DHP and DINP. And I think we had a look at the raw data yesterday shortly. That's where he showed that there was literally no data on DINP and food stuff, for example, or so he couldn't capture these routes. But that would explain why. It's partly because the data or the food data are old, mostly old data and also not people, you know, a lot of times don't always look for D or didn't always look for DINP. It's like with the PBDEs, they didn't look for DECA, partly because it was harder to do. I mean, I'm not sure what the technical reasons were, but it can give you a false impression. So the fact that we've got all the two sets together on this table, I think we really need to have a strong footnote. I mean, I guess we should still include it in the same table. Yeah. Again, it goes back to the, in essence it goes back to the points we made about some of the toxicological weaknesses. More data is needed because there is a deficiency. The only difference is at least there's some monitoring data to give us some degree of confidence as to where the margin of exposure may sit. So at least for pregnant women, so therefore at least we have some, at least we're in the right ballpark. We just are not sure how many players are going to be on the field. But on the other side, the ones that we have more data rich exposure modeling cases, that's remarkable agreement between the biomonitoring and that. And this was the absolute worst case, right? Right. For the high intake estimates. And that's why we think we're just data poor. Because if it was, if there was an inconsistency among all of them, then we'd have a bit of a problem looking for, you know, associations or even identifying whether or not what's reason for this dichotomy. But we're just looking at data poor situation and is a good recommendation for these chemicals. Would you again update me on the data you used for the external exposure models? Did you only use data from the American market or was it all literature data from all over the world? I think it was. Well, the priority was to use data from North America in the last 10 years or this century if it were available. Right. You know, the most of the food data is from Canada in the might have been the 90s, I guess. And in some cases, you know, all we have is your because there's more data and more recent data from Europe than there is from from here. So, you know, in some cases, there it's all we have is the European data. It's going to be important for, for example, in the children's scenarios because the baby formula in the milk, there aren't a lot of North America or U.S. data. The reason I'm asking for, I ask that is because for diabetes, for example, your model shows about 10-fold higher values. And these values kind of more reflect the European situation. So in Europe, we have higher dibutyl phthalate values. But also because I think when I'm trying to remember, I think it's dibutyl, maybe I'm thinking diethyl. But the manufacturing, it's changing in the biomonitoring data are probably more current or more up to date than the other data. I just want to say everything is very plausible here in the end. You can, you can explain most of the things really by either lack of data or. And that also bodes well for some of the recommendations we have to make. Yeah. And I put together a major taking surges spreadsheets. I put together a matrix to see, you know, which pathways had data on which chemicals. So when there's a gap, I mean, cosmetics, we didn't, don't expect to see DINP, DHP. So that's okay. But for when you look at food and, you know, if you're missing that data, then that says maybe you have to go back and well, geez, because they weren't looking for it. They were only measuring, you know, certain phthalates. I think we're okay. I knocked this together quickly in the break. So the wording is not perfect. But hopefully it will be a basis. So DINP, first of all, adversity. We've heard there are three well conducted experimental studies on this. They, more or less, there are differences in detail, but they more or less are quite compatible with each other considering that they were conducted in different labs using different rat strains. So we see, really see, we see suppressions of fetal testosterone production and changes in end rental distance in all of these. So we will study admittedly only at a later time point. And one study, the Baubach observed retained nipples. The doses required to elicit those effects are in the range of 750 milligram per kilogram or higher. These are, I would say, the three decisive and three important studies. The human evidence, there's no epidemiological evidence available to, as far as I know, to say anything really about DINP. I'm not so sure. Was this measured in the Inshaal National Swan studies? I don't think so. No, because of the time of when it was done. I think it was not evaluated, but I think we have the data of DINP for our model. Yes, so at the time, 2003 or 2004, when the measurements were done, it was not included as, I guess, later. We have the data. Oh, it has, you've measured it. We have it in the model. It's in the, what is it called, the SFF, Study of Future Families. The data are there, but it's less observations like in some cases only 18 subjects. So, in other words, an epidemiological, a proper epidemiological evaluation of this is not available currently. Correct. In relation to AGD. In relation to other things? Other things in the developmental reproductive realm or, there, no. I mean, it hasn't been measured. It's being measured now in epidemiologic studies, but I think samples, because it's kind of come online in the last year or so. There's not enough data points or association studies. Yes, I think with the doses required, I would put it are in the range of 250. That's what we have seen in the, so did you place this assumption on the Boeberg and Hanna study? Yeah. You see, I've knocked this up roughly. I mean, this has to be detailed, investigated in detail. But what I'm trying to say is that this clearly is one of the less potent phthalates we know of. I mean, I will modify this for you. All right. Next one, human relevance. The effects indicative of andrininsficiency in, well, these are indicative of andrininsficiency in fetal life in the rat. And these are currently generally to be judged to be relevant to the human. We heard some evidence on Monday that would cast some doubt onto that, some doubt. But the payoff of, I say, the trade-off would be that what we heard on Monday, not on Tuesday, it was, would highlight the importance of neonatal expertise more. So it swings and roundabouts, I guess. I would say that we, well, in the absence of evidence, to the contrary, I would judge this as relevant to the human. The weight of evidence. If we look at the Clemesh scores, I think these studies can be judged to be reliable without restriction. Although, well, the Baubach lab works not, they work according to GLP standards, although they are a university now, they're not operated. But these are GLP-like standards. And I guess that is also fulfilled with a clueless study. The Grace lab, I don't know. But I think that's no doubt. The technical quality. We have fairly large studies there. Sufficient numbers of doses and animals per dose groups were included, in my opinion, sufficient enough to base estimations of points of departure on that. And we have to mention here that we have here a replication by three independent labs using slightly different rat strains, but the effects are amazingly concordant. Andreas, to follow our own criteria, I would suggest to put an asterisk to the three independent labs, because only two of the studies have been published and peer-reviewed, while the clueless study has not been published and peer-reviewed yet. So it was just the presentation from yesterday. Is it published? Just to follow our criteria. Yeah, fair enough. That's a good point, yeah. I don't know, maybe. I guess I would expect that during the lifetime of the work of this committee, this study will appear in the literature. I hope. Can I show you what we're doing next? Risk assessment considerations. So first of all, exposure, based on biomonitoring, we're dealing with high exposures of around 27 microgram per kilogram