 Okay, welcome to the Second meeting of the chap on phthalates and phthalates substitutes We're a little bit delayed Due to the weather issues and in fact some of the chap members are still on their way Hope I'm looking around. I'm hoping the speakers all made it in but if we have to we'll adjust the schedule accordingly But thank you all for coming for braving the storms and We look forward to all of your testimony Bill again my welcome on behalf of the committee We've got a full schedule for these three days and thank you all for participating and I thought we'd start off by introducing ourselves so Some of you don't know members of the chap and as Mike has indicated not all of us are are here yet But my name is Philip mercus and I was I spent most of my career at the University of Washington in Seattle in the Department of Pediatrics and I'm a developmental toxicologist and I agreed to to be the chair of this committee And I'd like to now have the other members of the committee Introduce themselves and tell you a little bit about themselves Andreas. I'm Andreas Colton. Come professor at the School of Pharmacy Center for toxicology at the University of London My background really is in mixture toxicology cumulative risk assessment both experimental studies But also thinking about regulatory approaches and regulatory Implications we've carried out a number of experimental studies in that direction Good morning. I'm Chris Jennings professor professor of biostatistics at Virginia Commonwealth University in Richmond, Virginia I've spent many years doing methods development for statistical methods for evaluating and designing studies for chemical mixtures I'm Michael Babbage from the directorate for health sciences at CPSC I'm the project officer for phallates I'm Cheryl Falvey the general counsel here at the commission. Nice to meet all of you as I understand Russ Hauser is on his way Burn Schwetz will hopefully join us early this afternoon And Paul Leoy is not able to join us at this session So I'd like to start now by having Cheryl Falvey talk to us about the charge Thanks, I think I'm gonna just stay here so that we can have a give-and-take I really wanted to be available for your to answer your questions today and The chairman asked me to speak to you Really about two things first is to review the statutory Provision with you in case you had any questions about the scope of the work that you're to do if if Excuse me if I can interrupt there's a copy of the statutory language in your Folders under the tab business if you go past the two Copies of the meeting notice. There's a copy of an extract Says consumer product safety act and there's an extract that includes the language describing the the chap Sorry, that's fine So I want to go over that language with you and answer any questions that you may have if I can't answer them now I'll know what the questions are and we can get you answers later over the course of the next two days The other thing I wanted to do is explain how your work may be used by the Commission in other ways beyond the statute As we're thinking through issues relating to implementing the statute So those are the two things I want to talk about First to get into the statutory mandate you've been given a lot to do Congress has asked you to be at least four things Independent they wanted to take a de novo look at the issues of health presented by the Thalates In addition to being independent They want you to be very scientific and you can see that in a in a string of the relevant data You're supposed to review the most recent best available peer-reviewed scientific studies So they want you to look at objective science in reaching your conclusions here In addition to being independent and scientific they certainly want you to be comprehensive and you can see how Comprehensive when you look at the detail that they've given you in terms of the scope of your examination You're to examine all the potential health effects of the full range of Thalates That's not just the six that the three that have been permanently banned and the three that have been in Internally banned but all of the Thalates you're to consider the potential health effects of those Thalates both in isolation and in combination with one another you're to look at the likely levels of Children's pregnant women's and others exposure to Thalates So that asks you to look at an exposure level and that's very important for us as you'll see as we Continue your work once the chap has concluded its work and you'll be making reasonable Estimations under both normal and foreseeable use and abuse of such products those words normal and foreseeable use and abuse We use all the time when we're dealing with children at the Commission. There's an awful lot that children do that is Falls into the foreseeable abuse category that there's certain activities by children putting things in their mouth That are foreseeable Even if that's not what was intended by the manufacturer and so you'll you'll particularly want to look at those exposures. Those are important does You need to consider the cumulative effect of total exposure of Thalates Not just from the products necessarily under our jurisdiction We have jurisdiction over consumer products, but we don't necessarily have jurisdiction over products where FDA has jurisdiction there. I say not necessarily because They have jurisdiction over food cosmetics and drugs Medical devices falls into a different category. We we've shared jurisdiction over medical devices with the FDA over time and there are some things that you wouldn't think of that fall into the definition of medical device like toothbrushes and Sleep positioners things where medical claims are made and those Fall into both of our jurisdictions for you You're to consider the cumulative effects of total exposure From both the children's products and all the other sources in the home such as personal care products that could be bath Soap that's used it could be the vinyl shower curtain in the bathroom it could be Deodorizers and other things in the home You're to look at all the relevant data as I mentioned and it has to be the best the peer reviewed objective Scientific and best available in most recent studies and consider the health effects not only from ingestion But from other routes of exposure including dermal hand to mouth or other exposures and then finally Consider the level at which there is a reasonable certainty of no harm to children pregnant women or other susceptible individuals and their offspring Again considering the best available science and using sufficient safety factors to account for uncertainties regarding exposure and susceptibility of children pregnant women and other potentially susceptible individuals and our scientists including Dr. Babbage and others in the commission can help you In thinking about the way we think about Safety factors and because we're using those both in our work here But also with things like lead and cadmium in trying to understand How those work in both the pregnant woman and the child and One other charge you have is to consider possible similar health effects of phthalate alternatives That might be used specifically in what's been banned, which are the children's toys and child care articles I'll go over quickly what's been banned Just just to make sure everybody is clear about that and to tell you how your work might be relevant to our definitions The permanent ban bans children's toys used by children 12 and younger as well as Childcare articles which are specifically defined in the statute as a consumer product that's designed or intended for the manufacturer To facilitate sleep or the feeding of children age three or younger I like to summarize it as things that children can use to play To sleep or to eat. That's kind of a quick rule of thumb that we use We are going to be defining by role children's toy Childcare article to give some more clarity because we've got numerous questions on What's covered what's not covered by the statute? and Understanding some of the work you're doing on exposure mechanisms may be relevant in in in that determination For example You are going to be working on The interim ban phthalates and one option at the end of your work is to leave the ban in place Another option would be to remove the ban and in between those two extremes There may be other things that you would recommend to us Leave it in place for some products that can go into the mouth The interim ban only applies to those toys that can be placed in a child's mouth Or perhaps there are other types of products not just toys that go into a child's mouth That would be relevant for you to consider those are the kinds of things Your work will help inform us on I'll give you an example right now Children in the United States are all wearing these these little bands they they come out in a shape Like a fish or a star and then you can put it on your wrist Well, that's not a toy and they don't contain phthalates. They're made of silicone But you can see that that's a good example of a product that doesn't fit into our play sleep and eat Categories nicely. It's more of a novelty that you're wearing but it could easily go into the mouth and If the if they were to have contained phthalates, they might technically not fall into the definitions in the statute if you were to find that Phthalates shouldn't be in a product like that because the exposure in chewing on something like that Would create a risk that would be something that would inform the commission as they move forward way beyond your work To looking at other products One of the things that Is a particularly sensitive issue right now that the chairman wanted to make sure I talked to you about Was the concept of inaccessibility? So certain phthalates are used in The soft plastic that goes on the outside of wiring for example on a cord and We know that there are toys for example Let's just take a a baby doll a generic toy The baby doll is used by a young child It might have a foot or a hand that could go into the child's mouth If the baby doll can talk because inside of it There's a steel box with wiring that enables the doll to say mama or cry or whatever it's going to do the question is Should the phthalates inside of the doll that are not accessible And they're not even in the foot or the hand that's being chewed on by the child do those present a risk That's one extreme But we also know that there are things that a child can chew on That might also have an inex technically inaccessible part So for example, I've been told although I haven't seen it that a teething ring might have two layers the outer layer and the inner layer and If there were phthalates in the inner layer and the child was chewing on the teething ring, which is its intended use For hours a day those phthalates and the inner ring might present a risk And so you wouldn't want to have a rule about inaccessibility That might work well for the baby doll example But not work so well when we're talking about a teething ring where there might be an inaccessible layer That could present a risk In between those extremes, there are other examples for example mattresses mattress covers or the mattress itself for a baby's crib might have vinyl that could contain phthalates a Sheet might go over that so you could have a sheet and then you could have a plastic cover to protect the mattress and then a vinyl covering on the mattress itself and The plastic covering on the crib or the vinyl on the mattress could contain phthalates Are there any exposure risks from that? Is it inaccessible because of a sheet? if a baby lies on the crib for eight hours with the heat and Drooling and that kind of thing are there any risks there and so it you know when you think about our jurisdiction and All the different types of products and the different uses of phthalates in those products Your work will help inform us on making decisions On what we might recommend to Congress as to the scope of this this this law is very Prohibitary and it's a prohibition on the use of these phthalates at all Whether inaccessible or not and some debate that and certainly if we wanted to Exclude something that was inaccessible. We would need to have the scientific basis for doing that from our staff or from the chap and At that point the Commission could decide whether they felt they had the jurisdiction to do it themselves or go back and ask Congress to allow for an inaccessibility provision similar to something that we have in the lead portions of the CPSIA so that gives you a General sense of what we see some of the complexities of the legal issues in terms of the scope of the products that are covered by this It gives you a sense of how comprehensive we think Your work will be how it will interrelate to the work that we will be doing as a Commission The final thing Congress asks is that the work be done in a timely manner. They've given 18 months to the chap All I can say is you've gotten a lot more time than we've gotten to do a lot of other things in the CPSIA I think what's most important is we get it right and While the timing is there and is important to follow What's most important is to be working progressive in progressive hard work towards a goal To get this done correctly. So With that, I think I'll stop and take any questions you might have on The charge or some of the issues that I've raised any questions. I have one question and that is As far as the timing goes the language says 18 months to complete their examination and then six months For a final report In my mind those two steps tend to blurt together So I see it as a total of 24 months essentially. I mean is that not correct That's correct. I mean those statutes pretty clear that they want 