cir-safety.org2 1 participants: 2 voting members: 3 wilma f. bergfeld, m.d., f.a.c.p. head of...
TRANSCRIPT
120th COSMETIC INGREDIENT REVIEW EXPERT PANEL
MEETING
MAIN SESSION
Washington, D.C.
Monday, September 26, 2011
2
1 PARTICIPANTS:
2 Voting Members:
3 WILMA F. BERGFELD, M.D., F.A.C.P.
Head of Clinical Research and Dermatopathology
4 The Cleveland Clinic Foundation
5 DONALD V. BELSITO, M.D.
Clinical Professor, Medicine (Dermatology)
6 University of Missouri, Kansas City c/o American
Dermatology Associates, LLC
7
CURTIS D. KLAASSEN, Ph.D.
8 University Distinguished Professor and Chair
Department of Pharmacology, Toxicology, and
9 Therapeutics
School of Medicine, University of Kansas Medical
10 Center
11 DANIEL C. LIEBLER
Director, Jim Ayers Institute for Precancer
12 Detection and Diagnosis
Ingram Professor of Cancer Research
13 Professor of Biochemistry, Pharmacology and
Biomedical Informatics
14
RONALD A. HILL, Ph.D.
15 Associate Professor of Medicinal Chemistry
College of Pharmacy
16 The University of Louisiana at Monroe
17 JAMES G. MARKS, JR., M.D.
Professor of Dermatology
18 Chairman, Department of Dermatology
Pennsylvania State University College of Medicine
19
RONALD C. SHANK, Ph.D.
20 Professor and Chair
Department of Community and Environmental Medicine
21 University of California, Irvine
22
3
1 PARTICIPANTS (CONT'D):
2 THOMAS J. SLAGA, Ph.D.
Department of Pharmacology
3 University of Texas Health Science Center
4 PAUL W. SNYDER, D.V.M., Ph.D.
School of Veterinary Medicine
5 Department of Veterinary Pathobiology
Perdue University
6
Liaison Members:
7
LINDA LORETZ, Ph.D.
8 Personal Care Products Council
9 CAROL EISENMANN, M.D.
Personal Care Products Council
10
RACHEL WEINTRAUB
11 Consumer Federation of America
12 ROBERT BRONAUGH, Ph.D.
Food and Drug Administration
13
Staff Members:
14
F. ALAN ANDERSEN, Ph.D.
15 Director
16 LILLIAN C. BECKER
Scientific Analyst
17
HALYNA P. BRESLAWEC, Ph.D.
18 Deputy Director
19 MONICE FIUME
Senior Scientific Analyst
20
CHRISTINA L. BURNETT
21 Scientific Analyst
22 IVAN BOYER, Ph.D.
Senior Toxicologist
4
1 PARTICIPANTS (CONT'D):
2 KEVIN STONE FRIES
Technical Librarian/Editor
3
BART HELDRETH
4 Chemist
5 WILBUR JOHNSON, JR.
Senior Scientific Analyst
6
Other Attendees:
7
DR. ROBERT GOLDEN
8 ToxLogic
9 DAVID GOLDSTEIN
10 JANE VERGNESS
11
12
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5
1 P R O C E E D I N G S
2 (8:37 a.m.)
3 DR. BERGFELD: There we go. Thank you
4 very much. And welcome, everyone, to our 120th
5 CIR meeting. This is our 35th year. This is a
6 milestone for this particular panel. We are going
7 to celebrate this tonight but in the meantime
8 we've been given an unbelievable chore of 17
9 ingredients that we all built a few muscles
10 bringing in and a great deal of time reviewing.
11 And in this group we have eight finals and several
12 of them having to have much discussion today in
13 the team meetings.
14 I do want to congratulate the CIR staff
15 for the documents keep improving and improving.
16 And thank you so much. Really. I really like the
17 tables at the end and the chemistry. It's great.
18 And I see now that we're beginning to incorporate
19 the titles of human and non-human. A little hard
20 for me to get used to but I guess that's the way
21 the science is written today. At least that's
22 what we decided last time.
6
1 For the teams there are several things I
2 would like you to consider when you're going
3 through these. There are statements within the
4 discussion areas that say read across or
5 extrapolate. And I want you to consider read
6 across as a statement or use of the phrase
7 extrapolate from blah, blah, blah.
8 Then there's another concept that snuck
9 in this last time and that's components. And I
10 don't know if those -- I gather they're chemical
11 components of the main ingredient. I'd never
12 heard that comment but I'd like you to discuss
13 that in your teams. And the third issue is a
14 nitrosating statement and we need to declare how
15 we're going to put that into both our discussion
16 and our conclusions.
17 And then the last is active versus
18 reported concentrations. It's all over the place
19 in the documents as to what is active in the
20 concentration.
21 And I also want to thank very much the
22 CIR Science and Support Committee from the
7
1 Council, really a great edition in these
2 particular documents, so thank you for all your
3 hard work.
4 So before I move on I'd like to call on
5 Jim Marks who has something to tell us.
6 DR. MARKS: So at the risk of
7 embarrassing Alan, I want to acknowledge an honor
8 he's soon to receive. And this is a letter from
9 Graham Spanier, who is the president of Penn State
10 University.
11 "Dear Alan, on behalf of the
12 Pennsylvania State University, I am pleased to
13 congratulate you on your selection as a 2011
14 alumni fellow. You have been chosen to receive
15 this most prestigious award in recognition of your
16 outstanding professional accomplishments. The
17 Alumni Fellow Award is the highest honor conferred
18 by the Penn State Alumni Association. The Alumni
19 Fellow Award is a permanent title authorized by
20 the Board of Trustees and attested to by a
21 personalized statuette and certificate."
22 There are over 4,000 alumni at Penn
8
1 State University and Alan is one of 24 selected
2 this year, including people like the chief
3 executive officer of the University Hospitals of
4 Cleveland, the COO of Turner Broadcasting, etc.
5 And so as I don't have something as elegant as a
6 certificate and statuette, but I thought to go to
7 Remote University Park, and when Penn State was
8 founded it was found with the idea it was equally
9 remote from everybody in Pennsylvania. Alan, I
10 have some traveling attire for you.
11 (Applause)
12 DR. BERGFELD: Congratulations.
13 DR. ANDERSEN: Well, thank you.
14 DR. BERGFELD: Now, we'll turn this part
15 of the meeting over to you.
16 DR. ANDERSEN: I couldn't have done it
17 without you guys.
18 We've started over the last two or three
19 meetings looking at both our boilerplate, our
20 precedent setting, and we've devoted an awful lot
21 of energy to focusing on the question of potential
22 exposure to aerosols. And we're going to continue
9
1 that discussion today. Hopefully, we'll make some
2 ongoing progress.
3 I think it's important to notice that
4 this is -- the whole topic has been fraught with a
5 significant level of uncertainty. When we receive
6 information that an ingredient is used in an
7 aerosol, what we're really saying is potentially
8 used in an aerosol because the category in which
9 it's listed may include aerosols but whether or
10 not it's actually used in an aerosol requires some
11 more information. And the counsel through its
12 surveys and the information that Carol has
13 provided often is able to clarify that. And we
14 know at that point that it is either used in an
15 aerosol or not used in an aerosol.
16 But we don't always get the
17 clarification. So we are stuck discussing
18 aerosols without really knowing whether or not the
19 particular chemical is used in a product that's
20 going to be sprayed or not sprayed. And then at
21 the last meeting as we talked about silylates the
22 question of particle size came up in the context
10
1 of powders. And that added another layer of
2 discussion, no pun intended. And I think it's an
3 ongoing discussion but we have the benefit of some
4 effort that's been taken. And I refer for the
5 panel members. We didn't include this in the --
6 in what was put online for the general public
7 because we're not allowed to send out publications
8 to everyone in the universe but all the panel
9 members got the mini review published in Tox
10 Letters on Special Aspect of Cosmetic Spray Safety
11 Evaluations: Principles on Inhalation Risk
12 Assessment.
13 And I'm very happy that we have this
14 morning with us Dr. Helga Rothe, and she's going
15 to talk about inhalation exposure assessments.
16 And we'll know more at the end of this than we
17 knew at the beginning. Dr. Rothe. We're
18 connected so I think we're all set to go.
19 DR. ROTHE: Can you hear me? I'll try
20 to stay here.
21 So good morning, everybody. I would like
22 to thank you, the expert panel, to give me the
11
1 opportunity to talk to you today about the Special
2 Aspect of Cosmetic Spray Safety Evaluation.
3 The cosmetic industry over the past
4 years has developed prediction models for the best
5 estimate of inhalation exposure assessment by
6 combining simulated computer modeling as well as
7 actual measurements from each product and with
8 market experience. This impact is driven by the
9 toxicological profile of each individual
10 ingredient, and I would like to talk today about
11 -- oops, sorry that I included the agenda -- about
12 typical products and ingredients, general
13 considerations for exposure assessment, impact of
14 particle size, and exposure assessment methods.
15 And here I will focus on modeling, as well as
16 measurements with a few examples.
17 I was also asked to talk about, or more
18 or less start a discussion about, special aspects
19 of powders in decorative cosmetics. And here I
20 would like to introduce some strategies, how
21 industry is preventing airborne particles.
22 So when we think about cosmetic products
12
1 which are sprayed, we all know that they are a
2 combination and composed out of active
3 ingredients, how we call them. These are the
4 polymers in the hairsprays or the antiperspirant
5 active in the ADPOs, but also a lot of solvents
6 like ethanol, water, oils, or whatever, and also
7 some fine fragrances or perfumes to mask the smell
8 of the product.
9 We have to distinguish between two main
10 product types. These are aerosols and the trigger
11 pump sprays. In the aerosols, we have
12 additionally the propellant gas phase and this is
13 packed in a pressure resistant can. Both of the
14 different product types, the aerosols and the
15 trigger pump sprays, are equipped with a
16 product-specific pump unit and nozzle and this
17 will generate the airborne fractions. So the term
18 "aerosol" is also used sometimes for other
19 products, like mousses and other two-chamber
20 systems. But when the nozzle is very, very
21 different here, so what will come out of the can
22 is not an aerosol-borne particle or droplet; it's
13
1 really more a compact thing so there is no
2 airborne fraction from that.
3 So when we do an exposure assessment,
4 first of all, you all know the target of such a
5 spray product is not to generate something in the
6 air; it's really to target the scalp or the skin
7 or the hair. So therefore, for the risk
8 assessment here for this portion, we have to
9 assess it similarly to the conventional cosmetics.
10 But we do have the airborne fraction; so
11 therefore, additional exposure of the emulation
12 has to be taken into account. As you all know,
13 the respiratory tract can serve as a portal of
14 entry for systemic exposure, like the vapors or
15 gases, but also as a target origin. And here we
16 have especially particles and fibers.
17 So what are the specific considerations
18 for safety assessments of sprays? So as I said,
19 we have from the (inaudible) of products and
20 additional inhalation exposure, we have to assess
21 the deposited portion on the scalp in the same way
22 as we do it usually for cosmetics. For the total
14
1 systemic exposure, it's important to know that we
2 have to sum here the portion which is coming from
3 the deposition to the skin but also from the
4 inhalation route.
5 And it's important to know that the
6 appropriate inhalation toxicity assessment is
7 depending on the knowledge of the quantity and
8 composition of the ingredients as well as from the
9 exposure pattern of the finer products. So that
10 means what about the particle size distribution
11 here?
12 So when we look to the construction of
13 the respiratory tract, we divided in three main
14 regions. That's a nasopharyngeal region, the
15 tracheobronchial region, and the pulmonary region.
16 The construction looks like a tree and you have
17 the brighter lumen in the tracheobronchial region
18 and the smaller ones in the pulmonary region. But
19 that also explains why the particle site by itself
20 dictates how deep a particle is going into the
21 lung. So what we know is that in the
22 nasopharyngeal region we have particles which are
15
1 larger, 50 micron, which can deposit there by
2 impaction or diffusion. In the tracheobronchial
3 area we have deposition of particles between 10-50
4 microns, and this is by impaction, sedimentation,
5 or by diffusion. The clearance effect here is the
6 sneezing, blowing, and the coughing, but also via
7 the mucous (inaudible).
8 In contrast to that we have in the
9 pulmonary region also what we call the respirable
10 fraction. That means particles below 10 microns
11 can go there, but the clearance effect here is
12 very different. So we have on one side the
13 (inaudible) that it goes into the intestinal area
14 but we have also the phagocytosis by macrophages
15 which is limited. Therefore, we have here -- and
16 I will come to that later -- what we call the
17 overload effect by the lung or the deep lung.
18 So, as I said, the impact of the
19 particle size -- so particle size is very
20 important. The particle size distribution is an
21 important parameter of central relevance in the
22 exposure assessment for the spray products. The
16
1 particle size distribution depends on a number of
2 factors. It's not only the formula compositions,
3 so that means how much solvent you have. Which is
4 your solvent? Is it more evaporating? Less
5 evaporating? Is it more oils? It's also the pump
6 unit by itself, so it's also driven by the
7 technical equipment of the pump unit and the
8 spray, which is individually. So that means every
9 time when we see a reformulation of the given
10 spray product, we generate a new particle size
11 distribution pattern if we see a modification of
12 active ingredients, solvents, or propellant, but
13 also when we have a change in the can size or in
14 the pump unit, that means the nozzle, which will
15 generate the airborne fractions.
16 So one important aspect on the
17 respirable particles is that we have particles
18 that are hardly soluble ingredients and these are
19 mainly the polymers we have in the hairsprays.
20 These are non-absorbable and therefore, we might
21 get local effects, especially the fraction below
22 10 microns will deposit in the deeper lung.
17
1 Because we have the limited clearance effect by
2 the macrophages here, it will come to a chronic or
3 might come to a chronic inflammation here. So
4 what we have in Europe in several countries and
5 also under reach is a threshold which is taking
6 this into account and this threshold is at the
7 moment with one microgram per cubic centimeter and
8 this is coming from the occupational use for dust
9 and so therefore it's not a daily dose exposure,
10 it's the exposure for eight hours, five times per
11 week, and compared to a cosmetic spray product
12 it's independent -- if it is an ADPO or hairspray
13 or whatever, this is a very conservative one.
14 So how do we do an exposure assessment?
15 We have the French methods here. First of all,
16 very simple is that you model it. You can do a
17 simple model, what we call the one box model.
18 This is assuming that the whole formulation is
19 sprayed in a specific volume. More complex models
20 are what we call the two box models. Here we
21 assume that you have an initial phase the
22 formulation sprayed in a very small cloud around
18
1 your face or your body and then in a longer phase
2 you have the exposure or the distribution of the
3 formulation in a whole room so that therefore,
4 it's a first box and the second box. And we have
5 a lot of models around which are publicly
6 available. First of all, the ConsExpo model and
7 then we have also the IKW model which we published
8 earlier this model and which is a very simple one
9 and you can use it by using a calculator by
10 yourself. Very easy to do. The ConsExpo model
11 has a lot of other factors in like air velocity,
12 air exchange rate in the room, etcetera. And you
13 can use it as a refinement as well when the IKW
14 doesn't work.
15 You can do also some measurements and
16 here we have to distinguish between different
17 methods. And it really depends on what you would
18 like to do and then you decide which methods you
19 are using. So first of all, we have the point of
20 expulsion. That's an acute exposure. So that's a
21 laser defraction element. You can simulate the
22 consumer exposure by time flight average -- by
19
1 time flight spectrometers, and this you can do for
2 intended and forcible use scenarios and you detect
3 the amount of the particle size distribution and
4 concentration of the product in the breathing
5 zone. And you can do an ambient sampling by
6 cascade impaction to measure the residual air
7 quality.
8 So one example for the modeling. The
9 key advantage here is that it is conservative as
10 long as you use conservative defaults here, and
11 these are published at different places. So when
12 you think about the amounts (inaudible), you will
13 find there are a lot of studies out about how much
14 of the product is really used per usage and also
15 the frequency, and you will find also the defaults
16 about room size, etcetera, in the literature.
17 So one example is a consumer applies the
18 product. It might be an ADPO product or it might
19 be also hairspray in a small bathroom of 10 cubic
20 meters as instructed. The aerosol will distribute
21 into the initial two minutes first application
22 around the consumer's head -- whoops, sorry. This
20
1 goes one way -- around the consumer's head in a
2 cloud of one to two cubic meters. The consumer
3 will stay there for a total of 20 minutes, so the
4 remaining 18 minutes, and during this time you
5 have the distribution in this larger room. So the
6 total amount of spray product will distribute
7 homogeneously in the entire room, bathroom, and 25
8 percent of the inhaled ingredients will be
9 exhaled. And this number was published by the
10 European Commission in 1998.
11 So when we think about the particle size
12 which is then inhaled, we use for these
13 assumptions here the measurement by the point of
14 expulsion. That means the real particle size
15 distribution pattern which comes out of the can at
16 a distance of about 10 to 20 centimeters. You see
17 here the numbers for pump spray and a aerosol
18 spray, and what you can see here, the red line is
19 the 10 micrometers and the 100 micrometers is the
20 green line. And the mean distribution of a pump
21 spray is larger -- it depends really fro product
22 to product. It's always in the range between 60
21
1 and 80 I would say in the mean. The aerosol spray
2 is a little bit smaller. It depends also again
3 from product to product and for the hairsprays
4 it's usually around 30, 40, 50, 25, something in
5 this range.
6 But the important point here is the
7 particle size, which is below 10 microns. And you
8 can see for the pump spray it's really below one
9 percent. It's really extremely small but you
10 still see some of it. For an aerosol spray it's
11 also very, very small. It's usually in the range
12 of two percent, one percent, two and a half
13 percent. It's always small but I would say never
14 above five percent. So nothing I have ever seen
15 is above five percent but I wouldn't exclude that
16 there is sometimes something.
17 So another option is the simulated use
18 studies to do a measurement in the breathing zone.
19 So the key is always how much is really in the
20 breathing zone. So the model has really taken
21 this into account by just saying how much of the
22 formulation in which volume or cloud this -- sorry
22
1 -- the formulation is distributed and then you
2 have the breezing concentration, but you can also
3 use, simulate really, is this in a study that
4 means you put -- you put technical -- so a
5 measurement device in the breathing area. You
6 spray it in use conditions. That means you use
7 realistic amounts for the product and you measure
8 it in the breathing zone. And you do it usually
9 for 10 minutes or until it goes below the limit of
10 detection. And usually you are using here the
11 time of flight spectrometer. The output you get
12 here is the respirable dose and the inhalable
13 dose, but as I said at the beginning, all the
14 different kinds of measurements, the different
15 methods, have advantages and disadvantages and
16 have their limitations here.
17 So you see here the outcome of such a
18 study and don't get confused here. The scale on
19 the X-axis is going only to 20 microns, so it's
20 not really the whole distribution pattern. So
21 when you remember what I showed you at the
22 beginning, the distribution pattern which was
23
1 going up to 150 microns, you see here only the
2 very, very small portion which is below 20
3 microns. So that's important to note. And also,
4 when you look at the Y-axis, so you have here an
5 ADPO aerosol on the left hand side and a pump
6 hairspray on the right hand side, but the scale is
7 more than one magnitude of order lower for the
8 pump spray.
9 So but what you can measure here is not
10 the percentage of mass volume, so the particle
11 size distribution. What you measure here is
12 really the particle number or the particle mass in
13 (inaudible) cubic centimeter. And what you can
14 see here is that the particle number by itself is
15 extremely low in all -- in both cases. And
16 depending on the chemical you are looking to, then
17 the particle mass is showing a peak.
18 So the output of the simulated use
19 studies is that you have to correct to emulate
20 human breathing conditions. You can do it by 10
21 liters per minute for a resting rate, which is a
22 number published by the EPA. You can also use 20
24
1 liters per minute, which is the EPA number and
2 relates to light exercises. The data output is
3 the aerosol concentration in the breathing zone,
4 the particle size, particle mass, (inaudible)
5 discharge rate, and inhalable and respirable dose.
6 And as I said for the inhalable dose, it's just
7 the fraction below 10 microns. It's not the whole
8 spectrum; that's important to know. And it's also
9 important to know that it is not comparable to the
10 point of expulsion because you don't see the mass
11 volume here.
12 So a very important finding is also when
13 you compare the real time measurements with the
14 models that when you look to the drop out with
15 time in the breathing zone, you will see here --
16 do you see the cursor? So you have here the
17 portion of the total exposure on the Y-axis, the
18 time in minutes on the X-axis, and you see the
19 dropout is by 35 percent in the first minute and
20 it's starting with 60 percent in the second
21 minute, and that's an example from the ADPO. So
22 that really tells you when we use the modeling
25
1 with two minutes for the initial phase, that this
2 is a very conservative number.
3 What this also shows you is that you
4 have drop- off of 90 percent after six minutes and
5 95 percent after eight minutes. So when we model
6 something and we use 18 minutes for the remaining
7 time and we use the distribution in the room, this
8 is again very conservative because we can
9 demonstrate here by these measurements in the
10 breathing zone that we have a drop-off of 95
11 percent of everything within eight minutes and
12 it's going below the limit of detection in most
13 cases within 10 minutes.
14 DR. BELSITO: On that slide can you
15 define what you mean by inhalable and respirable?
16 Respirable less than 10 microns and inhalable,
17 greater?
18 DR. ROTHE: Yeah, that's 10 to 20. So
19 that's only 10 to 20 because we don't measure the
20 huge portion which is, I would say, 98 percent.
21 This is not detectible by this method so that is
22 one of the limitations.
26
1 DR. BELSITO: So you're seeing no
2 difference between particles less than 10 microns
3 and those between 10 and 20?
4 DR. ROTHE: Right. So, and when we go
5 back here you could see that it is going up for
6 the aerosols and for the pump hairsprays you have
7 the peak around 10. And then it's going up and
8 then it's going up again later, what you have seen
9 on the other side before where I showed the
10 complete pattern.
11 So to summarize that, beyond the
12 situation of the application site safety
13 assessment for cosmetic products requires
14 consideration of potential exposure to the inhaled
15 portions of the products. Qualitative and
16 quantitative exposure assessment is key for
17 importance of this part of the evaluation. The
18 particle size distribution in liquid or particular
19 aerosols will determine penetration depth of the
20 material into the respiratory tract. The local
21 effects of inert particles smaller than 10
22 micrometers by deposition in the deeper lung.
27
1 Particle size distribution is product specific.
2 As I said, it's not only the composition of the
3 formulation; it's also the technical equipment of
4 the pump unit. And you can do an exposure
5 assessment by modeling (inaudible) assumptions or
6 by these real-time measurements which also have
7 some limitations.
8 So I was also asked -- if you don't have
9 questions to that or we do it at the end -- I was
10 asked also to give some aspects just as an
11 introduction to the discussion you will have here
12 with PCPC members about Special Aspects of Powders
13 and Decorative Cosmetics. I will focus here only
14 a very few strategies or on very few things, that
15 means on strategies, how we prevent airborne
16 particles in powders.
17 So, first of all, this is driven by the
18 ingredients in the powder formulations. So we
19 have what we call the dedusting effects. That
20 means we use binding material to agglomerate
21 particles. So when you look how we generate
22 powder formulations, so you have a mill and a
28
1 blender and you put first your dry ingredients in,
2 you mix it, and then you spray oils or the melted
3 (inaudible), you mix it, and then you get an
4 agglomeration of small dry ingredients. We also
5 have hydroscopic ingredients in and this will
6 increase the particle size through absorption of
7 water.
8 So the production of the powder
9 formulation as I said before is very important and
10 is also controlling more or less the particle
11 size. That's on the mill conditions. And it's
12 also by mixing the dry and the wax oil phase you
13 get a relative high cohesivity. I can speak here
14 only for P&G. I don't know what the exact numbers
15 are for the other companies here but we usually
16 have a cohesivity between 60-
17 Of cohesivity on a scale of 100. And we
18 need this to ensure that the pressed powder
19 survives the shipping, otherwise they will break
20 into pieces. And the loose powders, like for eye
21 shadows have to stick to the applicator, otherwise
22 they would fall down.
29
1 Measuring the particle size from final
2 products is a little bit more difficult and mostly
3 does not reflect the actual size of the powders
4 under use conditions because you always have to
5 disperse the powder in a solvent or you disperse
6 it with pressure and then the agglomerated
7 particles would break. There are also some
8 methods out and under development that you do it
9 by photography, but honestly, I'm not familiar how
10 good these really reflect the actual particle
11 size. What you can really see is the particle
12 shape but this is nothing P&G has a lot of
13 experience with. So it's mainly really driven by
14 the cohesivity.
15 Thank you.
16 DR. BERGFELD: Any questions? Will you
17 be available to the teams today?
18 DR. ROTHE: I have to leave in one hour.
19 DR. MARKS: So considering the safety of
20 these products, you've shown us it's much more
21 complex than just the particle size since with
22 pumps in aerosols it depends on the technical
30
1 aspects of how you deliver it and with powders on
2 solvent pressure. Do you have any ideas in which
3 we could word our safety assessment to take this
4 in effect? If we said just to be non-respirable,
5 that isn't quite enough I don't think but have you
6 thought about that?
7 DR. ROTHE: I cannot talk about how you
8 do it here in the U.S. because I come from Europe
9 and therefore I am more in the discussion with the
10 SCCS. So what we are doing is really that we
11 measure all the time the particle size, especially
12 for the hairsprays so we have it under control.
13 And as I said during my talk we really do with
14 every change where we think it's a real change to
15 the composition of the formulation, we measure it
16 again to keep it controlled at just extremely low
17 and then we do the safety assessment as I said by
18 these different approaches.
19 DR. MARKS: So if we said it was
20 formulated in a way that's not respirable, that
21 would take care of particle size but then how
22 would you deal with the mechanics of the delivery
31
1 system?
2 MR. JOHNSON: Well, we've given some
3 thought to some boilerplate which would reflect
4 that, suggesting language perhaps along the line
5 of potential for in-use exposure to respirable
6 particles is minimized to reflect that what we're
7 interested in is not the abstract particles but
8 rather the human safety through actual exposure.
9 DR. MARKS: You've interpreted where I
10 was going, Jay, quite well.
11 DR. BOYER: And just a quick question.
12 You mentioned -- your talk was focused basically
13 on hairsprays, at least the first part of your
14 talk. Can you tell us a little bit more about
15 other types of sprays -- deodorant sprays in
16 particular -- where it seems that the particle
17 sizes generated seem to be lower, particularly
18 going in the propellant sprays, propellant
19 deodorant sprays. Can you tell the panel -- give
20 them a good idea of what the difference is between
21 -- comparing hairsprays to deodorant sprays, for
22 example?
32
1 DR. ROTHE: So we do not do a real
2 difference here in the risk assessment. So we
3 always measure the particle size, and you have
4 seen there also one example for the real-time
5 measurement. That means a portion below 20
6 micron. And you have seen there also that the
7 number is extremely low. It's one order of
8 magnitude higher regarding the number of
9 particles, but it's still extremely low.
10 DR. BOYER: Okay. So for the deodorant
11 products, the fraction -- respirable fraction is
12 still a very, very small fraction of the entire
13 particle size distribution?
14 DR. ROTHE: Yes. Yes. Because also the
15 distance to the face is much larger. And you
16 spray it not in the direction to your face. You
17 spray it below it. So it is just a very small
18 portion which is really reaching the breathing
19 zone.
20 DR. BELSITO: One of the issues that we
21 were discussing at the last meeting was that you
22 could have various chemicals that are put into
33
1 aerosolized forms that would in that form not be
2 respirable but would get down, say, into the
3 tracheobronchial tree and then release a gas or
4 something that then moves down into the alveoli.
5 Your comments on that? Does that happen? Is it
6 realistic that we should be thinking along those
7 lines, or would something like that not be
8 probable?
9 DR. ROTHE: There was a publication from
10 earlier this year. It was -- the last author was
11 from RIFM, Dr. Singal, and they published the
12 example of formaldehyde and they modeled that.
13 And what they could show is that because it's a
14 reactive compound it's reacting very fast with the
15 tissue. So it's very unlikely that it goes really
16 deep into the lung. And you also have to take
17 into account when you look to the small, let's
18 call it channels, so I would assume when you
19 inhale something that every particle gets a higher
20 speed and then the density is increasing. So
21 therefore, I would also assume that some of the
22 particles would again agglomerate in the lung. I
34
1 think it's difficult to test but that is what I
2 would assume just from the physical behavior of
3 the particles because they tend to agglomerate
4 when the density is high enough.
