 Okay, we're back in session. Next thalite for discussion is DNOP. Hogar, I think you wanted to lead the discussion on this one. I think from toxicity side, we are more or less in the less critical range of the thalates for DNOP. Exposure-wise, detection rates and levels are very, very low. Exposure-wise, Paul, from your side, is it an issue? No, it's not an issue. We have to be aware that there is not too much toxicity data out there. But the data out there is indicating that it seems to be outside of the window of activity. Talking about reproductive and developmental endpoints. Yes. And aggregate exposure all across the board. Certainly some liver and thyroid effects, though. And the one developmental toxicity study, which was done at the right gestational stages. Multiple doses that covered the dose range that typically for the active thalates. If this was one, it would have shown an effect. And there were no anti-androgenic effects. So, again, one study, no anti-androgenic effects. Could we state that in the hazard section? Yeah. Want me to say no anti-androgenic effects? But in the developmental section, doesn't it say the NTP, CURHR concluded, available studies suggest development of toxicity response with kivage. Very high doses up in 1B. That was very high doses, right? Yeah. It doesn't say what doses were. And that was five older studies. And then cell and fight. I don't know how to. Yeah. But those are done at a stage in gestation not relevant to inducing anti-androgenic effects. Okay. Let's test the supernumerary rips and the recent type of bisonon effect. Again, that's an effect, but not the one that we're most concerned about. I think we could say it like that. Yes. That's why I specifically said the anti-androgenic effects. But we could start off, Mike, by saying although DNLP did produce. Yeah. It's, yeah, skeletal variations. There was no evidence of one study. Now it was a dose dependent. So it was done. It affects it non-maternally toxic doses. I don't think that's necessary. Now I think we should add, oh, I don't know about hand. I think we need to say something about the presence in toys and child care products. Currently it's not. Exposure section part A there, the margin of exposure part needs to, I think, be cut out. Because that was an earlier version of what we looked at, but then we noted that the detection rate in in Haines was only about 1% of the population. So what do you want to say about exposure and see? There's no exposure. I think we should say that not just for toys, but also it's. The aggregate exposure is basically the minimus negligible. The risk, aggregate exposure to DNLP, negligible. Now the thing is negligible. Because it's the aggregate risk, the aggregate exposure we don't have enough to show it's exposed at all. It's safe on the biomonitoring, it's only about 1% detection in the United States if you want to be that specific. 1%? And at very low levels. So only the detection rate, but also the quantity of, if it's detected it's very low. Any additions? We did draw the attention to the fact that in our thinking the risk that we're looking at is the reproductive and developmental. We're not, there could be other effects that we're not, that we have not done literature searches for. I mean, we, you know. Well, the, I mean, there are other effects. So you could derive no AL or a reference dose for the. And from this one study it says it's lower benchmark dose and confidence interval. The benchmark response of 5% is the 19 milligrams per kilogram. So there could be, but, so whatever we, that was right at, right there. Top of the page. Oh, ceiling. My point is that the risk evaluation comments are going to be based, our comments are going to be based on reproductive and developmental, not on. Yeah. General. Point of departure. Reference dose. Or benchmark dose. Point of departure. Risk is minimum. But that was only for the, that was for the. Gelato. Gelato. Variations. Doesn't say thyroid effects. 58 was the estimate that 19 is the lower confidence interval. So, I mean, in terms of reproductive effects, there, there seems to be very little concern. But our focus has been just, you know, we haven't really considered those kind of skeletal. So that's the point I was trying to make. It could be something other than what we're focusing on. We're not trying to be. I would, Mike, what I would do is leave that last sentence in there. But at the end have, however, no point of departure in this could be determined in this study for the anti endogenic effects. So recommendation. Andreas. Yeah, this. The picture that is before us. Would suggest that it's totally opaque why, why this compound ever was suggested for an intermediate ban or interim ban. Recommend delisting. Or intermediate ban. On the one hand, it would be justified to recommend lifting this on the, the only, the only thing that is slightly worrying in my opinion is this. Preparatory rip effect. You'll turn either lifting the ban or to say that this, it could be left intermediate pending further clarification of that rib effect. I think that's a good way to. I think that's reasonable. I think that's reasonable. Recommendation is to no lift. We just said maintain the ban pending further evaluation of the. Yeah, until, you know, let maintain the intermediate ban until. The rib effect is clarified and then decide again. You mean, either confirmed or not confirmed. The decision then will be either either continuation of a ban or or a lifting. I'm not sure. Well, I'm not sure. Can you say with your hand on your heart? What is this? Supernumerary. I was going to ask that question. Yeah, that's those are effects that are there often seen in these kinds of studies. And it's. It's often hard to know what to make of them. What do they mean? I guess the only hesitation I have here is that we only have this one study. I just can't see how it can maintain. Or when you're not, you're not talking about a major. You're about something that you see in quite a few different types of studies, right? For me. Seeing this in other types of studies. Oh, yeah. This is not uncommon. This is not uncommon. What is it indicative of? And what does it mean? A birth defect? Is this a problem or not? Is it a problem in what sense for the rat? Well, it's a developmental. It's a developmental risk for a human being. You never, I don't think you ever see this in humans. Supernumerary ribs that you're asking now. Well, then that's. But it could be of relevance. You know, in terms of indicative of a developmental process gone awry. I don't know. I don't know very much about the implications. I don't know. I think it's one of those that people. Whether it's. A basis for. Assessment in human health, like whether it would meet the level of a. A probable toxic. Possible. And I can't see this being a reason for maintaining a band. It certainly is not part of the late syndrome. It's not. That's right. To me, it's not a powerful argument at all for maintaining a band. Well, if this is so, then that points need to need to need a little. Elaboration really. All right. Other than that, I would then also be prepared to go along with. With lifting that intermediate ban. I have a follow up question there for Phil. You said. This is one study that this has been seen in. Right. So for this. So are you comfortable then, given that it's one study. That the anti. Androgenic effects are. Really not there. I mean, is one study enough to say. That it's negative for, I'm just kind of flipping it around. Yeah. Well, of course, one would always like to have things replicated, right? If there