18 months of hard study and then Not later than 180 days six months after completing the examination you're to Prepare a report to the Commission and I think everybody understands that in the writing of the report Oftentimes you have to take even a close and closer examination as you're trying to say things certain ways So I think we are all intending that the work will Continue through the writing of the report to a final and I don't see any reason why you can't start writing your report Sooner as well if if by writing it forces you to get issues Crystallized you can do that as well. And one thing that my kid made asked me to make sure I addressed It's a scopa de novo review You need to be looking at this Completely independently of the work that's been done by the Commission in the past That's not to say that you can't look at that work You can but they want you to look go back and look as all scientists do at the underlying studies that were part of the first report and Think of it anew don't feel constrained by any prior Determinations by us or prior chap you're to look at this Completely independently of that and and afresh that's an issue that several of us have discussed a The day de novo aspect The NRC published a report not long ago that was really comprehensive and and reviewed a lot of what not everything but a lot of what we're tasked with and And it seems to you know to plow that ground again doesn't really make sense They had experts looking at it. They wrote their report So what we would like to do is to build on that report What because that's only a Current I think through 2007 as I recall So what's new since then we would also look at the issues they address but In terms of the literature me it's it's huge and even having 18 months A lot of literature to go through and there are going to be some you know some very I Would think some contentious issues that we're going to have to deal with in terms of risk assessment as well, so Viewing everything that the NRC committee review doesn't to my mind make a whole lot of sense If we could build on what they have done Would facilitate our task tremendously and I think give us an opportunity to really address some of the other questions that that they did not How does how do you respond to that? Well first I'd want to see and hear what the comments are from the public on On that issue whether that's you know hear from both sides on the issue about that I do think that scientists tend to rely upon Official reviews of literature And give weight to certain organizations like the NRC And so in your normal work if you were doing this outside of the chap You would approach that document in a certain way And give it credence, but also give it critique. So That's one way to look at the document. I think you Want to look at the underlying sources that the NRC? Relyed upon, but I don't think you have to replow ground that as a scientist you would say these other scientists I I respect their work. I think the work is solid. I've critiqued it with my own lens as well as Looked at some of the underlying science I wouldn't go so far as to say that you don't that you can just start there and build upon I don't think that's what Congress had in mind when they said a de novo review but I do think all scientists look at reviews like that and Well, I heavily on them with with the appropriate scientific evaluation of them and I that would be my advice Issue that that Bern and I have talked about at some length is endpoints And clearly there there's Distribution of the amounts of data with respect to different endpoints. So the the developmental reproductive effects probably Have more literature to to speak to that endpoint than than the others And how far of feel are we to go in exploring? Because the endpoints are almost limitless that we could we could look at Although I think for many of them there probably isn't any information So I'm a little bit concerned about that to open-ended Look at all endpoints all health effects up Can you give a little more counsel on? how we might Define that world a little bit more specifically again, I think Congress expects you to be using scientific judgment and Looking at the endpoints with the same prism that you would in the universities and in your work as scientists that you would give so the developmental aspects deserve The important scrutiny because there's obviously much more science that's developed in more recent science that's developed on those issues Congress has asked you to consider and examine all of the potential health effects the full range, but they want you to do that with In exercising your own scientific judgment, and if there are some where there's no science You would give those less consideration Than those where there's considerable science that's been built up. So again, it's just a matter of Exercising I wouldn't say common sense but scientific common sense so to speak in Taking what are you know scant resources in terms of 18 months and trying to tackle this in the way that be most protective of children Yes, Chris. I don't have you have any questions I have a couple a couple of things one is Going back to the NRC report That was done Recently I think Less than two years ago. It was done specifically To describe methods for doing a cumulative risk assessment on phthalates It wasn't done by us. It was sponsored by EPA, but it was it Really tailor-made for our purposes So, you know, it's not just a review it's Tells you how to go about Doing such a thing Such an assessment, which is no simple task As far as the many endpoints go As we often do or typically do in a risk assessment and our seed did essentially the same thing they Looked at all the endpoints review at all of the data But in the end they focused on the developmental effects reproductive developmental effects And I guess my question is do we have to literally Do a quantitative risk assessment for multiple endpoints or is there some room for judgment where we weigh all the the endpoints and You know decide on which one is the most important to look at in more detail I want to emphasize how important it is that we're getting public input on these issues In a meeting like the one we're having today where you can hear from the range of Perspectives on that very question. I I would say that what's important What the what the statute is asking you to do is to complete an examination of the full range of phthalates on the full range of potential health effects, but as scientists you need to Put on your own filter to that to make certain that you are Looking at or the most likely scientific Endpoints that are going to harm children. I mean the most important thing to keep in mind in making those decisions is Congress wants to make sure that children are protected from exposures to these chemicals And so what are the endpoints that are going to? Be relevant when you're looking at things like the children's exposures pregnant women's exposures and other exposures that might be Causing these endpoints If at the end of your review Having considered all of that one particular endpoint Beeps out as being the most deserving of a quantitative look As opposed to two or three or four That would be fine, but I think it's too early to make decisions. We are just beginning your work as to how to How to do that? But over the course of this I think the science needs to drive it And that's really what the chap is all about having independent scientists Driving to a conclusion and and again I think you know relying on the NRC report with regard to making exposure assessment decisions is Good science. You're not going to reinvent the wheel. However, if in the course of that something Unique to our products and unique to children's exposures the malving whatever it is In the course of sleeping or eating that jumps out that was not Addressed by the NRC report bioavailability whatever that turned out to be and I'm not I'm not a scientist So I'm not saying what that would or wouldn't be then you have an obligation to To consider that and and take the NRC report to the next step It's really the way I would look at it. I guess I want one other question is there Are so many phthalates there are we've identified 29 in addition to the the six mentioned in the act There I mean they're more in existence. Those are the ones that Seem to be commercially important and we are well Gonna maybe hear some testimony on that today, but Again, given the large number of them. It's I don't think it's literally possible To look at all of them. I can do is tell you that the statute expects the commission to be looking at the exposures to the full range of phthalates that might be in the products that kids are in Exposed to in their environment in the home not just those that are in toys and Childcare articles but in the home generally as well. So I think you at least need to keep a broad open mind to What those exposures might be I also think Congress knew that they gave you 18 months and you can't be expected to You know tackle You know beyond what can be reasonably done in 18 to 24 months either So there's a tension there built in between the statutory deadlines and the comprehensive nature of what you've been asked to do because there I mean there's a little to me a little bit of ambiguity it talks about the full range of phthalates from all sources, but then they mentioned specific sources and And they talk about Let's see susceptibility In and so on, you know, they're focusing on children and the mothers and then other times They're talking about everyone. It's it's a little a bit ambiguous in places. I Know that one of the that the commissioners are very interested in knowing about Valid alternatives and the risks associated with them Taking one out. What else is going in and how do we? adjudicate the relative risks of the various substitutes so I would hope that no matter the number whether it's 29 or 35 that you're really focusing on commercial application and The likely substitutes so that we can know Again, we're trying to be most protective of the children and the last thing anyone wants to see happen is Something taken out but something more dangerous substituted in and that's why I think it's important to not Try to quantify we don't have to look at this you do have to look at this You need to keep a broad open mind because Dalit's alternatives. I'm assuming those are other types of Dalit's But I don't know that either. Yeah, well, I mean there are 29 other thalates not to mention the non-palate alternatives It's also I think clear from what you said though that when we filter all this in terms of all health effects So one health effect could be a Cancer endpoint with exposure to adults That that would be less under our purview as exposures that would result in Possible effects on children. Is that am I reading you correctly on that that we could say Yes, there may be an issue in terms of an exposure to an adult For this particular endpoint, but we're going to focus on exposures that children The examination is defined in the law to Require a complete examination of the full range of thalates that are used in products for children and Shall examine all the potential health effects Including endocrine disrupting effects of the full range of thalates There are several places where they talk about pregnant women But I think that the thrust of this chap was to focus on children uniquely and probably differently than the NRC report in in That's that's another one when it says the full range of thalates used in Children's products essentially That narrows the scope Considerably it does accept that it says consider the cumulative effect of the total exposure to thalates from both the children's products And from other sources Such as personal care products, and I don't think they were limiting that to those to just children's products I think they're asking you to look in the home and see the other things the shower curtains the What are those the Air fresheners those kinds of things that are adding to that exposure that you wouldn't really think to be Children's product. I'll give you one other example of since we're talking about this children's product issue one of the Issues that we have in food preparation for children there are products that are Uniquely marketed as baby food mills. So that would be a product that would grind the food up so that you could make baby food That might have a plastic dish where the grinding is occurring a questions come up In the comments on our rulemaking and in comments asking us what's covered Is there a risk of phthalates when you're milling, you know getting into the food? We look at the phthalates provision is talking about the total content of anything that Facilitates feeding FDA has jurisdiction over Migration of the phthalates into the food So it's one of these unique situations where both agencies have relevant authority There might also be phthalates in the cord that used to plug the food mill in and that would create a Completely different exposure scenario than the plastic that's actually touching the food as it's being ground up Those are the kinds of things we're wrestling with right now. It's whether that's the kind of product That's presenting a risk in how and so to extend your work can inform some of those decisions. It would be helpful Yes I have a question relating to this number seven the quantitation of risks or Consider the level at which there's a reasonable certainty of no harm to children and You you explained that and you offered kindly advice from the commission In terms of dealing with Those assessment factors or uncertainty factors. My question is this this would tie the panel into a specific approach to Deciding on on levels of harm which has come and