5 DR. BOYER: Also, based on what I've
6 read, particles below about 40 micros or so,
7 whatever is volatile, even water in those
8 particles will tend to evaporate very, very
9 quickly within a fraction of a second. So that
10 whatever is volatile in those particles as they
11 come off of the nozzle is likely to evaporate
12 before any of those particles are inhaled or
13 respired.
14 DR. ROTHE: Yep.
15 DR. ANDERSEN: I think there is an
16 opportunity for an ongoing panel discussion of the
17 aerosol boilerplate at this point in time if
18 you're interested. Otherwise, you have several
19 ingredient reports on the agenda for which the
20 question of use in aerosol products is relevant
21 and you can discuss it ad nauseam at that point.
22 But there's an ongoing opportunity now if there
35
1 are other issues.
2 Jay, I think I captured the language
3 that you said, but if you could repeat it to make
4 sure I got it right as a potential alternative to
5 how we might describe this.
6 MR. JOHNSON: Yeah. The example I used
7 was trying to capture the idea that it's not part
8 -- it's not the particles that sold. It's not the
9 particles as they appear in the can, but what
10 we're really concerned about is the human
11 exposure. And so the language that I was
12 proposing is safe when used, etcetera, when the
13 potential for in-use exposure to respirable
14 particles is minimized. That's perhaps a starting
15 point.
16 DR. BERGFELD: Would James care to make
17 comment now?
18 DR. MARKS: Yeah, I'd like to ask one
19 more question. It would appear from your
20 presentation, the endpoint of non-respirable is
21 really not scientific correct. It's really to, as
22 you said, minimize and presumably if there was a
36
1 concern, a margin of safety would be generated.
2 But to say that if a particle -- you showed the
3 tail off and it was maybe a one percent exposure
4 to the VLI with formalin pump and aerosol two to
5 three percent. Just saying non-respirable
6 wouldn't be scientifically correct. Am I
7 interpreting that correct?
8 MR. JOHNSON: Well, that's what we were
9 trying to -- you know, that's what this language
10 was trying to capture. And it's kind of modeled
11 on when we talk about incidentals. Is that what
12 we -- we never say zero. That the incidentals
13 have to be reduced to zero. We use language like
14 minimized consistent with GNPs. I didn't see how
15 to work GNPs into this language but that is the
16 idea -- is that industry recognizes that these are
17 aerosols. The potential for respirable fraction
18 is there but that it's controlled through the
19 selection of solvents' formulations. Cans, the
20 little spray nozzles, all of that goes into
21 determining what the potential for human exposure
22 is, and as we've heard in today's talk, industry
37
1 is aware of that, monitors that, and tries to
2 reduce that potential to minimize the respirable
3 fractions.
4 DR. BERGFELD: Could I ask a question?
5 In the past we have eliminated or eliminated the
6 need to have aerosol testing or inhalation testing
7 if the particle size was appropriate. It sounds
8 to me that we would have to incorporate other
9 testing in animals. For instance, lung biopsies
10 to see what has occurred. There must be -- we
11 cannot just dismiss it on particle size. What is
12 --
13 DR. ANDERSEN: I think, if I get the
14 thrust of what Dr. Rothe presented this morning,
15 it's embodied in those distribution profiles that
16 you saw in which for pumps it's very unlikely that
17 there's anything less than 10, not that much less
18 than 20. For aerosols it's a bit more problematic
19 because the tail is pretty continuous but it's a
20 small portion. Now the focus of the rest of her
21 presentation was on that small portion. So we're
22 already small. Now it's going to get even smaller
38
1 in terms of what's going to get where. And I
2 think there's no question that that is dependent
3 on formulation. And if we don't acknowledge that
4 we're missing the boat. It's dependent on the
5 physical characteristics. If it's an aerosol, of
6 what's the can pressure, what's the nozzle
7 diameter and shape? So there's lots of factors
8 that are going to influence it.
9 What we've been doing is simply
10 asserting that there aren't going to be anything
11 -- any particles less than 10 so no mas. We've
12 basically given our blessing to that whole
13 category. And what's on the table now is, I
14 think, a bit more reasonable look at it. Yeah,
15 you can produce particles that are going to get
16 into the front end of the respiratory system and
17 maybe even all the way down, but the goal, which
18 is attainable, is minimizing the end- use exposure
19 to such particles. I think that shifts the monkey
20 from us simply asserting that there's no problem
21 to a responsibility on the part of industry to
22 look at each formulation, match the formulation
39
1 with the pressure with the nozzle to minimize
2 exposure to respirable particles. And the use
3 circumstances are a little different for
4 deodorants versus hairsprays. We can acknowledge
5 all of that. And I think we're painting for the
6 scientific community a very accurate picture of
7 our understanding of the whole thing.
8 DR. BERGFELD: Don.
9 DR. BELSITO: I would agree that, you
10 know, we're painting a clear picture of our
11 understanding of particle size and the fact that
12 some things may be respirable and clearance rates
13 over time of those things that are less than 10
14 and 10-20. But I guess even if we say that in-use
15 exposure to respirable particles is minimized,
16 they're potentially respirable and we have
17 absolutely no inhalation toxicity. How do we know
18 that minimal exposure doesn't pose a risk? You
19 know, before we were told there's no exposure.
20 There's a difference between zero and minimal, and
21 so that creates really issues, at least in my
22 mind, as to if we have no inhalation toxicity at
40
1 all and there's going to be minimal exposure, how
2 can you ask me as a dermatologist in particular to
3 sign off and say, that's fine. You know, if I had
4 minimal exposure to a bullet wound in my aorta I'd
5 be dead.
6 DR. LIEBLER: So that was a very helpful
7 talk. Thank you. And I have a question. One of
8 the things that you said is that you had never --
9 if I remember correctly, when you were talking
10 about the distributions for aerosol particles
11 below about 10 microns, I think you said something
12 like seldom ever see more than five percent in
13 this part of the distribution tale. So this
14 actually comes right from Don's question. We're
15 probably going to find ourselves in some cases in
16 situations where we need to have some type of
17 number that provides sort of an upper limit of the
18 amount of the particle size distribution that will
19 be respirable or that will be able to penetrate
20 the lung parenchyma. Are there other sources that
21 we could cite that represent a relatively broad
22 range of aerosols -- hairsprays, deodorants,
41
1 sunscreens, whatever -- that would provide us some
2 numbers to use as reference for this? How much
3 vari -- and that's one question. And second, how
4 much variability is there in your experience in
5 this distribution tale for aerosolized particles?
6 DR. ROTHE: So I think there was no
7 reference out there because industry is not
8 collecting the numbers to publish it so far. So
9 maybe this is something we should think about.
10 The number of five percent is just my experience
11 from the hairsprays. Insofar as I know that for
12 ADPOs it's not very different but it might be
13 different. So, well, maybe we should really
14 collect the numbers. What you can do is you run
15 it through the models and then do kind of a back
16 calculation to come back with a number which is
17 really acceptable but that really also depends on
18 the tox profile of the ingredients, which makes it
19 more complicated. And that's the main reason why
20 industry is doing the risk assessment for each of
21 the products and we are measuring the particle
22 size all the time for each individual product.
42
1 DR. SHANK: I almost say this
2 reluctantly but every time we talk about aerosols
3 on the panel we seem to have comfort if the
4 particle size is large and it just deposits in the
5 nasal sinuses. I would like to remind the panel
6 that the evidence is increasing that particles
7 that lodge in the nasal sinus can be transported
8 by the olfactory nerve directly into the brain.
9 Most of this work has been done with particles
10 that contain metals -- aluminum, iron, thallium,
11 other compounds -- but it's now been shown in
12 humans. The Japanese have just published a couple
13 of studies where particles that lodge in the nasal
14 sinuses are transported along the olfactory nerve
15 directly into the brain. So I don't think we have
16 to mention this in every report but we shouldn't
17 have total comfort in the fact that if it's in the
18 nasal sinuses it doesn't matter. Sorry to bring
19 that up.
20 MR. JOHNSON: Well, we're aware of those
21 papers and they tend to be very small particles at
22 very high concentrations instilled. And I don't
43
1 think we're arguing that the safety need not be
2 assessed. I think what we've been talking about
3 is whether inhalation is a relevant route of
4 exposure and to what extent we need to pull that
5 out. I think if we find that there's a
6 significant -- if it is a relevant route of
7 exposure, then we would need to assess the impact
8 on the lung. And I think what we're arguing in
9 these data is that based on the practice, industry
10 practice, inhalation to insoluble particles is not
11 a significant route of exposure in comparison to
12 the topical route.
13 DR. LIEBLER: So big particles are
14 nothing to sneeze at?
15 (Laughter)
16 MR. JOHNSON: Au contraire. That's
17 exactly what we do, is we sneeze them.
18 DR. BERGFELD: I wonder, Jerry, if you
19 would elucidate when you say relative. I heard,
20 one, soluble versus insoluble. Second was
21 probably particle size. Would there be another
22 definition?
44
1 MR. JOHNSON: We were talking about
2 gases.
3 DR. BERGFELD: And gases?
4 MR. JOHNSON: I mean, the (inaudible)
5 issue of volatiles is entirely different than
6 particles. Particles are, you know, physical
7 states. They settle. You know, the exposure is
8 very time limited because they do settle. One of
9 the problems we often have is you go into a salon
10 and you have this odor associated with it so the
11 presumption is that there's high exposure. But
12 it's not being exposed to the particles, it's the
13 fragrances. And so when we talk about the concern
14 about deposition in the lung and then the gases
15 being off gas, I think the amount that would come
16 from that route of exposure versus the fact that
17 they're volatilized and will be consistently
18 distributed through the room is a whole different
19 model. Fortunately, we have the REXPAM Panel to
20 worry about fragrances.
21 I think the same issue is with
22 deodorants. Deodorants by definition, at least in
45
1 the U.S., do not contain the antiperspirant
2 particles, the polymers, that they are fragranced
3 materials. And so we need to be very, very
4 precise in the questions we ask because water
5 soluble lipophilic gases or either respiratory
6 rate dependent in terms of exposure, insoluble
7 particles are distributed based on the rate of
8 circulation. And all of these need to be
9 integrated into the assessment. But the question
10 we asked was I think much narrower which is the
11 inhalation exposure to particulates when used in
12 aerosols like hairsprays a significant route of
13 exposure? And we say because of the particle size
14 it isn't. In fact, most of it would be deposited
15 and then swallowed, so oral studies would be far
16 more relevant to their assessment than lung
17 effects.
18 DR. BERGFELD: Well, I think that the
19 teams are going to have to wrestle with this today
20 as to what they want to do. Hopefully, some
21 resolution can be made but maybe not. This is a
22 big subject and may entail a lot of study and
46
1 added studies to what we've been looking at.
2 Rachel?
3 MS. WEINTRAUB: I just had a question to
4 Jay. I mean, your previous statement rested on
5 the assumption that fragrances' particle size is
6 sort of insignificant. I mean, I'm not sure. I
7 just sort of drew this distinction. Are you
8 saying that because something is a fragrance its
9 particle size is so small it's not a concern? Or
10 were you more saying that fragrances fall under
11 the jurisdiction of another body? Because in
12 terms of your example of a salon and the
13 fragrances, you seem to imply, and maybe I'm just
14 misunderstanding which is why I'd like a
15 clarification, that the fragrances and the odor
16 wouldn't be a route of potential exposure.
17 MR. JOHNSON: No, I think what I was
18 trying to say was that when one looks at the
19 potential for exposure, the modeling of particles
20 -- solid, insoluble particles -- is really very,
21 very different than vapors, gases, smoke, the
22 whole spectrum of things that we see, fogs. All
47
1 of those will impact the deposition. And so I
2 think when we -- the common sense approach, which
3 is often misleading, is that if we can smell it
4 there must be particle exposure. No, there's not
5 particle exposure; there's exposure to the part
6 you're smelling. And that they're different
7 assessments, not that one can be ignored or were
8 not.
9 DR. BERGFELD: Don.
10 DR. BELSITO: I guess I would agree with
11 you that the bulk of exposure to any given
12 chemical we're looking at will be on the scan or
13 will be oral compared to what will actually reach
14 the alveoli. However, if the toxic endpoint is
15 the alveoli, what actually reaches the alveoli may
16 be, you know, critical because what gets absorbed
17 or what doesn't get absorbed through the skin or
18 absorbed through the GI tract is going to be less.
19 So the, you know, the greatest exposure could be
20 the inhaled exposure to the end organ of concern.
21 That's, you know, in the absence of having any
22 data on inhalation, at least for me, how do I know
48
1 that that end organ is or is not a concern?
2 DR. HILL: And I think what's troubling
3 me at the moment and we need to think about it is
4 because we review ingredients and not
5 formulations, when we're talking about alveolar
6 exposure and if we're talking about a 2.5 percent
7 of a particle distribution and we may have the
8 toxicology impacted by the presence of other
9 things besides the ingredient we're considering,
10 that's an issue that we do talk about in some
11 things but I think we need to consider maybe more
12 greatly than we have in the past if we know that
13 maybe 2.5 percent of the particles -- I said
14 particles -- perhaps 2.5 percent of droplets could
15 get into the alveoli and potentially expose us
16 there.
17 MR. JOHNSON: You know, I certainly
18 agree with Wilma. I think that the issue of
19 inhalation toxicity and the assessment of the
20 safety of products which can be inhaled is going
21 to require more than a couple minutes around the
22 table. As informative as Dr. Rothe's presentation
49
1 was, there's a whole lot of history that goes into
2 this. And I would argue that we do know quite a
3 bit about the behavior of particles, insoluble
4 particles in the lung, and what are the drivers of
5 toxicity? And the concern about particle overload
6 and the issues of transport alone from inhalation
7 into the brain. There's a lot of stuff out there
8 and we would not argue that they're not worth
9 assessing. But I think we've gone way beyond the
10 question that we were trying to address, which is
11 do we get exposed? Is there a significant
12 potential for exposure? And we continue to argue
13 that inhalation is not a significant -- not that
14 it doesn't occur, not that we don't need to look
15 at it, but you know, we could throw in ocular
16 exposure and conduct extensive assessments along
17 those lines. So I think it's something we need to
18 continue to talk about over a series of meetings.
19 DR. BERGFELD: Don.
20 DR. BELSITO: Well, I mean, and I think
21 we usually do look at ocular, I guess my point is
22 up until this meeting my assumption, what I was
50
1 led to believe was that we had no concern because
2 there was virtually no exposure. And now I'm
3 being told, well, we really have no concern
4 because there's minimal exposure but, oh, there is
5 exposure. So I sit on this panel and my name goes
6 out on these documents and I'm a dermatologist. I
7 don't know about Tom and Ron and Kurt and Paul and
8 Dan, I'm not comfortable signing off on that. So
9 if my other colleagues aren't, then I think we
10 probably need on the panel someone with a good
11 degree of respiratory expertise because we're
12 going to be struggling with this every time. I
13 mean, literally for almost every ingredient
14 there's going to be some inhalation exposure. And
15 while as a dermatologist I can say, yeah, chemical
16 X, we only have sensitization data to two percent,
17 but it's been around for 100 years and I've never
18 seen anything happen. I'm comfortable doing that.
19 That's my area of expertise. I'm not comfortable
20 signing off on anything that's potentially
21 respirable, and I don't know about my colleagues.
22 DR. LIEBLER: So I think the fundamental
51
1 difference as a result of our discussion today is
2 we used to think of particle sizes as being a
3 number and we could make a yes-no decision based
4 on the number. And now we realize that particle
5 sizes are distributions and there's essentially
6 with each device there's a probability that a
7 certain percentage of the product and the
8 ingredients will reach the lung -- either the
9 upper airways or the parenchyma and produce
10 potential toxic effects. So I think that's going
11 to be a case by case consideration, depending on
12 the toxicology of the compounds and we will never
13 be able to really have a real handle on the
14 distributions and all the products because as Ron
15 said earlier, we really talking about ingredients
16 as opposed to the products, but we have to
17 anticipate the likely exposures in a product as it
18 would be encountered.
19 I think, you know, I would agree that
20 having some respiratory tox expertise on the panel
21 would be valuable and barring that, at least in
22 the near term, I would recommend that we consider
52
1 perhaps inviting a speaker or two in the next
2 meeting or two to talk with us about aspects of
3 respiratory toxicology that we think might be
4 important to our decision process.
5 DR. BERGFELD: That's a good idea. I'd
6 like to add as a dermatologist that we're very
7 much aware that mucosal membranes absorb
8 everything faster. And it isn't a closed system,
9 the respiratory system. If it's absorbed, it can
10 be absorbed and taken anywhere. So Alan?
11 DR. ANDERSEN: Message received. The
12 transition that I think we're seeing is from the
13 aerosol boilerplate being a decision-making
14 process. It is maybe better relegated to an
15 informational thing to acknowledge that
16 distribution is what we're seeing as opposed to a
17 sharp cutoff. It's certainly information that can
18 and should be part of any safety assessment that
19 involves the ingredient in a product that's
20 aerosolized or sprayed or yada yada yada. But the
21 thought process for safety determination can --
22 must go a bit farther than that. I think that's a
53
1 good bit of progress. The boilerplate has some
2 limited functions here, and what you do in terms
3 of the conclusion about safety is going to be a
4 case by case determination. Inhalation toxicity
5 data could be hugely valuable in making those
6 decisions. In many cases we have those data so
7 that it may not be as much of a leap as we might
8 think. But where we don't it deserves some
9 careful consideration.
10 DR. BELSITO: Just one last, I guess,
11 question to our speaker because it's going to come
12 up later in our determinations, we had gone
13 insufficient on a silylate because under certain
14 sheer forces it had particle sizes of less than 10
15 microns, which would be respirable and it was
16 creating granulomas in mice. So we have a
17 toxicologic endpoint but it's been argued that the
18 silylate particles will agglomerate quite quickly,
19 that those sheer forces that cause those particles
20 to be less than 10 micrometers is not something
21 you would see in a cosmetic product. Are you
22 knowledgeable about the silylates and is that a
54
1 reasonable argument in your -- from your
2 understanding?
3 DR. ROTHE: No, I'm not familiar with
4 that but I think as soon as you can derive a no
5 effect level or a no effect concentration you have
6 a threshold and then you need to know how much is
7 really in the breathing zone. What is the
8 particle size, distribution, and concentration in
9 the breathing zone?
10 DR. BELSITO: So you would need those
11 numbers before you would be able to come up with
12 some level of comfort as to safety?
13 DR. ROTHE: That is what Industry is
14 doing at the moment.
15 DR. BELSITO: Thank you.
16 DR. ANDERSEN: I think that ends the
17 discussion with respect to inhalation exposure.
18 The aerosol discussion. Dr. Rothe, thank you.
19 We have an additional presentation
20 before the team's break. I did not put it on the
21 agenda because I wasn't sure we were going to get
22 the information but those of you that have been
55
1 watching the website will be aware that the
2 Professional Keratin Smoothing Council came in at
3 the 11th hour with additional information and Dr.
4 Robert Golden is here to introduce that
5 information. You'll discuss it in your teams but
6 it seemed like it made a lot of sense for Bob to
7 say his piece once as opposed to repeating it in
8 each of the team meetings.
9 And then not linked to Bob Golden but a
10 separate piece that I handed out today is the
11 submission we received on Friday from the American
12 Chemistry Council, which is blessedly just three
13 pages. For those of you in the audience that want
14 to look at the American Chemistry Council's
15 submission, there were extra copies on the back
16 table. So without further adieu, let's see if we
17 can find Bob's presentation.
18 DR. GOLDEN: I appreciate the
19 opportunity to give these brief remarks. As Alan
20 mentioned, the last time you had the meeting here
21 we -- I was here and promised that there would be
22 some additional data collected by the Professional
56
1 Keratin Smoothing Council, and I'm here to just
2 tell you about, just very briefly, what that has
3 showed.
4 I'm going to talk about two main issues
5 here, two datasets, the first being the results of
6 a salon air testing that was undertaken by
7 Exponent and the second being the preliminary
8 results -- we're still -- more results are still
9 coming in from Analytical Sciences. And those are
10 also quite interesting.
11 The first set from Exponent, it was an
12 air sampling exercise that had this general
13 format. It was -- we got pre- and
14 post-application air samples and then something
15 that really hadn't been done with this sort of
16 deal, the various task-based samples. That was
17 product application, blow drying, and ironing.
18 And there were also several back-to-back
19 procedures performed to see if there was a buildup
20 of formaldehyde in the air. There was also an
21 attempt to evaluate local source control. That
22 didn't work out as well as we thought. And this
57
1 was done in six different salons with four
2 different products. And a lot of samples were
3 collected as part of this exercise.
4 This graph shows the results of the
5 testing program, and these are all the
6 task-specific formaldehyde concentrations in these
7 salons. So as you can see, the higher levels were
8 associated with application and blow drying with
9 lower levels with all the other activities, but
10 importantly, none of the exposures exceeded the
11 OSHA action limit, the TWA or the STEL for the
12 entire period of time.
13 And looking at the results in a slightly
14 different way, these are the averages. So as you
15 can see, even the whole treatment period is way
16 below any sort of OSHA level with pre- and
17 post-treatment pretty similar with post-treatment
18 50 minutes after the procedure is even lower.
19 What we're finding out is that measured
20 formaldehyde levels in the air do not necessarily
21 represent the actual concentrations that would be
22 in the air. As you probably know, most of these
58
1 products contain methylene glycol, is the source
2 of formaldehyde. And methylene glycol has,
3 obviously it has a vapor pressure as I've
4 indicated and a boiling point of 194 degrees
5 centigrade. So it's readily volatilized at
6 temperatures from blow drying or flat irons. And
7 depending on the temperature and the equilibrium
8 kinetics -- recall that there is an equilibrium
9 between formaldehyde and methylene glycol -- some
10 amount of the methylene glycol vapors that are
11 generated are captured and they're indirectly
12 derivatized and measured its formaldehyde in the
13 standard OSHA method using this agent DNPH.
14 Another way of looking at this is the
15 free formaldehyde that is emitted with water vapor
16 generated by these activities is instantly and
17 quantitatively hydrated as methylene glycol and
18 subsequently reported as formaldehyde. Obviously,
19 the only way to know or to be able to separate
20 these into the two components is to have a method
21 that is capable of derivatizing methylene glycol
22 and formaldehyde separately and then measure it.
59
1 And this new data that we have just recently
2 received from Analytical Sciences have empirically
3 demonstrated that this actually occurs. And in
4 this first experiment -- and there's more to come,
5 it's actually ongoing right now -- the
6 determination of the formaldehyde-methylene glycol
7 ratio was investigated and a couple of the
8 smoothing products vaporized in a closed chamber
9 using a 440 degree Fahrenheit flat iron to mimic
10 salon use. And this derivatizing agent,
11 abbreviated BSTFA, is based on its documented high
12 sensitivity to formaldehyde as well as methylene
13 glycol which produces two stable derivatives which
14 can be each positively identified by GC mass spec.
15 So in this first experiment, two of
16 these keratin smoothly products which contain
17 methylene glycol were used and also 37 percent
18 formalin was used. And these were individually
19 vaporized. The vapors were drawn through a tube
20 that contained this derivatizing agent. And while
21 methylene glycol and several of the short-chain
22 algomers were readily identified in the vapors, no
60
1 formaldehyde could be detected at the limit of
2 detection of one PPM.
3 These results are compelling and they
4 really make sense because, as I had mentioned in a
5 previous slide, formaldehyde is really reactive
6 and reacts almost instantly in the presence of
7 water to form methylene glycol. In other words,
8 the equilibrium kinetics in the presence of water
9 will always favor methylene glycol as opposed to
10 gaseous formaldehyde. And obviously, the lack of
11 detectable formaldehyde at this high temperature
12 needs to be confirmed at lower temperatures. And
13 this is ongoing. This is a couple of more
14 experiments that are now underway, two being done
15 at Analytical Sciences using two different
16 measuring protocols that will measure the ratio of
17 formaldehyde to methylene glycol at different
18 temperatures. This was done at the highest
19 temperature. Obviously, this relationship will be
20 a function of how much water vapor is present.
21 That itself is a function of different
22 temperatures.
61
1 So these two are ongoing; another one is
2 underway at a different place, Process NMR
3 Associates, to use high resolution NMR to directly
4 measure the true so-called free formaldehyde
5 concentrations in products at room temperature
6 without any modifications of the product to
7 provide data on hypoethical concentrations.
8 The conclusions of this are that while
9 obviously some formaldehyde is released from these
10 products because there have been sporadic reports
11 of a sensory irritation, I think it makes sense to
12 have a better understanding of the dynamics of
13 these processes and the confounding errors that
14 appear to be present in some of these standard
15 measurement techniques which will obviously
16 benefit manufacturers, salon workers, and
17 consumers. I think that with the heating involved
18 it introduces an element that had never really
19 been thought through very carefully on previous
20 analyses of air in these salons under these
21 conditions. And really, when the complex
22 chemo-dynamics of formaldehyde are accurately
62
1 considered, salon exposures to formaldehyde from
2 these products are well below regulatory limits in
3 virtually all instances.
4 Obviously, exposure to formaldehyde can
5 be further reduced through the use of proper
6 application techniques that would be product
7 portion control. In fact, in one of these
8 products that contained one of the higher
9 concentrations of methylene glycol, it had the
10 lowest -- it produced the lowest levels during all
11 different phases of measurement of these various
12 tasks, and that was simply because they used less
13 of the product on the hair to start with. Now,
14 don't ask me about the details of how much product
15 is used, but apparently their instructions call
16 for less of the product to be used and it
17 obviously showed less levels.
18 And I would just leave you with a couple
19 of suggestions that the PKSC has in terms of these
20 issues. Really, the use of this 13C NMR technique
21 should be really the only relevant method to
22 accurately characterize methylene glycol and free
63
1 formaldehyde or other ingredients in products
2 known to release low levels of formaldehyde
3 without the confounding that now is apparent with
4 some of the methods that are not capable of
5 detecting each one independently.
6 Obviously, this applies as well to
7 measuring air samples with methods that because of
8 the heat introduce artifacts and can over report
9 the amount of formaldehyde in the air. And we
10 also recommend or suggest that you recommend that
11 the use of these products be restricted to trained
12 and licensed professionals with the requirement of
13 even more training and certification on the proper
14 use and safe handling and understanding of
15 ventilation issues. Also, that methylene glycol
16 and formaldehyde not be considered as
17 interchangeable and/or synonymous with specific
18 safe levels for both should be required. And
19 finally as I had mentioned, minimizing the amount
20 of product and the heat used with sufficient
21 ventilation to ensure that stylists and their
22 clients don't experience any sensory irritation.
64
1 If there's any questions or -- sure.
2 DR. BELSITO: I guess just regarding
3 your next to the last bullet that we shouldn't
4 consider methylene glycol and formaldehyde to be
5 interchangeable but set specific safe levels for
6 both, that's sort of hard to do when the level of
7 formaldehyde that will be released by methylene
8 glycol will be dependent upon how it's used. And
9 for us to sit down and set all the parameters and
10 say, okay, methylene glycol is safe for use at a
11 pH when the temperature does not exceed -- it is
12 safe for use at a certain level when the
13 temperature does not exceed -- it's not something
14 that we're going to be able to do despite rather
15 pedantic letters that we got from individuals
16 telling us that on stick and board structures
17 they're very different chemicals. I actually
18 really appreciated that letter, but we know that
19 in fact when you take it off the board and heat
20 it, it actually becomes formaldehyde. So while
21 the stick structure might not be the same, the
22 chemicals that we're dealing with in real life,
65
1 not in the classroom, are the same. So I have
2 problems with trying to do something like that
3 when there are so many variations that we really
4 cannot separate the two.
5 DR. BERGFELD: Rachel.
6 MS. WEINTRAUB: I have a question about
7 the criteria that was used to select the salons
8 for the Exponent study. There's no information
9 about that provided.
10 DR. GOLDEN: The criteria, I couldn't
11 tell -- it was just the availability. I mean,
12 nothing was rigged in any way. They just needed
13 to find salons that had the availability and the
14 customers. All of these were just in regular
15 salons. I couldn't tell you how they were
16 selected. There were six different ones and with
17 four different products.