were two studies that showed it, I'd be much more comfortable. Saying. Because in this case, it's kind of the opposite of sometimes where you have one study that shows. An association say, well, we'd like to see replicated, but it's one study. Maybe it means something in this case. It's one study that. Did not show. It's one negative study. Is that sufficient to then. Change changes listed. I'm just asking in terms of. I don't. Know how. Well done. The study was and the timing, etc. Is it enough? I mean, I think. Yeah, I think the numbers and multiple doses. Good study. I think we went through this the last time we talked about this study. It's what we have. Well, can I suggest then that we, we at this point recommend lifting of that intermediate ban, but the, I mean, we can't do this now, but the, this rib effect needs to be elaborated why this is of sufficiently low importance for us to. Motivate that decision recommendation rather. This is. Calculated for. Can you make it bigger, please? Yeah, I have a milligrain per kilogram per day. More like a microgram. Or a magnitude. No, three orders. There's. Sorry. So they clearly dismiss the, the rib. The effects. I think the rib effect. What came later, but I think the, the rib effect would. GDI wouldn't even be that low probably or no lower than this anyway. Well, I agree with Andreas. I think put lift demand, but we do have to put a statement in about the rib effect. So we cover ourselves and indicating as you say that it is this comment and it's animal type of effect and not seen in humans. I think that's more an appropriate way of. Solving that question. But what about the liver and thyroid? It's, we're not. Eliminating ourselves to. Developmental endpoints. Which. I'm kind of flipping it around in my head. It seems to me that would be. Maybe reason not to place a band, but do we have evidence of. Really that we want to. Lift a band. Evidence of toxicities other than what we're looking at. Well, there's. There's. In there's toxicity, there usually is. But what's the toxicity relative to the. Question since. If it's not anti androgenic, then. You're not worried about the cute, you know, cumulative effects with other phthalates. So it's simplified. I mean, it. Simplifies things. At the another end point. Absence of. Androgenic. The ADI was pretty high. Well, one, one. Yeah, that's pretty high. I mean, and that's. Actually the. Famous with it. Do these 20. Makes. But the divide that by 100, it would still be point to. That's still probably more than the. Exposed. Well, the current. If you put it in the toys, we have no idea. Well, are we are we going to complete this or. I just say lifted at this particular point. In. In three weight of evidence, a experimental design, the last line. It says the recently published Salon Fett study was of appropriate design to have confidence in observed toxicological effects. I know this was written a while ago, but can you. Interpret that for me or what. What's meant by. I don't that. Probably was. I didn't write that. I think it's just saying it's a. Properly done study. Confidence in observed. So it's saying there's observed toxicological effects or. I mean, I would have thought it would have said something like it was well designed. And. Have confidence in seeing no observed. You know, apart from the rib toxicological effects. At least in relation to the anti-androgenic. It was missed. Yeah. In the observations. That there were no. What did the authors themselves make of those ribs? No. What did the. What did the authors themselves make of those rib observations? I don't remember. I'd have to go back and look at the paper. Can I suggest we leave it there for the time being with the proviso that the papers checked and. The relevance or otherwise of these observations are discussed. Yeah, I will, I will look into this and then. Have my complete this based on what I find and then I'll. Submit it to all of you for. For review. Okay. Where are we leaning? Well, I think if, if, if. Come down and aside that the, the, the rib effect is, is really a minor effect. Which is what I think it will be. Then I think we're leaning more toward lifting. We need to put that in context to what we've been talking about though. Related to the other endpoints that. Aren't part of what we're looking at. Let me, you know, write something Chris and then. Send it around and. All of you can make comments and we'll come up with a. Final version. We all agree upon. Okay. So we'll move on from. Dnlp to dinp. DHP. Well. DHP again. I'd suggest a copy and paste job from either dbp or bbp. With the same recommendations in the direction of the other US competent authorities. You have to have a risk part. Copy that. The 99th. Pile of the margin of exposure. I calculate here. 22 to 36. That's for the, that's for the infants. Yes. It's similar for pregnant. Pregnant women 23 to 39. In contrast to other materials, it's still found. In children's toys up to a level of 12%. It's one of the infants. I believe it was 12%. When you say still found. Mean is found. But that's based on. That based on older data. That's not. Stuff is still out there. Well, it shouldn't be. I mean, that's. Based on. Assuming that it's in toys. Mm hmm. Oh, it's also. HP. If you want to say something about the relative contribution. To the total. Burn the total. Risk. I would at least. Change the. For C pot. Distinguished from that. And the others. I would say here. The margins of exposure for total. Exposure are. Too small or insufficient. Distinguished from, from that. To. Still haven't said anything about the cumulative risk. It drives the, the hazard index analysis. But we have, we haven't referred to that. For any of the other substances. No, but I think that's part of the charge. I mean, it's in the report, but I think. To point it out here would be important that it's, it drives the. The hazard index analysis to where. Estimates of. Perhaps 10% of. Pregnant women in the United States have. Hazard index is greater than one. Largely based on. We say that. So now that's based on 2005. And six data, but. It dominates the hazard index. So now. What you have to. Pregnant women. I think the verb is not. Estimates that about 10% of pregnant women. Exceed. And do you want to put the date on the enhance data that we looked at. There. 2005 and six. Additional. Comments. Hearing none. Move on to the next. Val 8. Oh, we didn't do 6. Well, it's, it's, yeah. Because. Oh, because it's already. And. And. Well, from. Dave. Hey. Here we have. One developmental toxicity study where. The root of exposure was not appropriate. Don't really have access to the data. They found apparently some soft tissue abnormalities. But. Don't really know. Much about it other than that. No human. Studies. Apparently. No reproductive studies. Has been found in tethers and pacifiers. Because of the structure of the DIOP is it similar? Would it be similar? Could it possibly be similar to DNOP? In terms of its toxicity. We should state that somewhere, Mike. Risk. Or hazard. We should go to risk then. Mike. Should we be more. General about the. Hazard. I'm reluctant to mention the HP. I would say due to. Structural. Characteristics. We have to assume that it's within the. Window of the active. Delay it somehow. Not necessarily. The HP. Sentences written. Associated with. Andrea. That's okay, but the last part. Associated. Hogar. Is it a mixture as well? I'm looking here at the case. At the case. Number and. Definitely means that it has a train. Backbone train length with less with seven. Carbons or less. Which would put it into the window. Of. 27. 