Scrutiny or criticism lately I'm referring to the nrc report science and decision where they And Developed on the problems of this bright red line philosophy, which which is inherent in using Uncertainty factors my question is this how Tightly are we bound to this specific way of Quantitating risks or defining levels of no harm I'm asking this because for example, this nrc report science and decision Advocates a different approach depending on the context of the questions that are asked for example Under certain circumstances Instead of saying here's a bright red line risks can be described in terms of Probabilities So my question is how I mean does that provision here not To what way does it tie it tires in to using a Specific approach which has come under pretty stiff recent criticism I'm going to take that question under advisement. It's a good one It's not one that I want to answer just from a legal perspective without talking to some of our scientists But I see the point and I've read the Green book there and so Let me circle back and maybe tomorrow we can find a time to squeeze me and then we'll come back and talk about that in more detail Any other questions? All right. I think we should then start Presentations Oh, we've still got time I guess we've we've scheduled a break Actually, yeah, because the first panel discussion doesn't start until 10 according to the Well, we can take a break That's probably a good idea to start a little bit early because I think we're going to need all the time Okay, so we'll take a 15 minute break and Back at quarter to 10 if we could have The second panel come up and take a seat Um, oh, yeah is is jim Okay We'll just get it we'll get them in Thank you And I on this panel We have dr Rainer otter from basf in germany and dr mark Holt from easman chemical company And dr otter would you like to begin? Ladies and gentlemen, I would first like to thank the organizers for inviting me to give the presentation here We have already sent in written comments on those products where we found or thought that you would be eligible for commenting Because these are all products that we are producing I'm now concentrating on two products and in my talk I specifically will concentrate on three main topics of interest The first is the understanding of data ownership Because I think we should make you aware of that issue Then there is some discussion on the availability and validity of the data that I have seen especially in the part provided by the consultant There needs to be some clarification in my view And then I will elaborate a little bit more on the database of hexamal dinge and the diapropyl heptyl phthalate you have published in the federal register That you would like to have this panel working as transparent as possible and therefore Any information that you get is supposed to get to the public record There is another sentence in that you are Not happy with summaries from toxicological studies prepared by manufacturers as substitutes for the full study reports And now here comes the issue that I think you were not aware when you wrote down that part on the reach Any producer or importer that has a study Has a data protection for 12 years As long as this whole study report is not made publicly available elsewhere In that case that you put up the stuff on the internet third party Would be eligible to just put together a robust study summary only has to comply with copyright issues and could then bypass the data compensation issue So what we need here is a decision from your side how this can be reconciled of this data ownership issues I think that is not only affecting european producers that is affecting any producer Also american producers And that is a very serious issue Then in the report on the substitutes I saw a strange table Indicating data availability based on tox line citations And in my view this gives the totally false and wrong impression that Those alternatives that are already in use wouldn't have the right database um A proof of that is that The consultant and his data mining strategy Failed to Get the whole nicknows evaluation report of the australian competent authority He did a hell of a lot of work To pin down OECD guideline Requirements, however It was unnecessary the whole study report Robust study summaries Including our commands including the commands from the command and authority Are published in the internet and I have provided to you the link Then we have an issue of peer reviewed journals versus industry data summaries And i'm now coming back to the second part that you would like to see Not so much the manufacturers Data compilations, however In the epa hpv program in the ocd hpv program and in reach All the study summaries Are done by industry By those people very often that have done the studies and Under reach we have two articles article 119 120 that regulate the data Exchange between competent authorities of the member states and of other regions We are supposed to put in robust study summaries and robust and study summaries to echo And whatever they get They will hand over to another competent authority provided data protection claims Are respected And here you have again the problem with conflicting legislation um In regard to these study reports, we just would stress that all the labs Involved they are doing this on the good laboratory practice. They are regularly inspected and the test facilities are On regular independent reviews. So I think there is no reason to Yeah, put doubt on these data With regard to hexamoltinge There is a very broad and solid database available with regard to physical chemical data ecotoxic and toxicological data The original study reports have already been Evaluated I have to say around the world from Several tens of toxicologists in competent authorities During the notification process in Germany in the Netherlands And from the european Senia the scientific committee for newly identified and emerging health risks Here I think was a misunderstanding of the consultant putting together the data evaluation of the alternatives because I was reading here that Study summaries were there that were lacking essential information That is not the case That was all written by senia And they have got under a nondisclosure and confidentiality statement all our original reports and that is what they have concluded So it's just what they wanted to publish um, as I said the database was also evaluated by switzerland by australia Where the reports are available the canadian competent authorities have had the data and the us nsf In a nutshell and in brief There is no genotoxicity It's not a reproductive toxicant What I had to read in the report from the consultant is that he criticized The foster protocol as being a non-oacd study I think tomorrow morning there will be paul foster here and probably he will explain What are the details of that study? Um, we have a full generation study two generation study available on that product And when I prepared for that meeting here, I had to see that Another presentation will be showing here that on dinge we would have Change in unigenital distance This is Only part of the truth This comes when you are not You have no direct access to the data However, what we have provided to you there is the whole story is included It was a reduction In both in males and in females And this was related to body weight And we couldn't find the same effect in the two generation study Then um For that compound We have the Teratogenicity study in rats and in rabbits Um, and we couldn't find any developmental toxicity there Also in another presentation that you will hear today There is an indication that hexamalding has caused thyroid adenomas It's indicated possibly Non-specific or not relevant. It is not relevant And this is based on the fact that we have identified the mechanism which is enzyme introduction with an increase In t3 t4 turnover and elimination This is based on epa and ayak documents and has been accepted by several component authorities around the world For this two propyl heptyl phthalate the dphp Again, it's not genotoxic We have an oasd 414 in the rat for that compound And as you can see we have covered the critical window Paul Foster has published several Um Stuff on on these things on the critical window on phthalates. This is covered in that study here. It is a study by oral gavash Again, I had to read in another presentation that you see in a couple of minutes probably That there would have been Yeah Early resorptions these early resorptions Are clearly indicated also in what you have seen And but we present it as roba study summaries to you These are related to maternal toxicity. Why is that? Because we have already a significant reduction in the early pregnancy And so it's not the case that at the end of the whole story 10 times 3 grams are missing. It's already at the beginning and at the end we had a 30 percent reduction It comes from three dams that essentially produced no liable pops But we have dealt with that and you have it in the Data that we provided to you further to that there is also a full two generation study available According to osd 416 Including an agenda distance on a gentle index. There is no effect on that Again, it's a proxies on proliferator like most of the phthalates are This was a question that We have been made aware of by the european commission that you have approached them with regard to issue is Depropyl heptyl phthalate just an other d isodesyl phthalate The clear answer is no Why is that? A production process is completely different b Last year my colleagues have shown you a chromatogram where dphp cochromatographed with dinp with a c9 Here i'm showing you um A gzms where we spiked In the lower graph A depropyl heptyl phthalate Sorry You can clearly separate it so this Has been also the decision of the EU and The formal stuff is there was a risk assessment on d isodesyl phthalate And depropyl heptyl phthalate was not included because it's different substance Opposite to that in case of the dinps The two different dinp species were lumped together Despite the fact that the production process is a little bit different, but they are too close so then there was mentioning of The fact that dinge is new in the market and lacks essential toxicological and Exposure information for the tox part. I think I've clarified the issue. That's not the case. That's because of the yeah missing Consequent data mining strategy of the consultants and I understood that They have said september 2008. They just missed the critical documents that came out later on Yeah, so that's I think this is an issue that can be resolved very quickly With regard to the fact that human biomonitoring data are missing or exposure data are missing. Yes, that is normal for new and innovative products However, we will take care of that There is a program within the German environmental protection agency in cooperation with the german chemical producers association In the next couple of months, we will develop and provide to the german epa With a reasonable documentation the human biomonitoring methods for detection of dphp and hexamal dinge metabolites in urine and so I think So far as I have heard from the discussions, they are already interested in measuring on their database So I can only say this is just a matter of time to get the data the exposure data The other thing is that I want to mention here that The dutch competent authorities they have already made a market survey and like the austrian the swiss and the germans they have realized that The hexamal dinge is used already in roughly 60 percent of the toys for children and therefore they focused on looking for real migration data They took the head over heels method developed at the joint research center, and it's I think already the world standard in the meantime and the migration report from hexamal dinge and other plasticizers used in toys is published and I have sent a copy to Mike Barbish so that you can have a look on these data And that is I think all what I wanted to concentrate on any questions well, let me Let me start by commenting on the The versar report your Uh In the the table where they listed the toxeline hits was toxeline hits versus probability to get it in toys And that was a preliminary screen. So that was not meant to be the final answer That was the screening process for selecting which ones to look at at Uh in more detail Let me see Mike may I just comment on on that thing here? I think you see that The the public Is respecting the work you are doing so Everybody is interested in what you do. So the published stuff was out And we were approached by some customers whether this means that There are questions Because it gives in my view the false impression that toxeline hits Would say anything about the safety of the substance and by the x-axis Where you say the probability goes higher Based on this toxeline score And based on this data protection issues, of course, you can't win that game. Yeah So the the key issue in in in my view is how can we reconcile that and how can we support your valuable work? with help Or comments that on questions that you have based on the data compilations that we already have provided Yeah, and I guess I understand that reach gives you protection Um Because you're your data you have a significant investment in in these data But that is in a sense, uh, uh, I guess that was a something a decision you made You had to submit those data to reach in order to presumably manufacturer Dinch in uh in europe but Here Where reach does not apply. I'm wondering what Would be the consequences if you were to release Some of those studies to the public Um, Mike that is that is exactly the issue when we would provide the study reports