per day. Directly lifted from Chris's table, which we just saw a minute ago. Bee hazard considerations, points of departure. Points of departures have been estimated to be 50 milligram per kilogram per day. I think that is with suppression of testosterone synthesis as an endpoint. And I think that is from an experiment with sufficient numbers of animals. Is that correct? It's data from the Kulul study, I think. Maybe that could be refined by benchmark dose consideration. Her NOAL was 50. Now, I don't know. Yeah, I mean, I don't know if it may also be similar to one of the other studies. Posterone and germ cell morphological changes. So then, taking on board what is in Chris's table, the margin of exposure, looking at high exposures, which we have to do now. We have to base this on reasonably worst case assumptions. The margin of exposure is 1800. And one could argue, and there's a precedent in the literature for arguing along those lines, that in consideration of the severity of potential risks, you would want an MOE in the ballpark of 1000. So this would be, you know, you have to have only a doubling in exposures to reach that grey zone. The consideration that drives this now is that the ANP is slated to replace DEHP, with which the concern now is that this will reduce the margin of exposure further. Then move on. On the basis of that, the recommendation would be, so in view of the present MOE and the anticipated reduction of this MOE for future use patterns, as well as the potential gravity of effects for children, it is recommended to implement a permanent ban on DEHP in children's toys and care products. This could be worded better, I know, but that's a suggestion which we need to discuss, or we discussed it yesterday already. Will this be expected to reduce exposure to children? I do not know, but the experts can quickly say that. Why is it to say something, Mike? Should we say something? About exposure? I mean, I think of it as a conditional, if you, I mean right now, because of the interim ban, all you're doing is maintaining the status quo, so that in itself is not going to change the exposure. But if you consider the alternative of allowing it, then of course it would. Yes, I think that's a terribly important point. We have to consider here what the consequences would be of removing the restrictions. With the restrictions, what's our number again? Was it 1800? With the restrictions. The levels that we're seeing in the population, pregnant women, are such that we still have an exposure unit of 1800, and that's with an interim ban. That's based on the monitoring high intake switch, was 2005-06 data? Well, the ban went into effect, I mean you're talking about toys and childcare articles, it went into effect in 2009, February 2009 I think. Important point, I mean, there is no ban in terms of personal care products. Right, I mean, I don't think there's DINP in personal care products or not much, but I mean it's used in other, yeah, there's nothing for other products. So the sources for pregnant women probably haven't changed, or may not have changed, who knows? Correct. They probably haven't. Well, if anything, you could speculate if DINP is replacing DEHP, they might have actually gone up over time. But I'm wondering, because we're doing this in the context that we're looking at both individual cumulative risk, DINP is one of those where the other endpoints are probably more sensitive than the anti-androgenic effects. And I think we need to make it clear so people, you know, don't look at this and say, you know, read this as the POD is 50 for everything. It's 50 for these effects. Do we have a lower POD for other effects? Mike, my feeling is that with this POD, we might be lower than for the other effects. Well, I mean, it depends on who, I would say the POD for the other effects is about 15, but it depends on who you do. But that's maybe even more true for DEP and DMP, I don't know. In the write-up here, Andreas, you did a super job in such a short limit. Should there be, instead of just the statement of the POD, some sort of evaluation of the quality of that? I mean, so from the previous discussion, we have, Archer, you don't have a confidence interval. I mean, you know, it's based on points or whatever, some kind of a qualitative. Olga, mostly. We need this here because I think we already did the discussion and for the talk studies on the other slide before. Yeah, I don't think we need it here. The question I have, okay, continue. My point was though that, you know, it was in a point of departure based on something. It didn't just come out of the air and it needs to be clear how solid we think that point of departure is from the earlier studies. And if that point of departure could actually be reduced if other endpoints are considered, then I think that's the kind of evaluation that would be helpful at that point. But then again, that would be swings and roundabout. Mike just informs me that there are lower PODs for liver effects, but for these probably you wouldn't demand such a high margin of exposure. True. So they would cancel, but it's just, I was just thinking, you know, we're looking at this as a single piece and I'm trying to look at it. You know, what's the context? I just want that to be clear. I guess the question remains in my mind is you focus on 27, but all the other data is so much lower in our calculations. So there's a dichotomy. There's a factor of 10 differential. Is that because of lack of data? I think that's the important point. We have to go back to the versatile data and check if there is a considerable lack of data. And I think we, yes, they went back to the data and so for the INP that there's a considerable lack of data, which might explain these lower values. I think so. The question becomes, if we have a band now, 27 come from? That was my question as well. I think, do I get this right? The biomonitoring data, this 27 is based on 27 microgram per kilogram per day, is from before the interim band came into effect. But that's the important point. I think what the interim band is for toys. It's not an interim band for the products that have exposed the pregnant women. But my point is this. Do we have any data post 2009 to see whether anything has changed? I don't think we do. 2005 and six. 2005 and six. The versatile data is whatever is available and it's not going to be 2009. That's for sure. The warmest data is what, 2003? Something earlier than that. Publications 2006. The German data on the specimen bank data indicates that the DINP, at least in Europe, is on the rise. And the HP is on the fall. I think similar. Where do you get that data from? Where's that data available? Because saying it's on the rise, it means our base point is well taken. Where's the data to show that? Data on the German environmental specimen bank. That's archived during samples and they have been analyzed until 2009. That's the last data set. And it has been published. Yes. So comparison to Sharma Swan's data, that 27 is about two to three times higher. I think that's what we gave us in February. I'm not sure when that study began. When it began, I think 2002 or three. That's when those urine samples are from, but I'm not sure if there were additional ones that were collected later. I don't think so, but it was just from the pregnant women that it would definitely be before 2004. But I think the key argument in any case, despite all the detail, is this. So this product, sorry, this chemical is designed or slated to replace DEHP in the critical object we're talking about. Children's toys, which can be moused, et cetera, et cetera. Probably not so much in personal care products. But therefore, any recommendation saying, okay, the ban is relevant, can be released, will lead to a rise in exposure, which will probably take place anyway. There are doubts, I know, whether a ban in children's toys, et cetera, will have any effect on halting this uncomfortable trend in exposures. But I think judging against this general trend, it would look rather weird if this panel would conclude, oh yeah, nothing to worry about. Let's release the ban in toys. The message should be, in my opinion, that something needs to be done to stem this rise in exposures. And against that background, then