554. 26-3. Based on what you said. I think what Mike said. Instead of saying maybe within it is. Within. Small change. Is within. Certain of that. We're staying that there is some risk. How do we. State that. We would anticipate some risk. But we have very little data base. You know it's. We can't quantify it. We can't quantify. Part of. Of where it's is it present in we say it is it is present in T. There's and pacifiers correct. Or no. That's what it says here. I mean. Okay. No measured values and no estimated. Those. Compound. Our reports. So we have to say currently there's no exposure. exposure data indicates any exposure therefore there's no risk no risk or de minimis negligible look at the exposure section that's written here as it's found in not in teeters who dissociated products and teeters and pacifiers it says it has been found but not not currently it's not current I mean we this has got to be consistent yeah I mean in one place say it's not in the other place say it is or has been doesn't matter there's no data or no worth that statement that's fine that needs to be removed yeah if it is it didn't come up I mean I know you should I wouldn't simply I would check it for the reference at least because if it once has been in there there might be a chance that it gets in there again but right now nothing points that direction going back to see currently there is no exposure right limited I mean it can we really say no negligible like we said before well negligible information well there's no data and there's nothing it there's nothing in in Haynes there's nothing but no I think it needs to read like there's no data not that there's no exposure we don't know about well people did these other studies and they didn't find it wasn't detectable are they measuring the correct metabolite I do not measure we do not measure the mono Easter for it but I assume that we would see some kind of structure similarity in the chromatograms and we don't see something there but together yeah either or really question when we need more data more toxicity data and it's unfortunate that we're in a position where we have to anticipate what we would expect and not have solid data you can say the same thing from the exposure side we don't have any data or quantifiable data is that the sort of thing that we would we would put in our recommendation whatever that is a qualifier that you need more you need more beta city and exposure data to make a decision sitting in the middle of nowhere yeah but the structure suggested that could be a wouldn't it be in the hazard part yeah well it's it's there I don't think so I think we should go on for the recommendation paste in the part we prepared for the dye and hexyl phthalate but let's see what it's written that will be designed really do we really say it can be permanent done we don't have enough data we should we could probably was an interim then we can say an interim brand and that we revisited after toxicology and exposure data are acquired to reduce the large very large uncertainties we have with this compound period we have recommends that and there's an interim band placed on an interim band ending and that cause of the lack of exposure toxicology and other data to assess risk it's incumbent upon whoever is going to do this to reduce these very large uncertainties not adequately it's not even we not even close to adequately able to assess and moving on to dinp that's why not being used we don't know if it's being anything I would say yes because it prevents the introduction of this material into commerce until such time as the toxicology and exposure does in fact confirm or deny the reason was wording for that worded no but now but this is different yes but because because we're not sure we're not sure we don't have any information to tell us one way or the other as there whether there is or is not whereas in other cases we know it's not being used well I mean we haven't seen it in the products that we tested that doesn't mean it doesn't exist there's no data on Haynes this this didn't even do it an exposure assessment with exposure factors yes would mean that it would minimize potential for any introduction until the data is sufficiently sufficient to prove or disprove the notion that it should be banned because there has been the indication that it has possibly has been used in heathers and toys yeah I would say yes I think it would agree I think yes I all agree difference I'm convinced that yes is the right answer I accidentally here we go I actually no I didn't delete it I accidentally open the new document yeah about every sentence at lunchtime I should have copied it to the other drive I think a lot of this dinp stuff has to be updated because in the last couple of last years new studies came out this has definitely to be updated with the current state of the art I guess so can I ask a question is the clueless study is that out in print now has that been published no I don't think so that's a shame the imp is it in a lot of the studies the humans not always there but there must be something in Haynes I'd say yes but I turns to the health but not in epi studies it's probably because more recently Holger is is when certainty regarding the right metabolite to measure so because all the epi studies you know basically are even if they're published 2011 it's using data from a few years ago but I think in Haynes now includes right the carboxylated metabolite and the mono is the of my and of dinp definitely is the wrong biomarker to capture exposure the proper metabolite what's the oxidized metabolites secondary metabolites hydroxy oxy or carboxy metabolites over the abbreviations be just Chris in our study it's the cup carboxy octal mono carboxy octal cellate yep MCO P at COP and in Haynes oxy iso octal one thing that we're using in the case to termination of reference doses is the is the result from the Hanas about 2011 paper that looked at relative potencies of various chemicals and thought was that DI NP was too less potent than the HP so if that if we could say that somewhere elemental section just because we put it here no well I don't know there's a reference paper in the developmental section but it just know the top of the screen the top of the screen we have to be aware that the Hanna study was not designed to derive nobles or nobles it was a study with focus on the relative potencies is it but Chris here we could state that looking at the relative potencies Hanna's found that the IDP was less potent the INP was less potent than DHP by a factor of point three terms of testosterone what is testosterone and yes 2.3 or 2.3 2.3 production we have to check the exact wording you should let's check that because it may be for gene expression as well and I think these findings have been confirmed and that's why it's not out in the global study has it it's less potent by a factor of three I think it will study it was also mentioned that the INP is less potent than DHP by a factor of three I mean in some of Earl Grey's studies I mean I factor factor of seven biological or the sample on a risk what's this I mean we can we have exposures yes for if it's in toys for all exposures like a lot of them it's driven by diet but we still have exposures well we can you know we can say what it is when it's in the toys yes I mean presumably today it's there's none but it's been there in the past yeah and we have data to estimate exposure from that scenario and should we so indicate that under risk in terms of percentage right now the absolute values stick in a number from now by a monitoring data the INP and