to you Which we still can do provided That you can guarantee The confidentiality of the full study reports and data protection for the full study reports Because in that case where you post it in the internet Then reach says this is a publicly available study And any third party can just write down an own robust study summary That is at least the interpretation of our lawyers And also the sapphic our lawyers Would go, um here in the same way So in that case where you have that full study report available on the internet You might run into problems. We have the same issues For example with the biocide regulations in europe Where you get study Ownership protection in the biocide Directives and if these studies would then be used under reach and also would go public They would lose their thing. It's a I think an essential thing That also would apply to a u.s. Company If they would provide you study reports in the best shape for transparency, you would put them up And they have lost their money And that's I think what you did not mean to do Well, I I I guess My question is you it's the What you would lose is the investment in your studies In perhaps Market share Would you be breaking any laws under reach if you were to make those data public? No, definitely not and You also could probably work Based on the published robust study summaries That an independent competent authority the australians did Because they are here In that way that they take the report They keep them confidential, but they do their own Study summaries and they post them in the internet And we have provided you also this link right so if That would be Okay for you The way to deal with the issue you could work on that one And if there are detailed questions, and I'm pretty sure the toxicologists know Where to ask when they need some information, we would be happy to support you there It's just a matter of data protection And we do have the the actual well, we have the the robust summaries you have them. Yes Yes, I appreciate your concerns about data ownership That's that's only understandable on the other hand, you know the charge We are supposed to make judgments about alternative products to the best Of the science that's currently available and you pointed out yourself. That's a that's a serious conflict. So If we ask the panel don't Get those data to look at That could be done either confidentially or not, but if they're not available to us the only Course of action open to us is to say we cannot properly investigate DINCH as an alternative Yep the I think that as you said And you said a very important thing that you might Be in a position that you can treat a full study reports in a confidential manner If that is the case that should be not a problem We just want to avoid that the full study report For example a two generation study with more than 1000 pages is going up to the internet And it's not a problem of the robust study summaries that you will then do as you can see Lignas has done that The dutch guys have done it. We have provided you study reports and when you would apply Or when you would just wait until dissemination of data You would get the same study summaries from the EU Because that is foreseen on the reach that after a certain time The full registration files will be might publicly available So if there is a way forward we are happy to assist you well, I you know, I think For I can't speak for the panel, but it's it's the issue of transparency and and and whether The studies that the chap reviews are available to public scrutiny They would have to be available to the public not necessarily Posted on the internet, but they would have to be available As far as the cpsc staff is concerned It's it's clear we Would want the data to be public The panel has expressed that sentiment at the last meeting But again, it's it's How to proceed is uh, I think their decision man Okay I only can offer that we are open for that Uh, we can hand over the full study reports for your review Provided we get some data protection And then you are coming up with robot study summaries That's not the problem but I hope you appreciate our dilemma If if these data are not made available one by all the other and I'm not sure about the implications Of them being made available to us confidentially. I have to take advice from uh, dr. Babbage But it's very easy very simple. We cannot evaluate the Harmlessness let me put it this way of dinge in any way But there's one you could help us out. You could help us if you are so certain about Dinge and that there's no harm. Why don't you publish in the peer reviewed scientific literature and then everyone's happy That is the problem at the moment of the workload that we have with reach sorry for that Uh, we have to meet the deadline for several hundred other products And you need some time Because the thing that you address here is the published the the published journals What do you get in the published journal? Because these are journals that you take and also for other Plasticizers you have given reference to niggas The niggas report already is available With all the summaries I'm sorry, uh, bisf is the world's biggest chemical company I'm sure you have the resources if you want to to publish that in the scientific peer reviewed literature We are working on that but uh, you need it very quickly and so There might be a conflict of timing Because we have heard this morning Yeah But in the 18 months we have still six months to go for reach For several hundred of other products But we will consider that That's if that is the only way The other way I have already Designed for you because you have used for other products the niggas evaluations And you have got study summaries And if you have specific questions where you want to have more details No problem We even could come And discuss with you or the Consultants these specific questions Um, the only thing is that we have to to sort out the issue of the whole data protection And that's for every company involved So that's our dilemma at the moment Yep Well, you know, you mentioned that uh, I was at the netherlands or in europe where 60 percent of the toys have dinge And I think that's probably true here as well So, uh, you know, it's it's It's literally going into kids mouths and you know, we we don't have the day the full studies yet Yeah, but but the netherlands they have already Uh done that independent review and they have had access to the full study reports The scientific committee of the u they have signed a nondisclosure agreement They have had access to the whole study reports The australian combatant authorities had the same The swiss combatant authority the canadiens already Have to study reports evaluated I mean, this this is a little bit different because we're not talking about a registration Process we're talking about a a major risk assessment that will be That will have broad implications And I think it's a very different situation. Um, you know, you mentioned some of the other programs HPV program, for example, it's it's a purely voluntary program. So That makes sense that The robust summaries would be uh, uh, the primary means of submitting data But you you have seen that Um, a the combatant authorities in europe on this, um Meeting in berlin already address the upcoming alternatives. They do their own Evaluations they do that because they have the data in-house and they do their own exposure Measurements by doing own and independent migration studies for lots of plus decisors and I think you can profit from these guys because There should be a clear exchange under the Parties and I am pretty sure that when you as the Jab of the cpsc would approach a combatant authority in europe that you would get At least what they have compiled This is the german government. It's the german environmental protection agency and the german federal institute for risk assessment the bfr Okay And we can Provide you also with the details of the persons involved sure But but it would be good to have a bit more cooperation from you in these matters I'd like to highlight to you our dilemma with your robust summaries Which we studied carefully already On page 113 of the red dinge robust summary. There's a table Giving data about carcinogenicity and the table is cut off In the higher dose range for the females at least in the pdf version i have so we cannot We cannot even properly evaluate the robust summary Concerning the reproductive toxicity in the same robust summary It is a little unclear to me whether The studies you mentioned this morning Were carried out changes in anal genital distance et cetera et cetera the As far as is obvious to me, you did a reproductive toxicity study mainly looking at limb malformations et cetera et cetera and there were no effects But in this robust summary, I cannot find any data that hint at what you mentioned this morning about changes in anal genital distance These are the end points that are really relevant. I have found these hints They are in oh, maybe I should get new glasses and no no no it's not a matter of glasses probably it What you Describe to me That tables Are cut on the the edge. That's right. That is very often the problem of different printer settings I'm sorry for that. That's the stupidity of the pdf files. I know but you see our dilemma We can't even properly examine your robust. No problem at all. We will provide you In these tables in a form that you really have all And It's already published. Sorry for hammering on that by the niggas They have the whole incidence tables In the internet, but we will provide you the corrected version Okay, can I just carry on with with another detail? You mentioned the foster protocol In your presentation dr. Otter and what you have found you say you found changes in anal genital distance Reductions in both males and females Okay at 1000 milligram per kilogram in both sexes Yeah, um, did you look at changes in nipple retention? That was exactly the reason why we discarded that because a Anal genital distance and genital index is dependent on body weight and second volume Propusal separation all the other parameters none of them was affected It was just this so nip retained nipples was also not affected. Nothing. Nothing The weight of Sex accessory glance did you look at that? Yes, not affected. I did not affect it at all and it is also contained in the study summaries that we have provided and Sorry, let me that at this This laboratory and you can find the citation for example in the c er hr Is very much experienced in anal genital distance and anal genital index measurements because it's not an easy task and They know how to deal with the issue and we have addressed that again in the two-chain Where we couldn't see anything The question I have actually is of a different direction, but you had mentioned about developing um Methods for the germany pa for biomonitoring. Yes for dinge. Could you tell us more about that and Is it for specific metabolites? Yes Russ, it's um pretty clear This project will address the dinge metabolites and Also the dphp metabolites we do it for both Because we see that these products are more and more coming into use And therefore we wanted to provide clear facts to Be able to respond um currently the metabolites are synthesized They have D4 labeling and we Are developing the methods in the next couple of months And then I think we will also go for this conversion factor study type So somebody and most probably myself we will swallow the stuff And have some urinary metabolites detected And so we can then go from the urinary level to a back calculation To the external dose We have within the european council of plasticis and intermediates done exactly such a study with Establishment of conversion factors for 10 males and 10 females Which roughly Yeah, confirm the results Published by holger and by jürgen holger koch in jürgen angler It's the same a ballpark of percentage of those that arrives in the urine What we could see is no difference between the 10 males and the 10 females and no age difference Which was quite interesting and I'm pretty sure that it will be in a couple of months in the position to Provide the same robust conversion factors for these chemicals And at the moment we are currently in the stage of synthesizing for the dphp. It's just Contracted last week for the dinge the metabolites are Nearly completed and we are about to start And it's both in urine. That's the primary focus The primary focus is there because the german environmental protection agency They want first of all to screen and marike kulesagering probably you have heard some presentations from her or will put it in their Presentations, they would like to screen their environmental Biological database that they have From human specimen in the refrigerator and they want to screen them whether it's important based on Concentration based on prevalence And that things That is the project Sounds like within a few months some of this information will be available At least until end of the year Is the target to have the methods established then we have to Hand over the method to the uber guys We will also hand over The method how you produce the standards and we will indicate where the standards can be ordered from So that they are equipped and there will also be some In the laboratory some small not not a full-round dropping but you have to transfer the method to another independent Laboratory and this help will also be given The data will come in And not only for the insurance or for tphp Okay, thank you I think we'll Move on to the next presentation dr. Holt Thank you My name is mark Holt and I represent eastman chemical company Eastman chemical companies here is both the producer of several phthalate plasticizers