to say, nothing should be done, no recommendation here, no action which seemed rather, shall we say, incongruous. That's what I would argue is the main argument. Isn't part of our purview also include products that would be used by pregnant women, not just toys? Yes. Is it? Yes. Well, if you, it's, I mean, the wording's in tab 12, but it's, you're supposed to consider all of those things. And I think what they're getting at is exposures to the mother. And that would include exposure to the kid's products. Although, you know, how much is that going to contribute to the mom is another issue. You're not talking about... Well, we're looking at total exposure to the mom. And I mean, including everything, including personal care products, and including the mom's exposure from the children's products, like the toys and so on. The answer to your question is definitely yes. So the pregnant women could be products that are not from the toys, but other things that pregnant women are using. Is that possible? Yeah, definitely, definitely. So if we demand, if we're looking at a, at this on the point of view of DINP being a band in children's toys, continuation of the banner may be becoming permanent. Are we then by, as a consequence, because of the fact that we're seeing these kinds of exposures, or at least these potential exposures in pregnant women based upon the data we saw, are we by inference saying that should be banned there too and somebody else should pick it up? I don't know whether that's within our remit, but I would agree with your general concern. I mean, that's more of a concern than the toys because it's clear that the frequency and the behavior and the potential contacts are much greater for the pregnant woman. And as a consequence for fetal transfer and postnatal transfer. So I would be more, I'd be inclined to want to see if we're going to make a recommendation, we make a recommendation that hits the target. I think our recommendations are directed to CPSC and what they can do is limited, but so we can't make a formal recommendation about this, I would guess. But I thought that was in our charge. But we can make a note on that, noting this and flagging up the need for perhaps regulatory action by other competent authorities. Mike, how could we handle, is there a way of handling that? Well, I mean, they're strong enough without. I mean, obviously, you can recommend whatever you think should be recommended. Some of these are things that we, that CPSC couldn't do, but you could, you know, however you want to word it. As a note, as a recommendation to the broader regulatory community, you know, to put everything in context. That this is only part of the problem and we can only address certain exposures. That be done by, by two things. One, adding another question at the end, the sort of part that says something about exposure to children, but then also adding something, a parallel question to exposures to pregnant women. But then answering those questions by going back into the exposure modeling data and those pie charts and saying, it appears as if a primary, you know, 75% of exposures come from whatever. So it gives a very clear statement about what kinds of products would be very impactful in terms of. Sure. I think that would be doing justice to the, you know. And, and I guess in terms of process, I mean, this is, these are the criteria for making these recommendations. But it's not the recommendation itself. The bottom, well, or it is okay. And yet they certainly could be crafted in that way. But I guess number five is the recommendation. And could, could we simply add another sentence here to the fact of, for example, this may not be correct. And that DINP is found primarily in, in food products. We would also recommend that. Yeah, and I think that, you know, that's consistent with like the silver book and, you know, people are getting away from these, you know, yes, no answers. And, you know, putting a little more of a narrative. So that's great. But based on the poor data, the poor lack of data or whatever for the DINP, would we be modeling? Are there such high? I can't say for certain what the problem is. But, but in other valleys, we could say something. Question there is, you know, if we're going to ban it, say, you know, find the right sources and do the right data collection so that the ban is implemented in the right way. So that exposure reduction occurs in both the woman and fetus. I think, you know, I think we will be able to estimate a child's exposure from toys. Yeah, I think that's true. And by virtue of analogy showing it's so low that anything else that occur would have to be come from the mother. I initially know until some data collection was. That could be part of our recommendation though in order to actually nail down. I can provide some words for that. Now? Now. All right. Let me see if I can get my head straight. In consideration of a ban, either permanent or maintaining interim, it's clear that there are exposures to pregnant women. But that we don't know. Wait a minute. I'm a hunting peck. Oh, okay. All right. In consideration of a ban. I can sit here now for hours and think my words out really well. In consideration of a ban. Okay. There are high exposures noted or documented for women exposures documented for pregnant women. Period. Yes. In addition to consideration of banning DINP children's toys. I'm back up. There are high exposures to pregnant women. Write it down, man. All right. Think slower. Where are we now? Look up there. And there are high exposures to pregnant women. I had a really good idea now. I screwed it and they screwed it. But our, you know, we are only able to make recommendations about ban in children. However, here that there will be transfer of DINP mother, this or child and products for pregnant women. Well, this can only occur once the route's highest exposure. That's long, but that's the essence of what we have to, you know, whittle down the say that meet with. I can, I can wordsmith that. Right. Missing anything, Chris? Largely you're saying that the exposure data now, there's holes in the exposure data now. That last sentence saying. Yeah, right. Well, I'm saying it in such a way so that they don't lose the thread of the argument. You have to look at the different routes of exposure to figure out where you want to make your bank. Document. If we have such a comment at the end of other little back to the exposure modeling, then that'll be clear. Well, that's going to be, I mean, this, this will be derived. This is basically an example of what we're going to say in the introduction saying it's a total exposure issue and understand the consequences of exposure to a child. You have to understand the consequences. Do you have to understand the relationship between the mother and child and transfer of material? But we should say this kind of stuff particularly about DVP and DEHP. I think this is an important point and I think we really, I think people have necessarily understood that when they're looked at it with lead. We look at it with narcotics. Why haven't we looked at it with toxic chemicals? Crack babies. Transfer. I've never seen a crack baby. Paul, we might, we might even add to that that we could say possibly neither a ban in childcare products and toys and neither a ban in products for pregnant women might lead to a significant reduction in exposure. One more time again. Neither the ban in the childcare products and the toys nor the ban in products for pregnant women might lead to a significant reduction in DINP exposure. We don't know yet because we haven't done the analysis. Exactly. I think that with further exposure categorization we can probably find where. Because we've seen for DHP that the major root of exposure is direct or indirect ingestion. Right. Right. That comes from mother's milk. Until we have these characterized we have an uncertainty. Uncertainty truly needs to be reduced. I think make the statement that you clearly. Okay. Great. Okay. What I'd like to do next is start the next. Valet and Holger is going to lead the discussion on DIDP and Mike's going to type in the wording into the template. Can I make a suggestion before some of us have to leave? I really think we need to know a little bit