the SSF yeah so that the in the infants the upper range for DI NP is 411 400 to 27000 that's the 402 7000 a measure MCOP or MI NP in SFF sorry it's actually 400 to 27000 and that's because there's a wide range of reference doses I'm using the potency estimate to the last sentence of the exposure Mike are not correct I think we should get rid of the MOE in the exposure section and move it down to the right right that last sentence on that exposure yeah leave the estimates of the intake values but get rid of the margin of exposure part of that the margins of exposure for the pregnant women that's 950 to 62,000 950 950 62,000 when the in the cumulative risk I mean it all depends on what you're considering you know as a sort of place you want to that the hazard quotient for DI NP range of concern with in the infants it gets up in the high in the 99th percentile the point two five of the hazard motion of point two five we should use the same terminology as before for let's say dilapidated did we talk about the cumulative individual thing now I will take it out because it's not 400 take out the brackets just take out the stop just take out the brackets 950 to 62,000 the margins of exposure that's all right but take out the numbers now the recommendation what would you say the logic in it would be that we would propose to make the inner and then permanent then that sounds fair like that I think we should always add that text about getting other valuations other agencies to look at this as well sure that is you don't have to do that now that's just something you just fill it out right now it's right there so it's there put there about six in p using pharmaceuticals evermore get rid of well yeah yeah that's now need to say something about then turn you about these numbers not that they're small but that they're part of the cumulative yeah the margin of exposure for that are are small considering the severity of the effects described above and but it's in combination other similarly acting chemicals I don't understand the need for that we're banning it that's may is not to me more rationale to me is bill is more rational but made is not necessarily mean much of anything doesn't support an argument it may it doesn't support an argument add there and that chaps hazard index analysis indicates that the INP will act in combination with other idea I think the chaps what analysis has it index indicates we'll act or acts no but already interim band right so but yeah no what I've left to do to the IDP and dphp that's to that we know we need a five minute break a lot of that a lot of weekbacks in the room 20 minute break okay let's continue on with DIDP no no developmental toxicity data during the relevant gestational period it was the microphone not the throat yeah I think it's another example of a light where it is a little opaque why it ever ended up on the list of intermediate things from the toxicological profile and I suggest it's a it's an analogous case to the previous example DNOP but without the proviso of supernumerary ribs because of that we did not we chose to use DIDP in the hazard index approach however we had no underlying tox data to use and we only chose or we chose the point of departure or DIDP being four times higher compared to the INP because of the possibility that there might be 25% of C9 components within DIDP however we have to say that the IDP is this point of departure has been derived from the INP now do you want to start with what you just said not like in analogy is it used in currently no well there definitely is exposure as the biomonitoring data indicates then I would go on however there is no evidence of anti-entertaining effects it was recently some of that was published it's not in here no because it was it just came out recently yes it's it's support for that I think that really adds weight to what we're saying you know because the two studies that we have here really don't bear on the issue because they weren't done at the appropriate time in gestation Earl Gray study was negative yep mines work now it's on okay so if we're if we talk about margin of exposure which we have in the other cases I think we should hear but I think it should be based on a condition that the it's a very conservative estimate for the reference dose I think we might at nevertheless we included DIDP in the as an index approach and in the calculation of a margin of exposure and in the calculation of the margin exactly assuming the maximum overlap of din p with d8 dp by 25% and therefore multiply the DI NP by 4 does it that complex you may not need all the details we've I mean we've described those details you know in the other sections but I mean it's a very conservative estimate for a reference dose just leave it at that it's a conservative estimate I think that says volumes especially for what we're trying to use it for here just say assuming if you are yeah necessary current conservative not conservation so the the margin of exposure in infants when you're ready for that like okay I'm giving you the 99% ranges 700 to 43,000 and it's more than 10,000 and pregnant women they cut out the margin of exposure values in the top part there they're based on old numbers I would include the s the the yeah just the last part of that sentence those numbers those numbers are old Mike okay oh you want me to take a mile yeah sorry I think the sentence you just took I would leave the sentence you just took out at the end section C okay but just the way it was get rid of the range part there for me to give you the range or you just want I think it's oh they're just big numbers yeah I pointless say what the those MOE's mean I think by saying that the reference dose was so conservative I don't I don't want to I think we should and we could say that chap didn't give it given that this is a conservative estimate yeah the low end wasn't consistent wasn't whatever we're kind of using a thousand as our guide there but here we're saying it's such a conservative estimate for the reference dose I don't think it's needed I think we should add something about the developmental toxicology is up on top we say can cause developmental effects and I think what we should say is that although early studies indicated that DIDP can cause developmental effects more recent studies indicate that DIDP does not cause anti-androgenic effects no down in the risk I would put it to the hazard pod well we've had this sort of thing in the risk part before but I don't it doesn't matter to me wait yes oh girl you want to give us wording for the recommendation I think we agree that based on the above we propose to recommend to lift the interim man the recommend means six is not applicable to get out or put an applicable well based upon our recommendations not applicable could I said not applicable can simply erase this point here huh can be erased this point yeah take number six out we don't need it it's a consequential comment oh it's because I cut and paste that's why last but not least a question Phil so apart from anti-androgenic for DIDP there's there's no evidence or concern in the relevant window of exposure that's correct for DP HP well I don't think we have any exposure data all we know is that production has been increasing okay I don't mean to so but if you look back maybe this needs to be edited but the developmental part under DIDP talks about numbers of cervical and lumbar ribs yep growth and survival we're also adversely impacted to address that here like we did in the other that we're focusing on genetic effects and not well that's that's why I added that sentence