18 MS. WEINTRAUB: I mean, was there a
19 thought to getting a cross section of urban,
20 suburban, rural or higher end or lower end or
21 independent or chains or anything like that?
22 DR. GOLDEN: Honestly, I couldn't give
66
1 you -- I could find out but I don't know the
2 answer with that sort of specificity.
3 DR. BERGFELD: Don.
4 DR. BELSITO: Because to follow up on
5 that we got similar data the last time from salons
6 which showed that some of the salons exceeded
7 levels. So now we're getting data that shows
8 that, okay, another set of salons they don't. So
9 I agree with Rachel. I mean, how were these
10 selected? And also I guess to address another
11 point, how would industry anticipate restricting
12 these products to trained and licensed
13 professionals with requirements for additional
14 training and certification of proper use and safe
15 handling when we know that products like methyl
16 methacrylate, which aren't supposed to be
17 available to the nail industry, are widely
18 available and used on an ongoing basis in many
19 salons?
20 DR. BERGFELD: A response? Ron.
21 DR. SHANK: I have two questions. The
22 first is about sampling. These were air samples
67
1 collected in salons in California and immediate
2 derivatization and then analyzed in Utah. So you
3 say the derivatives are stable but there was
4 nothing in the analytical chemistry that actually
5 convinced me that there couldn't be conversion
6 between the formaldehyde derivative and the
7 methylene glycol derivative didn't see in terms of
8 standards. So how do we know the chemistry didn't
9 change during the sampling and the storage before
10 analysis took place?
11 DR. GOLDEN: I can't address that issue.
12 I wouldn't even want to speculate. I could find
13 out.
14 DR. SHANK: Okay. That would be a
15 question I'd have.
16 The second one was do all keratin
17 smoothing products require heat?
18 DR. GOLDEN: It is my understanding that
19 all of them do require some level of heat. Now,
20 they're finding out that it may not need as much
21 heat as has traditionally been used, and I know
22 that stylists have been told not to use the high
68
1 temperatures and to use lower temperatures for
2 blow drying. I think one of the things that was
3 found here that I'm not sure had been anticipated
4 is that it had always been thought that the flat
5 ironing step was the one that had -- because it
6 generates obvious vapors from the high temperature
7 use, but that wasn't where the highest levels were
8 show. It was from the application where there's
9 no heat at all in the blow drying. So the
10 application was literally due to using so much
11 product on the hair. And so I guess when it's
12 combed into the hair it's a surface area thing and
13 those were the two highest levels. Still below
14 OSHA levels but those produced more than -- of
15 course, it also could be that the amount of free
16 formaldehyde had already been exhausted by that
17 time so by the time it got to flat ironing there
18 was no more left to volatilize.
19 DR. SHANK: Thank you.
20 DR. BERGFELD: I wonder if you could
21 answer the question are this type of product
22 applied to wet hair or dry hair?
69
1 DR. GOLDEN: It's applied to -- I'm not
2 an expert on this but it's my understanding the
3 hair is washed first and then it's dried but not
4 completely dry. And then the products are applied
5 to the hair after it's dried.
6 DR. BERGFELD: So I would assume then
7 some hydration of the formaldehyde could take
8 place on this wet hair or damp hair.
9 DR. GOLDEN: Anytime there would be
10 water around it would be affecting the kinetics.
11 And I think the generation is the result of the
12 evaporation.
13 DR. LIEBLER: So I would just like to
14 make a comment. One of the consistent arguments
15 presented in your presentation, Dr. Golden, and in
16 the written documents that we've gotten at this
17 meeting and the last meeting from both the
18 Professional Keratin Smoothing Council and the
19 American Chemistry Council has essentially been
20 methylene glycol good, formaldehyde bad; methylene
21 glycol lots of it; formaldehyde, very little of
22 it. Therefore, risk of formaldehyde exposure and
70
1 toxicity is overblown, pardon the pun.
2 (Laughter)
3 DR. LIEBLER: So, and in fact, there's
4 been a lot of emphasis on analytical methods that
5 measure just the formaldehyde part of that
6 equilibrium. I think the problem with all of this
7 is that it really ignores the equilibrium part and
8 the fact that if a droplet of methylene glycol, 99
9 percent methylene glycol and one percent
10 formaldehyde lands on your hair and then the first
11 molecule of formaldehyde reacts with an imino
12 group on your keratin protein, then another
13 methylene glycol dissociates to become
14 formaldehyde to replace it. And then one of those
15 reacts with another protein and another
16 dissociates. And this essentially means that even
17 though you start out with a lot of methylene
18 glycol and a little bit of formaldehyde, you can
19 consume the methylene glycol by driving it to
20 formaldehyde if the formaldehyde has things to
21 react with. This is the basis for the
22 derivatization -- the hydrazine
71
1 derivatization-type methods to measure
2 "formaldehyde" which is really a measure of total
3 formaldehyde and formaldehyde precursors in a
4 sample that can be converted to formaldehyde.
5 This is also the reason that the product
6 "works." It wouldn't work if it was just all
7 methylene glycol because methylene glycol isn't
8 really going to react with proteins in hair to
9 achieve the desired effect. If it did, then
10 methylene chloride would be an even better
11 ingredient for this purpose, and of course, that's
12 not used. So I think that this discussion of the
13 analytical methods and the suggestion that we just
14 measure free formaldehyde is sort of academically
15 interesting but really irrelevant to the question
16 of the safety of the ingredient, which is the
17 focus of our discussion.
18 DR. GOLDEN: And I agree. And
19 obviously, the bottom-line, as some in this room
20 had concluded the last time, is that the goal is
21 to prevent sensory irritation, and that's the --
22 somebody used the term "the eye was acting sort of
72
1 as a spectrophotometer" or something like that.
2 And that really is the goal and in the absence of
3 sensory irritation, that's the goal, to keep it as
4 low as possible. And so the levels that were
5 measured in these studies show they were below the
6 levels that would -- now, could those levels
7 produce sensory irritation in some people? Yes.
8 I think that the concentrations that are known to
9 produce sensory irritation, some people can be
10 affected at 0.4, but 0.3 is a level that almost
11 nobody will experience the symptoms of sensory
12 irritation and this has been confirmed with lots
13 of controlled human studies with just
14 formaldehyde. So I think the goal is to drive it
15 as low as possible and still be under the
16 regulatory limits.
17 DR. BERGFELD: Any other questions?
18 MR. HELDRETH: I have one.
19 DR. BERGFELD: Yes.
20 MR. HELDRETH: Regarding your silylation
21 derivatization method, in one of the papers you
22 submitted, Little, it goes over what is commonly
73
1 reacted with a silylating agent, such as an
2 alcohol. And that occurs quite easily. Whereas
3 reacting with an aldehyde, like formaldehyde, is a
4 mere artifact and the reactivity is much lower.
5 So my question is if you have methylene glycol
6 that's very reactive with the silylating agent and
7 formaldehyde that's not very reactive with the
8 silylating agent, isn't the end result skewed in
9 detecting methylene glycol over formaldehyde?
10 DR. GOLDEN: Honestly, I'm not a chemist
11 and I won't even speculate on that. It's probably
12 a really good question but I don't know the answer
13 to it.
14 DR. BERGFELD: Okay. Thank you very
15 much.
16 MR. JOHNSON: I just --
17 DR. BERGFELD: Yes.
18 MR. JOHNSON: Just one minor comment on
19 Dan's comments, I'm not sure ACC did make that
20 argument. I think they've been much more
21 consistent with the Council's comments.
22 DR. SHANK: Well, but biologic -- from a
74
1 toxicology point of view, biologically,
2 formaldehyde- methylene chloride doesn't make any
3 difference. Okay?
4 MR. JOHNSON: Right. I don't think ACC
5 has made that argument.
6 DR. SHANK: Methylene glycol, sorry.
7 MR. JOHNSON: I'm just -- I'm not here
8 representing ACC but I don't think in their
9 comments they've made those arguments. I mean,
10 keep in mind that the methylene glycol or
11 formaldehyde equilibrium is the way that this
12 chemical exists in us, with the predominant being
13 methylene glycol but we do breathe out small
14 amounts of formaldehyde in our breath due to this
15 dissociation at 98.6 degrees. So it does occur.
16 DR. ANDERSEN: Okay. So I think -- go
17 ahead, Ron.
18 DR. HILL: What I was going to say, what
19 is relevant, however, is that we know if you
20 dissolve methylene glycol in a solution, like
21 formalin, higher order polymers get formed. Now,
22 if you subject those to heat, you're probably
75
1 depolymerizing those back to methylene glycol. So
2 if you were to do an NMR measurement in that
3 solution you will get a false answer versus what
4 would happen if you would then heat and then
5 redeposit because you will have a lot more
6 methylene glycol in the small droplets of vapors
7 initially and also we have information that
8 suggests that methylene glycol itself can react
9 with proteins under the right circumstances. You
10 don't even need free formaldehyde. So, things to
11 keep in mind.
12 DR. GOLDEN: Thank you.
13 DR. ANDERSEN: Thank Dr. Golden for
14 presenting the new information from the Keratin
15 Smoothing Council. And you've got all of those
16 data plus the recent submission from the American
17 Chemistry Council. I failed to mention the
18 separate piece that came in from Jim Hall at USC,
19 a separate discussion of formaldehyde and
20 methylene glycol that Dr. Shank mentioned.
21 So we have a lot of information
22 additionally on the table. We had previously
76
1 received input from the Nail Manufacturers Council
2 that appeared to suggest formaldehyde/methylene
3 glycol in nail hardeners was on the order of two
4 percent. The one piece of data that I had seen on
5 FDA testing, Don's products, since I can't
6 pronounce it, it was 2.2 percent. So there was a
7 level of consistency in those findings.
8 Were there any additional data from the
9 FDA testing, Linda, that would be
10 relevant/important in that regard?
11 DR. LORETZ: No, there's no additional
12 information to present here.
13 DR. ANDERSEN: Okay. So I think it's
14 time for the teams to break out into their
15 respective rooms. The collective institutional
16 memory is that Dr. Belsito got to stay put last
17 time, so now you're taking a hike, Don.
18 SPEAKER: Where are they going?
19 DR. ANDERSEN: I have no idea. I assume
20 it's out the hall and to the right.
21 DR. MARKS: I'm going to ask those
22 individuals who are sitting back there, there are
77
1 plenty of seats up here. Don't worry, I won't
2 call you by the nametag but if you want to make
3 comments you'll be at the microphone.
4 Well, this could be pretty quick with
5 Christina, so does anybody want to reopen? So our
6 first is the re- review of 4-Chlororesorcinol.
7 And in 1996, the CIR Final Report found this
8 ingredient was safe as currently used in hair dye
9 formulations, generally less than one percent.
10 And the uses have increased significantly, 33 to
11 210, and the concentration has increased some
12 also.
13 Ron, Tom, Ron. R-T-R. Does anybody
14 want to reopen?
15 DR. SHANK: No, don't reopen.
16 DR. SLAGA: No.
17 DR. BERGFELD: No.
18 DR. MARKS: No, okay. Let's move onto
19 the second ingredient. No, actually, is there any
20 discussant points that we should -- other than
21 obviously we need the hair dye epidemiology
22 boilerplate, is there anything else?
78
1 DR. BERGFELD: I have a question. Did
2 anyone ask us to reopen this to increase it to 2.5
3 percent? I mean, if the Europeans have okayed it
4 up to 2.5, have we been specifically requested to
5 relook at it? I didn't see anything.
6 DR. MARKS: I didn't either.
7 DR. BERGFELD: Have we been requested to
8 look at a higher concentration? No? That would
9 be the only question I had.
10 DR. MARKS: So Christina, we've decided
11 not to reopen and the discussion will be, of
12 course, the boilerplate.
13 MS. BURNETT: Okay.
14 DR. MARKS: Next.
15 DR. HILL: They'll make some editorial
16 comments about some of the stuff in the discussion
17 so you've just got to take note of them.
18 MS. BURNETT: Just in the discussion
19 section?
20 DR. HILL: Yes.
21 MS. BURNETT: Well, the format will
22 completely change.
79
1 DR. HILL: Yes.
2 MS. BURNETT: Okay.
3 DR. HILL: And we'll be looking at it
4 again, correct?
5 MS. BURNETT: You will see the summary
6 at the next meeting.
7 DR. HILL: Yeah, okay.
8 DR. EISENMANN: Sorry to interrupt but
9 we would like, if you cannot reopen it but have
10 the concentration be up to two percent because
11 that's how it is being used.
12 DR. MARKS: How can you if you change
13 the conclusion?
14 DR. EISENMANN: Because it was a safe as
15 used conclusion and back then the concentrations
16 were not -- I mean, came from, you know, were
17 (inaudible) in the FDA database. It wasn't -- I
18 mean, it was -- that was -- although the date of
19 the report was 1996, the concentration of use
20 information was actually from the last time the
21 FDA reported it, which was 1984 if I'm not
22 mistaken. So you really didn't have a good use
80
1 concentration at that point. But the current use
2 is two percent. So if you --
3 DR. MARKS: Yeah, so the local lymph
4 node assay would suggest that that's a safe
5 concentration. And of course, we've heard also in
6 Europe they felt up to 2.5. So I don't know that
7 we need to reopen that. That's just in the
8 discussion portion.
9 DR. EISENMANN: Right. If you can
10 handle that in the discussion that would be
11 appropriate.
12 MS. BURNETT: Okay. Because the way the
13 conclusion is worded is "safe as used." And if
14 the concentration --
15 DR. MARKS: Correct.
16 MS. BURNETT: -- that should cover past
17 and current concentration.
18 DR. MARKS: That's correct.
19 MS. BURNETT: So.
20 DR. MARKS: So, if I hear you correct,
21 Christina and Carol, was it that we really didn't
22 know what the concentration was in that initial
81
1 report? Or was it one percent?
2 MS. BURNETT: It's old.
3 DR. MARKS: Oh, I know it's old but I
4 got the sense that there was some uncertainty as
5 to what the use concentration was then.
6 DR. EISENMANN: In the past they
7 reported in ranges so it wasn't exact. And so
8 again, although it was reported as being 1996, it
9 was 1984, so we really didn't have a good
10 knowledge of what it was used in 1996.
11 DR. MARKS: Okay. So as long as --
12 DR. BERGFELD: Are you suggesting we
13 could go to 2.5 as well?
14 MS. VERGNES: Well, I would suggest that
15 perhaps you stay with the value that's consistent
16 with what the European Union SCCS' opinion was,
17 which is two percent, I believe.
18 DR. EISENMANN: I think it was 2.5.
19 MS. VERGNES: Oh, was it 2.5?
20 DR. MARKS: Yes. But it still doesn't
21 change the conclusion of the original report,
22 which is it's safe as used concentration and we
82
1 still feel it's still safe at the use
2 concentration as it's used today. So we can put
3 that in the discussion certainly.
4 DR. BERGFELD: The question I had, would
5 it be two percent or 2.5? And if it's 2.5, it
6 does agree with the European.
7 MS. BURNETT: The EU is 2.5.
8 DR. BERGFELD: Yeah. So why don't we do
9 that and put that in the discussion as well?
10 DR. MARKS: Well, I think we should
11 mention that.
12 DR. BERGFELD: Yeah.
13 DR. MARKS: Any other editorial or
14 discussant points? Not reopen.
15 We'll move on to sodium
16 lauriminodipropionate. And so at the last meeting
17 we reopened this safety assessment. It was
18 originally reviewed in the late 1990s. Now we
19 have available data that addresses the safety of
20 the asset and the sodium I-compound.
21 MS. BURNETT: We have two published
22 studies that we did not incorporate into the
83
1 report because Alan and I felt that they really
2 didn't contribute anything, but I brought them.
3 We're free to look at just in case. One discusses
4 the disodium lauriminodipropionate and tocopheryl
5 phosphate complex together in a shaving cream. We
6 felt you couldn't really discern what the action
7 was, whether it was from the tocopheryl or from
8 the laurimino compound but we brought it along
9 just in case. And the other one discusses how
10 surfactants inhibit staph RAS production in Toxic
11 Shock Syndrome. So I'll pass them down. You can
12 take a look. If you feel that they should be
13 incorporated, we can incorporate them.
14 DR. SHANK: In the first paper, was
15 there a health effect due to the --
16 MS. BURNETT: It's mediating shaving
17 irritation.
18 DR. SHANK: Okay.
19 DR. HILL: Because one of the major
20 issues that arose was the fact that the
21 lauriminodipropionate -- I wanted to crosscheck
22 that -- could be present as an impurity in at
84
1 least the raw material up to five percent. We
2 were awaiting concentration of use data for this
3 particular product, excuse me, ingredient. Do we
4 have that information yet?
5 DR. EISENMANN: No, not yet. It's not
6 done. It takes about four months usually to get
7 the use survey and it's not complete yet.
8 DR. HILL: Understood.
9 DR. EISENMANN: So far I don't have any
10 uses report of the disodium or the acid. It's
11 still the same.
12 DR. HILL: Right. And that's what I
13 would expect. And it's sort of an academic issue
14 anyway because you're going to have a product
15 that's probably buffered at some point in the
16 production to a particular pH where what's in
17 there is in there.
18 I just wondered because even right up
19 front in the memo and in the transcript when Alan
20 was discussing this, he says, he writes a little
21 -- he said "a little glitch." Now we're talking
22 about five percent and we don't have the
85
1 concentration of use data and we have insufficient
2 on that lower iminodipropionate to draw
3 conclusions. So if we knew what the total
4 concentrations of use are and we knew what the
5 relevance of that five percent might potentially
6 be and could make some conservative estimates,
7 then we'd have a better chance of knowing what the
8 conclusions need to be here. I know we don't
9 review based on the safety of the impurity per se,
10 but at least our discussion could say the impurity
11 level needs to be kept below thus and such percent
12 if we had something to go on.
13 DR. MARKS: So we issued the draft
14 tentative amended report with the I-, the
15 iminodipropionate and the acid and the salts as
16 being safe. Do we want to move on to issue a
17 tentative amended report with that conclusion?
18 DR. HILL: If we do that we're going to
19 need some work on the discussion from where I sit.
20 DR. MARKS: So I think in the
21 discussion, picking up on that, Ron, is in the
22 previous report it included the amino, the
86
1 A-compound. Now we're splitting this out so we're
2 not including that in this report. So I think we
3 have to have that in the discussion. And the
4 reason that we split it out was chemically it was
5 different. Is that correct? So it really
6 shouldn't have been included in the original
7 report as a group. So that should be in the
8 discussion.
9 Any other discussant points?
10 DR. BERGFELD: I'm wondering about the
11 current concentrations of use, if you need those
12 before you move forward on this.
13 DR. EISENMANN: That's what I would
14 think.
15 DR. HILL: That's what I was trying to
16 state is we're lacking key information. Is this
17 why we --
18 DR. MARKS: So would you suggest then we
19 table this until we get the concentration of use?
20 It sounds like we have to.
21 DR. EISENMANN: I wouldn't have brought
22 it to you to begin with but, yes, that's --
87
1 DR. MARKS: Okay. So, team members,
2 table until we get the concentration of use?
3 Okay, since I will be the presenter tomorrow.
4 DR. BERGFELD: Could I ask a question?
5 Is there any further discussion items other than
6 those mentioned? I mean, everything is borrowed
7 in this document. Do we need to discuss the lack
8 of carcinogenicity data? Do the genotox cover
9 that and the 28 day?
10 DR. SLAGA: That's a good question. We
11 have genotoxicity data.
12 DR. BERGFELD: Right. That will cover
13 it?
14 DR. SLAGA: Both bacterial, as well as
15 the mammalian.
16 DR. BERGFELD: So if we could put that
17 in the discussion though.
18 DR. SLAGA: Mm-hmm.
19 DR. HILL: I will, you know, say it is a
20 little bothersome that we're really making an
21 assessment based on analogous compounds and likely
22 routes of metabolism without actually knowing
88
1 anything about that. So I am bothered by that.
2 But yet on the other hand, the things that are
3 likely, including ones that aren't further
4 mentioned like continued change shortening by beta
5 glu -- excuse me, beta oxidation cycles and so
6 forth, don't lead to anything that cause an issue
7 in my mind. It's bothersome that we're going by
8 analogy to similar compounds without any sort of
9 data on the add-me. I wasn't sufficiently
10 bothered by it to say we have to just shut this
11 down or that we need a lot of new data.
12 DR. BERGFELD: So would you make a
13 comment in the discussion regarding the lack of
14 that information "but because of" whatever you
15 said?
16 DR. HILL: Yeah. Tabling it would allow
17 time to say what should that "but because of" need
18 to be.
19 MS. VERGNES: Excuse me. Just to be
20 clear, that invoking the ADME and likely
21 metabolism was done in the context of the
22 developmental tox because that was an endpoint for
89
1 which there weren't data.
2 DR. HILL: Correct.
3 MS. VERGNES: Just to be clear on that.
4 DR. HILL: Yes.
5 DR. MARKS: And then --
6 DR. HILL: Well, we had no
7 carcinogenicity data and no developmental tox
8 data. That's the thing.
9 MS. BURNETT: Back to the concentration
10 of use, in the past we have issued reports where I
11 wouldn't say that we haven't received a survey yet
12 and I anticipate we probably will receive that by
13 December, but we do have some data on the
14 disodium. Up to 1.5 percent, they didn't see any
15 systemic effects in a hair dye solution, nor did
16 they see it in repro. There's only two reported
17 uses for the disodium VCRP and there are no
18 reported uses for the acid. I'm pretty sure we're
19 not going to find anymore data unless something is
20 submitted as unpublished.
21 DR. HILL: It was the low concentrations
22 that we had that gave me the comfort level that
90
1 even though we're missing some pieces of data and
2 the lack of any structural alerts in this molecule
3 or any structural alerts in any of the metabolites
4 that could reasonably be expected to be formed,
5 gave me enough comfort to say I think we're okay
6 here. But if we suddenly discovered that there
7 was a leave-on use at 10 percent, then that will
8 be potentially a different deal.
9 DR. EISENMANN: I don't think that's
10 going to happen.
11 DR. HILL: I don't either.
12 DR. EISENMANN: But like I said, I just
13 don't have the information yet for sure. So, I
14 mean, you could go forward and say if it changes
15 you're going to have to come back with it, but
16 when it gets to going to a final, I would prefer
17 to see the reports delayed until I get a chance to
18 actually get the information. When you're going,
19 I mean, earlier on, no, there's no reason to delay
20 them for more concentration of use information,
21 but when it's going to be final it would be nice
22 to have a pause in order to let them have a
91
1 chance to get the information.
2 DR. HILL: Right. And quite frankly, I
3 mean, there might not even be a safety issue if
4 it's leave-on at 10 percent. It's just that we
5 don't have the data to support that. That's the
6 main thing. And also given that --
7 DR. EISENMANN: It's going final.
8 DR. HILL: -- that potential impurity,
9 we have to reflect on that.
10 DR. EISENMANN: Or going tentative.
11 DR. BERGFELD: So what are you going to
12 do with it?
13 DR. MARKS: Well, first thing, I had
14 another editorial comment on page one under the
15 introduction, the last paragraph also refers to
16 the amino, the A-compound that was in the original
17 report. I would just, again, clarify that and
18 make sure it corresponds with the discussion.
19 It's the reason we actually did reopen the report.
20 We're just not including the amino compound in
21 here because it was chemically different.
22 My understanding is tomorrow we're going
92
1 to move that we table this tentative amended
2 report for needing the concentration of use table
3 updated at this point. We assume we're going to
4 move on with safe as used for the
5 iminodipropionate acid and its sodium salts, but
6 we need to see that use table.
7 Is that fine, team?
8 DR. HILL: And also whenever we get it
9 back, this is the book that has the imino. If
10 we're not going to rule any of that data into the
11 report for the imino, if we discover that there's
12 a five percent concentration of use in leave-on
13 and knowing that there's a potential five percent
14 impurity, then we either need to capture it or I
15 need this book back. It has what information we
16 do have on imino or the references to that. Do
17 you get what I'm saying?
18 MS. BURNETT: You want your book back?
19 DR. HILL: Well, I mean, or -- because
20 this is the June book.
21 MS. BURNETT: You can keep that.
22 DR. HILL: I could hang onto that?
93
1 MS. BURNETT: Yeah.
2 DR. HILL: Okay.
3 MS. BURNETT: I don't need that.
4 DR. MARKS: Okay. Any other discussant
5 points? I'm going to move that we table this
6 until we get the use concentrations for these
7 ingredients.
8 DR. BERGFELD: I'm just going to come
9 back as a devil's advocate here. In your
10 discussion then at the present time you're going
11 to discuss the concentrations and it would be 1.5
12 percent or lower unless so stated by the new use
13 concentrations. You're going to discuss lack of
14 carcinogenicity that the genotox covers. You're
15 going to report no reported use of the acids. And
16 then you have to put a caveat in your conclusion
17 on that if you should be blah blah blah. We've
18 done those caveats if used to be in concentrations
19 of use as reported in this document.
20 DR. MARKS: And we're going to discuss
21 the imino compound and why that was not included
22 in this report.
94
1 DR. BERGFELD: Good, okay.
2 DR. MARKS: Okay. Glutaral. That's in
3 the Pink Book.
4 So in June of this year we decided that
5 this ingredient could be reopened and amended so
6 that glutaral is safe for use at concentration up
7 to 0.5 percent in rinse-off products, safe at
8 concentration up to 6 x 10-6 when present as an
9 impurity in leave-on products and unsafe for use
10 in aerosol-wise products.
11 This now would be issuing a tentative
12 amended safety assessment for glutaral. Comments?
13 DR. SHANK: Why do we put in a
14 concentration limit here that's 1,000 times the
15 use concentration? Can't we just say safe --
16 DR. SLAGA: As used.
17 DR. SHANK: -- as used? Currently used?
18 The standard thing? I don't see the point in
19 putting in a number which is so much higher than
20 the use concentration. Unless I'm wrong, the use
21 concentration, if that's correct, is pretty small,
22 6 x 10-6 percent?
95
1 DR. EISENMANN: Yes. And that's -- we
2 did confirm that's an incidental concentration.
3 DR. SHANK: Okay.
4 DR. EISENMANN: It's not --
5 DR. SHANK: It's not a use.
6 DR. EISENMANN: And so I didn't -- if
7 you want to -- I didn't ask the question and
8 somebody gave me that answer so I don't know what
9 the highest incidental level would be because I
10 didn't ask that question. This is what somebody
11 happened to give as a response.
12 DR. SHANK: So the only time it's
13 present in cosmetic formulations is as an
14 incidental compound? It's not an ingredient?
15 DR. HILL: Leave-on versus rinse-off.
16 Leave-on versus rinse-off.
17 DR. EISENMANN: Not that, I mean, I'm
18 not aware of. And actually, after the meeting,
19 the last meeting, Don Havery sent us the list of
20 companies who were reporting to the VCRP that they
21 were using it in leave-ons and I went back to
22 those companies and they've indicated to me that
96
1 they're not using it in leave-ons.
2 DR. SHANK: Okay.
3 DR. EISENMANN: So, and they were
4 supposed to go back to the VCRP and tell them but
5 I don't know if that happened or not.
6 DR. SHANK: Adding it as an ingredient
7 at a level of 60 PPB, I wonder what does it do at
8 that little concentration? It doesn't do
9 anything.
10 DR. EISENMANN: It doesn't do anything.
11 It may have a role in an ingredient.
12 DR. MARKS: I like the way you've
13 simplified it, Ron. It makes great sense. Safe
14 as used.
15 DR. SHANK: But if it's not used --
16 MS. BURNETT: Yeah, well, and as you can
17 see, the uses have decreased, well, yeah pretty
18 significant since the last time it was reviewed
19 from 60 to 13. And if they're saying that the 13
20 uses might be incorrect, it might not be used at
21 all.
22 DR. HILL: I was puzzled and I guess I
97
1 didn't notice this when I was looking through,
2 yeah, I thought on rinse-off products we did have
3 it being used essentially as a preservative up to
4 0.5 percent possibly but we have most of those 13
5 uses, they're not giving us concentrations of use.
6 But my impression was that it was used in
7 rinse-off products and only incidentally in
8 leave-ons. Except when you look at the table,
9 she's only got concentrations of use 6x10-6
10 percent even in the leave-on. But I think that --
11 or the rinse off -- but I thought that might be
12 because we're simply not getting reports on the
13 rinse-off ones. Because of you look at --
14 DR. EISENMANN: It's possible but I
15 think the 0.5 percent is the limit in Europe.