more about how we're going to approach these substitutes. Because we haven't really discussed that with our conversations today and yesterday about, you know, not wanting to go from the fine to the fire. I think it's a real significant issue. I would support that but maybe without talking about substitutes itself. I mean, the problem is essentially we should consider a phthalate where there's very little data available. So the substitutes would also fall into that category and by looking at such an example we can then in unset important principles and then see where that leads us. So we should look at one of our phthalates which is poor data and use that by analogy. Perfectly fine with me because I think that will help us address this issue of large uncertainties we're going to have with substitutes. As we pointed out yesterday we see this as a kind of exercise. So we have done the exercise for one sort of for DINP now. I would really support going over to let's say DNOP or DIDP for example. Yeah, yeah. This is an exercise. This is not yet a decision. Right. I promise to prepare a slide for DIBP and I will send it around as based on the discussions we led yesterday but I think we should move on to the next exercise. Okay. Just as long as we don't lose that thread because I think we all were discussing that yesterday as being a major concern and we have to deal with it at some point and the sooner the better before a December meeting. Okay. I'm fine. Now I'm fine. Good group. We still have the two phthalates on preliminary band. Could we have this MOE table again? MOE table. Could we have that again? Yes, we can. That's why I was going to go to DIDP next. What we're doing. DIDP. DIDP. That seems like an easy one. Or you choose. Either one of them seems... Now we go for DIDP. Which one? DIDP. Did DIDP. Yeah, we could go through DIDP. It has actually analogous almost to DNO. Some more types of ranges. You put on the draft table, too, or the draft for our considerations? Unfortunately, I don't... Well, I can give you something, but it's not... I can give you as the draft for DMP, which has information, but it has the six points. Is that okay? Yeah. Mike, are you prepared to take notes to... Okay, good things. Well, that would be even better. As long as you are working on the template. I have a document that had the first... Well, Mike. Good. So we should try to list the studies in animals that we can regard as relevant for us. And I think here, although we have a European risk assessment report on DIDP, Mike, I think we don't have much data here reporting or finding effects on the androgen regulated pathway for DIDP. So that would be burn fill again to jump in and tell us something about possible studies we might use. So you're saying it hasn't been tested in appropriate experiments? Or has it been tested and nothing came out? DIDP now. Just starting on the... We're looking to find the... Developmental? Yeah. There's only one study. Large numbers of animals per dose, they found a slight but significant increase in the pre-putial separation at 300 milligrams per kilogram per day, which would make a no well of 150. In the paper, they didn't consider, although it was statistically significant, they didn't think it was biologically significant. Make of that. I mean, again, it's one of those end points that's part of the phthalate syndrome. Light but statistically significant. One study. Large number of animals per dose. Large number of doses. But has dosing taken place during the critical period? Yes. Okay. GD1 to PND21, so yes. And have those other end points, AGD, nipple retention, et cetera, been evaluated and looked at? Yes. No observed effects on AGD or nipple retention at any dose. That's one of those studies where, yes, there was this slight effect. End point that's put for one study, good study, get to the weight of evidence, I think, we'd have to make some comments. That's their term, what they say in their paper, slight but significant. I don't know. I mean, I don't know the animal literature or the terms that much, but let's say you were using this as a corollary of pubertal development in humans, slight or small delay would be maybe delay of a month versus a clinical delay of 12 months in a child or two years and probably in this case, right, they're talking about delay in timing. Timing, yes. Yes. For that, do you, from your experience, have a feel for what that might mean? Is there a concern? I mean, in terms of read across, I think you might be able to understand this. It's di-isodosyl phthalate. So do we have concerns in terms of reading across two phthalates with a similar chemical structure, which have shown these effects, or can that be ruled out as well? I have to be aware that in some commercial preparations, a certain extent of di-np might be present in di-dp. As for di-np, there have been different... What ratio? Di-np is higher, di-dp is lower, or what? We'd have to check the details, but some percentage of di-dp can be also, depending on the producer, can have nine carbon atoms in the alkyl chain length, so it would be in the di-np region. Yes, but that would be dealt with under di-np. Right. We have here, we're dealing with a carbon side-chain length of 10. Right. As far as I can see, I can detect no evidence from the literature that would give rise to concern. Is this correct? That's my feeling, yeah. Well, except that I don't think it's 10. I think it's mostly 10, 9 to 11, but mostly 10. And I'm not sure if that the ECHO report, I thought, didn't give a lot of details about the makeup like it did for di-np. For di-np, I know the numbers. For di-dp, I don't know the numbers. But what you're saying right now is the bar, you're not raising your eyebrows that much about this point as being a source of exposure. Mike, just to clarify, that was a two-generation study. So is the potency low or high in your mind? Having in mind both the literature that has been compiled here in the report and the presentations from Earl Gray three meetings ago or four meetings ago, we might face the same issue like with di-p. So we are on the other tail end of activity. So I would say if at all, there would be more activity. I think Earl, it's a two-gen study. And I think Earl would say that it might not have the statistical power to detect these subtle effects. There were subtle effects. Probably won't see them. So that's what I tried to say. We are at the other side of the carbon chain length and the tail end of possible effects. I mean, not to mention the branching. Nipple retention, they also looked at vaginal patency. So we would have minimal concerns there, is that correct? Would that be a fair summary? At least that's what I'm getting from this. What about the exon study? It's in here. How do we deal with this one? Where is it? Di-p? I think it's on your part of the list, isn't it? There are two other reproductive types. For Di-p, there was one exon study that was reported in the year 2000. A two-generation reproductive study done in rats levels from about 400 to 800 grams per kilogram per day. No adverse reproductive effects were observed in the other two-generation study that they caused decreased weight gain and increased liver and kidney weights in the adults. So no adverse reproductive effects in the reproductive study that was professionally designed. Multiple doses, those levels up to non-reproductive toxic effects in the adults. Mike, is that the publication that wasn't... HUSHKO, which is the exon-mobile study, I think. I think it's the same study. The trick is, can I find the appropriate tables? Right here. Well, compared to the control about a day, the roll is 44.7. I have to take into account how many... That's also affected by how many times per day they looked. They looked once a day, then the intervals between yes and no is 24 hours. If they checked every three or four hours, it would make a big difference in how these data are interpreted. But there's no data out there looking at the endpoints we considered relevant like testosterone reduction and germ cell modifications. I think, I mean, that maybe whoever writes this up has to back this up by detail. But considerations, but for the purposes of our discussion here now, we can conclude that the criterion of adversity