at the bottom of the risk and as conservative approach page xx right which is case 2 if it's 25% dinp you'd have to make sure we reconcile it with what our recommendation was for dinp right because 25% will be dinp yeah but in the test it's negative IDP how can that be if it's 25 I mean I guess that the dose is just not high enough if it does contain 25% dinp see what I'm saying if we made a recommendation for dinp and the DIDP is 25% dinp are they that was the conservative approach we chose to take account of the exposure for DIDP to handle it in terms of putting some sort of reference dose to it actually not derived for DIDP but takes account of possible traces of dinp that case if you're then saying the study here I guess it's one of Earl Gray's studies on DIDP even though it contains or comprised of 25% dinp you're not seeing any anti-indrogenic effect no the problem is then have any we we are now to use them for anti- androgenic kind of flipping it the other way right he's kind of see because you I guess you can't really have it both ways where you assign an RFD because you're saying it's 25% dinp and then now you get to DIDP saying the study shows that there's no anti-androgenic effects so then you're ignoring the presence of 25% dinp for which you then assigned a reference dose which we did for the cumulative approach but I think the interpretation is correct that the contamination of dinp and DIDP was sufficiently low for dinp effect not to show up in these studies I think we discussed that some time ago for practical purposes then the question reduces to if you say if hypothetically DIDP is now used in toys is then the provision in the law that says no more than 0.1% dinp still safeguarded yeah that's another way of saying it or or if it was used and its use went up fourfold let's say based on the 25% dinp then you'll see that 0.1% I think when we last discussed it the question to that sorry the answer to that question was yes so any the contamination issue with DIDP is covered by making a permanent ban on dinp if you get my why don't we say that here difficult because you know it's very different in a way than the other chemicals and I would just want to make sure it's consistent with what we said for dinp because because you can't use that information at one point to derive an RFD and put it in cumulative risk assessment and then and pages later or later in the report ignore that and say well this one study showed that DIDP is not anti-antigenic and you're basically assigning it in RFD of whatever affinity or something right but that's what we tried to explain here that we said however there's no evidence of anti-antigenic effect nevertheless we included DIDP in the next approach and calculation of the MOE that's literally what you said we explain it yeah and we could go on explaining it saying 25 no no I agree that it's explained but then then you're so the lifting of the interim ban then is based on the fact that margin of exposure then is so high irregardless of the presence of the dinp because it's not anti-antigenic in the test but it contains dinp which is a portion it's not a pure chemical which makes it difficult to as you're we're saying at one point it contains a fraction that is anti-antigenic but then chemical itself as it's a conservative approach and we don't know whether the the fraction of dinp the alkyl chain composites that from dinp are the ones that cause the endocrine activity in dinp that are present in DIDP dinp in itself is a mixture too and we are not sure whether those parts of dinp that are found in DIDP actually are responsible for the anti-antigenic activity of dinp. Taking that one more step then if so if you're saying dinp comprises part of DIDP and then dinp is not a pure chemical right and it's comprised of something else which may then be accounting for the anti- endogenicity of dinp then our conclusion on dinp and DIDP should be consistent because we're concluding on dinp and you're saying maybe it's not really the dinp but it's a minor component of it right that's yeah that is that is one decision we might have to take we can still take out the DIDP from the cumulative acid index approach but that's the other choice. Mike can you put us the screen up and have the dinp part C up above so we can see what that says but you agree you know in terms of reconciling yeah how we're I think the point is we were just conservative in the way we handled it in the cumulative analysis but looking at DIDP by itself maybe a dose problem that we haven't looked high enough but in the doses in the studies that have been done we don't see an effect. Commendation for dinp just down a little bit. So dinp by itself is bad but dinp as part of DIDP. Right yeah okay yeah that was that we haven't seen maybe a dose effect. The faulty logic I think well it's like saying you know apples are poisonous here's a bushel of pears and there's two apples in it is the is it you know basically harmless or because of so the concern about DIDP is that there could be a part in it that could be hazardous we have not seen evidence of that we've seen no anti-indigenic effect and the dinp is going to be limited because of the ban on di you know the dinp part of DIDP will be limited because of the ban on dinp. But can I just point out that it is not well you can only regulate specific chemical entities in this way we are talking about DIDP that there is a contamination with the dinp that is clear but I think I get rid of it. That's the dilemma there's no other way of dealing with it. You make a statement about DIDP. Then they have to clean it up. DIDP doesn't seem consistent I mean I agree but I think in a way of maybe putting that in well for the DIDP you know there could be a there could be an antagonistic effect between DIDP and dinp and so therefore there's no demonstrated to logical effects you don't know whether or not it's just an additive it could be a could be canceling out the dinp I mean you have no idea what's going on in the chemistry you're assuming this is just linear additivity and it's obvious in toxicology it's not. Looking at it really from like a straight logic you know if you say A is toxic and B contains A within it and B is not toxic that's illogical. But that's assuming it's the dose. It's not. It's not. Okay then we should say that. It's not only the dose it's whether or not there's some kind of you know antagonism between the two chemicals that reduces the possibility of an effect. Because of the dose it's a minor fraction and that study. How about this? It could be anything. The point is that it's not demonstrating any toxicity in a DIDP study. And do we know that the DIDP that was used in a developmental talk study had dinp in it? I don't know that do we? If others feel this is comfortable with this then I would go along with it. I just wanted to. Well it's all the tests are done on the commercial product which is a range of device embers and it overlaps with the DIDP. I think Russ your point is well taken and I share your concerns but do you what are you proposing as a way of dealing with that? You want them to scrub the dinp out before they use it? Russ I think that's reasonable. Based on what was said before that I think Andreas you were you were saying that that if DIDP is used and it contributes then to greater than 0.1% dinp in that product then and you've never really separately just added dinp then it would exceed dinp. And they'd have to get rid of dinp. And to do that they'd not use DIDP. Or they'd have to figure out a way to scrub the dinp out of DIDP to make sure that the product is