that the chap is Uh considering but also as a producer of eastman 168, which is die to ethylhexyl terephthalate Which is being considered as a phthalate alternative We're also a member of the phthalate ester panel of the american chemical council and representatives of the Phthalate ester panel. I think you're going to be making some presentations later on today I'm just going to be speaking about these alternatives this morning die to ethylhexyl terephthalate deht But sometimes also abbreviated as dotp has been around for approximately 40 years Despite the word phthalate in the name deht is is not a considered a phthalate ester Deht and in fact, all terephthalate plasticizers are based on terephthalic acid Which is one for benzene die carboxylic acid and not one to benzene die carboxylic acid Which is the building block for phthalate plasticizers Uh this simple distinction which may seem trivial is actually uh important for several physical properties of terephthalate plasticizers For example deht is significantly less volatile than d o t p or sorry than uh deht Uh, it's approximately as as volatile as dinp. So a higher molecular weight phthalate It's also approximately 10 times less soluble than deht These properties are important when considering exposure via for example indoor air processing or direct contact The metabolism of deht is also different from deht and other phthalate plasticizers Many studies have shown that deht readily breaks down to terephthalic acid and two ethylhexanol with very little mono two ethylhexyl terephthalate being formed So we get complete breakdown from the plasticizer to terephthalic acid and and alcohol Uh url gray has studied the metabolism of of phthalates and uh concluded in one of his Reports in order for a phthalate ester to be metabolized to an active mono ester The ester groups must be in the ortho position D o t p remember that's another name for uh deht Which is isomeric with deht but reportedly not metabolized to mehp mono ethylhexyl phthalate Uh was inactive in the current study And that that result we see over and over again Deht exhibits in metabolism studies complete and rapid breakdown into terephthalic acid and two ethylhexanol Uh terephthalic acid has a wealth of toxicological data. It's a key component of pet Which is a common plastic used in water bottles like you have on the table there So that's the t in in pet Uh terephthalate plasticizers don't exhibit reprotox concerns endocrine disruption nor modulation Paroxysm proliferation nor carcinogenicity concerns Uh despite many comments that alternatives to phthalate plasticizers do not have adequate data to support their use Deht has a complete toxicological data set including acute toxicity genotoxicity Repet exposure Developmental tox reprotox carcinogenicity And in all these studies you can note the very high no observed at adverse effect levels So I think this is one of the things that's been mentioned over and over again Is that alternatives to phthalates don't have complete data sets and there certainly are alternatives to phthalates that have complete data sets All of this data is available in published and peer reviewed manuscripts that have been submitted to the chat We do have some specific comments on the cpsc document review and exposure Review of exposure and toxicity data for phthalate substitutes The document states on page 12 That the bioconcentration factor of deht is 1.4 million Um And in the summary on page 68 it states that based on an estimated bcf of 1,400,000 deht should bioconcentrate in aquatic organisms However, deht which is structurally similar to deht has a measured bcf of only 637 Eastman has measured the bcf of deht And measured it as 393 In addition, there's a report by turi The lag of the reference where they report a bcf of 25 for deht So we would just like this correction to be noted In the same document on page 60 it states that deht has been shown to be a sensitizer in guinea pigs The particular study cited was deemed invalid in the context of the oecd review Furthermore, no evidence of sensitization was seen in two subsequent studies on guinea pigs and on a human patch study And these these reports have also been submitted So we just like this correction to be noted We'd also like to point out an additional report on the differences in the metabolism of deht Here again abbreviated dotp when compared to a variety of phthalate plasticizers The table shows the estimated potencies Describe the potential of each phthalate to disrupt testicular function and or produce malformations in male rat offspring And here we again see dotp or deht showing no activity So in conclusion, uh eastman 168 deht is a well-studied material with a robust set of data All the data are published and were peer reviewed by countries participating in the oecd sids program phthalate esters have little or no potential to form an active mono ester phthalate esters demonstrate rapid and almost complete metabolic hydrolysis back to phthalic acid and the corresponding alcohol They do not possess the same toxicological issues as ortho phthalate esters I have a couple of comments about some regulatory clearances and approvals around the world Die ethylhexyl terephthalate has a food contact notification FCN 770 which comprises a quite a long list of typical food contact notifications for use in Adhesives and pressure sensitive adhesives gaskets A variety of applications for food contact Also is listed under the european food safety authority under ec 975 2009 You've heard a lot about this report In the last couple of minutes Deht the dutch rivm in their in their risk assessment of non phthalate plasticizers and toys measured the migration of several non phthalate plasticizers from toys The low migration of deht is in accordance with the low migration recently reported by the cpsc report Ann is in both studies the lowest migration of any alternative So here's the deht So we see that uh in addition to having uh Low hazard potential exposure for deht is is significantly lower than some other alternatives The rivm also calculated margins of safety for deht And so for example the margin of safety For exposure due to mouthing is seven thousand three hundred and twelve thousand for exposure due to dermal contact The report's conclusion was that the calculated margins of safety for deht and dinch are very high leading to the conclusion that these compounds are not expected to pose any health risk For toy users at the migrated levels And again, I would point out that the extraction levels that Were measured here are very very similar to the ones that are measured by the cpsc in the in the recent cpsc report Deht has recently been commercialized in medical devices in the eu It was based on a thorough risk assessment by an independent toxicologist Very low extraction was demonstrated in use And of course the final medical device was tested And this this these products are commercially available in in europe right now And in the u.s. A drug master file for for easement 168 is available and uh, it's being referenced by various medical device manufacturers Who are testing uh, easement 168 for use in medical devices One other comment, uh, I know we had a Small discussion this morning about the amount of work that you have to do And I hate to point out that there is another alternative to the highlights that's available out there And that is benzoate esters There's a variety of them. So it's it's a it's a class of compounds. There's a variety of them commercially available They've been reviewed by kawi for for ecca And they focused on on them as a replacement for bbp dbp and dehp And they recommended specifically di propylene glycol di benzoate as a replacement for either bbp or dbp in their study I will be submitting Significant amount of data to the chap on these particular compounds Thank you for your time Thank you questions Yes, you you didn't mention txib Which is a I understand not used by itself as a plasticizer But it's used in combination with others, but we do see it In in toys, um Can you tell us about the the database on txib in in what might be available there? I'm not a toxicologist and I don't have all of our data In my mind right now the list of data the database is not as robust as eastman 168 Although we have a quite large database Txib is not used as a plasticizer per se It's used in plasticols to lower the viscosity of the plastic. It has some plasticizing ability So you're correct. It's never used on its own. It's also generally used at Very low levels compared to a normal plasticizer where a normal plasticizer might be used at 30 or 40 percent in a toy Txib might be down at 5 percent so A lot of the studies Where people have looked at txib they don't take into account the use level being significantly lower than a typical plasticizer So, uh, we will submit data on txib It's it's uh For its typical uses it's been a sufficient dataset, but we probably need to fill in some holes now given the given the kind of Uses that people are looking at It's a kind of a general question When you when you do your studies you're saying you're submitting these data Do you ever look at these chemicals together in your studies or do you do them one at a time? What we do them one at a time because for all the agencies that Ask for it. That's the way they ask for the specific studies The old idea of doing mixtures is For the chemical companies in particular a new a new question It's the same line of questions in terms of biomonitoring. So, um, You know i'm out of chemists, but looking at the Metabolites they seem very non-specific. So Would there be methodologies available to monitor human exposure? Or or no We haven't looked at that Generally speaking and again, I'm not a toxicologist But metabolites that i'm aware of that people look at for orthothalates are Oxidized mono esters as a as a common metabolite to look at Since with deht you don't form mono ester You tend to find that the material breaks down to tpa and the alcohols. So Again tpa has a terephthalic acid has a has a lot of data on it in Just in general because of its use in In plastics and two ethylhexanol as well. So When you say when you say it has a lot of data in general do you mean Data in humans biomonitoring or do you mean toxicity toxicity data biomonitoring? I don't I don't know that there's any been any biomonitoring at any of the alternatives yet because it's a fairly new area Okay, thanks Good morning. My name is Sarah Jansen. I'm a physician uh board certified and occupational and environmental medicine I'm also trained as a reproductive biologist And my comments to you this morning are From the natural resources defense council where I serve as a senior scientist and focus on endocrine disrupting chemicals and consumer products NRDC has been closely watching this process and I Viewed your first meeting over the web. So my comments to you are largely based on Responses to some of the things that you were discussing at that meeting as well as some of the concerns and interests that we have as you go through this process so an overview of what I'm going to talk about today And I'll make sure that you all get copies of this presentation. I apologize. You don't have them in your binders are They're relatively brief. I'm going to talk about the standard reasonable certainty of no harm A little bit of a discussion and I know you have some experts coming tomorrow to talk about peroxis and proliferation our list of phthalates of concern and then Just a mention of what many of you on the panel already know about the nas report so The reasonable certainty of no harm standard was actually defined in the food quality protection act in 1996 And this amended how us e pa evaluates and regulates pesticides It established a new standard for safety for tolerance of these chemicals in or on residues of food and Um, it was the intent of congress at least as I listened to congress when they put together the CSPA that the same standard would apply for looking at the use of phthalates and children's products and in that standard, which is denoted by the legislative history, which I'll also supply to the panel if you don't already have it From the energy and commerce committee report These are direct quotes from that committee report That safe means that there is a reasonable certainty of no harm That will result from the aggregate exposure in this case. The discussion was about pesticide chemical residues but you could apply that to phthalates and second that aggregate exposure to the pesticide chemical residue includes Dietary exposures under all tolerances And exposure from other non occupational sources as well, which is consistent with the standard that you guys have all been charged with using And then the the language goes on to discuss both threshold and non threshold effects. I've pulled out the quote for the non threshold effects here because As you're also going to hear later on in your discussions of the meeting The nas has recommended in risk assessment that we no longer assume threshold effects Unless there is evidence to support that so for the non threshold effects The standard is if there is any increase in lifetime risk based on quantitative risk assessment Using conservative assumptions will be no greater than negligible And then this next paragraph defines what negligible is and that essentially comes down to epa's Interpretation that a negligible risk is no no more than one in a million lifetime risk so The committee report ended by saying that the statutory language was not set in stone that is risk assessment methodologies progress That epa could amend them But that they should be at least equally protective of public health And so then my own comments here at the bottom are is that