16 DR. HILL: And I don't think there's any
17 problem with that if it's rinse-off. I think we
18 had all the data to support that that would be
19 fine in rinse-off and so --
20 DR. EISENMANN: As far as we're
21 concerned, you could change your mind and not
22 reopen it but -- because we clarified this. I
98
1 mean, the last time you voted to reopen and to ask
2 for the clarification and we provided the
3 clarification and now you can change your mind if
4 you wanted to. But, I mean, there are new data.
5 There are that new inhalation -- cancer study. So
6 how you deal with that I'm not sure.
7 DR. BERGFELD: If you change your
8 conclusion you have to reopen. And so if you
9 change your conclusion on your leave-ons, you have
10 to reopen.
11 DR. EISENMANN: Right. But we don't --
12 I mean, if you don't change the conclusion, I
13 don't think we would mind.
14 DR. MARKS: So the original conclusion
15 was that it was insufficient to support the safety
16 on leave-on products because of that concern with
17 carcinogenesis.
18 DR. SHANK: And it shouldn't be used in
19 aerosolized products.
20 DR. MARKS: Right.
21 DR. SHANK: So that's probably the most
22 logical thing, is don't reopen it or --
99
1 DR. HILL: But it's showing one use in
2 sprays and six uses in hair non-color according to
3 the 2011 survey. Now, if it's only there
4 incidentally at 6 x 10-6 but we don't have -- we
5 don't have any concentration of use data at all on
6 either of those.
7 DR. MARKS: So if we don't reopen we
8 could put that in the discussant point that we
9 believe this is incidental glutaral in there and
10 at that concentration it wouldn't pose a health
11 hazard.
12 DR. HILL: Let me clarify what I just
13 said. On the hair non-coloring we do have the
14 concentration. That's the one where it's 6 x
15 10-6. Sprays, we don't have a concentration
16 report. Dermal contact, we don't have a
17 concentration report. Mucous membrane, there's
18 one reported use and it says -- that might just be
19 a bath product where it's diluted ridiculously
20 before we ever get contact with it. But we don't
21 know that. Right? Or do we?
22 MS. FIUME: It's not a bath product
100
1 according to the use table.
2 DR. HILL: Do we have the full use
3 table? We just have the summary table here. Was
4 the full use table out there on the web and I
5 should --
6 DR. BERGFELD: Page 18.
7 MS. FIUME: Page 18.
8 MS. BURNETT: He's looking for the raw
9 data.
10 MS. FIUME: And FDA is checking the VCRP
11 to see if it's been changed or not.
12 DR. HILL: So where am I looking on page
13 18? I apologize.
14 MS. BURNETT: I'm sorry. You're asking
15 for the raw data.
16 DR. HILL: Yes.
17 MS. BURNETT: And I don't have the raw
18 data incorporated in this report. I put it in the
19 previous version.
20 DR. HILL: Yes.
21 MS. BURNETT: But I didn't carry it over
22 to this. So I apologize.
101
1 DR. HILL: I've got -- I've got -- that
2 means I have it here, right? Because I have the
3 past book.
4 MS. BURNETT: Right. The mucous
5 membrane is not likely a diluted bath product
6 because if you look at the new concentration use
7 table, we have a line now, line entry that
8 accounts for diluted bath products and it's not
9 there.
10 DR. HILL: It's not.
11 MS. BURNETT: So it must -- I don't
12 remember what it was but it's not a bath product.
13 DR. HILL: Well, the raw data here
14 doesn't seem to be any more enlightening,
15 actually. I've got the book here if you want to
16 have a look at it.
17 DR. MARKS: So it seems like the present
18 propose conclusion acknowledges that it may be an
19 impurity in leave-on and that we do not feel it's
20 unsafe at that concentration of 6 x 10-6. I think
21 the question, Ron, is do we go back to -- there
22 are three options as I see it. One, do not
102
1 reopen, which reaffirms what we had before.
2 Handle the impurity in the discussion. The second
3 would be just say safe as used. Again, handle the
4 impurity in the discussion. The third is reopen
5 and have a new conclusion. What does the team --
6 how does the team want to handle this?
7 MS. BURNETT: We just were updated by
8 the FDA. There's currently 14 uses.
9 SPEAKER: There are 14 uses, six of them
10 are on leave-on products.
11 DR. BERGFELD: Do you have a
12 concentration?
13 SPEAKER: For rinse-off it's reported
14 from PCPC as 0.5 and 10-6 as we have said
15 (inaudible).
16 MS. BURNETT: From the previous raw data
17 that I have that was for the 13 uses. The one
18 mucous membrane is for a bath soap detergent. But
19 it's not a diluted bath.
20 DR. SHANK: Okay.
21 DR. MARKS: So team.
22 DR. HILL: Nonetheless, that would be
103
1 concentration in the soap.
2 DR. MARKS: Yes.
3 DR. HILL: You wouldn't actually be
4 exposing mucous membranes to that kind of
5 concentration.
6 DR. MARKS: Correct. It would be
7 diluted out. Ron, which way do you want to move?
8 DR. SHANK: Well, if we're not going to
9 change the conclusion, I don't see any reason to
10 reopen it. And what we've just talked about can
11 be put in the review summary.
12 DR. HILL: I agree.
13 DR. MARKS: Tom?
14 DR. SLAGA: I agree, too.
15 DR. MARKS: Okay. So tomorrow we move
16 that we not reopen. And the main discussant in
17 the re-review is going to be the issue of the
18 impurities in leave-on or incidental finding. Do
19 we want to really -- do we use the word
20 "impurity"?
21 DR. SLAGA: (Inaudible) compound.
22 DR. MARKS: Yeah.
104
1 DR. SLAGA: So it's really not impurity.
2 DR. MARKS: No. It's the incidental
3 amount in leave-on. Or how do you -- or the small
4 amount. I think I'll word it in the discussion
5 it's going to be the small amount of glutaral
6 which is present in leave-ons. And that's safe.
7 Any other discussants? Okay.
8 DR. BERGFELD: The aerosol statement
9 (inaudible).
10 DR. MARKS: The aerosols.
11 DR. BERGFELD: The aerosol --
12 DR. SHANK: That was in the original?
13 DR. BERGFELD: Was that --
14 DR. SHANK: That was in the original
15 conclusion.
16 DR. MARKS: Yes.
17 DR. BERGFELD: Did you want to just
18 discuss aerosol just a moment here -- an animal
19 study here and the meaning of that animal study?
20 The inhalation study was on mice and rats. Is
21 that -- that's a meaningful study. It can be
22 translated to humans. And the reason for saying
105
1 it's not good or safe in aerosols based on that.
2 Just out of -- I mean, it doesn't have to be a
3 turning point here but we have a lot of aerosol
4 questions coming up so how much emphasis do you
5 put on that animal study when you have no human?
6 DR. SLAGA: That's all we have.
7 DR. BERGFELD: Okay. So that's why you
8 say it's unsafe.
9 DR. EISENMANN: I think the original
10 conclusion was unsafe because you didn't have that
11 study. Now if you have -- I mean, and you don't
12 need to change it because there's not that much
13 use. But if you were going to consider that study
14 you might be able to say a safe level now because
15 you have an animal study. But we all have a good
16 level to say what is being used in an aerosol
17 product. So you don't really have a comparison.
18 I mean, that's the reason why, because you don't
19 have the use concentration. Not because you don't
20 have the study; because you have a negative cancer
21 study.
22 DR. SHANK: Those inhalation levels are
106
1 quite low and with reasonably significant
2 toxicological results. So on the basis of the
3 inhalation data I think we're right to say it
4 shouldn't be used in aerosol products and not try
5 to find what would be a safe level depending on
6 aerodynamic properties.
7 DR. BERGFELD: I agree. But shouldn't
8 that go in the discussion as well?
9 DR. SHANK: Yes. Well, in the --
10 DR. BERGFELD: In the new discussion.
11 DR. SHANK: Yes.
12 DR. HILL: Yeah.
13 DR. SHANK: Since we're on that study,
14 the last paragraph on the inhalation it says the
15 temperatures were 60 to 65 degrees centigrade. I
16 don't think anybody does an inhalation study at
17 that high a temperature. The animals would die.
18 That must be a mistake.
19 MS. BURNETT: I'm sorry, which page are
20 you on?
21 DR. SHANK: Oh, sorry. Panel Book 15,
22 Report 5.
107
1 MS. BURNETT: Thank you.
2 DR. SHANK: On the inhalation non-human.
3 Just above repeated dose toxicity it says "the
4 temperature was 60 to 65 degrees centigrade."
5 DR. BERGFELD: Christina, can I ask you
6 a question about format? You have non-human and
7 human. I got that. On page 8 you get into
8 reproductive and genotoxicity and you switch to in
9 vitro in vivo. Is that non-human and human? No?
10 Just out of curiosity.
11 MS. BURNETT: Let me think about that.
12 Well, for the most part they're all going to be
13 non-human but I think we still wanted the
14 differentiation between a cellular study versus a
15 --
16 DR. BERGFELD: I agree.
17 MS. BURNETT: -- we can say cellular
18 non-human and human.
19 DR. BERGFELD: I don't know but I think
20 there has to be some consistency.
21 MS. BURNETT: Okay.
22 DR. BERGFELD: I'm not sure I can solve
108
1 it because under the non-human you also put the
2 lymph node assay. Under the human versus
3 non-human and irritation sensitization studies.
4 So that's not consistent with what you just did
5 under (inaudible).
6 MS. BURNETT: Okay.
7 DR. BERGFELD: But whatever.
8 Consistency.
9 MS. BURNETT: We will take this back and
10 discuss it and try to work out a solution.
11 DR. BERGFELD: What's the problem with
12 using animal?
13 MS. BURNETT: I'm not sure.
14 MS. FIUME: My understanding is the new
15 terminology is to be non-human and human. This
16 was discussed in a staff meeting.
17 MS. BURNETT: Yes.
18 MS. FIUME: But can I ask, so the local
19 lymph node assay --
20 DR. BERGFELD: It's a sensitization.
21 MS. FIUME: So is it under -- I saw it
22 under non-human. That would be as opposed to in
109
1 vitro or something like that?
2 DR. BERGFELD: Yeah.
3 MS. FIUME: I had that misunderstanding
4 as well but I think it's because it's worked with
5 the animals. I was told that it's actually a
6 non-human study and not an in vitro study because
7 it's in animals.
8 DR. BERGFELD: Well --
9 MS. FIUME: When Ivan comes back in the
10 room he can probably be the best person to define
11 all of the --
12 MS. BURNETT: I'm not sure if this is a
13 movement through the Journal wanting us to do it
14 or if it's through the toxicology community or
15 what. I just know that we've kind of just been
16 told to start using that. So we can hash it out
17 and see what we can do.
18 DR. MARKS: So, tomorrow I'm going to
19 move that we not reopen the safety assessment of
20 glutaral, that we reaffirm the conclusion that it
21 is safe for use at a concentration up to 0.5
22 percent in rinse-off products. There is
110
1 insufficient data to determine a safety glutaral
2 in leave-on products. Glutaral should not be used
3 in aerosolized products. And since there's no
4 change in the discussion or in the conclusion and
5 in the discussion, we'll mention it is safe in
6 leave-on products since there's such a small
7 amount of the impurity. We're aware of the
8 impurity but that's such a small amount, not
9 enough that we would reopen what we had previously
10 concluded. And that, too, we will discuss the
11 inhalation. Does that sound okay?
12 So next we have anisole, the 2-Amino-4-
13 Hydroxyethylaminoanisol and its Sulfate Salts.
14 This is the first time we've seen this report.
15 It's a hair dye. There is zero uses of the lead
16 compound I saw in 94 uses of the sulfate salts and
17 the maximum concentration is three percent prior
18 to dilution. I'll open it up for discussion.
19 Ron, Tom, and Ron, I particularly -- Tom, why
20 don't you address the nitrosamine mentioned on
21 page 7 of book? And do we have any add-ons that
22 we want to --
111
1 DR. SHANK: I don't know about add-ons.
2 This is an oxidated hair dye. We have sufficient
3 data to say I think it's safe for that use, both
4 the sulfate and the free base.
5 DR. SLAGA: I agree, safe as used.
6 DR. SHANK: The nitrosation would be the
7 boilerplate, whatever we decide that's going to
8 be.
9 DR. MARKS: So Tom, fine. And Ron Hill?
10 DR. HILL: When I look through this, and
11 up until I'm sort of reviewing my notes, I kind of
12 come to the same conclusion but I'm noticing that
13 we don't have any carcinogenicity study. The
14 structure of this is such that I would have liked
15 to have seen that data. I need to sort of have a
16 sense for how much suggestion from the muta --
17 excuse me, the genotoxicity data we would have
18 concern for that because what I'm noticing is that
19 I don't know anything about the vehicle when
20 they've done these toxicity studies in the hair
21 dye formulations because I don't have information
22 about the pH which would be all important in terms
112
1 of any dermal absorption, but I notice a lot of
2 the dermal tox and the dermal absorption studies
3 were done with either the dihydrochloride or the
4 sulfate in tap water, which means we're not going
5 to get a good picture of how much free base is
6 present, which would be the one that would be
7 penetrating any skin layers. So it almost seems
8 to me that there's an artificial skewing of the
9 data towards safety if we, in fact, don't know the
10 key piece of information, which is how much
11 freebase is actually available in these dermal
12 studies. And that should be zero if you take the
13 sulfate or the dihydrochloride and dissolve it in
14 tap water when you do that work. Or nearly zero.
15 DR. SLAGA: There's sufficient
16 genotoxicity data even though some of the
17 mammalian is plus or minus. Most of the essential
18 (inaudible) in vivo mammalian data is negative, as
19 well as the --
20 DR. HILL: Okay. So I need some tox
21 consult here. When it says the compound was
22 mutagenic and that a mouse lymphoma assay -- I can
113
1 ignore that?
2 DR. SLAGA: Well, by ignoring it --
3 DR. HILL: High concentrations.
4 DR. SLAGA: -- in some cases it's
5 positive and in some cases it's negative.
6 DR. HILL: Okay.
7 DR. SLAGA: But if you take the total
8 mammalian genotoxicity, it's more negative than
9 positive. That happens on a lot of mammalian
10 (inaudible). In a lot of cases it's more
11 clastogenic instead of truly genotoxicity.
12 DR. SHANK: Gene mutation assays were
13 done on the ingredient itself but the way it's
14 used, it's used in an oxidative hair dye and most
15 of that ingredient dissipates while it's still on
16 the hair.
17 DR. HILL: So it's being converted --
18 it's being converted to something else.
19 DR. SHANK: Right. So the actual
20 exposure to the individual --
21 DR. HILL: And that was my gut response
22 when I first read through this.
114
1 DR. SHANK: Okay.
2 DR. MARKS: Any other comments? So the
3 discussant points but the bottom-line is that we
4 would support a motion that a draft tentative
5 report be issued on these two compounds as safe
6 for use as a hair dye. Is that correct?
7 DR. SLAGA: Yes.
8 DR. HILL: Let me ask a question.
9 DR. SHANK: As an oxidative hair dye.
10 DR. SLAGA: Yeah.
11 DR. HILL: Let me ask the question then
12 because I guess I was thinking about it that way
13 but then I didn't go back and re-read until now.
14 On page -- the first page of the report, which is
15 Book page 7, we have then a structure of recorded
16 dye but we don't have any studies done on that to
17 know do we have a problem biologically with the
18 activity of that dye? Is that dye getting formed
19 only in hair, never having exposure to the scalp?
20 Because we're talking about 1.5 percent. That's a
21 nontrivial concentration (inaudible). And I'm
22 looking at the structure of that dye and thinking,
115
1 yeah, there could be some biological activities
2 there and that's not been studied best I can tell.
3 We're only going by the studies of the parent
4 compound and again, in many cases that's done with
5 dihydrochloride with the sulfate. We're not
6 looking at an absorbable species if it's in tap
7 water and we don't have information at all about
8 -- or at least I don't have information from what
9 I have here about what that formulation is
10 actually like when they do the studies in the hair
11 formulation. I don't know what the pH is. I
12 don't know if they were co-solvents, any of that.
13 The question is if we have the dye and it's there
14 at 1.5 percent, if we assume complete conversion,
15 which is kind of what the assumption is here, what
16 will be the consequence of having that dye under
17 the conditions of use? Will it penetrate the
18 skin? Will it be absorbed? Will it have any of
19 the biological consequences that we're trying to
20 avoid here? I don't have any information to know.
21 But looking at the structure, that
22 surely should be absorbable. That surely could
116
1 have potential for biological activity looking at
2 the structure. I mean, there are structure alerts
3 in that dye structure from where I sit and we
4 don't have any information on that.
5 DR. MARKS: Julie.
6 SPEAKER: I just wanted to make sure the
7 panel was aware that the reaction products, the
8 oxidative hair dyes, have been the topic of a
9 considerable body of work done by the industry to
10 submit in the European Union to the SCCS and they
11 have issued an opinion on the reaction products
12 this last year. And so this hasn't been brought
13 to the attention of this panel because you have
14 focused only on the ingredient rather than the
15 reaction product, which is technically not an
16 ingredient but if you chose to, you could invoke
17 that reaction product's opinion to address the
18 questions that Ron is raising here.
19 What we've discovered is that we've done
20 dermal penetration studies on a series of reaction
21 products that were intended to cover the span of
22 molecular weights and log Kws for the large number
117
1 of reaction products that can be formed from
2 oxidative hair dyes. And what we've discovered is
3 that the dermal penetration of these is
4 substantially lower than the parent than the dye
5 itself, the pre-cursor. So in reality I think the
6 key thing still remains the safety assessment of
7 the ingredient rather than the reaction.
8 DR. HILL: Well, I totally disagree with
9 the last thing that you said because if we want to
10 know is it safe to a human being, then we need to
11 know whatever products are formed. And I'm
12 looking at the structure on Book page 1 and saying
13 this should be imminently absorbable. I don't see
14 anything that suggests the log p would be -- would
15 render it unabsorbable. The molecular weight is
16 nice and small. I don't see in this particular
17 case with this particular purported dye, and also
18 I sketched some possible cyclization products that
19 might form from that purported dye. All of those
20 would be absorbable, and I think we need to know
21 something about that to make a conclusion.
22 So I didn't have access to the review
118
1 that you're talking about, nor was it referenced
2 in here. I can't say I didn't have access because
3 obviously it's got to be publicly available. I
4 didn't -- I wasn't -- it wasn't brought to my
5 attention and I'm sure I should have noticed this
6 three weeks ago right before Labor Day when I
7 first got this book, but the fact of the matter is
8 I'm just noting this now.
9 DR. MARKS: So Julie, yeah, could you
10 answer why it's not absorbed and --
11 SPEAKER: Yes.
12 DR. MARKS: -- perhaps I would say this
13 should be included in the discussion and then
14 referenced. But what you're saying is reassuring.
15 SPEAKER: Yeah, let me just answer Ron's
16 question.
17 The basis for concluding that the
18 absorption is low of the reaction products versus
19 the precursors or couplers was based on empirical
20 experimental data and under conditions of use in
21 the presence of hair and the amount of reaction
22 product that actually forms is relatively small so
119
1 that factors into the amount that could
2 potentially be absorbed then if the amount formed
3 is small. So rather than from a theoretical point
4 of view, from an actual experimental point of view
5 under simulated use conditions, the exposure is
6 small.
7 DR. HILL: Okay, we have a circular
8 argument here because we're saying up to 1.5
9 percent in the formulation. So either we've got
10 somewhere near 1.5 percent of the parent compound
11 before it reacts or we're saying, well, most of
12 it's converted under conditions of use to a
13 purported dye, which as I say, I'm looking at this
14 structure and a couple of things I could see
15 potentially could happen to it and thinking we
16 have a very absorbable molecule in this particular
17 case for this particular oxidative ingredient.
18 Actually, this is not an oxidative ingredient.
19 There's nothing oxidative about that 2-amino-
20 4-hydroxyethylaminoanisol. It's not oxidative but
21 it is reacting in a way that's being oxidized with
22 this iminium. So, but once it reacts with the
120
1 iminium, we have a very absorbable molecule.
2 DR. MARKS: Julie, is that published?
3 SPEAKER: The opinion is published.
4 It's on the website.
5 DR. MARKS: Okay, so --
6 DR. HILL: I want to know about this
7 specific ingredient, not just, you know, in
8 general these kinds of ingredients in reaction
9 products. I want to know how much of this
10 particular dye forms and can be absorbed because
11 --
12 DR. MARKS: Ron Shank.
13 DR. SHANK: In the chemical reaction
14 you're looking at there's one molecule missing and
15 that's hydrogen peroxide.
16 DR. HILL: Isn't that what makes the
17 imminium? Hydrogen peroxide is not going to react
18 with that anisole.
19 DR. SHANK: Well, my understanding is
20 the chemical reaction takes place in the hair --
21 the protein, etcetera -- and becomes part of the
22 hair. That's why it's a permanent hair dye. When
121
1 hair is shampooed, the dye is still part of the
2 hair. It does not come out.
3 DR. HILL: Okay. Grant you. But you
4 put it on, I mean, it's all over the scalp as well
5 as the hair. Right? So there's no thing --
6 DR. SHANK: You don't put it on like a
7 shampoo.
8 DR. HILL: I know that. I've seen my
9 wife dye her hair. But there's plenty of scalp
10 exposure, is there not?
11 DR. SHANK: There is not. If it's done
12 right it's not.
13 SPEAKER: There shouldn't be.
14 DR. HILL: You do it like this and I
15 guess what I'm saying is how do you preclude scalp
16 exposure?
17 DR. SHANK: We've gone over this.
18 DR. HILL: I know, but I haven't been on
19 the panel when you've gone over this 100 times so
20 educate me. I need to be educated here.
21 DR. MARKS: I'll tell you what, let's --
22 hmm. Let's do the education. We'll move on the
122
1 next and I'll let the two Rons discuss offline and
2 then we can bring it back up tomorrow if that
3 sounds good.
4 Julie, I think it's -- actually,
5 Christina, I'm going to put it on you to get that.
6 I think that's helpful information on reactive
7 products and should be in the discussion along
8 with obviously that we have the hair dye
9 epidemiology.
10 DR. HILL: I have been on long enough to
11 see the last round of epidemiology.
12 DR. MARKS: Yeah, exactly. I know.
13 DR. HILL: I appreciate its usefulness
14 and its limitations.
15 DR. MARKS: Yeah. Julie.
16 SPEAKER: Yeah, I just wanted to also
17 add that, you know, the last time we presented on
18 the epidemiology I had a section of the
19 presentation I had to eliminate because we had
20 that new study that we needed to spend time on,
21 but I would offer that in the future I could give
22 the panel a presentation on oxidative hair dyes.
123
1 So everyone, the new members, can also.
2 DR. HILL: Yeah. I was here for the
3 epidemiology. It was great and we had a large
4 study from Japan, I think, that was particularly
5 enlightening. I don't know if you talked about
6 it.
7 SPEAKER: There was the New England
8 study.
9 DR. HILL: Or was it China? It was -- I
10 think it was China because it was a huge number of
11 individuals involved and it was s--
12 SPEAKER: Oh, that was the prospective
13 cohort -- the cohort study.
14 DR. HILL: Yeah, and it was great and
15 valuable. And with that, along with your
16 presentation, I had 8 --
17 DR. MARKS: So, Ron, Tom, and Ron, would
18 you like Part 2 of Julie's presentation on the
19 reactive products?
20 DR. SHANK: I think it would be good for
21 the panel, especially the new members of the panel
22 to hear.
124
1 DR. MARKS: Yeah.
2 DR. SHANK: Hear that because it was not
3 intuitively obvious to me until I heard the
4 presentation from the hair chemists that what's
5 actually going on.
6 DR. HILL: Because I see exactly how
7 that applied with hydroquinone. I mean, and there
8 have been several other ingredients that have gone
9 by that I have also had no problem with we've
10 discussed and I've thought about numerous of these
11 things. This is the first one where I feel less
12 comfortable.
13 DR. MARKS: Monice.
14 MS. FIUME: I just want the panel to be
15 aware we have been trying to fit it in but as you
16 are well aware with the workload that the panel
17 has had the last few meetings, it's the timing of
18 trying to fit it in because have talked about --
19 DR. MARKS: Good.
20 MS. FIUME: -- the chemistry of hair
21 dyes. So we are trying to fit it in.
22 DR. MARKS: So you've wetted our
125
1 appetite and we're looking for the main course
2 here in the future.
3 MS. FIUME: I'll try to get it in really
4 soon.
5 DR. MARKS: Well, I'm not sure of the
6 urgency. I'm reassured by what we've heard and
7 we'll be able to get the actual reference to
8 review also about that.
9 Okay. So even though I'm not the one
10 who's going to be moving this, although they may
11 have a different opinion with the Belsito team,
12 I'll move that we issue a draft tentative report
13 that these two hair dye ingredients are safe as
14 used.
15 Do you want to put in the conclusion as
16 an oxidative hair dye or you wouldn't put that in,
17 Ron Shank, would you, just to safe as used?
18 DR. SHANK: Safe as used.
19 DR. MARKS: Yes. And the discussion
20 will entail, as I mentioned earlier we do with all
21 these hair dyes, the epidemiology boilerplate and
22 link to our website and also we'll have some
126
1 discussion about the reactive products.
2 Anything else?
3 DR. BERGFELD: Could I ask a technical
4 question? Usually in the discussion you don't
5 reference something. So if you're going to
6 reference this particular piece it should go
7 somewhere in a paragraph before the summary.
8 DR. MARKS: Yes. Next we're to the
9 Crosslinked Alkyl Acrylates.
10 So at the March meeting we were
11 concerned about the residual benzene that may be
12 present in these crosspolymers and issued an
13 insufficient data announcement requesting impurity
14 data. At the June meeting it was confirmed that
15 there was benzene and a 0.5 residual level. And
16 then we were -- issued a tentative safety
17 announcement that it's safe as used except when
18 they are polymerized with benzene.
19 So one thing we could do is handle the
20 benzene to make an effort to reduce the benzene to
21 the lowest possible level or else we can amend the
22 conclusion insufficient if polymerized in benzene.
127
1 How does the team want to go? And I have -- is
2 Ivan here? Because I wanted Ivan to talk about
3 that but he doesn't -- he's not present.
4 MS. FIUME: Actually, yes, I would like
5 Ivan to be here for the risk assessment talk also
6 because this was mostly his work on the risk
7 assessment. But I have a feeling they might still
8 be discussing formaldehyde.
9 DR. MARKS: So shall we come back to
10 this then since I actually -- thank you, Monice,
11 because I had Ivan starred here to put this in
12 perspective.
13 So I think what we'll do until Ivan
14 becomes available -- how are we going to identify
15 to bring him? If not now, after lunch. Is
16 anybody in the visitor's -- does your time
17 schedule not permit us to delay discussing these
18 ingredients? Okay.
19 DR. BERGFELD: Can I ask a question? Is
20 that the only pivotal point that you need to
21 clarify in this document? Because you could move
22 to clear up everything else if there is something
128
1 and leave that as the only pivotal point to be
2 clarified.
3 DR. HILL: I thought we were down to --
4 I thought we were down to that.
5 DR. BERGFELD: Okay. That's what I
6 wanted --
7 DR. MARKS: Yeah, that's the way I felt,
8 too.
9 DR. BERGFELD: Could I make a comment
10 again? I mentioned in my introductory remarks
11 about components. Instead of the word reactive
12 ingredients, precursor chemical, whatever you
13 might say as in combination with other chemicals
14 what you get, they're now referred to as
15 components. Is that a term that is used? I
16 didn't think so.
17 DR. HILL: You could say component acids
18 and everybody will know what you're talking about
19 if we're talking about amides. So it is used in
20 that way. But to say components, I don't think
21 even Dan would believe that that was a technically
22 accurate way to reference it so we might need to
129
1 be a little more careful with the wording. If you
2 say structural moiety, then that's perfectly
3 accurate and it doesn't roll off the tongue quite
4 as well. But I think if we say component acid in
5 an amide as an example, I think that's clear and
6 it's appropriate use. It just might be how the
7 sentences are structures might need to be more
8 cautiously exercise.