usable without exceeding the concentrations you would expect for the dinp. If the chemistry of that allows. That I don't know. It's not maybe not only the chemistry it could be the cleanup process. I have no idea. It's all in the alcohols that are used for the production of the respective phthalates and since there are complex mixtures of isomers like for dinp we don't know which are the active isomers. It might be the case that the overlap of the overlapping isomers are not the active ones. So that the scent of activity is let's say further to the left. But that is the conservative approach as we say there's the overlap and we assume that the active isomers are overlapping. That's the worst case assumption. But it might be and it probably is the case that the activity is more to the short chain parts to the short chain isomers. So should we put a line somewhere or maybe I don't know the next is the recommendation or put it you know mention this somewhere else in the report. I mean when I researched the way these these bands were justified in Europe and the European Union I it's really very difficult to get anywhere with this because in no way is it coherently properly justified. But Holger do you know do you know the the background was the motivation for banning this in Europe the contamination with dinp or there must be a reason. Astrid or or something you know say however the chap recognizes or points out that dinp is a minor contaminant of idp or some way of qualifying that. Assuming that the dinp product is um minimizes the amount of dinp contamination would that be helpful. Yeah all right I could accept that without any difficulty. From a chemical perspective it would have to be expressed much more complicated. I know but you know we have a short. It's not that easy to express. I know that. What would you like it to say? Say it again. Holger it needs to be more specific or or you you don't think it's worth qualifying. Product that had dinp in it can you figure out how much dinp is in that product. I'm sure they can. You can only look at the the alcohol spectrum. Probably figure it out. I just say minimize the amount of contamination with dinp and leave it. Hard to come up with. Wording it just doesn't get either too convoluted or too so specific that it difficult to. Under under hazard that the the chap is aware that there's some overlap. Yeah dp and dinp. And what? And and that dinp and dinp could pose a risk or a hazard. Well I'd say that it should be minimized so it doesn't pose a risk or hazard. Well no I mean just in the in b in the hazard part. Oh in the hazard yes it could pose okay I'll leave it there. That sounds good. That's fine. That's fine. So the chap is aware. Okay. Preparations of dinp contain. You're you're better at. There's a certain a certain overlap between dinp and dinp. What are you trying to say now? I don't understand. Is there an overlap between isomers? That is. Didp contains or small percent or comprised of? No you can't say that. Can you not say say it straight as it is. Didp is contaminated with dinp. Yeah right. The chap is aware that. Yes. Didp is normally contaminated with dinp. It's not a it's not a contamination it's a it's it's a intrinsic property of the product. Or contains also contains. Yeah contains some dinp. Period. Okay. Some dinp which may pose. Hazard. Right. And it's up to others to get rid of hazard if they want to use it. Perfect. Yeah okay. To address the fact that this we recognize that we would expect that the ban on dinp would limit their overlap. They're actually now saying it kind of in the other way because if dinp is the end to less than 0.1 percent and it's I don't know chemically not possible to make a dinp that's less than 1 percent dinp. Then it can't be used. Then it can't be used right. I mean kind of that's what you're saying from that perspective. I only get to 0.4 percent. I just think Lee the recommendation is it is and I think I think that it's clear it's clear that if you're going to use it you got to get rid of the hazard. So moving on to DPHP. Yeah I think we all are. Something in this room. Well there are a thally in this room. I think it's the lack of ventilation maybe. I think Andrea's brought something across the pond I think is what it is. Cross the pond. It's wonderful. Okay. I'll take that for the hour of the day. The right windows and the study. For development. Yeah. The 2003 spans the relevant window that 2006 does not. And these are both studies. I don't know we don't have details of those right. I don't think so. Just the summaries. The dilated renal pelvis was a common effect in with some of the other phthalates the INP in particular. I remember Earl having used it in his studies. Did he? Well I know it was in the early studies I don't know about his but it did show up in in the early studies when they were not in the right window to see anti-androgen. Still saw that. We don't have any exposure information at all either there. I don't think it was much. It says it's in use up to 18 percent. Currently with the biomonitoring data we cannot distinguish between D. I. D. P. and D. P. H. P. Because strictly speaking it's also a C. 10 a C. 10. Delayed. So it's D. P. H. P. Is something like a less isomeric D. I. D. P. This one we're basically completely in the dark. Lovely lost. How do we do punt or say we can't make a recommendation but there's no reason to believe that we can say it can be used because there's no data. I mean there was it in Earl Gray study. What I asked you I think it wasn't I don't have and he mentioned it was inactive but it's not in Earl's multi-dose study but it's it was only the presentation he gave us I think four meetings ago. It hasn't been published. No I think it was just published. It wasn't was it Hanna's the first author. I don't remember. I'm doing D. P. H. P. It might not be in the paper. He did it but. Well it doesn't help us does it. Well unless he did D. P. E. P. Yep. But is that is that gentle. Okay. I don't ever remember publishing D. P. H. P. Okay. But I'll check again. No it's not it I have the paper it's not in here structure wise is there any concern based I mean is it in there. Well it's too substituted. It's it's like D. H. P. except instead of ethyl it's propyl so you might have I would have thought it would have been positive in his assay but it wasn't and the actual is the propyl. It's propyl is the propyl and the actual. No it's die. It's propyl heptyl. Okay. It's one carbon edited. Yeah. Yeah. Okay. Would have thought it would have been positive in whose assay. Well at least in Earl Gray's assay because of the to the branching at the two position. But we don't know that he. Well we think he tested it but it's not in the publication yet. Talk to us about it when he was here. I think he think he did. I mean do we have can dig those slides slides. We didn't see it in any children's toys. It wasn't. But could it be used. I think it could be the manufacturer says it's not intended for that use but that doesn't mean someone wouldn't to try to use it. What's the intent it's intended to use. They said the manufacturer says it's not they're not marketing it for use in toys and we haven't seen it. But what are the marketing for use in. I think that's a whole value. Can we go down to risk and start putting that in. Yeah. Let me get rid of this. DPHP was not in his first talk. It may have come up later or maybe it was. So it's it's not found in children's toys and personal care products. Correct. Currently. Yeah. Not that we're aware of. I'm monitoring approach. DPHP is currently not distinguishable from the