this really sets a pretty high bar For a level of confidence that the exposure is going to be safe in all populations As well as Reiterates that you must consider exposures from multiple sources Moving on to proxies and proliferation. I am by far No means a proxies and proliferation expert, but I In listening to your discussions at the last chat meeting it seemed that there was A tendency to dismiss some of the Study findings from proxies and proliferation because it was thought that perhaps that mechanism is not relevant in humans And I just wanted to bring up and I know that you're probably going to discuss this in more detail later that there is emerging scientific evidence that epa Is probably a little bit more complicated than just a single mechanism that there's actually no single hallmark event But a combination of Molecular single signals and multiple pathways that contribute to the formation of tumors, especially in the liver And based on this emerging Science iARC the international agency for research on cancer which has previously downgraded The carcinogenic carcinogenicity level of dehp is going to be reevaluating The carcinogenic carcinogenicity of this chemical this fall Based on evidence of p-par in alpha independent mechanisms And Um, I thought it would also be helpful for you all to review some of the recent nas report recommendations Which discuss proxies and proliferation and these are quotes with the reports referenced after each of them The first is that there is evidence that hepatic testicular and pancreatic cancers are associated with phthalate exposures quote May be mediated by mechanisms independent of p-par alpha and quote And the second from science and decisions Which are also which you're going to hear about later in your meeting Was that it calls into question concluding Conclusions regarding dehp's carcinogenic risk to humans And finally from the tetrachloroethylene report, which just was published in 2010 Important knowledge gaps remain to be addressed The committee is not yet convinced of the proof of the hypothesis that p-par alpha Modes of action is the sole mode of action and that it's premature to draw definitive conclusions Regarding the relevance of p-par alpha modes of action to human hepato carcinogenesis hepato carcinogenesis So, uh, that's all to say that, um As you're deliberating the different health effects associated with phthalates that I think you Need to consider liver toxicity, especially in light of these p-par alpha independent mechanisms Which have been identified in the literature as well as some human epidemiological Literature as well as non-human primate literature. So these are just a couple of studies The first is a relatively old study from the 1980s which found persistent changes with IV exposure to dehp And we're continuing to see evidence of liver toxicity, especially in Infants in the neonatal intensive care units who are exposed to dehp From medical devices. So there was a study published last year which demonstrated that Infants in the neonatal intensive care unit developed cholestasis after use of dehp containing medical devices And when the hospital switched out to dehp free the incidence of cholestasis dropped dramatically And then a second study looking at the incidence of hepatoblastoma, which is a very rare but aggressive and malignant tumor in infants, which also was associated with the use of dehp in medical devices And then I wanted to turn to p-par gamma, which is another Paroxysm proliferation Motive action, which has been shown to be activated by phthalates P-par gamma is very important and adipogenesis and adipocyte differentiation endocrine disruptors have been shown to activate this form of paroxysm proliferation And in particular the tributyltins where it's been shown to increase fat mass in rodent studies And this was shown after a single or perhaps even just a small episodic exposure Which resulted in permanent changes in the way that the adipocytes differentiated Phthalates have also been shown to activate p-par gamma And there's recently been some Epidemiological studies published Linking phthalates, especially the metabolites of beetle benzyl phthalate And dehp with increased waist circumference and insulin resistance in men, and this is from Shauna Swan's group, and I know that she's going to be speaking with you tomorrow as well So hopefully she'll talk about this in a little more depth This is a list of phthalates in addition to the six that You all are considering That i've identified as being of concern for their developmental or reproductive toxicity Which have been published either by an authoritative body or in the peer-reviewed literature In particular diisobutyl phthalate Is a replacement for dibutyl phthalate and if you look at the latest and hanes human bio monitoring You'll note that most of the phthalates have either plateaued in levels of exposure or are starting to decline With the exception of diisobutyl phthalate where levels seem to be Rising slightly which indicates that perhaps this phthalate is increasingly being used As a replacement for some of the other phthalates and I want to tell us to talk about sources of exposure In 2007 NRDC went to our local drug store and bought 14 air fresheners Sent them to a lab That is EPA certified and had them tested for phthalates We tested for about A dozen different phthalates and i'll supply the full report and methodology to the committee but in general there were eight aerosols five Freestanding continuous emitting liquids and one solid that sat on like a desktop The majority of them 12 were found to contain Phthalates none of them of course were on the label and a couple of them were even labeled as being unscented or all natural products um The concentrations varied widely from 0.1 parts per million to 7,300 parts per million Three of the samples contained greater than a hundred parts per million and over half of them had more than two phthalates Most of the phthalates that we found were either dbp dehp dibp or dmp P But we also found in a single sample di isohexyl phthalate so um We know that there's a wide range of of different types of exposure to phthalates in addition to toys fragrances Including the air fresheners building materials, especially vinyl flooring food and food packaging automobile interiors artificial leather printing inks paints adhesives Garden hoses, which is especially relevant I think in the summertime as people are drinking water out of the hose in the hot weather um shower curtains medical devices and pharmaceuticals But unfortunately, we don't have the information about which types of phthalates are used in which types of products And so I think it would be really great as we're hearing our Talks from the industry representatives today if they could give us some more information about where Phthalates are being used in these different types of consumer products And then I wanted to end um with an urge for the committee to have one of your own members who sat on this nas report Give a summary of of this report The cumulative phthalates and cumulative risk assessment, which is published at the end of 2008 Several of the chat members sat on this committee They made some very strong recommendations for how a cumulative risk assessment for phthalates should be done And made the conclusion that a cumulative risk assessment based on common adverse outcomes is feasible and a physiologically relevant approach for the evaluation of the Multiplicity of human exposures and directly reflects in this case epa's mission to protect public health I would argue it also directly reflects cpsc's mission to protect the public health So um in conclusion congress has set a pretty high bar and a pretty ambitious agenda for this panel But we also feel that by using the standard of reasonable certainty of no harm that this Is a high bar for confidence in the conclusions of safety about the use of phthalates It's important that you fully consider the range of different health endpoints associated with phthalate exposure Not just the male reproductive health outcomes, but also female reproductive health outcomes liver toxicity effects on the breast adipose tissue and metabolism as well as the cumulative and aggregate exposures to different Types of phthalates and the sensitivity to vulnerable populations. So thank you for your attention. Thank you for being flexible in your scheduling for those of us who can't control when our flights land and I'll be happy to take any comments or questions Any questions the definition of a level of where there's reasonable certainty of no harm is Comes from the fqba Is that different or how does that differ from a reference dose or an acceptable daily intake? um Well, I'm not a risk assessor. So there are probably people here who could explain that better than I but um A reference dose is based on a risk assessment methodology and For cancer effects typically has represented a one in a million lifetime risk of exposure And then a reference concentration has to do with air Our inhalation exposures an acceptable daily intake is calculated somewhat differently I'm more familiar with fda using that Reference standard, which is based more on a margin of safety but in in uh in the fqba, they also stipulate that The safety factors should account for extrapolation from animal studies to humans as well as Vulnerable populations such as children infants and um pregnant women and you mentioned breast Tissue could you uh clarify that a little bit? Uh, well, my colleague here from the breast cancer fund is going to be speaking next and talk about some of the studies Where phthalates have been shown to um Interact with breast tissue Yeah Do you want me to um eject this discord? Do you want to save it on the computer up here? I can leave it until the panel's done. Yeah, that might be helpful. This is on okay Yes, it is Uh Good morning. Let me hello, okay My name is daniel pencina and i'm here representing the breast cancer fund the only national Organization focused on preventing breast cancer by identifying and advocating for the elimination of the environmental And other preventable causes of the disease The breast cancer fund was a strong supporter of the phthalate provision within the consumer product safety improvement act We are pleased that you have begun your work Reviewing the science on the health implications of phthalates and we're grateful for the opportunity To present these comments As you know phthalates are used in a wide variety of consumer products in addition to toys and children's products including food packaging Personal care products such as soap shampoo deodorant hand lotion nail polish cosmetics and perfume Home vinyl siding flooring furniture car interiors detergent solvents lubricants glue paint and medical equipment including iv bags Biomonitoring has confirmed that phthalates migrate into the air into food and ultimately into people Including babies in utero Phthalates have been found in indoor air and dust in human urine blood and breast milk levels are highest in children's Aces ages six to eleven and in women and African Americans have higher levels of phthalates than Caucasians Phthalates are known endocrine disruptors and can affect normal hormonal processes Phthalate exposures have been linked to reduced testosterone levels lowered sperm counts in adult men genital defects in baby boys And early puberty in girls Moreover several studies and humans have shown some of the toxic effects of phthalates at levels similar to what the average American is currently exposed to As an organization working to prevent breast cancer were extremely concerned about the endocrine disrupting qualities of those chemicals Despite the growing evidence. We know that scientific certainty is rare And often policy questions need to be answered before the science is clear As you review the available evidence on the health impacts of phthalates We urge you not to require absolute certainty Before recommending action be taken to reduce human exposure to these chemicals to the consumer product safety commission In the cpsia congress wisely to ask you with considering a number of factors before making a determination on phthalates Traditional toxicology methods one chemical at a time from a single source on an adult assuming a linear dose response Relationship are outdated and do not provide an adequate or frequently even accurate Description of how a particular chemical impacts human health We're therefore pleased that congress explicitly listed several specific elements to guide your safety assessment in the statute Including reviewing all health endpoints combinations of phthalates impact of the timing Of exposure cumulative impact of all sources and routes of exposure All of the relevant peer review studies and the impact on vulnerable populations including children pregnant women and other vulnerable populations congress also called for the safety review to consider quote The level at which there is a reasonable certainty of no harm to those vulnerable populations Continuing using sufficient safety factors to account for uncertainties regarding exposure and susceptibility of children Pregnant women and other potentially susceptible individuals close quote as advocates We were heartened to see that congress placed the burden of proof on manufacturers of phthalates And phthalate containing products to show that phthalates are safe not on the government to prove harm In our work on state of the evidence, which is a document that The breast cancer fund releases by annually in which I believe has been provided to you all We found a number of themes in the data Which are particularly important in assessing endocrine disrupting chemicals and reflect the concerns