9 DR. SLAGA: But in this case it would be
10 considered just a residue, right?
11 DR. BERGFELD: Residue, yeah. In this
12 particular case you would call it residue, what is
13 left behind?
14 DR. SLAGA: Yeah, it's a residual part
15 --
16 DR. BERGFELD: Yeah.
17 DR. SLAGA: -- of the reaction. Right?
18 DR. BERGFELD: Yeah.
19 DR. HILL: If we're talking about it as
20 an impurity --
21 DR. BERGFELD: The byproducts, I mean,
22 what, yeah.
130
1 DR. HILL: But in many cases when we've
2 got the information on an additional component
3 it's with the conjecture that it could be
4 metabolized back to that component. And the
5 problem with using the word "residue," although I
6 don't have a real problem with it because when we
7 digest protein we say imino acid residues and
8 everybody knows what that means. It's just that
9 if we're thinking about residue as something as
10 there is an impurity, which it could be from
11 process but we're also -- then that's one thing.
12 If we're also considering it as a potential
13 metabolite that might have toxicological
14 relevance, that's another thing. So I think it's
15 in the way that word is used.
16 DR. BERGFELD: Do we have use to figure
17 that out?
18 MS. FIUME: The Crosslinked Alkyl
19 Acrylates report, Dr. Birdsall? Is that the
20 report you're on with (inaudible).
21 DR. BERGFELD: I had written this in the
22 front. I'm not sure if I just kept reading it and
131
1 I thought that wasn't a proper citation or
2 component.
3 MS. FIUME: I know I haven't in the
4 others.
5 DR. BERGFELD: Yeah.
6 MS. FIUME: I believe in this report I
7 have that benzene is a residual, that there's
8 residual monomer left or residual solvent. So do
9 I have a term used incorrectly in the crosslinked
10 alkyl acrylates that I need to correct? Or is --
11 I know it's in the other reports but I just want
12 to make sure I'm not missing anything in this
13 report.
14 DR. BERGFELD: It may be that I just had
15 an epiphany there because I'd been reading it and
16 not liking it.
17 Here it has monomer component on page --
18 it looks like it starts on 33. Is that okay?
19 DR. HILL: The monomer component would
20 be a perfectly reasonable way to use that.
21 DR. BERGFELD: Okay.
22 DR. HILL: Because everybody will know
132
1 technically exactly what that means.
2 DR. BERGFELD: Okay.
3 DR. HILL: At least in my opinion.
4 DR. BERGFELD: Okay.
5 DR. MARKS: I'm going to refer to page
6 39 in the discussion and I want the two Rons and
7 Tom to comment on the next to the last paragraph
8 where it says "if residual benzene was present at
9 a 0.5." There are a lot of percentages there -- 5
10 percent, 0.025 percent benzene, 0.025 percent
11 benzene. Do you like the way that -- when that
12 sentence -- or couple of sentences referring about
13 the residual benzene is worded?
14 DR. SHANK: No.
15 DR. MARKS: Okay.
16 DR. SHANK: Are we going to discuss this
17 now or wait for Ivan?
18 DR. MARKS: Ivan. Okay. So we'll come
19 back to that. I think --
20 DR. SHANK: I thought, well, I think we
21 should add both of the risk assessments to the
22 report so we can refer to them in the discussion.
133
1 And then Dr. Heldreth worded it very, very nicely
2 I thought. I would replace the sentence you
3 referred to, Jim, with one based on what Dr.
4 Heldreth had in -- that he gave us last time. But
5 we can wait until Dr. Boyer is here.
6 DR. MARKS: Okay. So anything else
7 before Dr. Ivan Boyer comes? So we'll set this
8 aside from the time being. How are we going to
9 know when Ivan is available?
10 MS. BURNETT: It should be any minute
11 now. They're finishing up formaldehyde right now.
12 DR. MARKS: Okay. So he's going to come
13 over at that point.
14 So let's move on them while we're
15 waiting to Decyl Glucoside group. It's in the
16 Pink Book.
17 In June, the panel issued an
18 insufficient data announcement. We've received
19 new data. There was concern about the
20 sensitization. I think we could move forward now
21 with a tentative safety assessment, safe as
22 formulated to be non-irritating. Comments?
134
1 DR. HILL: I have a comment in that the
2 new data does not include the ingredient of
3 greatest concern, which was a long chain branched
4 decyl glucoside. The data that was supplied as
5 far as I can tell doesn't have any such because
6 the sensitization potential of its C12-16 APG.
7 And then they did some additional studies and
8 didn't show up anything but it seemed that the
9 greatest alerts in terms of data we had the last
10 time was from branching -- long-branch chain.
11 Specifically, C18 branched.
12 DR. MARKS: Now I --
13 DR. HILL: And then the other question I
14 had was -- pardon to interrupt but just thought
15 I'd toss this out in the same because it's the
16 same issue -- is in the discussion it says the
17 concern with the potential exists for dermal
18 irritation but I thought the main concern was
19 sensitization, not irritation. And so I was
20 surprised that that showed up that way.
21 DR. MARKS: As in Monice's memorandum it
22 was primarily dermal sensitization and decyl
135
1 glucoside concentration at 11 percent. And in
2 point the new data received in leave-ons it's
3 really at five percent. So we have that concern
4 is now addressed. There was no sensitization at
5 five percent with laurel and decyl glucoside.
6 DR. HILL: Right. But I was surprised
7 reading that memo because I didn't think the
8 concern was necessarily with decyl glycoside at
9 all. I mean, there was an irritation question
10 about that one and that was resolved, but I'm not
11 sure it was ever real in the first place. But
12 then the sensitization, there were some structure
13 activities or there were trends in terms of
14 structure activity that suggested longer chain and
15 branching might cause the sensitization problem.
16 We didn't get any data addressing that best I can
17 tell. That was a concern I raised several times
18 in several different ways that shows up in the
19 transcript.
20 MS. FIUME: If I could first address the
21 decyl glucoside actually was the concern. Dr.
22 Belsito had mentioned that they were doing testing
136
1 in the North American Contact Dermatitis Group on
2 decyl glucosides, so there was nothing in the
3 report and that's why he wanted to see decyl
4 glucoside at 11 percent.
5 DR. HILL: Oh, yes. I remember that.
6 DR. MARKS: That's actually on --
7 DR. HILL: That was what Dr. Belsito
8 raised.
9 DR. MARKS: Yes. And I didn't have
10 quite the concern that Dr. Belsito -- if you look
11 on page 10 in the transcripts, actually at the top
12 of the page, it's exactly as Monice said. You'll
13 see that Dr. Belsito is referring to decyl
14 glycoside at 11 percent. And that's -- he either
15 wanted to have an HRIPT with decyl glycoside but
16 now we know it's not at that concentration.
17 DR. HILL: Well, I would be comfortable
18 with everything if we had a non-sensitizing
19 disclaimer in our discussion of conclusion, but we
20 don't have that in there best I can tell.
21 DR. BERGFELD: Are you proposing that
22 you put in the discussion that the longer chain
137
1 ingredients could be sensitizers? Is that what
2 you're saying? A potential sensitizer?
3 DR. HILL: Yeah. So there's an LL -- I
4 know it's just an LLNA. The bottom of Panel Book
5 33, page 10. "One C12-C18 glucoside C14 glucoside
6 and C18 branch glucoside might cause skin
7 sensitization so the concentration is at 8.4
8 percent, 5.9 percent and 0.43 percent,
9 respectively. And then they came back and used
10 C12-C16. So my question was C18 branched because
11 there's nothing in those C12 -- I don't know APG,
12 what all is in there. We typically don't get a
13 full analysis of all the components present in
14 that sort of thing.
15 MS. FIUME: Excuse me, Dr. Harrell, on
16 Panel Book, pages 45 and 46 --
17 DR. HILL: Yeah.
18 MS. FIUME: -- there are some irritation
19 data and sensitization data on the 18 branch
20 glucoside. Does that answer your question or no?
21 DR. HILL: Hang on.
22 DR. SLAGA: What was the problem?
138
1 MS. BURNETT: In animals.
2 MS. FIUME: I think there's also a human
3 on the bottom of -- see our Panel Book, page 46.
4 SPEAKER: It's the human data. All
5 right, so. See 18 branch, okay. Okay, so
6 irritation but no positive reactions that
7 challenge, blah blah blah. Yeah, I'm fine. Yes.
8 I'm good now.
9 DR. MARKS: So are we to the point,
10 team, that we, as I mentioned earlier, we can
11 support a motion that this is safe when
12 formulated? These ingredients are safe when
13 formulated to be non-irritating and a tentative
14 safety assessment would be issued?
15 DR. HILL: Mm-hmm.
16 DR. SLAGA: Agreed.
17 DR. MARKS: Okay. Any other comments?
18 Thanks, Monice.
19 DR. HILL: I find it's interesting
20 because we don't see anything on the humans but we
21 are seeing multiple occasions. The LLNA is
22 showing positive reaction so I'm not an expert on
139
1 LLNA. I need to gain some expertise on that.
2 DR. MARKS: Well, the local lymph node
3 assay, if you look in that transcript also I was
4 relying on at that end Dr. Belsito didn't like
5 that assay particularly even though it's a
6 standard assay.
7 DR. HILL: I remember that.
8 DR. MARKS: Which is widely accepted,
9 particularly in Europe.
10 Okay. Let's move on now. Since Ivan
11 hasn't shown up, we'll move on to the DEA and the
12 salts. That's in the Blue Book.
13 So a revised tentative amended safety
14 assessment on DEA and its salts was issued in
15 June. We are at the point now whether or not we
16 should move on from a draft to a final amended
17 safety assessment on DEA and its salts as used in
18 cosmetics.
19 DR. BERGFELD: Go ahead, Ron. You were
20 about to speak.
21 DR. SHANK: Okay. I thought the
22 discussion and conclusion were fine with the one
140
1 exception on the statement about N-nitroso
2 compounds. Are we going to decide on a standard
3 boilerplate or do we do this on a compound by
4 compound basis? Right now it says these
5 ingredients shouldn't be used in cosmetic products
6 in which N-nitroso compounds are formed. It
7 should be "can be formed" not "are formed."
8 Nobody produces a cosmetic product where --
9 DR. SLAGA: I thought we agreed to do
10 that in substandard.
11 DR. SHANK: Was that agreed to?
12 DR. MARKS: And then there's a new
13 wording that was suggested by the SCCC, the
14 Scientific Council favors the wording "should be
15 formulated to avoid the formation of
16 nitrosamines." So a little --
17 DR. EISENMANN: That wording was in your
18 draft boilerplate at one point, too. And I think
19 it's been used before to avoid the formation of
20 nitrosamines. But as long as you're not implying
21 that they're making products --
22 DR. SLAGA: Right.
141
1 DR. EISENMANN: -- that nitrosamines may
2 be formed, then that doesn't matter.
3 DR. SHANK: Okay. But don't say
4 nitrosamines, say N-nitroso compounds. Okay?
5 Please.
6 DR. MARKS: So do you like the wording
7 as -- so we're looking at page 46 in the
8 conclusion. And it's the next to the last, well,
9 it's the last sentence. And there's a phrase
10 which I would suggest the phrase be deleted on
11 these. It says concluded there, listed below and
12 then you say that's in the beginning. DEA and
13 related salts listed below are safe. And then at
14 the end of that paragraph you have the ingredients
15 found "safe as used are." I think you can
16 eliminate "the ingredients found safe as used
17 are." That's just redundant from what was said in
18 the first sentence. But the last sentence there,
19 "cautious that ingredients should not be used in
20 cosmetic products in which N-nitroso compounds are
21 formed. That's what you were talking about the
22 N-nitroso.
142
1 DR. SHANK: And make it (inaudible) they
2 are formed, can be formed.
3 DR. MARKS: Can be formed. Okay.
4 MS. FIUME: Dr. Marks, can I take you to
5 that last statement? The ingredients found safe
6 are. That's referring to the list on the next
7 page.
8 DR. MARKS: I know. I think you say
9 that in the first -- you say --
10 MS. FIUME: Okay, listed below. Okay,
11 I'm sorry.
12 DR. MARKS: Yeah. You say listed below.
13 So I don't know that you need to reiterate that
14 they're safe.
15 MS. FIUME: Sorry. I didn't see I said
16 it twice. Sorry about that.
17 DR. MARKS: That's a minor point but
18 still is redundant in conclusion to save words,
19 particularly since Dr. Shank is adding an extra
20 word "can be" in place of "are." So you like that
21 versus "avoid"? Ron?
22 DR. SHANK: I do.
143
1 DR. MARKS: Tom?
2 DR. SLAGA: I agree.
3 DR. MARKS: Ron? Okay. So those, to me
4 they're editorial comments and we could still
5 issue a final amended safety assessment. I don't
6 know that it needs to be sent out again. Is that
7 okay? Ron? Tom?
8 DR. SHANK: It does not need to go out
9 again.
10 DR. MARKS: Right.
11 DR. EISENMANN: But we need to clarify
12 what concentrations you're saying safe as used
13 because the issue is most people are not putting
14 DEA in products. So when I asked the original
15 concentration of use survey, the maximum was 0.3.
16 But then you link the reports together, and when
17 you add cocamide DEA or one of the amides, the
18 highest levels of EA are 0.65. So and that's what
19 this new table provides. So I want to be clear.
20 Is it safe as 0.65?
21 DR. SHANK: No, it says "when formulated
22 to be non-irritating."
144
1 DR. EISENMANN: Okay.
2 DR. SHANK: We don't give a number.
3 DR. EISENMANN: Okay. Okay. But you --
4 in other reports then you say at the
5 concentrations in this report.
6 DR. SHANK: We're going to change that.
7 DR. EISENMANN: Okay.
8 DR. SHANK: In those other reports. And
9 go back to "when formulated." So there's not
10 enough DEA in these other ingredients that would
11 cause irritation.
12 DR. MARKS: Okay. So safe as used.
13 Then we have the insufficient for the one
14 ingredient, which is not being used.
15 DR. HILL: Which one is that?
16 DR. MARKS: That's the
17 DEA-Lauriminopropionate. It's in the conclusion
18 on page 46.
19 DR. EISENMANN: The only concern about
20 including it in this report, I just don't quite
21 understand why you're including that in this
22 report and not the TEA ingredient in the TEA
145
1 report. That's why. To me it doesn't make sense.
2 It may be better to put all the insufficient data
3 sometime later in another report but I just want
4 to be sure you understand you're being
5 inconsistent. That's all.
6 MS. FIUME: The transmittals to both
7 reports actually pooled information from the
8 transcripts. It was discussed at the last
9 meeting. If you're still okay with what was
10 discussed at the last meeting, there are excerpts
11 from each transcript in each of the respective
12 transmittals.
13 DR. EISENMANN: But it's not consistent.
14 DR. SHANK: I think I'm missing here.
15 What is -- where are we inconsistent?
16 DR. EISENMANN: The
17 DEA-Lauriminopropionate is being put in the DEA
18 report but it's not -- there's a TEA, same
19 Lauriminopropionate but you're not putting it in
20 the TEA report and I don't quite understand the
21 reason for that. I personally would think you'd
22 just pull them both out and set them aside to be
146
1 someday reviewed with the lauriminopropionic acid
2 and other salts of it because it's really --
3 that's what's driving its sufficiency, is the
4 lauriminodipropionate and not the DEA or the TEA.
5 But if you're going to put the DEA in here, I
6 don't see why you don't put the TEA in the other
7 report, but --
8 DR. MARKS: Did that come up under the
9 discussion of TEA?
10 DR. EISENMANN: In one of the groups it
11 may have been discussed and I still didn't quite
12 understand the reason why you're doing one thing
13 and doing something else with the other report. I
14 mean, that's fine if you want to do that but I
15 don't understand it.
16 DR. MARKS: Well, I would leave it as is
17 since we're down to the final conclusion, and if
18 we change, this would be a significant change. We
19 would have to send it out for another period.
20 DR. EISENMANN: I wouldn't think you'd
21 have to do that for taking that out but it's up to
22 you.
147
1 DR. MARKS: To me that's a significant
2 thing when you take an ingredient out of the
3 conclusion. That would be a significant change.
4 So move forward with a conclusion as
5 stated and live with this potential inconsistency
6 at this point or once we get to TEA we could
7 decide whether or not we want to delay issuing the
8 final report to include TEA lauriminodipropionate.
9 DR. SHANK: The TEA
10 lauriminodipropionate is not in the TEA report.
11 DR. EISENMANN: Correct.
12 DR. SHANK: It's not listed as an
13 ingredient.
14 DR. EISENMANN: No, it is in the
15 dictionary.
16 DR. SHANK: Okay, then we -- that's an
17 omission. I didn't -- it wasn't in our list of
18 compounds to be considered so.
19 DR. EISENMANN: It may have been
20 originally and for some reason it was taken out
21 but that's what I'm saying. It's in one and not
22 the other.
148
1 DR. SHANK: Now I understand. Thank
2 you. Okay.
3 DR. MARKS: So Ron Shank, now that you
4 understand, we all understand, do you want to move
5 forward with it as stated here?
6 DR. SHANK: On the DEA?
7 DR. MARKS: Yes.
8 DR. SHANK: Yes, I do.
9 DR. MARKS: Okay. So we'll issue a
10 final amended safety assessment on DEA and its
11 salts. And as stated in the conclusion on 46 with
12 a minor change in the last sentence that N-nitroso
13 compounds can be formed, and we'll use that as the
14 boilerplate in the future when we're concerned
15 about N-nitroso compound formation.
16 Ron Hill, I saw some non-verbal
17 communication. Are you not happy with moving
18 forward?
19 DR. HILL: I was, you know, I was hoping
20 you might refresh my memory on this. I had
21 flagged pretty prominently in my book last time
22 the DEA-methyl myristate sulfonate. I didn't
149
1 notice in the transcript that I'd said anything
2 about it but it may be because it was -- I was
3 focused on other things at that point in time,
4 particularly the lipophilic salts and the
5 potential for them to dermally penetrate. But in
6 making this conclusion of safety we're apparently
7 referring a safe conclusion on methyl myristate
8 sulfonate, which is very structurally disparate
9 from all of these others and probably actually
10 fits in one of the other reports we're looking at
11 a lot better because it's methyl ester and if you
12 hydrolyze that you're back to alpha-sulfo
13 carboxylic acid, which we're entertaining. So I
14 just wondered if you remembered that we captured
15 anything about that being different. I'm going to
16 look back to see because I didn't notice whether I
17 said anything about that in open meetings, second
18 or first -- the group meeting or the joint
19 meeting. I'm fairly bothered by that because we
20 don't have any data on that component separately.
21 MS. FIUME: I don't remember. I know
22 when we first went through the list of ingredients
150
1 that stayed or didn't stay, sulfonate stayed
2 because we had reports on DEA (inaudible).
3 DR. HILL: Yeah. We were looking at an
4 extremely long list and for me this is kind of
5 like peeling back layers and having peeled back a
6 layer I looked to see if I flagged it last time
7 and I did. But I don' remember if I sort of
8 fought a battle for getting that out of there.
9 Now we're down to where that's not so easily done
10 but I'm just bothered that it's still in there and
11 I 'm wondering how I let that go without at least
12 discussing it.
13 DR. MARKS: Ron Shank and Tom, any
14 concerns you have? No? Okay.
15 DR. HILL: Maybe it was just because
16 it's fairly greasy and it is a sulfonate that I
17 wasn't even myself as concerned as I was when I
18 realized how glaringly that stands out. I'm just
19 bothered that it's in this report as opposed to
20 another one because this is a DEA-focused report
21 but that's a pretty different structure.
22 Okay. I've said it. It's captured.
151
1 DR. MARKS: Okay. Shall we move --
2 rather than forward should we move backwards?
3 Let's go back to the --
4 MS. FIUME: Dr. Marks, can I ask a
5 question before we move back?
6 DR. MARKS: Sure.
7 MS. FIUME: This is one of the reports
8 where I used the term "components." Can I ask,
9 structural moiety, would that be a better
10 terminology referring to reports from parts of the
11 ingredients? Or if I could get some direction on
12 what terminology you would like to see in that
13 report. It's --
14 DR. HILL: Actually, components when
15 you're talking about a salt is perfectly
16 appropriate.
17 MS. FIUME: Okay. So that's okay.
18 DR. HILL: Yeah. If it's salts. I
19 think where we had a greater difficulty is we have
20 to be a more careful if it's part of a covalent
21 compound. When we're talking about salts, I think
22 to say component is perfectly and technically
152
1 fine.
2 MS. FIUME: Thank you.
3 DR. HILL: We might get Dan's opinion
4 just to corroborate.
5 DR. MARKS: So we're going to go back
6 but move forward. Is that possible? And we're
7 going to -- Ivan, we've been anxiously awaiting
8 you, Dr. Boyer, to elucidate the issue of benzene
9 impurity in the compounds which are formulated
10 with benzene as a solvent as I recollect. Is that
11 right? There's some crosslinked acrylic acrylates
12 which do not have benzene used in its manufacturer
13 and others who do.
14 DR. BOYER: And in terms of numbers, I
15 think that there are more that don't involve the
16 use of benzene.
17 DR. MARKS: Right. So we were
18 struggling with, as I recollect, with the team,
19 the idea do we find safe only those crosslink
20 alkyl acrylates that are not manufactured with
21 benzene? Or do we include the benzene ones and
22 deal with the benzene residual in trying to
153
1 determine a safety assessment which would make
2 those crosslink alkyl acrylates that we feel are
3 safe for cosmetic ingredients.
4 DR. BOYER: Okay. I think one of the
5 first issues to consider is the association of
6 residual benzene with the polymer. And we're not
7 sure exactly what the character of that
8 association is. And just how leachable the
9 benzene might be from those polymers and how
10 available they might be to evaporation. We just
11 don't have that information. We do know something
12 about the levels, the concentrations of benzene in
13 the ingredient in the polymer as an ingredient.
14 And the risk assessments that PCPC did and that I
15 elaborated on were based on those residual levels.
16 Assuming that during the manufacturing process
17 none of that benzene evaporates and also repeating
18 the calculations assuming that about 10 percent or
19 so evaporates from the ingredient during the
20 manufacturing and during the formulation of the
21 actual product. And here the rationale is benzene
22 is highly volatile. It is processed typically.
154
1 It's -- the ingredient, the polymer is mixed up to
2 produce the products, the body lotions and so
3 forth at a relatively elevated temperature, and so
4 there could be at least 10 percent evaporation
5 during the manufacturing process.
6 When we compare -- do the simple
7 comparison to EPA's drinking water levels, the
8 levels that they say are associated with a 10-6
9 risk, a de minimis cancer risk, we find that
10 conservative standard screening risk assessment
11 protocols result in risk estimates that are
12 somewhat elevated compared to that 10-6 threshold.
13 And that's taking into consideration the possible
14 evaporation of benzene from the product. Without
15 having any data, again, about just how much might
16 be leached out of the polymer into the rest of the
17 product, the body lotion, for instance, we don't
18 have a good feel for how much of it would be
19 available for absorption through the skin. We
20 know that when it's applied neat to the skin it's
21 absorbed into the blood stream at a relatively low
22 level. On the other hand, a large component of
155
1 that is the evaporation of benzene on the skin.
2 It occurs very quickly. So to some extent benzene
3 in an actual body lotion may be available for
4 absorption longer than the simple application of
5 benzene to the skin. On the other hand, it may
6 not be available at all or to a minor extent if
7 it's basically trapped in a polymer in some way.
8 So those were the issues that went into
9 the risk assessments. The risk assessment that I
10 did was an actual risk assessment starting with
11 the EPA's cancer slope factors. Typically, EPA
12 issues a single slow factor -- cancer slope factor
13 for a chemical. Benzene has two slope factors,
14 and the guidance we get from EPA in a case is that
15 you want to be outside of that range. You want to
16 be outside of the range of risk estimates that
17 calculate using both of those slope factors. And
18 so far we simply don't have the information that
19 would enable us to refine the risk assessment and
20 to ensure that the risks are the maximal risks,
21 the upper bound risks that we calculate would be
22 within that range.
156
1 DR. MARKS: Okay. Thank you.
2 DR. EISENMANN: One comment on the
3 polymer. It's my understanding it starts as a
4 powder and then you put it in warm water and it
5 starts to uncoil. And then you add -- you
6 neutralize it and it completely uncoils which
7 would probably release all the benzene because I
8 was also looking at the analytical methods and the
9 first step is uncoiling the polymer to measure the
10 benzene. So if, you know, in other words, I think
11 -- of course, you can't say how much you can
12 evaporate because it's a large vat and a small
13 amount of benzene but I don't think it's going to
14 be part of the polymer because --
15 DR. HILL: Uncoiling the polymer in
16 water would not necessarily release the benzene.
17 It's a high chance it will stay absorbed to the
18 aromatic moieties and the acrylates.
19 DR. BOYER: And also we did some
20 calculations. I think you have them in your Wave
21 2 package to show that, you know, 96 percent of
22 the benzene would have to evaporate. Eighty
157
1 percent of the benzene would have to evaporate to
2 bring those benzene levels down -- the benzene
3 levels in the product down to what would be
4 associated with the 10-6 risk. So it's a
5 substantial evaporation that would be necessary.
6 DR. MARKS: So Ron, Tom, and Ron, do you
7 still like the conclusion where we say there's
8 insufficient data? Hearing what Ivan said, it
9 doesn't sound like you've reassured us very much
10 actually -- that insufficient when these
11 ingredients are polymerized in benzene? If you
12 remember, Monice puts in her memo here that we
13 heard there was a 0.5 percent residual benzene
14 could be present in the raw material of one
15 product. So do you still like the conclusion
16 where we call attention to the --
17 DR. BERGFELD: Or is it unsafe?
18 DR. MARKS: Well, that's what I'm
19 asking. Do you like that conclusion or should we
20 have a different conclusion, and as Wilma
21 suggests, make it unsafe?
22 DR. SHANK: Me? Okay. I think the
158
1 conclusion is okay, but the discussion has to
2 change.
3 DR. MARKS: Okay.
4 DR. SHANK: First, I would add the SCC's
5 risk assessment and Dr. Boyer's, I think very
6 important works on that. They have to go
7 together. And then in the discussion refer to the
8 need to assume a loss of benzene if we use risk
9 assessment. And then Dr. Heldreth, in one of the
10 documents I read, I think stated it very, very
11 well. I think I'm paraphrasing it. Rather than
12 having the last two lines in the discussion in the
13 second to the last paragraph, the last two lines
14 begin "if residual benzene was present." I would
15 take those two sentences out where all the numbers
16 are and say "since it cannot be predicted with
17 certainty, what quantity of benzene would be
18 volatilized or leached from the crosspolymers
19 during manufacture, formulation, or product use?
20 The panel determined that the data are
21 insufficient to conclude that crosspolymers
22 polymerized in benzene are safe for use in
159
1 cosmetic products." And leave out all of these
2 numbers. These are assumptions and things.
3 DR. MARKS: Yes. That's what I was --
4 obviously, before you came in I've been asking
5 about. So we would move that this become a final
6 safety assessment with those changes in the
7 discussion.
8 DR. HILL: And by the way, when I said
9 aromatic moieties into polymer, I meant
10 unsaturated, not aromatic. There are no aromatic
11 moieties in the polymer.
12 DR. EISENMANN: Question. If I'm
13 hearing you right, so if a company actually
14 measured benzene in the final product and it was
15 below the 10-6 risk level, that would be okay? Is
16 that what you're saying?
17 DR. SHANK: Not explicitly, no. We
18 would have to see the data.
19 DR. SLAGA: Right.
20 DR. SHANK: That's what we're saying.
21 DR. SLAGA: It's insufficient.
22 DR. SHANK: We haven't said that we
160
1 automatically default to the EPA water standard.
2 DR. EISENMANN: Well, he's not using the
3 water standard because the water standard is in
4 the middle. Correct?
5 DR. BOYER: It's in the middle.
6 DR. EISENMANN: And they set that
7 standard because that's technically achievable if
8 I remember correctly.
9 DR. SHANK: The problem is we anticipate
10 --
11 DR. EISENMANN: So you're setting it
12 lower than the EPA water standard based on the
13 lowest EPA risk level? You're not standing in the
14 middle?
15 DR. SHANK: No, we're now going to a
16 level that would have to be lower than the EPA
17 standard.