IDP or is captured together with the IDP. I like the first can't be distinguished. Currently. Currently. I don't know. Isn't this a case for no action or something. Yeah. But I think we should point out. I mean if this is to the description above that that the use of it is increasing in the marketplace exposure is going to be going up without a whole lot of strong information about the toxicity. So I would hope we could recommend appropriate studies be done. Well we should put that under risk than that. If we know a use is going up we should though indicate that under risk. We should say that we need toxicological studies and we need actual human exposure studies and also studies of what the sources would be. They're living in the dark. Under recommendation we want to say that although we cannot recommend any specific actions at this time we do recommend that you know further studies. Yeah. But all we can do. Or I would say given the the the general lack of information. CHAP is unable to make a recommendation at this time. However. What's the however. That's what we're going to do now. That's the way I would phrase or CHAP highly encourages the appropriate agencies generate necessary toxicological and exposure data to assess the risk DPHP. I mean to be clear some of that data exists but it's not public. And and also the I mean the agencies would argue as to whether it's the agencies who should do the work or or the manufacturer. Well agencies could be either. Right. It's not our responsibility. It just has to be done. Sees to obtain the necessary because that doesn't. Yeah. Put the burden on them to generate it. Right. Good. I mean the first line would I mean it's just a really small point but the CHAP does not recommend any action. Would it be the CHAP is unable to. Or they qualify lack of information are publicly available publicly available. A toxicological information or I mean I just leave it general. General. Just one Ellen public. Two. Documents. I can look at DN finished DNOP. That was the one that I was going to. Okay. Okay. Do some research on the paper here. But after having all these standards maybe make a short brainstorming whether we captured all of the relevant delights because after I had a look at grace publication there's the ISO Heptulf Delay and which is not covered in our approach. So we might discuss whether we should include the ISO Heptulf Delay also in the approach because as Earl shown in his publication it's clearly active. Are there any others besides that. It's just that came to my mind when I read the HANA publication because the ISO Heptulf Delay is one of the ones he tested. Can't put that together for us as well for tomorrow. So Heptulf. Can't be much there. Yeah. Yeah. I can't hear. Okay. Now I did send. Can't did do the substitutes the same exercise on the substitutes. It was a separate document and I overlooked it. So we have that for either today rest of today or tomorrow. Basically says there's no information for the most part. There are some studies but there's to do it. Is your email it to us? I just emailed it. He did. I looked it over. Yeah I mean there's not a lot. There's a dearth of information. I thought I had seen that. I sent about 340. Oh Andreas. Would you like to talk about the brainstorm the risk assessment section briefly before we break for the day? Something you said you would be willing to take on as a writing assignment. Want to get some input from the chap? Well I believe this section should very shortly and briefly detail the approach which we used to assess all the salads which we've just done which ends in recommendations. So it's about data quality etc etc the philosophy which we've used by margins of exposure all this. So you're prepared to write that without any input from us? No please give me some input but whether you agree with this general? I think it's you're going to do a framework literally. Basically you're going to say what the exposure information is what the hazard information is and whether any sources just the way we laid it out in the risk assessment that would be fine because at least you'll point the way to each one of the recommendations having that section. It shouldn't take you very many maybe one or two paragraphs. Send me tonight all your draft and I'll look at it or tomorrow morning or tomorrow mid-morning by 8 30. Is that okay? We'll discuss it over a beer. I'm just having a look at our contents where would that go I can't find it at the moment. Yeah. Short report? Yeah. Number three okay page 53 okay. I did get a poll did test dphp at 750 mix per kick day. It did not do anything. There were no anti androgenic effects. He says he probably this is in a poster an SOT poster for March. So we can I guess we can cite that. We remember correctly that he presented some of the data. Yeah. Yeah. He did. Sent it. Who did that? Earl Gray. Who's the first author on the poster? Do you think? I'll look it up. That was the March SOT. Can you send that to me? I forwarded the message and I'm looking for the abstract. Well, I'd like to spend then some time on 4a variability and uncertainty. You've already submitted a section and let's go around and see if we can get some input from others. I'll probably upgrade a little bit. Bill, I'll probably upgrade a little bit before it's all over. Sure. Let's get the cuts. Can I just get a bit more orientation on what the perhaps of this is just a brief critical discussion of uncertainties in the data which we discussed in section number Roman two or why what's the intention? I'm sorry. What are you asking? We are discussing on your suggestion the point Roman for discussion point A variability and uncertainty. Yes. Yes. Okay. What is the purpose of that? Do you want to have a brief discussion of uncertainties in all the data listed under Roman two background and strategy and then A, B, C, D, etc. Just give me orientation. What's the purpose of this section? I think then variability of what? Precisely. I think it's uncertainty in terms of the data that we used primarily to do the hazard and then the risk assessment for recommendations. You're not going to go back to the individual studies and look at the uncertainties in those studies. I don't think that's reasonable. Because what you're doing is saying how much data was there, how much it's basically coming up with a level of confidence knowing that there's a certain amount of uncertainty in one, the lack of numbers, two, some of the types of experiments were done, three, the gaps in experiments have done that were not done. Those are your uncertain, those leave your uncertainties. Variability is the between study variation in the levels of outcomes that you saw. Yes, but a lot of that is again summarized under Roman four recommendations. Roman four recommendations. What we just discussed today. Maybe the variability, but not the uncertainty. General statements of uncertainty. Like each one of those phthalates have a certain have much, as we've shown, some of the phthalates have more data, some have less data, some have no data. Based upon those levels of uncertainty, our recommendations can be ban, interim ban, remove ban, or we have insufficient data to do anything. Those kinds of sources of uncertainty, I think, are essential somewhere in the documentary before you get the recommendations so that people understand why you got to where you got. I agree that these are topics to be addressed, but what I have difficulty with is to address it as a separate point. I mean, we're constantly discussing this and reiterating when looking at very concrete data about specific