is not fulfilled. Not fulfilled. Not fulfilled. I would agree. Totally. I don't see testosterone. Okay, okay. That's my fault then. I was... But if you have this situation, I think that's warrant special attention now in terms of the technical considerations, the weight of evidence. Whenever you have a toxicological study that is a null, that doesn't produce any evidence for effect. Do you want to be very careful to checking about the technical standard to safeguard against the fact that we're dealing with a false negative here? Mike, about the composition of DIDP. The DIDP used in the Exxon, respectively, the HUSHKA study. Has it been... Did it contain C9 parts or was it purely C10? Could we check this? I can see if the cast numbers here. But I mean, I couldn't find... Like with DINP, the cast number, depending on what that is, there's slight changes in the composition. But for DIDP, I couldn't find any information to that effect, to cast numbers. Obviously, one of our quality criteria and the weight of evidence has to be... I've forgotten to say that. But the purity, the chemical purity of the material tested had to be obtained. I know it sounds very trivial, but often it's... I'm looking for the... Well, it says two different cast numbers. You're trying to find which one they used in this study. I'm looking for the materials. But I'm getting too detailed here. It's just trying out principles. I mean, whoever writes this up, I think it's going to be Holger. You have to check these things in detail. Before the purposes of our discussion... Oh, here. I'm sorry. It says C9 to C11. You see my problems? Yeah, sure. I do, yeah. Well, where do we go from here? I definitely would like to know how much C9 has been in this EIDP. But for this document, it would then be fair to note these considerations. But, yeah. It's not something that we're going to know at this time. But I think it's something we should note saying that, again, like with everything we want, transparency in this process, we need to know a little bit more about what's going on. Is there any other supporting evidence anyone else who tested it? No. Is that the only study? To my knowledge, in Earl Gray's group, the different types of the EIDP have been tested. But the results have not been published yet. Okay, I wasn't clear on that yet. And I don't know how different the two types are. But whatever C9 is in there, it's a small... I don't think it's a big fraction, but we don't really know. But I mean, our lab can certainly see, they might know, have a rough idea. I mean, they can tell the two kinds of DINP apart. They might know something about the DIDP. But had it been contaminated by a lot of C9, we would have expected to see DINP-like effects, correct? Exactly. But the other way around would mean that if they used an IDP low on DINP, can we use it? Is the study as relevant for DINP-rich DIDPs? I think one would then have to conclude by referring to results with DINP that there's a concern for DINP-rich DIDPs. That was my thinking. But this doesn't go anywhere because here now we're judging the qualities of the IDP. But we have to know to consider that some of the products on the market might not contain significant amounts of DINP. I think that's an issue well beyond what our charge is right now. And I think it's something we can note. Again, like anything else, we're bringing up, a lot of other things, we're bringing up other issues. But I think for the purpose of what we're doing right now, I think it's something that's not going to get us anywhere. You can note right here an experimental design. Yeah. That we do not know the composition of the DIDP in terms of how much DINP there is. And we should note that this should be considered in the design of any future experiments, period. So would DIDP products that contain significant amounts of DINP then fall under the proposed ban? Well, if it's significant amount DINP, then it's DINP. IDP. It's sold as DIDP. Used as DIDP, but containing C9. Well, maybe we have to get people to understand that this is an issue that has to be resolved. If DIDP is less than 50% of the material that's in there, then it's a lie. They're obfuscating at best what the true nature of the material is. I think the C9 is probably, well, it's also described. I mean, I think it's predominantly C10 or C10 rich, but I think the amount of C9 is probably not great. I also suspect that they could tell us. They probably know. I think it's something to note. I think I'm not going to get worried about at this point because I think that what Mike says is true. I think it's probably predominantly. But it's something to note just so that we don't get other products that are shipped in from other countries that may not have a labeling on it that's appropriate. I mean, another consideration would be Holger, and I don't know whether you would want to advocate this. I mean, that would be a pragmatic and practical consideration that if, for example, is there concern that the DINP content of DIDP cannot be controlled, that for that reason we have concerns about DIDP. The product specialist, I don't know. I'm getting confused with that. Where are you ending up? Well, DIDP is currently interim banned. God knows why, but the issue is this. On the basis of the data available to us, there would be a consideration to say no justification for interim banning DIDP. But if there's concerns that the DINP, the C9 content of that product cannot be controlled, then this would have to be judged in a different light, I would say. I think that's a very fair statement, and I think, again, manufacturers would have to demonstrate that the majority of the material in there, if we were not going to ban DIDP, it has to be demonstrated that DIDP is the majority of what's in a product, and it's not DINP as a mask. That would be fine, because then we can say what we want that DIDP should not be banned. I guess that's the point here, isn't it? That's the point, yes. I think it's the point, yes. I agree with that point. We cannot propose a permanent ban on DINP regarding DIDP as not critical and allow major parts of DINP and DIDP. Yes, I totally agree. Again, it'll have to be demonstrated that in toys that are in toys, that if you're using DIDP in toys, this is one where we get right to the heart of the matter. It has to be demonstrated that the material that's used is DIDP and not DIDP with a contamination of a lot of DINP. That would work. In this piece of law, there is a concentration threshold specified, I think 0.5%, isn't it? So these bans, permanent or interim, only apply if the products contain more than 0.5%. So if you were to use DIDP, would you exceed that concentration level of DINP? I think that's the key question. If the DINP content in DIDP would be 20%, this would lead to a margin of 2% in the final product. We don't know. I think the better way to phrase it is, it has to be demonstrated by the manufacturer that if you're going to be able to use DIDP because we're not going to continue a ban on it, it has to be demonstrated that DINP is not a major component of that product by virtue of the fact that there's a range from 9 to 11. But that's the solution, I think. The use of DIDP in the product must not exceed the DINP concentration of 0.5%, because DINP is banned. Does that work? Yeah, that would be logical, I think. Shall we therefore then recommend as long as that is guaranteed the interim ban on DIDP is not justified? I think we can do that. I think it's a very specific recommendation and it's actually something concrete that manufacturers can actually be adhered to and demonstrate in their products. Right? It's not fuzzy. But also, I mean in testing, if they test right now, they test for DINP in the cutoffs 0.1%, but the point it's either above it or it's not. This was interesting. We would point out that we propose to lift the ban on DIDP, but also point out that we still have to keep the limit of 0.1 or is it 0.1? 