18 DR. EISENMANN: And you're talking about
19 the lower 10-6 risk level that Ivan has pointed
20 out?
21 DR. SHANK: Yes.
22 DR. EISENMANN: Okay.
161
1 DR. SHANK: However, we're also saying
2 that the volatilization of benzene from the
3 finished product probably varies -- vary greatly
4 with the product itself and the use conditions.
5 DR. EISENMANN: Well, I think I'm
6 discussing more the volatilization while either
7 making the product --
8 DR. SHANK: No.
9 DR. EISENMANN: -- as they heat it --
10 well --
11 DR. SHANK: We're not there. We're at
12 the consumer level. That's where we're --
13 DR. EISENMANN: But if you measure -- if
14 you measured it in the final product and the level
15 was still below 10-6 in the final product after
16 you've heated it and mixed it and do whatever
17 they're going to do to it to make the product and
18 it was below the 10-6 level, would you be okay
19 with it?
20 DR. SHANK: It would depend on how much
21 product is used. The drinking water standard is
22 based on drinking two liters of water a day.
162
1 Okay? Now, to use that concentrate --
2 DR. EISENMANN: I'm not saying a
3 concentration. I'm saying a risk level. So they
4 would have to -- they would have to do a risk
5 assessment like Ivan did but instead of using the
6 level that we calculated as an estimate in the
7 product you'd have an actual measured level. And
8 then you did the -- finished doing the risk
9 assessment. If it was below 10-6 would you be
10 okay with it?
11 DR. SLAGA: I think the way we have it,
12 insufficient, until we see the data is the way --
13 you know, you're stating more of a hypothetical
14 and we -- we're saying we want to see the data
15 before we make that decision. We probably would
16 agree with what you're saying.
17 DR. EISENMANN: Okay.
18 DR. MARKS: Okay. So tomorrow I'm going
19 to move that we issue a final safety assessment on
20 these crosslink alkyl acrylates with a conclusion
21 that they're safe except when they're polymerized
22 in benzene and that the available data are
163
1 insufficient to make a determination of safety for
2 these ingredients when polymerized and benzene has
3 its data on page 39. It's going to be a very
4 robust discussion in this final safety assessment
5 of which Ron Shank, I may ask you to discuss
6 tomorrow if need be. But that's been captured.
7 The SCC. Dr. Boyer's risk assessment and then
8 Ron, those comments you made in terms of ordering
9 the discussion.
10 Is there -- I don't know if there's
11 precedent set. Since there's a number of changes
12 in the discussion, one would say that's editorial
13 but does the expert panel need to see the final
14 discussion before it's sent to the Journal?
15 DR. BERGFELD: No.
16 DR. MARKS: Good. Okay. Any other
17 comments about this? Otherwise, we will move
18 either to lunch or the next ingredient. Who has
19 the time? And who's hunger?
20 DR. HILL: 12:02.
21 DR. MARKS: 12:02. Okay. How hungry
22 are you, team members? Can we do one more or
164
1 should we adjourn for lunch?
2 Okay. We will adjourn for lunch and
3 other necessary activities.
4 (Recess)
5 DR. MARKS: Wilma said she would be a
6 little bit late. So we have all the team members.
7 Let's go ahead and start, then.
8 And do we have Monice?
9 MS. FIUME: I'm here.
10 DR. MARKS: Yes. Okay. Right behind
11 me. So I am on the right page. We're with the
12 DEA amides. And we have in front of us the draft
13 final amended safety assessment for DEA amide.
14 And it was, the conclusion was "Safe, formulated
15 to be non-irritating."
16 So I'll be moving tomorrow to issue a
17 final amended safety assessment on the DEA amides
18 with that conclusion.
19 Any comments about that, in terms of the
20 conclusion itself? And then we'll get into
21 editorial comments.
22 DR. SLAGA: I think the conclusion is
165
1 fine.
2 DR. MARKS: Okay. Let's go to page 44,
3 the conclusion, for editorials.
4 Monice, I didn't know whether -- like in
5 the first sentence, I would have just used the
6 same title as on the final amended report, "Panel
7 concluded that the DEA amides listed below -- " --
8 Ron, Tom, Ron -- is that okay with you?
9 Rather than "cocamide DEA, and a 32
10 diethanolamides"? I would have just used the same
11 as the title.
12 And then, obviously, from our discussion
13 in the DEA, in the sentence concerning the
14 N-nitroso compounds, change the word "may" to
15 "can." So it would be "can be formed."
16 And then I would eliminate that last
17 sentence, since you've already said, "Listed
18 Below."
19 DR. SHANK: So -- in many of the past
20 documents, where there have been so many
21 ingredients, we have listed them specifically in
22 the conclusion. So why --
166
1 DR. MARKS: Oh, no. All I -- the last
2 sentence is, "The ingredients reviewed in this
3 safety assessment are -- " --
4 DR. SHANK: Yes.
5 DR. MARKS: Well, and the first sentence
6 says, "Listed below -- ". So I just thought that
7 was redundant to say it's listed below, and then
8 say, "The ingredients are -- " -- but --
9 DR. SHANK: So you just want to remove
10 the sentence, not the list.
11 DR. MARKS: Oh, yes. Oh, yes. Just the
12 sentence, not the list. Yes. (Laughs.) No way
13 -- yeah. Okay.
14 And then, actually -- and then you added
15 the caveat about if they are not used now they
16 would be used in a similar use and concentration.
17 Let me see -- I had an editorial comment
18 on page 26 about the abstract. So obviously,
19 again, the wording with then nitroso compounds.
20 And then I had one other -- you can take a look at
21 it, Monice -- just, "although a few may function
22 differently," is that the second sentence?
167
1 Basically, I thought that could be eliminated.
2 You say most of them have the same
3 function. Any comments and discussion? Summary?
4 Ron -- and something that I need to mention
5 tomorrow, or is this basically editorial?
6 DR. SHANK: No, page 44, Panel Book, in
7 the discussion -- 19 in the report -- I don't
8 think we should say that, "The Panel stated the
9 amount of free DEA available in DEA amides must be
10 limited to no more than that considered safe by
11 the Panel."
12 Why don't we just say the same thing
13 that we said in the DEA report, that the amount of
14 free available -- the amount of free DEA available
15 in DEA amides would not be a concern as long as
16 the product was formulated to be non- irritating?
17 Because that's what we say in the DEA report. In
18 other words, repeat what we said in the DEA report
19 about DEA.
20 MS. FIUME: Doctor, can I ask a question
21 for clarification?
22 DR. SHANK: Sure.
168
1 MS. FIUME: I guess I always thought
2 when it said "safe as used," it was referring to
3 the concentration of use that it's given in the
4 report. So that link is not really being made in
5 the DEA report. It's more of "when formulated to
6 be non-irritating," not "at the concentration of
7 use."
8 DR. SHANK: Right. It was important if
9 they formulated to be non-irritating. We didn't
10 say a concentration in the DEA report.
11 MS. FIUME: Okay. Because I guess I had
12 always thought -- and I may be mistaken -- that
13 when we say "safe as used," that it's implied that
14 the concentration that's listed in the report is
15 what the safe concentration is. That's the use
16 concentration.
17 DR. SHANK: When we don't have a
18 qualifier -- yes. When we say "safe as used,"
19 that means whatever is in the concentration of use
20 table.
21 But here, with DEA, we said
22 specifically, "safe as used," so long as it's
169
1 formulated to be non-irritating. Because the
2 toxicity of DEA was associated with irritation.
3 I think we should repeat that in the DEA
4 amide, and in the other reports -- the other
5 ethanolamine reports --
6 DR. MARKS: Right.
7 DR. SHANK: -- where we're taking about
8 DEA --
9 DR. MARKS: I think you're being very
10 explicit in saying -- with the way you have it
11 stated in that sentence, Ron, one doesn't have to
12 refer back --
13 DR. SHANK: Right.
14 DR. MARKS: -- one doesn't have to refer
15 back --
16 DR. SHANK: Right.
17 DR. MARKS: -- looking for a potential
18 level. You're just saying "formulate to be
19 non-irritating. And that's the important
20 endpoint. Yep.
21 So that's an Editorial comment, which --
22 DR. SHANK: Editorial.
170
1 DR. MARKS: I don't Know that I need to
2 mention that tomorrow.
3 DR. SHANK: Okay.
4 DR. MARKS: What do you feel, Ron? Do
5 you want --
6 DR. SHANK: I think that's editorial.
7 DR. MARKS: Yes. Okay. Any other
8 comments? The report's okay? So tomorrow I'll
9 move to issue the final amended safety assessment
10 of DEA amides -- safe as long as it's formulated
11 to be non irritating.
12 Now we're to TEA. And we're basically -- a draft
13 final amended safety assessment was issued on TEA and
14 TEA-containing ingredients. And that conclusion was
15 similar: Safe as long as formulated to be
16 non-irritating.
17 Again, I think the same comments are as
18 before in the conclusion, the wording. Instead of
19 "are," we're putting "may be." Again, eliminate
20 -- since you already say it's listed below,
21 eliminate that last sentence, not the ingredients
22 themselves.
171
1 Any other comments, in terms of -- I
2 think this is now -- I almost hesitate to bring
3 this up, but Carol pointed out the potential
4 inconsistency in that do we add the "insufficient
5 for TEA-laurylaminopropionate?" And if we do that
6 -- and I don't think we could move on to a final
7 amended safety assessment, because we're adding
8 another ingredient.
9 And -- no, no, that's okay, Carol. I
10 want to bring it up now to see what my Panel
11 feels. I would move forward.
12 What are the number of uses of TEA-
13 laurylaminopropionate?
14 DR. EISENMANN: No uses.
15 DR. MARKS: No uses. Do we want to
16 handle it in the discussion?
17 DR. HILL: So was it in there before and
18 it's been taken out, or --
19 DR. MARKS: I'm not sure of that.
20 Carol, can you answer that?
21 DR. EISENMANN: I'm pretty sure it was
22 in there at one point. When the report first came
172
1 to the Panel, everything possible was listed, and
2 then things were thrown out as you went through.
3 So it would have been in that original
4 list, I believe. And Dr. Hill can double check.
5 But I believe that would have been one, if it was
6 there, it was thrown out at the last meeting.
7 DR. SHANK: When you say "the original
8 list," was that when we reopened this and split
9 the document? Or was it in the original document
10 where all there --
11 DR. HILL: I've got all three right
12 here. I'm researching that.
13 DR. SHANK: -- together.
14 MS. FIUME: I think it would have been
15 at the last meeting, was when the entire TEA list
16 was brought to you and the Panel went through it.
17 So it would not have been the very, very first
18 time you've seen it, it was at the last meeting.
19 DR. MARKS: Yes, I guess one of the --
20 well, at any rate, it's not on this list now, so
21 how do we want to handle that? Do we want to just
22 say, yes -- for the future, we were inconsistent
173
1 and ignore it now, or do we want to include it and
2 say "insufficient?" As I said, one way would be
3 to put it in the discussion.
4 MS. FIUME: Doctor --
5 DR. MARKS: I'm not sure that's exactly
6 the way we want to do that in an extra ingredient.
7 But -- Monice?
8 MS. FIUME: If you look at CIR Panel
9 Book page 22, Dr. Belsito, in the middle of the
10 page, sort of addresses it. So it was talked
11 about. And if you look further down, you did
12 acknowledge that some are in the DEA report that
13 are not in the TEA report.
14 So that was discussed at the last
15 meeting.
16 DR. MARKS: Well, I don't want to
17 further discuss it.
18 DR. HILL: TEA-lauraminopropionate was
19 in this intermediate report, at least in terms of
20 the list. It was there. And we deleted it. So I
21 know we had a discussion.
22 So what page was that on?
174
1 DR. MARKS: 22.
2 DR. SHANK: There it is.
3 MS. FIUME: Your team's discussion of it
4 is on page 18.
5 DR. MARKS: Ron, Tom, Ron? Just issue
6 the final amended safety assessment and leave this
7 out?
8 DR. SLAGA: I would say let's get the
9 final amended.
10 DR. MARKS: Not being used -- Tom, you
11 would go final amended -- yes. Okay.
12 Rons?
13 DR. SHANK: I'm a big fan of being
14 consistent. So, I think I would recommend putting
15 it back in and doing the same thing we did with
16 the DEA version, and say it's insufficient for
17 this TEA one, even though it's not being used.
18 The same line that we have in the DEA report, for
19 TEA-lauramino -- I mean, whatever it's called.
20 So I don't feel strongly. It would just
21 be for being consistent.
22 DR. HILL: I concur primarily because
175
1 I'm not sure our justification for leaving it out
2 was sound, looking at the two Panel discussions.
3 Unless --
4 DR. MARKS: And you feel comfortable to
5 put as "insufficient," Ron?
6 DR. SHANK: Yeah.
7 DR. MARKS: We don't have any data to
8 suggest the TEA-lauraminopropionate.
9 DR. HILL: But on the other hand, now
10 that I just said that, we actually removed the
11 whole category where we had amine and amide acid
12 salts. We struck that whole category with the
13 TEA. And that was really the justification, is it
14 fit in there. It's with the rest of them --
15 DR. MARKS: Right.
16 DR. HILL: -- it's gone.
17 DR. SHANK: That's different.
18 DR. MARKS: So the thinking there was we
19 just eliminated the whole group. And I think that
20 -- was that because, since we're doing add-ons, it
21 should be no- brainers?
22 DR. SLAGA: Right.
176
1 DR. SHANK: Okay, then I change. And I
2 believe the conclusion as it is, with the change
3 in the statement on "nitrosamines can be formed."
4 DR. MARKS: Okay. So, tomorrow -- let
5 me see, it looks like I'm not the one who's going
6 to make the motion. But I, hopefully, will second
7 it -- that the final amended safety assessment
8 will be issued for these ingredients: Safe,
9 formulated to be non-irritating.
10 And if the discussion comes up about the
11 lauraminopropionate, I'll say we eliminated the
12 group.
13 Do you know, Carol, is this technically
14 -- and Monice -- is this technically an add-on, or
15 was this in the original safety assessment?
16 Because add-ons is one way, no-brainers.
17 If it's in the original one, I'm not sure -- I
18 don't want to go back, but at the same time I want
19 to be, again, consistent.
20 DR. EISENMANN: The original report that
21 we were working on was DEA-TA and MEA. So, it's
22 an --
177
1 DR. MARKS: Add-on.
2 DR. EISENMANN: -- add-on.
3 DR. MARKS: Good. Okay, next -- MEA.
4 So there may be some -- this is the first time
5 we've seen this report. It's a draft amended
6 safety assessment of ethanolamine, which is the
7 new name for mono ethanolamine.
8 So I guess the question is, are we going
9 to change the cover of this to "Ethanolamine" in
10 the next rendition, from "MEA." But it's
11 historically good, because it's confusing, if we
12 go from one to the other without having recognized
13 that first.
14 So, Monice, I appreciate that you put
15 "MEA" on the front.
16 At any rate, in December we decided to
17 reopen the '83 assessment of TEA, DEA and MEA.
18 And, as you know, we decided to break these
19 ingredients up, and now we have the MEA or, aka,
20 the ethanolamine ingredients.
21 So I think the first thing we need to do
22 is, on page 12, decide if we want to include -- so
178
1 we have the inorganic salts, we have the organic
2 acid salts, the protein salts, the
3 organic-substituted, inorganic acid salts, and the
4 alkyl-substitute ethanolamines.
5 And, Ron, Tom, Ron, any either
6 individuals or groups that you want to eliminate?
7 DR. HILL: I would like to see the
8 alkyl-substituted ethanolamines removed.
9 DR. SHANK: I agree.
10 DR. SLAGA: I agree, too.
11 DR. HILL: And then unless we have
12 direct data on that phosphate -- that was one that
13 we removed on those others -- I'm not sure we need
14 to keep it in here, either. Although, just a
15 discussion point I'm tossing out there.
16 DR. MARKS: Actually, none of those
17 alkyl-substituted ethanolamines are being used.
18 So that's nice.
19 So the one you talked -- this individual
20 one, which is that again? Ron Hill?
21 DR. HILL: It would be the dicetearyl
22 phosphate, but I'm --
179
1 DR. MARKS: Di -- oh, yes. Okay. So
2 that's the organic-substituted inorganic acid
3 salts. That's the last ingredient there. That's
4 not being used, also.
5 Ron -- that's not a reason to eliminate
6 it. It's just do we keep it or not keep it?
7 DR. SHANK: It makes no difference to
8 me.
9 DR. SLAGA: Yeah, I'd just leave it in.
10 DR. MARKS: Leave it in.
11 DR. HILL: I'm trying to find it in the
12 structure table, because I thought I'd made --
13 MS. FIUME: Just so the Panel is aware,
14 in DEA and TEA the phosphates were removed because
15 there were no other phosphates that had been
16 reviewed to date. Just so that you're aware.
17 DR. MARKS: So shall we remove it? With
18 that -- being consistent?
19 DR. HILL: My concern with the
20 dicetearyl phosphate was not just that it was
21 phosphate, but that if you look at it, it looks a
22 lot like a membrane phospholipid, but with
180
1 saturated, rather than acyl lipid groups.
2 And from a personal comfort level,
3 without having some biological data on that --
4 even though I doubt there will be dermal
5 penetration at all. It's just leave-on use -- it
6 just seems scientifically inappropriate to keep
7 it.
8 DR. MARKS: Okay.
9 DR. HILL: But that's just my opinion,
10 for discussion.
11 DR. SHANK: That's good, because it's a
12 no-brainer.
13 DR. MARKS: Yep. So we have --
14 DR. SHANK: If we have questions about
15 it, we shouldn't have it.
16 DR. MARKS: So let me see. Now we need
17 to go -- so, Monice broke this into two sections.
18 If we go on page 25, we have the second section.
19 Do we want to continue to have this as
20 one report? And break it in -- this is more a, I
21 guess initially, as a stylistic, do we want to --
22 in the past, we've actually taken it and broken
181
1 things out.
2 Do you want to keep the "Part II," these
3 amides in? Or deal with them separately? Are
4 there ones that you don't feel comfortable with?
5 Or the whole group?
6 DR. SLAGA: Well, if we did it in the
7 past with one of the others, I'd rather see it
8 separated out.
9 DR. SHANK: I agree.
10 DR. SLAGA: To be consistent.
11 DR. SHANK: Yes -- well, and the
12 chemistry. The amides have a different chemistry
13 and a different conclusion -- at least on the
14 leave-ons. I think it's logical to separate the
15 amines from the amides.
16 DR. MARKS: Okay. So you would
17 actually, if we were going to deal with these,
18 have a totally separate report. Okay.
19 DR. HILL: And the other thing is, the
20 main logic for keeping them combined is that
21 somehow those amides were generating ethanolamine,
22 and I'm not sure that we have data that indicates
182
1 that.
2 DR. MARKS: Okay. So I think we've --
3 at least for this report, "Ethanolamine," or MEA,
4 we're going to include in this report, on page 12,
5 every ingredient -- starting from the bottom and
6 working up -- every ingredient about MEA-laureth
7 sulfate.
8 Is that correct? Will it be included in
9 this report?
10 DR. EISENMANN: So you've never reviewed
11 silk.
12 DR. MARKS: Pardon?
13 DR. EISENMANN: There's a hydrolyzed
14 silk one, and you've never reviewed silk. So --
15 at least I don't think -- Monice, has there ever
16 been a review of silk?
17 MS. FIUME: I'm checking the table. No,
18 we have not.
19 DR. MARKS: And we'll probably have
20 little data, at least in this, because it's not an
21 ingredient that's being used, the hydrolyzed silk.
22 So -- is that a problem? Do you want to
183
1 eliminate silk, since we haven't reviewed it?
2 DR. SHANK: Well, and the hydrolyzed
3 collagen MEA is the only one in this group, of the
4 ethanolamines, where there is a leave-on use. Or
5 at least there's a concentration -- no reported
6 use, but there's a concentration. Interesting how
7 that happens.
8 So maybe we should just eliminate both
9 of the hydrolyzed proteins.
10 DR. HILL: My recollection was a
11 statement was made -- I wasn't the one that made
12 it -- was the thought that if the toxicology of a
13 salt was primarily driven by the other component,
14 that we will try not to review it along with the
15 -- in this case it would the ethanolamine. That
16 if we had toxicology it might be driven by the
17 hydrolyzed silk component and not the
18 ethanolamine.
19 DR. MARKS: Right. That's the add-on.
20 DR. HILL: And in that case, we would
21 try to pare them out -- yeah.
22 DR. MARKS: So do you want to eliminate
184
1 the protein salts the, also, Tom, and Ron Hill?
2 To make it more straightforward?
3 DR. SHANK: Sure.
4 DR. MARKS: Okay. So let me restate
5 that again. We will have -- I'll do it a little
6 bit differently this time. The ingredients -- I
7 didn't add it up -- the ingredients will be the
8 inorganic acid salts, the organic acid salts, the
9 organic-substituted inorganic acid salts, the
10 lauryl sulfate and the laureth sulfate. And that
11 would be the ingredients that would be reviewed in
12 this report.
13 And then we would separate out, in a
14 separate report, the amides that are on page 25.
15 Okay. Is that -- we're okay with that?
16 Now, let's move on to, then, with those
17 ingredients on page 12. Are there any concerns,
18 in terms of moving this forward. Do we have
19 "insufficient data" needs?
20 I like, Ron, that you eliminated the
21 only leave-on, because there is some contradiction
22 on sensitization. And also there is irritation
185
1 with prolonged -- so it makes it simpler for me to
2 feel comfortable about a rinse-off, that these are
3 safe.
4 Any other needs?
5 DR. SHANK: We're still on amines?
6 DR. MARKS: Yes. Yes, we're only on the
7 amines. Should we discuss both? As separate? To
8 me --
9 DR. SLAGA: I don't think we should.
10 DR. MARKS: No. I would just do the
11 amines.
12 DR. SHANK: Okay.
13 DR. MARKS: What do you think, Tom?
14 Ron?
15 DR. SLAGA: I agree.
16 DR. MARKS: And then bring the amides
17 back in the future? What's -- what do you feel,
18 Ron Shank? You obviously said, "are we only doing
19 the one?" Or, actually, you're exactly right, it
20 would be basically do we have enough information
21 to feel that these ingredients are safe.
22 We didn't actually go down the list of
186
1 amides, but let's go back to the amines. We'll do
2 that, and then you would bring out -- you would
3 discuss, Tom, the amides at a totally separate
4 setting.
5 DR. SLAGA: Yes.
6 DR. MARKS: Yes, I think time-wise, that
7 makes sense.
8 DR. SHANK: Okay.
9 DR. MARKS: Okay.
10 DR. HILL: But I would have a lot of
11 ingredients on that list that I thought should
12 definitely come out.
13 DR. SLAGA: But we can make that --
14 DR. HILL: We could make that decision
15 whenever we saw them again.
16 DR. MARKS: Right.
17 DR. HILL: So long as --
18 DR. MARKS: Just hearing that --
19 DR. HILL: -- so I don't have to figure
20 it out all over again.
21 DR. MARKS: Just hearing that -- well,
22 better save that one, then.
187
1 DR. HILL: Yeah.
2 DR. MARKS: Just hearing that, it makes
3 me even more want to not delve into the amides.
4 So, how about the amines? Any problems?
5 DR. SLAGA: "Safe when formulated to be
6 non- irritating?"
7 DR. SHANK: Yes.
8 DR. MARKS: Yes.
9 DR. HILL: I agree.
10 MS. FIUME: Do you need the term,
11 "rinse-off" in the conclusion? Or is it --
12 because they're only used in rinse-offs, it could
13 be "safe as used, when formulated to be
14 non-irritating."
15 DR. MARKS: I think -- remember, we
16 always put the caveat "if not being used," so it
17 would be in the same the use and the same
18 concentration.
19 So that means it's implied it's safe in
20 only rinse- offs.
21 DR. HILL: However, it probably --
22 DR. MARKS: We can do that in the
188
1 discussion.
2 DR. HILL: -- in many, if not all of
3 these, might be safe in leave-ons. It's just --
4 DR. MARKS: Right.
5 DR. HILL: -- we'd have to see that.
6 DR. MARKS: So, "safe,"
7 "not-irritating." And then we would issue a
8 tentative amended safety assessment. And this
9 would only be for the amines on page 12.
10 Any other comments? Okay. And we will,
11 if it comes up -- I'm going to make that motion,
12 and then I'll also, if it comes up, basically say
13 we tabled the discussion on the amides, and
14 recommend that be a separate report, done at a
15 later date.
16 Does that sound good? Okay. Citric
17 acid.
18 DR. MARKS: Okay, this is the citric
19 acid group, its inorganic salts, alkyl and glycol
20 esters.
21 This is the first time we've seen this
22 group. And as we do when we -- in this case, it
189
1 doesn't have to be a no- brainer, since this is
2 not a reopening of a previous report.
3 Lots of product uses. Over 7,400
4 products contain these ingredients.
5 So let's go to page 16 on the Panel
6 Book, and look at the 46 ingredients listed on the
7 top of the page. Should any of these be
8 eliminated?
9 DR. SHANK: I had "eliminate the glycol
10 mono-, di-, and triesters." There's no tox data
11 on them, except for laureth-7, and that's only one
12 Ames test, "sensitization in eye." There's only
13 one use of laureth-7 citrate, and one use of the
14 laureth-9 citrate. Oh -- no, it's not even used.
15 It's only laureth-7 citrate is used.
16 And we'd have to extrapolate from that
17 to all of the others. And it's not enough data to
18 do so.
19 So I would eliminate all of the glycol
20 esters.
21 DR. MARKS: So, the other alternative
22 would be is you just include those and put
190
1 "insufficient data."
2 DR. SHANK: Okay.
3 DR. MARKS: Which -- Tom, Ron Hill?
4 Weigh in? I think now that we don't have to do a
5 no-brainer, we could keep it and put "insufficient
6 data." So it would indicate we actually did look
7 at these ingredients and we're --
8 DR. HILL: I like keep them with
9 "insufficient data." Because I think they're
10 probably potentially very useful ingredients. And
11 people -- we can suggest what data would be
12 needed, based on what you just said. And then
13 people can go to work generating it if they're
14 interested in those ingredients.
15 DR. MARKS: Ron, does that -- how do you
16 feel about that?
17 DR. SHANK: Than's okay.
18 DR. MARKS: So, "insufficient data" for
19 these.
20 DR. HILL: The other thing I was going
21 to say, while we're on that particular subject --
22 just for efficiency, so we don't have to come back
191
1 -- is actually all of them but two, I think,
2 should be called "alkyl PEG mono-, di- and
3 triesters." And then there are actually only two,
4 is the propylene glycol citrate and the
5 tripropylene glycol citrate are actually glycol
6 mono- or triesters. And if we group them that
7 way, which is what I suggested in the book, then
8 that will help, I think, focus on what things go
9 together.
10 DR. SLAGA: Good idea.
11 DR. HILL: Because those two really
12 aren't the same as the rest.
13 MS. FIUME: That's broken out in your
14 book, Dr. Hill?
15 DR. HILL: Well, it is. It's marked --
16 those two are marked.
17 DR. MARKS: Do you want me -- I won't be
18 presenting, but Ron, do you want to do that?
19 Mention that tomorrow? Because -- are you
20 breaking that out from the glycol mono-, di-, and
21 triesters in this list? Or do you have some other
22 compounds in the groups above -- the alkyl and the
192
1 inorganics -- well, obviously not the inorganic
2 salts.
3 DR. HILL: Just breaking out those two,
4 because the rest are actually alkyl PEG mono-,
5 di-, or triesters.
6 But those two are actually glycols. The
7 glycol groups are actually exposed.
8 DR. MARKS: Which two are those, again?
9 DR. HILL: It's the propylene glycol
10 citrate, and the tripropylene glycol citrate. So
11 there aren't any diesters there. There's a
12 monoester and a triester.
13 DR. MARKS: And the other one. Oh,
14 yeah, I see the two. So that's in the last group.
15 You would just break those out.
16 DR. HILL: I would break those two. And
17 those should be the ones called "glycol." It
18 would be just mono- and triesters.
19 DR. MARKS: Okay.
20 DR. HILL: And I think they would create
21 a new category, "alkyl PEG mono-, di- and
22 triesters."
193
1 DR. MARKS: I assume breaking them out,
2 it's still they're "insufficient data."