phthalates, but why should it be pulled out or are there, I don't see the point for that unless there are global overarching issues. I think it's the global, global issues. Yeah, but which are they precisely apart from not previously mentioned. Yeah. So you're saying we may not need that section. Yeah, I don't see what the purpose is. Well, think of it this way. You're going to be talking about them in chapter six, way, way down the road in terms of the actual recommendation you make. This is before we make those recommendations, saying this is what you have to be, you have to be aware of this before we get there, so you're not questioning why certain things went the way they did. But the recommendations chapter starts with a criteria. Right. That makes sense to me and obviously first you have to develop criteria for your recommendations and in doing so you have to deal with certain with uncertainties, data variability, missing data. Wouldn't it be better to deal with it then instead of having it? Well, the effect would be actually the same because the sequence would be. Yeah. I mean, we have that the way it worked in the exposure section is the same way in reverse our had its uncertainties. So the CPSC, I molded them both together and said, you know, these when you start looking at this in total for when you want to make your recommendations or work our recommendations, you have to understand there's a certain general level of uncertainty that we have inherent in this data because not all compounds are equal, not all sources of data equal and all these things will lead to us to have to make expert judgment in the way we address the final recommendation. And I think that's all you're looking for. Yes, I agree with everything, but wouldn't it be better to embellish point Roman five recommendations a criteria? I think it would read better. I mean, put all the answer to put all the uncertainty information there. Yeah, why not? Yeah, my my sense of what was going to go there would be for for Paul to write a paragraph or two about the uncertainties and variabilities that go into doing scenario based of aggregate approach to exposures. Holger would do the same for biomonitoring. You know, what are the uncertainties and variabilities there? And Chris do the same thing for the hazard index approach. You know, what are the uncertainties and variabilities that that go into that? Those were I think the three main sections that I envisioned that would go into that. Now, where it goes in terms of whether it's for a or part of five a matters, you say something. Yeah. Five. Well, five is the recommendations. Yes. Yeah. I mean, I think the recommendations are just, you know, summarize what's in section four, sections three and four. So, yeah, I mean, the basic information should probably go in for a maybe, maybe what it creates with me a little to call this discussion, maybe it could be called something else and then it would make more sense to me. Can you can you put up on the screen section five criteria to see whether Andreas's suggestion of expanding that to put in this information would make sense? I'm not sure it would. No, I see it wouldn't fit very well. Okay. It has to be in a previous intersection before that, but maybe we should reflect not calling it discussion, but something else that reflects better the content, but I'll think about it. So, I would need input from Holger and Chris for that. Okay. And Paul's already written. Okay. I've written a brief section, but I'll be more than happy to work with you to make it fit in yours of it. Okay. Holger, you something short and brief and sweet about the uncertainties and biomonitoring. And that would include the issues of spot urine samples versus 24 versus repeats versus single numbers. Those are where your uncertainties will be derived from largely, not the analytic methods since they're in pretty good shape. It's the strategy for sampling. And the next point under this section is B, species differences in metabolism, sensitivity, mechanism, et cetera. And I'm supposed to write something. I think I started. Again, wouldn't it be better to move this into section Roman II? Yeah. Yeah. I think it was there. And I think based on your urging, we moved it out of there. I remember last time during the teleconference, I suggested to put it into two. Oh, okay. So we could, would it make sense to put it right after two B? Okay. And then the final part of that is the missing data. And I'm, I'm not sure what will, what should go in there. Other than to say there, lots of missing data. I mean, that's a fair thing to say because how, how can Congress in any, with any kind of wisdom request us to do a comprehensive cumulative risk assessment without the data? I mean, it is it's somewhat ludicrous. I mean, they assume the data exists, but the funds are not made available to EPA, CPSC, or any other agency FDA to collect the data needed either by our monitoring exposure data. And in some cases it appears toxicology to make a comprehensive assessment. So I think that's a very critical failure in terms of how we have to, in a sense, backfill with our best guests for something that's so important. Sounds like you'd like to write that, Secretary. I guess I'll write it. Thank you. I should have kept my mouth shut. No, I'm pleased to do it, Phil. No, I think having a standalone section that does what you say is important. I think we've said that all along in the recommendations that the appropriate agencies need to change it from missing data to future needs or some other type of, because it sounds like what Paul was saying is more of a perspective of the field or decision-making, right, Paul, rather than a specific piece of missing data. Yeah, it's more of a view. It's not as if we had one piece of data we'd be able to solve all our problems. Yeah, it's just not going to work. Right, rather than saying we need one more talk study that, you know, more and every study more, you know, whatever it may be. I think Byrne envisioned that it would be a short section. Well, this will be a short statement. This has been a paragraph. Yeah, it could be a paragraph. It could even be blended in with the uncertainty. That's what I was thinking. Sure. Because it contributes a tremendous source of uncertainties of data gaps. Yeah, it could be. Can we briefly reflect on the timeline here? I mean, these are now, because of Byrne's illness, additional writing assignments. And I'm aware that originally the deadline for all this to go out to peer reviews first of March. Is it okay to delay this by one week or not? I think it's okay to delay a week or maybe more. I think it would just, what I am told is that a brief request from the chair, from the chairman, you know, saying we need so much extra time because I think, I think what we should do, perhaps at dinner this evening is to talk about how much time we need. Look at our calendars as we go out. All right, so then tomorrow we will. Well, you, yeah, you wanted to start a little bit early tomorrow, 8 30. Yes, because we will look at the phthalate substitutes. Yes. With Russ and I will be leaving here at 11 30. Right. So we've got six should be able to do that in. Yeah, and I think they'll be shorter. Yep. And several of them, I don't know if they'll be easier, but they'll be shorter. Once we do one, several of them should be the same format. Yeah. Okay. Well, thank you for guiding us through this, Phil. You've done a great job as chair. Thank you. You per day. All right. So we are adjourned for the day and we shall meet again tomorrow at 8 30. Thank you all. Thank you all.