0.1% for DINP. Okay. Less than 0.1%. That works. So does this mean that the toxicology data that we talked about which led to a point of departure of 150,000, I mean 150 milligrams per kilogram is suspect and so we can't use that? Is that what we're getting to? No. But why are you guys jumping so quickly to say that the margin of exposure is in a range that we're not interested in? I think it's based upon the toxicology because of the potency of the material. And basically that leads to the margin of exposure question. And also the fact that there's little material that we find. So are we willing to say that the point of departure was 150 milligrams per kilogram? Or is that suspect? I mean again that's based on what's up there on the slide and I think that's a very weak data on which to base a point of departure. So just in terms of process are we saying because it's a weak data in terms of point of departure that we're not going to look at margin of exposure? Or are we going to go ahead and say? I think the margin of exposure in this case is not the major issue. The major issue is points that were raised before about the potency. And the fact that if you want to put exposure into it even in pregnant women the concentrations are relatively low. At the 99 percentile while monitoring. I'm not concerned about this at this point. With the proviso and I think it's well articulated by both Andreas and Holger that it doesn't exceed what is it, 0.1 percent. I just want to make sure I'm right on the numbers. The margins of exposure were pretty large. Yeah they were very large. They were over 100,000. I think we should complete that aspect number four so we have that down. Yeah I mean the margin of exposure is over 100,000 so I'm not, you know, we're not talking about a thousand. We're talking about 100,000. No it's 15,000. We had two numbers, one was 15 and one was 100. Based on a lower quality evaluation of the modeling. Yeah I know but we're talking. The modeling, you put them both together and they're both high. You know we're not talking about 100 or 1000. We're not in that range where I get nervous because Andreas got nervous. Officer, can I hold your hand? But the margin, but the margin of exposure. As long as it's on TV I guess. I mean it's, that's what we're talking about. Right. It was covered by that. There's another consideration as we look particularly at samples that were tested by the industry, the manufacturers, it's easy to assume that what they tested is what they're making today. And often there are refinements in the process that change the composition of what's actually made and used today compared to what was tested at a very early stage perhaps of development of their method of the process. True. So I don't know how good it is for us to assume that what we're talking about recommendations for is actually what, I mean, what they tested isn't necessarily what we're concerned about today. I think what we're, I think it's not necessarily what they tested, it's the point that the IDP seems to be having lower potency. At least that's the question. Our concern is, is the IDP in current products or future products, if we're going to lift a pan, if we're going to be contaminated enough with DINP to warrant a concern, therefore it's up to the manufacturers to demonstrate whether current methods or future methods of analysis are in play in these products or the material they're used and finally distributing these products is in actuality have DINDP below 0.1. That's a fundamentally sound argument because it's all quantitative. There's no fuzziness there. But it implies that if it's a DINDP pure product that that's okay. And that's my question, or do we feel comfortable about saying that? Olga, you're the one to present it. I think you're okay, right? If we phrase it like that, then I think, I don't know, in my thinking we're okay because if the IDP is too much contaminated with DINP, then then it will exceed the close 0.5% for DINP and will be caught like that, wouldn't it? Yeah. That's right. I think we're on safe ground, Chris. I mean, even if you could purify DINDP, you would be okay. I don't know how much in control they have of pulling out DINDP from DINP. It depends on the alcohol mixture used. Right. How much clever engineering and chemistry provide to the process? Yeah, I think you're right. I think the best, I think we've come up with a reasonable solution to this. I think we needed to make this distinction for DINP and DINDP. Yeah, absolutely. Excellent. I have a separate question if we finish with that. So in the recommendation, would you recommend more toxicology studies or do you think this study is sufficient? Clearly it's from a reputable source, isn't it? It's not a, I mean, it's just one study. It's not a chemical probably that would undergo further study. So if that's the recommendation, then probably the science will stop there with it. And I was just asking, you know, in terms of the quality of the study, if you feel comfortable that one well-conducted null study is sufficient to, in terms of a recommendation for further research? Yeah, I mean, that might be the limitation. This may not be important, but the study that we're referring to as, you know, the one we've been discussing is not really a developmental tox study, the two-generation reproductive study. So to answer the question of do we have enough information, we don't have any developmental tox data in a study that's designed specifically for that. And it may well be that if you were to design a study to evaluate the reproductive toxicity of this because the dosing would be a shorter period of time, the dose levels might actually be higher. The maximum tolerated dose, the IDP might be higher in a developmental tox study than it was in a longer exposure of reproductive study. So I think the answer is we don't have a study for developmental tox assessment in the standard protocol sense of it. And you would make that as a recommendation? We might make it as a recommendation, but it also bears on the weight of evidence there are no developmental tox studies. There is reproductive study that was fairly well designed, but there are no developmental tox studies. But this now it gets interesting. Would you, Bernie, would you think a development, a properly designed development tox study is necessary? The question that's behind that is would a developmental, would a study designed in the mode of a developmental toxicity study be more sensitive in detecting effects of DIDP than a study designed to look for similar effects, but it's a reproductive study? I think the sensitivity in a developmental tox study might be a little bit greater. And keep in mind that this two-gen study was done in the feed. You would not do that mode of delivery in a developmental tox study would be an oral or garbage exposure. In terms of Andreas' question, do you think a developmental tox study is necessary? I would add to that sentence, is it necessary to inform a recommendation or is it necessary for future research? There could be two components to that. I'm bringing this up because of this. If we say, on the basis of the evidence available to us, there is no further concern about DIDP, therefore we can't see a case for continuing an interim ban. If you then say, but we want further data on developmental tox, a properly designed developmental tox data, we will not have lost the lever to get there. No one will do it. If, however, we say provisionally, an interim ban continued with a view of relaxing that, provided we have a properly designed developmental tox study, that would sound a little different. Well, I think, first of all, we need to move what we have under developmental to be productive because, technically, that's not a developmental study. I mean, it's exposures during the developmental period, but it's not designed as a developmental tox study, as Bern has said. So we really don't have strictly a developmental tox study, and I think your point is well taken, that if that's something we judge to be necessary, then we need to take that into account in our recommendation. And also, we don't recommend that other studies would be done. We're basing all of the weight of evidence on one study, one laboratory, one test sample, and that's below the threshold for being able to make a firm statement. I mean, the reproductive study being fairly well designed reduces the probability of a surprise here. I don't think there is a big surprise waiting around the corner if we did that study. But if we're talking about how confident are we