3 DR. HILL: I believe that's true.
4 DR. MARKS: Okay. How about the
5 inorganic salts? Okay?
6 DR. SLAGA: Okay.
7 DR. SHANK: Except there is no
8 inhalation data on the inorganic salts or the
9 alkyl esters.
10 DR. MARKS: So it sounds like we need
11 inhalation data on both -- all -- at least
12 representative. Is there representative ones that
13 --
14 DR. SHANK: There's no inhalation data
15 on any of them. Lots of these are GRAS, but
16 that's for oral.
17 DR. EISENMANN: Monice, did you actually
18 look for inhalation data? Because we were
19 focusing on dermal data, right?
20 MS. FIUME: I probably would have
21 searched anything except the oral. But I will
22 double-check to make sure there's inhalation.
194
1 Because for all of the ingredients except those
2 that are GRAS, I searched everything.
3 DR. EISENMANN: Right. I understand
4 that. But like for citric acid, there's a slim
5 chance that there could be inhalation out there
6 that wasn't picked up because the focus was dermal
7 for citric acid -- right?
8 MS. FIUME: Probably. I will
9 double-check it. Because I believe it's this
10 report -- right? -- where they are broncho -- the
11 cough-reflex information. So that probably -- I
12 will look and see if there's inhalation out there.
13 DR. MARKS: Yes, I picked that up.
14 That's on page 9, that citric acid is a tussive
15 agent, irritation of the larynx and trachea. So
16 you certainly wouldn't want to be formulating this
17 as a tussive in your cosmetic.
18 Do we need -- in the structure of these
19 chemicals, do we need any photo data?
20 Phototoxicity?
21 DR. SHANK: No.
22 DR. MARKS: No. Okay. I didn't think
195
1 so, either, but I wanted to be sure.
2 It would be nice -- let me see what page
3 -- 41. I wasn't really concerned about
4 sensitivity of these, but with citric acid having
5 over close to 6,800 products, you would think
6 there would be at least, somewhere, HRIPTs with
7 these products. Particularly since it's used up
8 to 35 percent.
9 DR. HILL: I'd also flagged that in the
10 two that I made note of that we didn't have any
11 data on -- were triethylhexyl citrate and
12 triisocetyl citrate. The rest of them probably
13 had less concern. But I guess I'm stuck on
14 branched-chains, still.
15 DR. MARKS: So, do we -- what do you
16 think about getting HRIPT, at least see some data
17 up to 35 percent?
18 DR. HILL: And those two also had
19 reported uses.
20 DR. BERGFELD: I'm not sure that on all
21 your pH adjusters you really ask for that. That's
22 low concentration, and known irritants.
196
1 DR. MARKS: David, why don't you come up
2 and --
3 DR. HILL: The alkyl citrates are not pH
4 adjusters, though. The salts are. But the alkyl
5 ones are not. The triesters -- that's the ones I
6 was just talking about -- those aren't going to be
7 pH adjusters.
8 MS. FIUME: And Dr. Marks, there is one
9 HRIPT on citric acid, on Panel Book page 49.
10 DR. MARKS: You know, I must have missed
11 that.
12 DR. HILL: But it's just citric acid,
13 right?
14 DR. MARKS: No, there are other ones.
15 MS. FIUME: Triethyl citrate.
16 DR. MARKS: Yes, triethyl citrate.
17 DR. HILL: And also, trioctyldodecyl
18 citrate, I think there's one, isn't there? No.
19 DR. MARKS: Yes, the tristearyl citrate
20 --
21 DR. HILL: Yes.
22 DR. MARKS: -- not an irritant or
197
1 sensitizer. The triethyl was a strong sensitizer
2 undiluted, but at 20 percent was not an irritant
3 or sensitizer.
4 I guess, you know, at 30 percent citric
5 acid was an irritant. Not surprising.
6 David?
7 DR. GOLDSTEIN: Jim, just to qualify one
8 thing. The work that I looked at for Health
9 Canada, 98 percent of all uses of citric acid was
10 pH adjustment.
11 DR. MARKS: Oh, okay.
12 DR. GOLDSTEIN: So that's why you're
13 getting so many hits for -- when it's just used to
14 adjust the pH.
15 DR. MARKS: So how about -- so,
16 actually, up to 35 percent is found in the final
17 product, it says here, on a leave-on, in citric
18 acid that can be up to 35 percent. That's what my
19 alert was.
20 DR. GOLDSTEIN: Yes, I think we didn't
21 find anything at Health Canada above 3 percent. I
22 believe, going back probably 20 years ago, people
198
1 were using high levels of citric acid as an
2 alpha-hydroxy acid, and that's why they would use
3 it at high levels. I don't think anyone's using
4 it that way anymore.
5 DR. MARKS: Well, all I can go is what
6 is the use and concentration. That's why I
7 alerted -- you know, is there an HRIPT on it, and
8 that's at the borderline irritation. But I was
9 willing to accept 35 percent from an irritant
10 point of view. I doubt it's a sensitizer, I'm not
11 aware of it. But at the same time, it would be
12 nice to have, like we have for those others -- the
13 triethyl and the tristearyl we have hard data that
14 it's not, at those concentrations.
15 DR. HILL: For the triisostearyl
16 citrate, it reports up to 80 percent
17 concentration. That's probably a lipstick -- in a
18 leave-on product. I'm not sure if it's lipstick,
19 without going to look at the raw data, which I
20 guess we have.
21 DR. GOLDSTEIN: It would probably be a
22 lip gloss. It would be a liquid. It would be a
199
1 lip gloss. Something like that.
2 DR. EISENMANN: But there are some
3 HRIPTs on that summarized on page 51.
4 DR. HILL: Not the isostearyl.
5 DR. EISENMANN: Yes -- 114 subjects,
6 "neat," triisostearyl.
7 DR. HILL: All right, wait a minute. So
8 I'm missing a check box in a table, is that the
9 deal? Because -- oh, wait a minute. Isostearyl
10 -- yes. "Dermal sensitization" -- I'm sorry. I
11 stand corrected.
12 MS. FIUME: Used as a lipstick.
13 DR. HILL: Yes. And it's okay
14 sensitization-wise -- right?
15 DR. MARKS: Yes.
16 MS. WEINTRAUB: I want to --
17 DR. MARKS: So let's just finish with
18 the citric acid, Rachel, before --
19 MS. WEINTRAUB: This has to do with the
20 citric acid.
21 DR. MARKS: Oh -- okay. With the 35
22 percent, do we need HRIPT?
200
1 MS. WEINTRAUB: No, it has to do with
2 another data need.
3 DR. MARKS: Should we query and see is
4 that really the highest leave-on concentration?
5 I'd like to know that.
6 DR. EISENMANN: It's a foot product. I
7 will check into it and see what I can find out
8 about it.
9 DR. MARKS: So, I would put that as a
10 data need. Okay -- I apologize, Rachel.
11 MS. WEINTRAUB: That's okay.
12 DR. MARKS: But I wanted to finish, to
13 make sure we're finished the sensitization issue.
14 MS. WEINTRAUB: Sure. I just wanted the
15 Panel to discuss the lack of carcinogenicity data.
16 DR. MARKS: Tom?
17 DR. HILL: Lack of carcinogenicity data.
18 MS. WEINTRAUB: I mean, on page --
19 DR. HILL: Well, didn't we say that we
20 would be -- oh, I take that back.
21 Yeah, didn't we say for some of them
22 we'd be in an "insufficient data" situation, and
201
1 that was specifically what would be mentioned?
2 DR. MARKS: Well, no. No, that's only
3 the bottom third here --
4 DR. HILL: Okay.
5 DR. MARKS: -- with the glycol mono-,
6 di-, and triesters, and then your alkyl PEG, those
7 two. Everything in the inorganic salts and the
8 alkyl mono-, di-, and triesters -- so we're going
9 through the needs. So that's an important --
10 Tom, do you feel, is the mutagenicity
11 enough? Or do you feel we need carcinogenicity
12 studies for those?
13 DR. SLAGA: I don't think we need
14 carcinogenicity. There's one of them that's been
15 tested. The aluminum citrate a while back. But
16 that was for a certain -- different type of use.
17 I think there's sufficient genotoxicity.
18 DR. EISENMANN: This is also a normal
19 metabolite. And the other thing is the focus was
20 not on systemic toxicity. So I don't know if you
21 really want -- she didn't put in the oral data --
22 correct?
202
1 Isn't there some -- I mean, for the GRAS
2 ingredients.
3 MS. FIUME: We did not put in oral data
4 for GRAS ingredients.
5 DR. EISENMANN: So there might be more
6 data out -- well, there probably is more data out
7 there, but --
8 DR. SLAGA: For oral, yes. There's no
9 concern for the skin, in terms of carcinogenicity.
10 DR. HILL: Yeah, I remember what my
11 concern was with the isocetyl was that there are
12 leave-on uses reported -- actually 33 of them --
13 up to 3 percent. So that's why. But we didn't
14 have any sensitization data on those. Maybe the
15 other group will have a different opinion about
16 the need, considering that we do have it on
17 isostearyl. But I wasn't so sure.
18 DR. MARKS: Any other comments? Tom?
19 Rons? Lots of uses, so we would issue a --
20 actually a data need, and what we want is the
21 inhalation data, and I'd like to see an HRIPT of
22 citric acid at 35 percent.
203
1 We're going to do -- and that's for the
2 ingredients in the inorganic salts and the alkyl
3 mono-, di-, triesters. So the triesters.
4 For the glycols, we're going to say
5 "insufficient data" for that.
6 And do we want to be more specific as
7 far as the "insufficient data" needs there? Ron?
8 Tom? I think we need to be.
9 Ron, your summary was we had almost no
10 toxicologic data on those, so we need almost
11 everything.
12 DR. HILL: Yes.
13 DR. SHANK: We have a little bit on
14 laureth-7, that's all.
15 DR. EISENMANN: Now, data -- laureth-7
16 is not enough?
17 DR. SHANK: Laureth-7, we have one Ames.
18 DR. EISENMANN: I'm talking -- I mean,
19 you're talking laureth-7 citrate, but I'm talking
20 about just the components, the other components.
21 So the citrate part, the laureth-7, or the
22 laureth-(inaudible).
204
1 PEG-5 tristearate -- without the
2 citrate. If there's data on those other
3 components, would that be sufficient? Or do you
4 want to see that data to decide whether or not it
5 would be sufficient?
6 DR. SHANK: I think I'd want to see the
7 data before I say it's sufficient.
8 DR. EISENMANN: But that would be
9 relevant. Maybe that's the correct question.
10 DR. HILL: Well, we don't know. And the
11 reason we don't know is because that's a
12 monoester, and we don't know whether any of those
13 triesters are actually metabolized, in this
14 particular case, because they're so large and they
15 have those PEG groups, down to a monoester.
16 So that, in my mind, invalidates reading
17 across from that monoester to those triesters --
18 in my mind.
19 I doubt there will prove to be any
20 problems with them, but with no data --
21 MS. FIUME: Dr. Marks, do you have a
22 specific list for the "insufficient data" for the
205
1 glycol triesters?
2 DR. MARKS: Yes. It's almost no
3 toxicologic data. So the list is virtually
4 everything, that we would look at.
5 DR. HILL: Well, right now there are no
6 reported uses. So, I mean --
7 DR. MARKS: Well, there's propylene
8 glycol.
9 DR. SHANK: Well, you'd start with
10 absorption.
11 DR. MARKS: Yeah.
12 DR. SHANK: And if it's not absorbed,
13 then you don't need reproductive, developmental,
14 carcinogenicity. If it's absorbed, you may need
15 that.
16 You'd need irritation, sensitization
17 data.
18 DR. MARKS: And sensitization.
19 DR. HILL: Since we, I think, can now
20 distinguish between absorption versus dermal
21 penetration, I guess I would like to see dermal
22 penetration, not just absorption. Because what I
206
1 think will happen with those triesters is we won't
2 see them leaving the upper layers of the skin --
3 at least not intact.
4 DR. MARKS: Okay.
5 DR. HILL: What that does for me is, if
6 nobody's using them now and then they want to use
7 them, come in with a little data.
8 DR. MARKS: Okay. And other -- Monice,
9 anything else you need?
10 (No audible response.)
11 DR. MARKS: Okay. So, when a motion is
12 made, I'm going to say we need, we have an
13 insufficiency-data notice, and summarize what
14 needs we have for the ingredients -- which we
15 expect we're going to move on to "safe." That's
16 the inhalation data in the citric acid, HRIPT up
17 to 35 percent. And then the "insufficient data,"
18 is for those glycols. And start with absorption
19 and any irritation and sensitization, and see
20 where it leads us.
21 Any other comments? Okay.
22 Sulfosuccinates.
207
1 MR. JOHNSON: Excuse me, Dr. Marks,
2 Lillian Becker, she's the author of the silylates
3 report. Would it be okay if we start with the
4 alkyl glycerol ethers? I mean -- I'm sorry, the
5 sulfosuccinates?
6 DR. MARKS: Yes, okay. Yes, we can
7 start with that, Wilbur. Lillian had alerted me.
8 Wilbur, of course we can change the order.
9 MR. JOHNSON: Thank you.
10 DR. MARKS: IP assume there's nobody in
11 the audience from industry, et cetera, who will
12 have a problem going out of order here. And
13 there's nobody in the other room who has an
14 interest to comment on sulfosuccinates.
15 So it's the sulfosuccinates you want to
16 move on to? That's the green book?
17 MR. JOHNSON: Yes, please.
18 DR. MARKS: Okay. So this is the first
19 review. As you could tell, Wilbur is the author
20 of this, and researcher. There's 19 ingredients.
21 And, Bart, you're here. Because there's a
22 chemical question you'll address as to whether or
208
1 not the disodium lauryl sulfosuccinate actually
2 belongs in this group -- since it's not like the
3 other ethoxylated chemicals.
4 So let's first go to page 7. And I
5 think that's -- are there any -- one of these
6 ingredients, other than the one I mentioned? And,
7 Bart, why don't you just start with your comment
8 about the disodium lauryl. So that's --
9 DR. HELDRETH: The disodium lauryl
10 differs from all of these ingredients in that it's
11 not an ethoxylated product. It just has straight
12 alkyl chain.
13 The only one of these ingredients that
14 doesn't have the ethoxy repeat-units is the
15 trisodium salt. But that, again, works in as
16 potentially a metabolite -- or at least a core
17 piece of all of the rest of the ingredients.
18 In my opinion, putting in the lauryl
19 group is very different from all of the other
20 ingredients. And if we're going to be consistent,
21 and try to build this report based on those side
22 chains, then we would need to add in all of the
209
1 other alkyl sulfosuccinates that don't have an
2 ethoxy group.
3 And that's -- that would more than
4 double the size of the report, and it would
5 require going back and doing all the research, and
6 searching for it.
7 DR. MARKS: So, presently, that's
8 actually not on page 7, that particular chemical
9 -- correct? It's not like we have to remove it
10 from the list. It's just we were --
11 Carol, can you comment? Apparently
12 there was a request from industry to add that?
13 DR. EISENMANN: Yes, a supplier thought
14 it was appropriate to add that.
15 DR. HELDRETH: Structurally, it would be
16 just like disodium laureth sulfosuccinate, but
17 without those ethoxy groups in between there. The
18 alkyl chain would be directly attached to --
19 DR. EISENMANN: Well, there would be a
20 whole series -- I mean, there's not more than one,
21 the disodium cetearyl, there would be a whole
22 series of them. If you added that one, it
210
1 probably would be appropriate to add the others.
2 DR. MARKS: So it seems to me, then, the
3 Panel has to decide whether you want to add that
4 group or not. And if we add the group, it seems
5 like we would have to table these ingredients
6 until -- we could certainly discuss what we have,
7 but then we have, as you said, Bart, we would have
8 to go back and look for the data on all these
9 others.
10 DR. EISENMANN: Bart, I have one
11 questions. It would be just as appropriate to
12 include the trisodium sulfosuccinate with the
13 ingredients they're suggesting to add, right?
14 DR. HELDRETH: Yeah, the trisodium sulf,
15 by itself, would work with either an alkyl group
16 or an ethoxylated group, or a group that had the
17 ethoxylated ones, or just the alkyl ones all in
18 one report.
19 But if we're going to add the purely
20 alkyl side chain ingredient, then we'd probably
21 want to add them all. And if I remember right,
22 that would definitely more than double the size of
211
1 this report -- probably needlessly. But that's
2 your decision.
3 DR. BERGFELD: Excuse me -- what does
4 "needlessly" mean? (Laughter.)
5 DR. HELDRETH: Well, here you have a
6 cohesive group. And they're asking us to throw
7 one in that's not necessarily like the others.
8 And therefore it would just radically change the
9 size of this group and the constituents of this
10 group.
11 So -- it could be done. But it's not
12 like it's a "missing" unit from what we already
13 have.
14 DR. MARKS: So, chemically, so we might
15 be in two or three meetings, chemically, saying,
16 "We should split these out and have two reports,"
17 after we've combined them.
18 DR. HELDRETH: Mm-hmm. Quite possibly.
19 DR. MARKS: Okay.
20 DR. HILL: And that's what he meant by
21 "needlessly," right?
22 Well, what was the basis for the
212
1 request? Is it a current "insufficient data"
2 situation that they're --
3 DR. EISENMANN: My guess is they're
4 supplying it, and they'd like to see it reviewed.
5 DR. HILL: Mm-hmm.
6 DR. BERGFELD: How does it stand on the
7 priority list?
8 DR. HELDRETH: It's definitely got a lot
9 of uses. So it would rank right up there.
10 DR. HILL: And particularly if you added
11 in anything else that fit in that group -- right?
12 -- I mean, it would --
13 DR. MARKS: So, you're saying the
14 disodium laurel sulfosuccinate has a lot of uses.
15 So, Ron, Tom, Ron? What would you like
16 to do? Go with what we have in front of us? Or
17 would you like to see it expanded into a much
18 larger group, with the paraphrase in parentheses
19 "needlessly?" No, I'll remove that.
20 DR. SLAGA: I would say don't add the
21 laurel sulfosuccinate. Leave it all with the PEGs
22 -- only.
213
1 DR. MARKS: Ron?
2 DR. HILL: I certainly agree.
3 DR. MARKS: Okay. So we'll move
4 forward. Now, is there anything on the
5 ingredients listed on page 7, now that we've dealt
6 with the "phantom ingredient" on page 7. Anything
7 that you see shouldn't be included?
8 Okay. So then we would move on to what
9 needs do we have. Or do we have enough data that
10 we can move forward with -- we either have an
11 "insufficient data" need, or move forward with a
12 tentative report?
13 DR. SHANK: Well, I think we need dermal
14 absorption data. And then, if it's absorbed,
15 perhaps reproductive developmental toxicology,
16 metabolism, mammalian genotoxicity. Many of these
17 compounds are bacteriocidal, so would not use a
18 bacterial system.
19 And then I would like to see toxicity
20 data on the sulfosuccinate salt.
21 DR. EISENMANN: Can you be more specific
22 about what you want to see on the --
214
1 DR. SHANK: Well, I'm sure this has been
2 looked at. Does it perturb the citric acid cycle?
3 DR. MARKS: And was that just for one
4 lead? Did you say, Ron?
5 DR. SHANK: Well, we don't have anything
6 on the trisodium sulfosuccinate. So that's the
7 sulfated version of succinic acid -- which is a
8 component part of the citric acid cycle, very
9 important to the life of the cell -- like energy
10 and things like that.
11 So it may do nothing, but it may also
12 perturb -- it would be a pretty simple study.
13 It's probably already been done.
14 DR. MARKS: So it's just for the
15 trisodium sulfosuccinate that you would want to
16 see what effect it had on the citric acid cycle.
17 DR. SHANK: Yes. We don't need
18 absorption data on that, because that's not an
19 ingredient -- is that correct?
20 DR. MARKS: No, I have that it has 44
21 uses.
22 DR. SHANK: Oh, it does. Sorry --
215
1 DR. MARKS: And at 2 percent is the
2 highest concentration.
3 DR. SHANK: Oh, okay. Then include it
4 with the --
5 DR. MARKS: So we need dermal
6 absorption. If absorbed, obviously reproductive
7 tox.
8 And then the second need was -- did you
9 say carcinogenicity data?
10 DR. SHANK: No, genotoxicity.
11 DR. MARKS: Geno tox.
12 DR. SHANK: Mammalian.
13 DR. SLAGA: Mammalian.
14 DR. MARKS: Any other needs?
15 DR. HILL: We don't have anything on
16 irritation or sensitization for any -- well, there
17 is irritation on two of them.
18 DR. MARKS: Yes.
19 DR. HILL: There's no sensitization on
20 any of them.
21 DR. MARKS: Actually, I have
22 sensitization -- we'll have to go back. I have
216
1 "irritation and sensitization in the animal" as
2 okay. I would have liked to have seen human,
3 HRIPT.
4 DR. HILL: But the only animal
5 sensitization we have is on the disodium laureth
6 sulfosuccinate.
7 DR. MARKS: Yes, what page are you --
8 DR. HILL: The salt itself, not any of
9 the alkyl PEG esters, monoesters.
10 DR. MARKS: What page?
11 DR. HILL: Well, I'm looking at the
12 Panel Book page 4. We just have a list-out of all
13 the data. There's nothing under the
14 "Sensitization" column. And there is a little bit
15 of dermal irritation data, animal. So maybe that
16 would include sensitization. But I'd question
17 that.
18 And that's one where I don't think you
19 can necessarily write off with lack of absorption
20 data. That's why I mention that one,
21 specifically.
22 DR. MARKS: So here on page 11, "Skin
217
1 sensitization was not observed in induction or
2 challenge with -- " -- I think it went up to 1.6
3 percent in guinea pigs. It's a mild skin
4 irritant. That's the disodium laureth.
5 DR. HILL: Disodium laureth? We are
6 just -- are missing a check-box that should have
7 been checked? Is that --
8 DR. MARKS: If you look on page 11 --
9 that's what I went.
10 DR. SHANK: And 12 -- humans.
11 DR. MARKS: Yes.
12 DR. SHANK: Human data, on page -- Panel
13 Book page 12.
14 DR. MARKS: Yes, I didn't think -- oh,
15 yes. Okay. Yes, one was patch test.
16 DR. HILL: Okay. Yeah.
17 DR. MARKS: In a series. The other one
18 was just 12 subjects. That's why I would have
19 liked to have seen the H --
20 DR. HILL: I saw that, too. In fact, I
21 even have it highlighted. So it's just that it
22 wasn't marked in the check-boxes on page 4.
218
1 DR. MARKS: Yes. So, Ron, I wasn't --
2 DR. HILL: Okay.
3 DR. MARKS: -- I thought it would be
4 okay, from an irritation and sensitization. I
5 just couldn't believe that there wouldn't be an
6 HRIPT. And I wouldn't say that's a "data need,"
7 but it would be nice.
8 DR. EISENMANN: These are primarily used
9 in rinse- off. So when they do an HRIPT for a
10 rinse-off product, they dilute it a lot.
11 So, yes, I can ask, but it would
12 probably be a very low concentration that will be
13 tested.
14 DR. HILL: That was because it was used
15 in rinse- offs, why it was less concerning? I'll
16 learn to take better notes -- instead of
17 scattering this stuff all over the book.
18 DR. MARKS: Inhalation okay? So, the
19 disodium laureth sulfosuccinate is used in 607
20 products. There is leave-on, up to 2 percent, is
21 reported. And, again, with that 1.6 percent, I
22 thought that was close enough that I didn't get
219
1 concerned about sensitivity.
2 But it is used in a few sprays. So,
3 what do you think? So, Ron, are you okay with the
4 sensitization and irritation?
5 DR. HILL: Yes. Sorry.
6 DR. MARKS: Okay -- no, that's okay.
7 How do we -- Carol, so you don't think there will
8 be a -- because most of it -- again, getting back
9 to that 2 percent leave-on, it would be nice to
10 see HRIPT, if it exists.
11 DR. EISENMANN: I'll ask.
12 DR. MARKS: Okay. Good. I don't look
13 at that as a need which would block moving
14 forward.
15 Inhalation? Is that a need, with the
16 two products which are incidental inhalation
17 sprays? That's from page 21. The use table.
18 Ron, Tom? Ron?
19 DR. SHANK: Yes, we would need
20 inhalation -- something about, pertaining to --
21 we'd need something pertaining to potential for
22 inhalation toxicity.
220
1 DR. MARKS: Okay. So we would move --
2 anything else, looking over it?
3 MR. JOHNSON: Dr. Marks?
4 DR. MARKS: Yes?
5 MR. JOHNSON: The possible consideration
6 of data from earlier CIR safety assessments is
7 mentioned on page 9.
8 DR. HILL: Those are straight laureths,
9 not the sulfosuccinates -- right?
10 MR. JOHNSON: Where it says "sodium
11 laureth sulfate and related salts of sulfated
12 ethoxylated alcohols."
13 DR. HILL: Okay.
14 MR. JOHNSON: That's one of them.
15 DR. HILL: Oh, page 9. I was looking at
16 8. Sorry.
17 MR. JOHNSON: Yes, under "Data from
18 other CIR Safety Assessments."
19 DR. HILL: Mm-hmm. The comment I wrote
20 next to that in my book was "Need to put all
21 structures into figures so that can compare the
22 structures and see how reasonable that read-across
221
1 was."
2 MR. JOHNSON: Okay.
3 DR. HILL: I probably wrote that note
4 yesterday sometime.
5 Because you make a comment about
6 chemical similarities and wrote, next to that,
7 "Can't be adequately defined." "Chemical
8 similarities," doesn't mean anything. What we
9 really want to know is biological/toxicological
10 similarities.
11 DR. MARKS: So, Wilma was pointing, on
12 page 9 there is inhalation studies at the top.
13 Where is that, Wilma? This is page 9?
14 DR. BERGFELD: Well, this is
15 (inaudible).
16 DR. MARKS: Yes, page 9. Oh, here we
17 go. Here are salt properties.
18 DR. SHANK: I guess I hesitate to use
19 material safety data sheet as a reliable --
20 DR. BERGFELD: This is "no data?"
21 DR. SHANK: No, it's a summary of
22 information on a chemical compound prepared by the
222
1 manufacturer.
2 DR. BERGFELD: Okay.
3 DR. SHANK: And you really need to see
4 the basis upon which that statement is made.
5 DR. MARKS: Okay. So I think what I'll
6 move is that we issue an "insufficient data"
7 announcement. And these are for the ingredients
8 on page 7. We'll include all those.
9 The needs are dermal absorption. If
10 there's absorption, then we're going to need
11 reproductive toxicity. We need mammalian geno tox
12 data. We need to know how trisodium
13 sulfosuccinate affects the citric acid cycle. And
14 then we need inhalation data -- to move forward
15 with a safety assessment.
16 Is that correct?
17 DR. SLAGA: Yes.
18 DR. MARKS: Anything else? Ron, Ron?
19 Nope? Okay. So it will be an "insufficient data"
20 announcement.
21 Okay. So, Wilbur, you're still here.
22 MR. JOHNSON: Still here.
223
1 DR. MARKS: And Lillian isn't. So which
2 one do you want to do next.
3 MR. JOHNSON: The next, benzoic acid.
4 DR. MARKS: So, benzyl alcohol, benzoic
5 acid, and its salts and esters. That's Blue Book.
6 In June of this year the Panel issued a
7 tentative amended final report, with a conclusion
8 of "safe." Or task is to move it forward to issue
9 an amended final report with that conclusion,
10 "safe."
11 Any problem with that? And that's on
12 Panel Book 33.
13 DR. SLAGA: The conclusion is fine.
14 DR. MARKS: Conclusion is fine. Okay.
15 Let's see -- Ron stepped out momentarily, but I
16 assume -- Ron Hill, I assume -- I'll ask him
17 again. So let's go to editorial comments. Page
18 32, Ron, I wanted to --
19 DR. HILL: That's the Panel Book?
20 DR. MARKS: Yes. Panel Book 32. I'm
21 sure, Ron Shank, you had some editorial comments
22 here. I wanted to ask Tom -- and this would be
224
1 the third paragraph, where it says "these adenomas
2 were considered benign by the NTP." I thought, if
3 it's an adenoma, by definition, it's benign. But
4 is that wrong?
5 DR. SLAGA: No -- it's benign.
6 DR. SHANK: Though I think there's one
7 mouse tumor called an adenoma which is malignant.