expressed by congress in the phthalate provision of the cpsia Timing of exposures matters We learned decades ago from the tragic legacy of des exposures to hundreds of thousands of pregnant women And they're developing fetuses in the 1950s that in utero exposure to synthetic estrogens increases the incident Of reproductive abnormalities and breast cancer in children and grandchildren of the women who took the drug Similar data from animal models continue to show that prenatal exposures to other synthetic estrogen mimics Alter mammary tissue development in ways that predispose animals to increase risk for mammary tumors later in life And that these effects may be passed on to subsequent generations through epigenetic mechanisms Early life exposure to phthalates holds the greatest risk for harm and prenatal exposure to very low doses can have irreversible life long effects Therefore it is essential to protect children and women childbearing age Of childbearing age from exposure to phthalates other times of high susceptibility to environmental exposures include adolescents specifically puberty and early adulthood prior to the first pregnancy and lactation Low doses may have profound effects, especially at critical periods of development The study of endocrine disrupting chemicals Many of which have been implicated in increased risk for breast cancer has taught us that the traditional model of toxicology that the dose makes the poison Is outdated and no longer the standard by which we assess the safety of chemicals particularly endocrine disruptors We have substantial evidence from wildlife and laboratory studies that exposures to environmental Excuse me to environmentally relevant levels of endocrine disrupting compounds Even when apparently very low dose in concentration can alter reproductive development and risk for disease including breast cancer Mixtures matter the effects of phthalates exposure depend not only on timing But also on mixtures of phthalates and their interaction with other environmental factors In our real lives, we are not exposed to one environmental challenge at a time Rather we live in a world where we daily breathe the air drink the water walk the grass work in offices Play with toys use household cleaning products supply cosmetics and other personal care products, etc We are exposed not only to a number of phthalates, but to a vast mixture of chemicals Each chemical does not act alone growing evidence indicates that many of these common exposures work Additively and sometimes synergistically both within the family phthalates and beyond Interactions matter some of the evidence that is most compelling Is the growing literature examining complex interactions between risk factors These studies are expanding our understanding of the variability of susceptibility to environmental as well as lifestyle reproductive and genetic factors The data are critical for understanding impacts on vulnerable populations and designing community-based studies that examine these important interactions All of these factors will be important considerations for you in getting an accurate and full picture Of how phthalates are impacting the health of children Both at the time of exposure and much later in life when some of these impacts may manifest In addition to hazard characteristics, you have been asked to look at exposure data Not just from toys, but from the numerous other sources of phthalates As I mentioned, we know some of these sources and by monitoring data gives us part of the picture of exposure However, it's frustrating to have to point out that we don't know all the products that contain phthalates Much less which phthalate because our chemical management laws are weak Not only is safety testing not required before various chemicals including phthalates are released into commerce But frequently our laws don't even require disclosure of ingredients We know that phthalates are a common component of fragrance used in numerous products from cosmetics to household cleaning products Which is air freshener But current law allows industry to hide the component ingredients of quote-unquote fragrance as confidential business information Thereby masking the presence of potentially harmful substances including phthalates Understanding parenthetically that often those products are under the jurisdiction of the environmental protection agency and the FDA not necessarily the CPSC Understanding the full scope and level of exposure to phthalates will be an important challenge for this panel to meet The breast cancer fund and our allies have Been focused on the impact of environmental toxicants and the incidence of numerous diseases Including breast cancer and the need to adopt a precautionary approach to science and policy As you determine how you will view the existing data on phthalates relative to the risks they pose We would like to call your attention to two new reports that have informed that discussion The endocrine society and the president's cancel excuse me cancer panel both release reports On it within the last year that with conclusions and recommendations calling for precaution The endocrine society as you probably know is an international association founded in 1916 with 14 000 members Representing medicine and a wide variety of scientific disciplines Last year this highly esteemed association relieved a scientific statement on endocrine Disrupting chemicals which included a section entitled endocrine disruptors mammary gland development and breast cancer This section discusses the impact of exposure to endocrine disrupting chemicals or edcs during critical windows of susceptibility And how those exposures can alter the structure of the breast Making the tissue more sensitive to carcinogenic exposures later in life The scientific evidence led the endocrine society to state in a separate position statement quote Until such time as conclusive scientific evidence exists to either prove or disprove harmful effects of substances A precautionary approach should be taken in the formulation of edc policy We encourage the panel to review and consider this important document Another voice calling for a precautionary approach to chemicals is the president's cancer panel That panel established in 1971 Is tasked with monitoring the development and execution of the Of the activities of the national cancer program In may of this year the panel released a report entitled reducing environmental cancer risk what we can do now In developing the report the panel did its own research and held four public meetings were over 45 invited experts Representing academia government industry environmental and cancer advocacy Communities and the public Contributed testimony on research policy and programs concerning environmental contributions to cancer Finding that the true burden of environmentally induced cancer has been grossly underestimated The reducing environmental cancer risk report called issued a call to action to the president and for our nation A call to reevaluate the role of environmental contaminants in the incidence of cancer To institute the use of precautionary rather than reactionary policies regarding chemical management And to create a true national cancer prevention strategy The public instinctively knows that chemicals in our daily lives threaten our health and the president's cancer panels review Of the scientific evidence confirm that belief The president cancer panels report also included several specific recommendations for what individuals can do The recommendations related to children reflects the growing concern about edc's by calling on parents to Avoid exposure to endocrine disrupting chemicals and known or suspected Carcinogens prior to a child's conception and throughout pregnancy and early life Both of these highly regarded institutions found the scientific evidence to be compelling and called for precautionary action Answers in science as I said are rarely absolute An absence of knowledge is not the same as absence of harm The impact of our inaction in the face of substantial evidence of harm is irreversible in terms of public health as a whole And the devastating impact of people's lives The breast cancer fund strongly urges you in your deliberations and conclusions To adopt a precautionary approach to interpreting the science and to advocate that precaution be That be the foundation for the cpsc's ultimate regulatory decisions regarding phthalates Thank you, and i'm happy to take any questions Thank you Questions from the committee Could you clarify what you mean by precaution because it's a it's a word We hear a lot about the precautionary principle and so on and I'd like to hear your interpretation I should preface this by saying that I may be the only non-phd in the room. So I should Be careful not to to play the part of a risk assessor or a scientist and and rather speak for the advocacy community and that is In the broad sense when you're taking a regulatory approach to assessing harm Potential risk to the health and the environment The burden of proof should be on the The manufacturer to prove safety and Not on the Government or the consumer to prove harm I guess unfortunately We are charged with the task of doing that And thank you for it. Thank you Thank you I'm dr. Diana zuckerman. I'm president of the national research center for women and families And our cancer prevention and treatment fund and our center focuses on health and safety issues looking at scientific data And trying to synthesize data from various sources explain what the differences are and why results can vary and why data are often inconsistent And try to make sense of it from a policy point of view as well as a consumer point of view Just briefly I'll Give you a little bit of information about my perspective In addition to being president of the center. I'm a fellow at the university of pennsylvania center for bioethics I was trained in epidemiology and public health at Yale medical school And was on the faculty at Yale and vassar and conducted longitudinal research at harvard So i'm really speaking From an epidemiological and public health point of view today and i'm going to focus on human health not Animal studies and i'm going to try not to repeat things that have already been said So i'm going to be shuffling through my papers and i don't have a power point presentation Oh, I should also mention that I I worked in the house of representatives in the u.s senate and the white house and so I've spent a lot of my career Trying to bridge the gap between research data and public policy and particularly health policy And I will try to do that a little bit today As you all know phthalates have been found in indoor air and dust and in human urine blood and breast milk Levels are highest in women and and also children ages six through 11 And african-americans have been shown to have higher levels So I think that's part of my perspective of trying to figure out what's going on and what the impact is going to be I'll talk a little bit about the most recent research Um, obviously, um, it's complicated. You know that it's difficult to look at individual phthalates when we have Exposure to many different phthalates from many different sources And we don't as has been said we don't even know sometimes what they are and where they're coming from So we do have to Do our best to look at the aggregate data and the cumulative effect and not just the individual products But also we do need to control for various other Confounding variables and I was a little disturbed I think I understood one of the earlier speakers on the other panel to talk about how difficult it is To look at certain genital abnormalities because you have to control for weight and size and so on Well, you just have to I mean, that's the nature of this kind of research It's very important to control for as many can potentially confounding variables as possible and It's possible to do that fortunately with the multivariate analysis A 2009 research review published in the philosophical transactions of the royal society Concluded that there was little correlation between prenatal and postnatal concentrations Of phthalate metabolites and I mentioned that only because it seems to show that those are quite independent The prenatal exposures and the postnatal exposures. They're both very important But they are independent of each other and we need to look at both of them very carefully A study by cho and his colleagues published in the environmental health perspectives in 2010 Found that iq and verbal iq were lower in elementary school children with dehp metabolites But not dbp metabolites and after controlling for various demographic variables and developmental covariates Both types of phthalates were associated with lower vocabulary scores And that was maintained for the dehp even when they statistically controlled for maternal iq So Controlling for every variable they could think of that could possibly affect iq and vocabulary That impact was still there boys with more dehp and mehp Had lower scores on the wexler intelligence scale for children on the vocabulary score But girls did not so again have to look at boys and girls. They might be affected differently But obviously when you're regulating chemicals in the environment you have to regulate them Even if they're only affecting boys and not girls in 2010 an article by angle et al Also in the environmental health perspectives Found a relationship between prenatal phthalate concentrations and parents ratings Of children's aggression Conduct problems attention problems depression and executive function, which I think you know is the ability to think An organized thoughts in a particular way. That's effective. So many of these measures Are obviously associated