of allowing millions of children to use a product with this in there, I don't think this one study is above the threshold for being able to have a weight of evidence that gives us confidence. That's what I was asking, because thinking about it on the flip side with epidemiology, if you have a single epidemiologic study which seemed good, well designed, if it was positive, would it be enough to make a recommendation or if it was not? You probably wouldn't base it just on that. But I haven't read this study, so I didn't know how well it was done or what the other needs were for further research to replicate or expand. As an example of how serious they were about this, they did a pilot study to pick those levels for a preliminary two generation reproductive study, which then was the basis for picking those levels for the final two gen study. That's a pretty serious event to go through that series. So they did it well. But it's one strain of RAT, one laboratory. The threshold that we work with is generally higher than that where we can make a firm statement. What would you rather do? I just can't see how we can continue. I think what we could do is make a recommendation that the band be lifted, but only after more sufficient data is provided on another study. Is that what you want to do? That's the other option. That might be the middle ground saying that right now we need verification. We are leaning toward lifting the band, but we need verification because one study is not sufficient. Can I ask Holger about the physical chemical properties of that, of the IDP? Were the interim band lifted? Would we then have wide application and wide use of this in children's toys? Mind you, the interim band is presumably there for a reason. One isn't so sure. I would say Mike is the better one to answer this question. Do you think the IDP might be? It might be, I don't know, because there are other alternatives, but it would be a definite possibility. You know what? This actually recommending another study would provide us with two pieces of information. One, the study has to be designed in such a way that we know that it's DIDP, getting back to the point of the matter that we're focusing on and not contaminating sufficiently or with the INP, and then also provides a better way of evidence for a decision. We're leaning there, but we need a little bit more data, and also it provides a way of reducing this uncertainty about whether or not we're dealing with a pure compound or not. I think that puts us in a much, much firmer position in the final analysis, but at least it shows that we're targeting toward that direction. We just need a little bit more data to firmly establish that. I think we should be very clear that we want assurance that a DIDP product is not a means of delivering exposure to DIDP. That's one aspect. And second is following on what you also said, Bernie. We would need a bit more assurance in a developmental talk study. So it's not just a replication. It's not simply more data. It's different data in different endpoints. And even in the reproductive study, testosterone was not measured, right? So a recommendation potentially about maybe a more relevant sensitive endpoint. So it's not really just replication. It's missing data. So recommendation is continuation of interim ban until provision of this data. We should state that we're leaning. And evaluation of the results. Right now we're leaning toward removal, but we cannot do it until we complete studies to verify what has been suggested. So I think it's a fair way of describing that, you know, in this particular case, go out and do the science. Move this ban. And if you can, prove it, we'll fine. If you can't, well, then the ban remains. Does that work for you, Andreas? I think we need to be careful not to promise that the ban will be relieved when you finish these studies. No, no, it has to be a value upon the results of the studies. Well, I think that's what he said. I mean, that's what we all mean. So the first part of we're leaning towards would be strike. We wouldn't include that language, you know. Well, it's implied. Well, depending on the outcome. Right. Before we leave, let's take a few minutes and talk about the December meeting. Do you think it's really necessary because I'm beginning to get second thoughts. It's places quite a heavy load on us Europeans. I don't know, I feel at the moment we've got into the swing of things and made great progress. I also think that something like a telephone conference in December would be good, but do you really think we need to meet in December? I would add to that if we didn't, what would our alternative plan be? I mean, would we then have a meeting in early January or have one in February? Not saying yes or no in terms of whether we need it or not, but I mean, I think I can be convinced, you know, potentially a conference call, but then would our next meeting, when would that occur and would that be, what would it entail? What would our alternative be? Well, if we stuck to the other part of our agreement, which was to have written materials in a week before the December meeting, if we stayed with that and had a conference call in lieu of the meeting, and then incorporated whatever we talk about in the conference call into that written material, resubmit, revise drafts of that say two or three weeks later, we could then have a meeting, which would probably be a productive meeting in mid, I guess, January? In February? Or earlier? I would think that maybe right now it's the 15th of February, if we could move that up to the seventh or around that area would probably be better. Yeah, because we're bumping up against the March 1st. I would rather have, I think Andreas has got a good idea about having a conference call in December, and your idea of making a little bit earlier for the meeting in February would probably be wiser. I think it would be more effective. With the plan B, maybe before Paul goes, try to find a date in early February to mid-February? If we're going to go with the conference call on the 19th and then... Can we agree to make it after? It could be on the 16th of February, but on the 15th I have a terribly important deadline. You want to make it later? Not much later, but not exactly, it would be for me personally awkward to meet before 15th of February. Alright, well then, 16th or 17th would be fine for me. But then we have to have the agreement that that meeting is going to be the meeting when we really finalize the draft. Because we've got almost no time between then and March 1st. If you want to meet the 16th and 17th, I can do that. I can nail that right now. Something in my calendar on 19th and 20th of January, what's that? Sunday and Monday. We're in February. February, February. 20th's President's Day, so that Monday is federal holiday. Monday would probably be not a good day. Do you have anything? 16th and 17th would be fine. I also had a 19th and 20th of January on my calendar. Is that now gone? Yes, long gone. Proposal on the table for meeting on the 16th and 17th? Mm-hmm. Two days sufficient? Let's play it safe and go for three days. I'd like that idea as well. But that means the 15th and Andreas? That means the 15th. You can't do that to the 15th. Unless you want to. I've got something on that Saturday. On Saturday, I have a family obligation. I guess I could travel on the 14th. You could for the 15th and 16th? Maybe object to that? No. Just asking what do you see in your minds in terms of the agenda? I mean, going through more of the specific chemicals that we've done? Well, hopefully we could, by mail, we could complete these kinds of summary recommendations so that that meeting in February would really be weaving that final document together. So what do you want to mean on the 15th and 16th? 15th, 16th, and 17th? 17th, yeah. February? 15th, 16th, and 17th. Anybody object to that? With a conference call on the 19th? December? December. On the 15th, I'll come down in the morning. Okay. Can I request something? I'm getting, I know what I have to do, I think, at the very least I have to write the DINP stuff, but in regard to all the other assignments, I'm a little confused. Can I call upon Bernie and Phil to maybe make a list, or with the help of Mike, to give us clear writing assignments? Yes. That'd be great. Yeah? We'll do. Have a good train ride back? Yes. Yes. We can address the issues of the substitution chemicals where there are some toxicology data, but no exposure data. Right now? Or we're certainly going to address all of them at some point. And using hopefully this template. But we don't have a, we haven't gone through that sort of case evaluation. Right, I know. Is that something we can do together before we depart? I'm not sure who's writing what about all of that, but I wouldn't have the faintest idea how to do it. Well, I'm not leaving for 45 minutes. I can, we can try one right now. We're going to try one of what? The substitutes. Do you have one in mind? You'd like to try? I mean, I don't, I don't know much about the substitutes. I know we, we haven't been, we don't have biomonitoring data for the substitutes. I'm looking through your sections. There are some toxicology data on them. Yep. But with that information about exposure, what's to be done? Okay, let's see here. Okay. Okay. We could do DEHA. Well, why don't we for fun discuss DINCH? DINCH. That's a good one. Yeah. Yeah. Let's wait for Mike to come back and we'll do DINCH. But that's actually a different case, because that's where we don't even have toxicology data on it, right? We know nothing about. But there are, there are some substitutes that have some toxicology data. I'm seeing some with no way else of like 11 and 15 milligrams per kilogram. There's a 2-gen, 2-gen study. Don't we need a prototype now where we do not have the data? I mean, we've played through various scenarios now with chemicals where they say, let's say limited data were available. Right. The one that's really not much. I think, I don't know if we have time to go through both of those scenarios, but I think one where there's evidence that there is some toxicity, but no exposure and one where we just don't know anything. Maybe that's asking for too much. Looking, I'm just looking at under tab 7, summarize on the back on page 44. There are some with not applicable. And then there's some with no AL estimates that are, 11, 5, sorry, there's 11, 16. But I don't see DINCH there. Is this just an early version? Yeah, DINCH, there's no developmental tox. I don't know about repo. The HA, there is a developmental tox study. DINCH, there's no developmental tox. HT, there are a couple of developmental tox. It may not matter which one we choose. I mean, you guys can just, I think, I have data on this. You want one where there's no data of anything? No data. DHP. Other Thales, DMP. So there are sort of two issues. One where we have some toxicology data, no exposure, and then maybe cases where we have no toxicology data, no exposure. No exposure data, not no exposure. Are there data to show that there is no exposure, or are there no data? I don't think that these guys did exposure modeling on these chemicals. As far as I know, we've seen the chemicals in the exposure modeling. I don't know of any biomonitoring data that have the chemicals. So, I mean, for example, DPHP, is that the one we want to speak about? Look through the substitutes, and from what I have in my part of the report, there are animal data for every one of those substitutes. So then I went back and looked at the other unregulated satellites, and DPHP is an example where there are no human studies that I had for review, and there were no published animal studies available for review. So that would at least be an example where we have no animal or human data. And for the developmental tox, it's just a brief report. At this point, then, is it a matter of sort of comparing it structurally to chemicals that we know something about? It's hard to say. I think we just have to pick one and work it through and see what happens. Okay, so DPHP. Mike, we've been talking about what a review look like for recommendations on a chemical in which there are no data. We have tentatively arrived at DPHP. Can I do the productive? We're talking about DPHP. And from the standpoint of animal reproductive data, there are no published animal studies that were available for review. There was a summary of a preliminary report of a 90-day dietary subchronic study in rats that was available from Union Carbide 1997. And this was a letter from Union Carbide to US EPA regarding this chemical. In a subchronic feeding study in rats, it was submitted under TOSCA, and there's an EPA document and an NTIS document. This is a reminder that it's a summary of a preliminary report. And that seems like a pretty long reach to find some information. And it wasn't... They reported a significant reduction in sperm velocity indices with an N of 6 rats per group. And there were some other factors associated with sperm function and concentration, like total sperm, static count, percent model, model count, et cetera, that were not affected. Nor was this endpoint reported in other studies. Further males had a 23% decrease in body weight. Spermatic endpoints there for, in my opinion, were of questionable value. So this was a broader study, not one looking at the specific question that we've been addressing, but it's a 90-day talk study which in general are a pretty thorough evaluation, but does not include the kinds of measures that we would be looking for specifically in addressing the question of anti-androgenic activity. So this is not a final report of a study, and it's only a summary of a preliminary report. My suggestion is that I would not put a lot of weight on this study to conclude that there were effects or no effects, because it's kind of a translation of a translation of a study that wasn't specifically designed for what we're looking for. It doesn't mean the study is unimportant, but I don't know how much it helps us. And there were no other published studies. In terms of the developmental, there was a brief report of preliminary results by BASF in 2003 of a gestational exposure study of DPHP and rats. And they didn't, from what they reported and I won't go through it, there was nothing of use to us. And then there was a study in critical review for toxicology by Fabian in 2006. Report of a screening developmental toxicity study. I'm not sure what a screening developmental toxicity study is, in which pregnant dams were treated with DP, HP, but it was gestational day six to 15, so they missed the critical window. Again, no, and there was no maternal or fetal effects at the high dose of 1,000 milligrams per kilogram per day, but again, they would expect to see what we would be looking for. So, most likely that was what we would refer to as a range finding study. It's a preliminary study to find out if the effect seen in a preliminary study is significant enough to warrant doing a definitive study. And if it is, then you've already done the range finding study to find out the dose levels that you might use for that definitive study. But again, it was done at a time in development that was not appropriate for what we would want. When we get down to experimental design, we would make comments. Is there any indication of hazard or toxicology studies on other endpoints besides reproductive and developmental? I know you haven't looked for that, but do we have any? They showed high dose females that increased post-implantation loss, but again, that was associated with maternal toxicity, so by what you'd expect. I'm just looking at the guidelines from the WHOIPCS report on cumulative risk guidelines, and they're suggesting as a tier zero analysis, in the case of lack of data, that it would be okay to use... I mean, they're focusing on hazard indices for grouping chemicals together, but they're saying it's okay at this very first level to even combine things across sort of non-comparable reference doses or points of departures. But it sounds like we don't even have that kind of information. The current method in human biomonitoring, you see DPHP exposure in the same area as you see DIDP exposure. DPHP is a C10 phthalate. So in a sense, it is a DIDP, but only C10. So we see the structures in biomonitoring studies. So all biomonitoring studies, also the ones from the CDC, that measured the carboxylated monoester of EIDP, would see the carboxylated monoester of dipropylheptylphthalate.