with adhd Hyperactivity disorders. So again, we're looking at different kinds of ways that These phthalate exposures can affect children and throughout their lives as they're developing A review published this year of the reproductive toxicity data of phthalates and animals um found some Alterations phenotypic alterations in male offspring rats Exposed during the prenatal period and I only uh, I said I'm going to focus on humans But certain kinds of studies you can't do on humans So it's very important to be looking at that and the authors concluded that biological changes Can be induced at low human quote low human relevant doses and that different active phthalates Can have cumulative effects unquote You know that and you've heard about The potential for safer Substitutes for phthalates and that's something that we think obviously is very important And it does appear that there are safer alternatives and you've heard some about that this morning already For the most vulnerable populations, I think it's clear the prenatal exposures are very important Um and just to mention that according to the fourth national report on human exposure to environmental chemicals quote Human milk can be a source of phthalate exposure for nursing infants unquote Children have the highest exposures to phthalates compared to teens or adults And uh last year the german environmental surveys found that the general population is quote exposed to phthalates to a large extent And that children are exposed to quote up to four fold higher levels than adults And obviously, uh, we agree that they are exposed to many different phthalates coming from many different sources Expected mothers of course are a particular concern to us as well the prenatal exposures The cumulative risks are the ones that are the most challenging because as I said, we don't know exactly where all these Exposures are coming from but you can't just look at one or just a two or just at four or just at six because These are affecting hormones and in the same way that you would not ever You have a young child Estrogen pills or estrogen injections You have to think about how these exposures how similar they are as if we were doing that And so even though The data are inconsistent And sometimes you're inconsistent because it's different animal studies and sometimes you're inconsistent I believe with all due respect because of the source of the funding of the studies Um despite the inconsistencies there are certain things that are consistent certain things that we know We know that when you affect that that when you um expose Children and adults to hormones it affects them Dr. Swan did a recent study showing how it can affect What's normally thought of as more feminine behavior in children We have enough We have children exposed to phthalates we can look at phthalate concentrations in their urine We know what Approximately what their exposure level is or at least we have that proxy measure I think we should be focusing on human studies not rat studies not mouse studies not animal studies You know non-human primate studies obviously are very helpful, but we already have kids Exposed to these phthalates and we should be focusing on what the data can tell us about what is happening to those children I just want to say a couple of things about some of the specific phthalates that you're looking at um As you know before the provisional band dinp was the phthalate that was most often used to soften plastic in some children's products and toys And it's also used in flooring gloves and straws and garden hoses It's considered an animal carcinogen And in an article by cock and his colleagues published in 2007 in the journal of chromatography He concluded quote. We also have to regard dinp as an endocrine disruptor modulator in humans Effects like nipple retention and testis atrophy are comparable to dehp And in a more recent article a 2010 article by danish scientists that was published in environmental health perspectives They found phthalate metabolites in the urine of all all of the four to nine-year-old children That were studied boys and girls had higher concentrations Uh, I'm sorry boys and girls who had higher concentrations of phthalates Had lower thyroid hormones lower igf one, which is an insulin like growth factor and less growth So it was clearly a relationship between the phthalate exposure and specifically dinp and That were negatively associated with igf one in boys I don't think uh, I have any good recent data on some of these other provisional Phthalates and that's really unfortunate that there is a lack of information And I know that's difficult for you all to deal with But again, I think we should be demanding That independent research be conducted human research before any changes are made in in the law We believe that the provisional The interim decision To ban these phthalates in the absence of better data was an excellent and an important decision And that we shouldn't be Changing that Just because of lack of conclusive data. We think we need better and more conclusive data and we should require that As you know cumulative long-term effects are of particular concern And that's why our center supports the provisional ban and thinks it should be made permanent or at least until data proves otherwise I think the The standard discussed earlier is an excellent standard We want to make sure that we're not doing any harm to children or to adults And we also believe that You all should be focusing not only on children's toys and children's products, but other exposures to children and because prenatally is so important particularly to adults as well And um, I'm happy to answer any questions Thank you One of the things I would like to encourage all of you if you haven't already done that is to submit to us peer reviewed Information that you wish us to consider Any questions? well First of all, uh, and if you could give us a copy of your testimony as well We appreciate that you know you mentioned Well, all the speakers mentioned a bunch of several great deal studies and if there's anything in particular that you think is key, please bring that to our attention and uh I've heard breast tissue and breast cancer mentioned several times and For the panel as a whole, are you aware of any studies linking valates to breast cancer? I believe a couple were referred to in my Written testimony, but I also Think I mentioned and I think we submitted a copy of the state of the evidence report Oh you all It's about to be updated and I will do my best to get you the 2010 version which I believe References some of those as well I see Off the top of my head, I know there's a couple of in vitro studies looking at breast cancer cell lines and exposure to butylbenzal phthalate and DEHP With some estrogenic effects and stimulation of growth of those cells and then I know that both of those studies are referenced in here. So there's two or three different studies With breast specific endpoints, which we can provide you with Okay, and I would just like to add that of course that's going to mostly be I assume animal studies. I mean the problem with Measuring obviously studying cancer is that particularly breast cancer tends to be a very slow growing cancer It develops over 15 or 20 years. You can't look at the relationship between phthalates and urine for example and breast cancer and have a meaningful association because Particularly we know that risks of breast cancer Pertain to hormone exposure as children. We know that When a woman started menstruating for example, whether she breastfed her children when she had children all of these things Which affect hormones? Historically affect her risk of breast cancer 20 years later. So We know that when you are affecting hormone levels Whether you do it through birth control pills or hormone replacement therapy or exposure to phthalates it affects breast cancer and I do want to mention in case since this is not an issue probably of study for many of you that the numbers of women Diagnosed with breast cancer and dying of breast cancer has gotten a little bit lower in the last few years And that is has been attributed by every expert in the country to the reduction of the use of hormone replacement therapy In menopause and just before menopause so Although that Lowering of use of hormone replacement therapy is quite recent Um, it's had this profound effect already statistically significant effect on breast cancer rates and it is just one example of how when you expose women To estrogen and whether it's synthetic estrogen as it is in hormone replacement therapy or natural estrogen it It increases the risk of breast cancer. So I think that's a really good example And if I could just add to that There's also I'm working on a separate breast cancer and chemical exposure project And so I've done a quite a bit of breast cancer research over the last year There is some evidence that while postmenopausal breast cancer rates have plateaued and are decreasing premenopausal breast cancer rates are actually still on the rise And which suggests that's a very different disease. We know that breast cancer is a very heterogeneous disease But it also suggests that in utero and early life exposures to endocrine disrupting chemicals which alter The development of the mammary gland can also be very important for the development of breast cancer And there is no research that I know of for phthalates that are specific to that But there is for other chemicals like bisphenol a which are estrogenic perfluorinated chemicals, which also activate proxazone proliferators and atrazine which is also An estrogenic endocrine disrupting chemical I Said I think we have a couple more forthcoming in here Take the chairman's admonishment to heart. We'll get you those studies Chris This may actually be a question that's A little bit removed from your testimonies, but I'm interested in longitudinal studies You mentioned some studies where you say, you know increased levels of dehp or whatever Associated with certain kinds of outcomes. Are you aware of any studies? Where there could be exposures outcome and then some change in exposures and a diminished outcome I'm thinking about the fact and I may be incorrect about this But many of these chemicals I think have relatively short half lives so Which could have the impact of you know, if you can get rid of them they could Is there going to be a change in them in whatever outcome? Just by reducing exposure I mean, I guess the one example I can give is that women who took hormone replacement therapy for years But stopped taking it were still less likely to have be later on diagnosed with breast cancer. So clearly Even very late in the game Changing exposures can have a profound effect. But what about exposure to children? Do you know of any studies in that in that regard? I don't know of any studies in children, but I think For phthalate exposure especially we've defined in rodents that very specific window of exposure where In utero exposure to phthalates causes permanent changes in the development of the male reproductive tract, which has lifelong impact So it's sort of it doesn't matter after that happens at least in the rodent studies So that has you know Implications for both development of the genitals As well as sperm counts and sperm quality later in life There is other evidence from some of your own panel members about Epidemiological evidence of exposures, especially in men to phthalates and sperm quality And fertility as well as thyroid hormones, but I don't know of any studies where We we have exposure going on and then we take it away I am doing a study at ucsf with shana swan and her group and maybe she'll talk about it a little bit more In detail, but we're going to be launching a study looking at In utero exposures to phthalates and pregnant women throughout pregnancy and then birth outcomes and development of the baby boy genitals Unfortunately, I don't think we're going to have any results from that study by the time your panel needs to make a conclusion But there is ongoing research An interest in this area I guess I just want to add that I don't think we've talked very much about early puberty But there's the of course the concern that exposure to phthalates might Be one of the reasons why so many girls are starting puberty earlier and Just to distinguish it's not that they're menstruating necessarily any earlier than their mothers But breast development is starting at ages eight and nine And so you're ending up with girls Whose bodies are starting to change to be like women who still haven't learned how to make change for a dollar It's a very young age that these girls have been Changed and that kind of exposure is going to be one of the Contributing factors for example to breast cancer later, but to answer your question about You know, what what's the impact of changing all of these things contribute To breast cancer. I mean we know that Age of menstruation is one of the things that contributes to whether a woman's at higher or lower risk of breast cancer but so is The age of her first child if she gives birth Whether she breastfeeds and for how long and how old she was when she does so Throughout the lifespan. There are exposures that affect Cancer particularly breast cancer So if you can change any of those exposures one would expect you can lower the risk As far as I know phalliates aren't Estrogens per se they're anti androgens. So it doesn't mean they couldn't have effects Like you described, but they're not acting by binding to the estrogen receptor. Yeah, I'm sorry. I should have distinguished Any other comments or questions? If not, I guess we're ready to break for lunch Is that what we're scheduled? Yeah, we'll reconvene at one Thank you all