8 So --
9 DR. MARKS: Oh, okay. So then we'll
10 leave it as such. The way it's written.
11 DR. SHANK: Yes.
12 DR. MARKS: Okay. Other comments?
13 Editorial comments? Go ahead.
14 DR. SHANK: I had an editorial comment
15 on the abstract. I don't think there's any need
16 to point out all of the specific effects about
17 carcinogenicity or sensitization. We should use
18 the same format that we use for all of the others
19 -- that is, what is its use, this is a re-review,
20 there's read-across, and the conclusion is it's
21 safe.
22 That's just my personal bent.
225
1 DR. MARKS: Okay.
2 DR. SLAGA: We need to be consistent.
3 DR. MARKS: Yes, consistency. So,
4 Wilbur, again, that would be editorial comments.
5 Rachel?
6 MS. WEINTRAUB: I have a question -- on
7 page 19 of the report (inaudible), Panel Book 32,
8 in the third paragraph.
9 There's two statements that I don't see
10 how they're consistent. It talks about testicular
11 atrophy was observed in rabbits that received
12 repeated dermal doses greater than.5
13 grams/kilogram per day. But then it says,
14 "However, overall, these ingredients were not
15 classified as reproductive or developmental
16 toxicants."
17 So either there's a clause missing that
18 explains that distinction, I think, or -- they
19 just sort of appear inconsistent to me.
20 So I wanted the Panel's thoughts on
21 that.
22 SPEAKER: What page?
226
1 MS. WEINTRAUB: Page 32 of the Panel
2 Book.
3 DR. MARKS: Page 32. It's the third
4 paragraph from the top. And the second sentence
5 begins with "Testicular atrophy -- " and the
6 following sentence states as Rachel said, " -- not
7 classified as a reproductive or developmental
8 toxicant."
9 So I guess you're asking, Rachel, how
10 can you have testicular atrophy without being a
11 toxicant? So --
12 MS. WEINTRAUB: And I realize this is in
13 the summary.
14 DR. MARKS: Right.
15 MS. WEINTRAUB: So I've tried to go back
16 and find where it was. But I couldn't find
17 anything.
18 DR. MARKS: No, this is good. I agree
19 with you -- particularly juxtaposition, the two
20 sentences seem contradictory.
21 MS. WEINTRAUB: Right.
22 DR. HILL: I'm looking at my last --
227
1 DR. MARKS: Wilbur?
2 DR. HILL: -- copy of the report, and
3 I've got that heavily flagged. And it seemed like
4 somebody had an explanation for that. But I don't
5 remember who had it, and what it was?
6 DR. SHANK: Yes, I think it was Dr.
7 Snyder said that the authors of the study
8 concluded that it was stress- related, not agent
9 related.
10 And I have that marked for another
11 report. I should have marked it for this one. I
12 think that needs a reference.
13 But I'd like Dr. Snyder and Dr. Klaassen
14 to respond to that, because I'm not aware that
15 this is a usual finding, stress results in
16 testicular atrophy. But I'm not a reproductive
17 toxicologist.
18 DR. MARKS: Right.
19 DR. SHANK: So I'd like the reference
20 supporting that conclusion.
21 DR. MARKS: So, Wilbur, we'll ask you to
22 touch (inaudible). Now that you bring that up,
228
1 Ron, I remember that issue, too. And that would
2 be -- the way this implies, it was at these doses
3 it was atrophic, but it's not that these rabbits
4 get testicular atrophy from stress.
5 So -- let's clarify that. I think
6 that's important. Thank you, Rachel.
7 Again, it seems like an editorial
8 comment, and nothing that's going to change.
9 So, Ron, while you were out, we
10 reaffirmed the conclusion, and that we would issue
11 an amended final report on these compounds, that
12 they're safe.
13 I assume that's what you felt, too.
14 Yeah? Good.
15 DR. HILL: Yes, sir.
16 DR. MARKS: Okay. Any other editorial
17 comments?
18 MR. JOHNSON: Dr. Marks, the testicular
19 atrophy --
20 DR. MARKS: Mm-hmm.
21 MR. JOHNSON: -- is first mentioned on
22 CIR Panel Book page number 22, in the "Repeated
229
1 Dose Toxicity" study -- it's in the second
2 paragraph, line six, under "Benzyl Benzoate."
3 DR. MARKS: Yes, I think the question is
4 what the explanation for that is.
5 MR. JOHNSON: Mm-hmm.
6 DR. MARKS: And we need to clarify that.
7 MR. JOHNSON: Okay.
8 DR. MARKS: Clearly, at the time this
9 came up we did not feel this was of concern for
10 the safety of these ingredients.
11 Any other comments? So can we just
12 handle that, Wilbur?
13 MR. JOHNSON: Sure.
14 DR. MARKS: Do you want me -- let me
15 see. Do you want me to bring that up and ask Paul
16 tomorrow, Ron? Or handle that off-line?
17 DR. SHANK: No, I think that should be
18 part of the discussion in the Panel meeting. And
19 the cause-effect, stress and testicular atrophy,
20 needs to be referenced in the report.
21 DR. BERGFELD: Do you think that was
22 mentioned by Paul last time, or the time before?
230
1 I just went through --
2 DR. SHANK: The time before. Because --
3 DR. BERGFELD: Not in June, but before
4 June?
5 DR. SHANK: Yes. In March.
6 DR. BERGFELD: Because it's not in the
7 minutes.
8 DR. SHANK: Because I brought it up. I
9 was concerned about male reproductive toxicity,
10 and Dr. Snyder said don't worry about that, that's
11 stress-related.
12 DR. BERGFELD: Okay.
13 DR. MARKS: Well, maybe Paul will have
14 already caught this, Rachel, and commented. So
15 I'll propose we still issue the "safe" amended
16 final report, and then under the discussion piece
17 tomorrow, Wilma, I'll ask Paul specifically to
18 comment about those, what appear to be
19 contradictory statements on page 32, about the
20 testicular atrophy, and then classify it as not a
21 reproductive or developmental toxicant.
22 Thanks, Rachel, for asking that
231
1 question. Any other comments? Okay, Wilbur.
2 Which next?
3 MR. JOHNSON: Ethylhexylglycerin.
4 DR. MARKS: So we're in the Green Book?
5 MR. JOHNSON: Yes. Mm-hmm.
6 DR. MARKS: I'm finding my notes, here.
7 I have it in the book, and elsewise. I don't want
8 to overlook -- so this is another where we're
9 reviewing for the first time. So let's go to page
10 7 on the Panel Book, and look over the ingredients
11 proposed in this group.
12 Anything that you feel shouldn't be
13 included? Ron, Tom, Ron? On page 7? The
14 ethylhexylglycerin has lots of uses -- over a
15 thousand -- up to a concentration of 8 percent.
16 And then there's the controversy -- or
17 I'm not sure I want to say "controversy," but is
18 acetyl glycerol ether the same as chimyl alcohol?
19 And, Wilbur --
20 DR. HELDRETH: They're the same. Just
21 somehow they got two names.
22 DR. MARKS: So there are two names in
232
1 the dictionary.
2 DR. HELDRETH: Yes -- for the same
3 ingredient.
4 DR. MARKS: Okay. So I think we can
5 hang onto what just how this list is, is put them
6 together, at least when we list them. And in the
7 introduction and in the discussion, and so on, we
8 can say they're the same ingredient. And then
9 whenever the next edition comes out, of the
10 dictionary, the authors can decide which name they
11 want to use.
12 Okay. So everybody's comfortable with
13 those ingredients, my sense is --
14 DR. BERGFELD: Could I ask a question?
15 DR. MARKS: Sure.
16 DR. BERGFELD: Most of your irritation
17 and sensitization data comes from the animal
18 model. Are you comfortable with that?
19 DR. MARKS: I have, in my notes, that
20 there was an HRIPT, 1 percent, which was okay.
21 And they actually did photo testing. So, let me
22 see -- that's page 16.
233
1 So I didn't flag a need for irritation
2 and sensitization. But Ron Hill actually keeps me
3 honest on that now, so that's good. (Laughs.)
4 Yeah, there it is -- 1 percent, neither
5 skin irritant or sensitizer. But -- that's 1
6 percent, versus up to 8 percent concentration, at
7 least in the ethylhexylglycerin.
8 Interestingly, when they did the guinea
9 pig testing they challenged up to 50 percent and
10 saw no sensitization.
11 So --
12 DR. BERGFELD: Yes, is the answer?
13 DR. MARKS: Yes.
14 DR. BERGFELD: Okay.
15 DR. MARKS: Rons? Tom? Needs, from
16 your vantage point?
17 DR. SHANK: I have no data needs.
18 DR. MARKS: Tom?
19 DR. SLAGA: I don't have any data needs
20 either.
21 DR. MARKS: And Ron Hill, I assume the
22 same.
234
1 DR. HILL: Well, I guess I took, you
2 know, comfort in -- a little bit of comfort -- in
3 the nature of the structures.
4 But on the other hand, they are
5 glycerins. We have no -- let's see, we have ADME
6 data on the chimyl alcohol, on the batyl alcohol,
7 but not ethylhexylglycerin.
8 We have got some arrows here suggesting
9 that we're very thin. I'm trying to interpret my
10 own notes. It's colorful, but a little confusing
11 now that I'm looking at it again.
12 DR. MARKS: The only other comment I
13 would have -- let me see, which page is this,
14 where the heading was? Wilbur, this is Panel Book
15 page 16. And that heading at the bottom, where it
16 says "Skin Depigmentation," it would be a real
17 toxicologic alert to me. It's really an effect on
18 tanning.
19 So, I would use as the title, "Skin
20 Tanning," if you want to, in there, that it has an
21 effect, actually has a beneficial effect, it
22 appears.
235
1 DR. SHANK: And also, in that same
2 paragraph, delete the last line? "Based on these
3 findings, a new concept was proposed?"
4 DR. MARKS: Yeah.
5 DR. BERGFELD: How about the statement,
6 "Study details will follow?"
7 DR. HILL: Okay, I now know what that --
8 I'm sorry. I now know what the nature of my
9 concern was. And it was we had no repeated dose
10 toxicity on any of these, except oral study on
11 ethylhexylglycerin -- if the check-boxes on page 4
12 of the Panel Book are accurate.
13 In other words, we don't have any
14 chronic tox on any of these guys, except for oral
15 ethylhexylglycerin. And I'll say, at the risk of
16 sounding like a broken record, whenever you do
17 oral tox, you always have the possibility --
18 especially if it's in rodents -- of having a very
19 high first pass extraction, which means you don't
20 necessarily capture the same thing that would
21 occur if you had very good dermal penetration.
22 And we don't have dermal penetration. And that's
236
1 why I circled and flagged this ADME so vigorously.
2 We have it on two of them -- chimyl and batyl, but
3 those are very long-chain ones.
4 And I think they're different enough
5 that it concerned me that that was all the ADME
6 data we had, in light of the fact that we have no
7 chronic tox on any of these, except ethylhexyl.
8 And we don't have ADME on that one, at a chronic
9 tox. We have ADME -- according to the check-boxes
10 -- on chimyl and batyl, but we have no other data
11 in terms of chronic tox on all of that.
12 So, it seems to be, from my way of
13 looking at this, a disconnect, and maybe some gaps
14 in terms of any read- across and extrapolation
15 when we have to extrapolate.
16 DR. MARKS: Ron Shank?
17 DR. HILL: And particularly that these
18 are glycerin- like, which means to me there's
19 always the possibility of they'd look like analogs
20 of monoglycerides, so we could have membrane
21 incorporation, membrane modification, if the use
22 of high-dose and they do dermally penetrate.
237
1 DR. SHANK: Do they? My understanding
2 is they're poorly absorbed from the skin.
3 DR. HILL: Well, we've only got two, and
4 they're very long ones. It's the chimyl and
5 batyl, which are a lot longer than some of these
6 others -- certainly a lot longer than the glycerol
7 allyl.
8 DR. MARKS: Okay, well we have, on
9 ethylhexylglycerin, oral reproduction and
10 developmental data, which was negative.
11 DR. HILL: But it's oral.
12 DR. MARKS: Oral -- yes.
13 DR. HILL: And I don't any comfort in
14 that because, especially with rodents, you can
15 have a very high first- pass extraction, you don't
16 get the molecule into the system. Whereas
17 dermally, you could get a lot if you've got good
18 dermal absorption, and we don't have information
19 on that, so that's the problem I had. It just
20 took me awhile to get back to what was bugging me
21 here.
22 DR. MARKS: Well, the developmental
238
1 studies were 10 weeks of dosing. So I think
2 first-pass effect would not be too important
3 there.
4 DR. HILL: Developmental studies --
5 well, yeah. Because if every dose you give to the
6 rodent, they're pretty much kicking it back out in
7 bile, because you've got a high first-pass
8 extraction, then you'll never see any effects.
9 Anytime you do an oral study, to me, if
10 I don't have something to back that up with
11 dermal, or I know I'm getting it into the system
12 because I've got analytical data that says, yes,
13 that's in the bloodstream and it's circulating,
14 then I don't think that oral toxicity is adequate
15 -- even if it's chronic.
16 MR. JOHNSON: Well, Dr. Hill, we do have
17 percutaneous absorption data on ethylhexylglycerin
18 on Panel Book page 11.
19 DR. HILL: All right.
20 MR. JOHNSON: An animal study, and in
21 vitro human skin penetration study on Panel Book
22 page 12.
239
1 DR. HILL: Okay. Yes. Not marked in
2 the check-box. Because we weren't considering
3 that to be ADME, I guess.
4 And I've got that highlighted, in fact.
5 So I didn't miss that.
6 MR. JOHNSON: Okay. Mm-hmm.
7 DR. MARKS: So are you reassured now,
8 Ron Hill?
9 DR. HILL: Mmmm -- maybe not. Because
10 there's pretty substantial absorption of that guy.
11 But then that's not the way the chronic tox were
12 done, right? We don't have any chronic tox that
13 was done dermal --
14 MR. JOHNSON: Right.
15 DR. HILL: -- at all. Am I wrong?
16 DR. MARKS: So, Tom, if I can paraphrase
17 while you were out, what Ron Hill was concerned
18 about is that with oral dosing, even if it's a
19 chronic dosing, is -- as Ron Shank pointed out --
20 that there could be a first-pass effect, even with
21 repeated dosing.
22 So Ron Hill was not as comfortable with
240
1 the oral tox, the lack of oral toxicity, and
2 wanted to know more about the dermal absorption.
3 And chronic dermal application.
4 Did I paraphrase that correctly, Ron?
5 Ron Hill?
6 DR. HILL: Yes. You did.
7 DR. MARKS: So, Tom, what's your feeling
8 with that?
9 DR. SLAGA: I have no problem with it.
10 DR. MARKS: So what we could -- let me
11 see. I don't present this tomorrow but,
12 obviously, I'll be seconding a motion. And what
13 we could proceed forward is with a tentative
14 report that's "safe," and then, Ron Hill, I'll ask
15 you to comment, and see if the other team has
16 similar concerns about the lack of dermal
17 absorption. Or I should say about the lack of
18 chronic dermal toxicity data.
19 Rachel, you were going to --
20 MS. WEINTRAUB: Yes, I had a few
21 comments.
22 DR. MARKS: Is that -- I want to just be
241
1 sure with Ron Shank and Tom that that's okay to
2 move forward as "safe."
3 DR. SHANK: It's okay with me.
4 DR. MARKS: And then Ron Hill, is it
5 okay? I'll ask you to raise your concerns, okay?
6 Rachel, I'm sorry.
7 MS. WEINTRAUB: That's okay.
8 DR. MARKS: I just wanted to be sure
9 we're clear.
10 MS. WEINTRAUB: Yes, I'm always trying
11 to figure out when to add my comments. So I seem
12 to have a timing problem.
13 The first question I have is on the
14 Panel Book page 7, Report page 1, about the
15 physical and chemical properties. Even in the
16 text, it talks about there being a disconnect
17 between information received by CIR about
18 solubility.
19 And is it sufficient to note it, in this
20 context, that it seems to have limited solubility
21 in water, but is highly soluble in organic
22 solvents? Is that sufficient? Or do we need more
242
1 information?
2 DR. HILL: Let me speak to that for just
3 a second. Log-p does not tell you anything about
4 solubility, per se. Hydrophobicity and
5 lipophilicity are not the same as water solubility
6 and lipid solubility. And actually, it's an
7 irritation to me that medicinal chemistry books
8 often say "lipid solubility" when what they really
9 mean is lipophilicity or hydrophobicity.
10 So, my research group has made numerous
11 compounds over the years -- this is on the
12 opposite end -- where we had very hydrophilic
13 compounds that were rocks in terms of water
14 solubility. So they don't necessarily track.
15 Typically, if something is hydrophobic,
16 a Log P actually is relatively hydrophobic, so
17 this really wasn't well cast in terms of what was
18 written, because if you have a Log P of 2.4, that
19 means if you divide it between octanol and water
20 and shake it up, 300 or 400-fold will be in the
21 octanol, versus just a little bit in the water.
22 So it's not surprising, and I don't
243
1 think there's a disconnect in those comments.
2 MS. WEINTRAUB: Okay.
3 DR. HILL: However, a Log P of 2.4 is
4 just about perfect for penetrating lipid barriers,
5 getting through skin, brain, whatever.
6 MS. WEINTRAUB: And I had one other
7 comment, and that is on page 2, just that since
8 ethylhexylglycerin was reported as being used in
9 three baby products, I guess it seems that the
10 most important issue that that would then sort of
11 lead to is skin penetration, which we discussed.
12 So I just wanted to make sure if its
13 being in baby products triggers concerns about any
14 other specific routes of exposure?
15 DR. MARKS: I assume the silence means
16 "no."
17 MS. WEINTRAUB: Okay.
18 DR. MARKS: Okay --
19 DR. BERGFELD: Could I ask for
20 clarification of the highest concentration of the
21 -- let's see, the ethylhexylglycerin? Is it 8
22 percent? Or is it 0.8 percent?
244
1 I looked back at the tables, and it
2 looks like it's 0.8 percent. I was going to page
3 55, Panel Book.
4 DR. EISENMANN: "Skin Cleansing?"
5 There's an 8 percent.
6 DR. BERGFELD: I was just looking at the
7 -- is the newest?
8 MR. JOHNSON: Yes, skin cleansing, on
9 page 2.
10 DR. BERGFELD: Page 2?
11 DR. HILL: I have it marked big and
12 bold, "8 percent."
13 DR. SHANK: It's on the next page.
14 DR. BERGFELD: Oh, next page. Okay.
15 DR. SHANK: The -- one, two, three --
16 fourth line down.
17 DR. BERGFELD: Oh, there it is. Okay.
18 So the skin cleansings are rinse-offs. So that's
19 important, because all your testing is under 1
20 percent, in leave-ons.
21 DR. HILL: If it's a cold cream do we
22 consider that a rinse-off?
245
1 DR. BERGFELD: Skin cleansing. That
2 means it's washed off.
3 DR. HILL: Okay.
4 DR. MARKS: Yeah, I guess I was
5 reassured that, not only that, but also, again,
6 back in the animals, in the sensitization, they
7 used 50 percent compound, and didn't see any
8 sensitization. So even thought the HRIPT was at 1
9 percent, with a 50 percent in animals, that gave
10 me a feeling of safety with these, and also a lack
11 of alert in terms of, in our literature, seeing
12 this coming up as a significant sensitizer.
13 So, we would move forward with a
14 tentative report, with a conclusion of "safe."
15 But I also asked Ron Hill to comment tomorrow
16 about the chronic dermal toxicity, and your
17 concern about that.
18 Okay.
19 DR. EISENMANN: I have one comment.
20 DR. MARKS: Sure.
21 DR. EISENMANN: This is about -- and I
22 don't know if you saw the supplier e-mail. In the
246
1 study they submitted, the 90-day oral study, the
2 study authors classified liver weights, increased
3 liver weights, as an NOAEL, and NICNAS classified
4 it -- that's the Australian government --
5 classified it as a LOAEL.
6 I would like to have both of those
7 values in the report, and then in the discussion
8 you guys can decide how you want to classify it.
9 DR. HILL: And, actually, that's --
10 although there's only the one compound, it's at
11 least a potential answer to the lack of dermal
12 chronic toxes that we were seeing some effects at
13 those very high doses. Which means there
14 presumably was some getting into the system. So
15 we've at least, with one compound, dosed enough
16 that we should be picking up anything toxic.
17 So, in a counter to what I said earlier.
18 MR. JOHNSON: And my comment, that I
19 requested the full study from the supplier,
20 because looking at the Australian data, compared
21 to the data submitted by the supplier, it isn't
22 clear that they're referring to the same study.
247
1 But just reading through, it seems as though
2 they're referring to the same study.
3 So I requested the full study, just to
4 confirm that both are referring to the same study.
5 DR. MARKS: Any other comments? If not,
6 we'll thank you, Wilbur. We'll move on to the
7 silylates -- now that you're here, Lillian.
8 So, in June, the Panel issued a
9 tentative safety assessment that concluded these
10 ingredients are "safe as used" in leave-on and
11 rinse-off products. But there is "insufficient
12 data to support the safety of ingredients in
13 products that might be inhaled."
14 And then there was a suggestion that
15 maybe we change that last to "when formulated to
16 be non-respirable." So we put we could remove the
17 "insufficient," just as long as we put "when
18 formulated to be non-respirable."
19 So -- comments? Do you like the
20 conclusion as it reads now? Do you want to sort
21 of put the onus, as we've done in the past with
22 some ingredients -- just as we just did earlier
248
1 today, "formulated to be non-irritating." Do we
2 use the same reasoning to say "formulated to be
3 non- respirable.?"
4 DR. BERGFELD: Well, what does that
5 mean? I mean, nothing gets into the nasal passage
6 at all? Or it doesn't get into the pulmonary?
7 DR. MARKS: Carol.
8 DR. EISENMANN: Well, have you looked at
9 the additional data that's in this report?
10 Because there are a couple of other studies that
11 identify, I know, effect level of I think it's 10.
12 So, to me, there's enough inhalation,
13 that really the conclusion should be -- however
14 you worded the conclusion for the silica report.
15 Because this is really not that much different
16 from silica. The amorphous silica, the other half
17 of the information that's in this report. It was
18 provided in the supplement. Lillian highlighted
19 the additional studies in here that will need to
20 be added to this report.
21 MS. BECKER: The Wave 2 information.
22 DR. SHANK: And that was on silica? Or
249
1 one of these ingredients.
2 DR. EISENMANN: It's on these
3 ingredients. There's more information in this
4 report on these ingredients that has yet to be put
5 into the report.
6 DR. MARKS: Was this the memorandum,
7 Lillian, from you, dated September 16, 2011?
8 MS. BECKER: Yes.
9 DR. MARKS: So it starts out, "Subject:
10 Wave 2 Data for the Draft Final Safety Assessment
11 of Silylates."
12 MS. BECKER: Yes.
13 DR. MARKS: So the average particle --
14 number 2 is, the average particle size is 5 to 15
15 µm. So it's below 10.
16 MS. BECKER: Yes. But there's other
17 information, saying that, especially from SASSI,
18 that the particles aggregate and are larger.
19 Where is that? -- and that for the testing that
20 they've had to do, the idea is that they've had to
21 shear the particles down smaller to get them into
22 the lungs of the test animals, and that they are
250
1 not the sizes that are actually used in the
2 cosmetics -- is SASSI's position.
3 DR. MARKS: So, Ron, Ron, and Tom, did
4 you happen to see this Wave 2, under bullet 3 of
5 SASSI's August 31, 2011, letter. It says, "Based
6 on information that has been made available, we
7 consider as not relevant the studies referenced by
8 the expert panel in forming their conclusion that
9 'inhalation data show that the particles do reach
10 the lungs in rats and induce granuloma
11 formation.'" There is also necrosis or atrophy of
12 the olfactory epithelium observed.
13 This kind of brings back what you said
14 this morning, Ron, about absorption by the
15 olfactory nerve in the upper respiratory tract.
16 "There are currently no data available
17 on which to base a finding of safe for use in
18 products which may be inhaled."
19 So -- comments?
20 DR. SHANK: Well, I agree with the
21 conclusion "not safe if they're inhaled." It's
22 just how do we state that? And I was waiting
251
1 until we'd resolved the aerosol issue, which we
2 certainly have not. So -- what we're going to do
3 with that statement here is quite a problem.
4 What do we mean by "not inhaled?" Are
5 you going to give a particle size? And actually,
6 I really objected, just relying on particle size,
7 because what's really important is aerodynamic
8 diameter, which is more than particle size.
9 Harder, much harder to --
10 DR. BERGFELD: (Inaudible) distribution?
11 DR. SHANK: That's the particle size,
12 the shape, how it flows through air at various
13 densities and temperatures. It's complex -- and
14 usually not measured except by very high-powered
15 inhalation toxicology facilities.
16 So if it gets into the respiratory
17 system, adverse health effects can occur.
18 So right now, I would have to say it
19 shouldn't be used in products that can be
20 aerosolized. Or we have to come up with a
21 boilerplate to handle aerosols. Because this is a
22 problem repeating over and over. Yeah, repeating
252
1 over and over again. Sorry.
2 DR. BERGFELD: So, can I ask you a
3 question? Then your comment on this morning's
4 presentation by Proctor and Gamble, that deal with
5 size and distribution and vehicle -- you're
6 differing because they didn't take up
7 aerodynamics.
8 DR. SHANK: Right. Most studies do not.
9 They measure particle size. That's a relatively
10 simple measurement.
11 But when you look at the distribution
12 within the entire respiratory system -- and I mean
13 from the mouth to the alveolus, it's aerodynamic
14 diameter, which the inhalation toxicologists use.
15 DR. BOYER: Yes. And, actually, it is
16 aerodynamic diameter that she was talking about
17 this morning. So if she's talking about particle
18 size distributions, and median particle sizes, and
19 so forth, that is the aerodynamic diameter that
20 they were measuring and reporting.
21 DR. SHANK: Uhh -- what I saw on her
22 slides were micrometers.
253
1 DR. BOYER: Mm-hmm.
2 DR. SHANK: And that could be just
3 particle size, not necessarily --
4 DR. BOYER: Well, actually, the
5 aerodynamic diameter is expressed in microns --
6 micrometers. But it does take into account the
7 other parameters that you've mentioned, including
8 the density and so forth.
9 So it's basically reporting the
10 effective size of the particle, based on a unit
11 density. And it's the settling -- it's related to
12 the settling velocity that an ideal particle would
13 exhibit.
14 DR. SHANK: Okay. Thank you. I didn't
15 understand she was really talking about effective,
16 you know, dynamic diameter.
17 DR. BOYER: Yes, I think it was
18 understood that she was talking about aerodynamic
19 diameter.
20 DR. BERGFELD: By whom? (Laughter.)
21 DR. BOYER: By her.
22 DR. SHANK: Jim returns just in time.
254
1 The presentation on aerosols -- particles, et
2 cetera -- when the speaker talked about particle
3 size, what, in fact, her data was aerodynamic
4 diameter, which is the better measure.
5 So if I've criticized that, I withdraw
6 that, because I did not understand that.
7 We're still left with the problem, what
8 do we mean by "inhaled," "respired." And until we
9 can decide that, I would have to say, for this
10 particular group of compounds, not safe in
11 products that can be aerosolized --
12 DR. SLAGA: Yeah.
13 DR. SHANK: -- or we have to come up
14 with a way to handle this. Because it is coming
15 up all the time.
16 DR. EISENMANN: So you don't think this
17 can be an overload problem? Because most -- I
18 mean, these studies were really using high
19 concentrations. I mean, one of them is like 35
20 mg/m3. And, you know, like the respirable dust
21 TLV is 5. And there's another monkey study in
22 here of one of those compounds at 10 that didn't
255
1 show any effects.
2 So -- I just think this is likely an
3 overload problem, rather than anything else.
4 DR. SHANK: I understand that. The
5 problem is we don't know what the consumer is
6 being exposed to in these pumps, and --
7 DR. EISENMANN: Well, if you remember
8 the data from her, I mean, in general, it's --
9 when -- I mean, it was very low, in terms of
10 milligrams per meter-cubed. And then this is a
11 small percentage of what would be in the product.
12 DR. SHANK: The distribution went low --
13 down to 5 percent below 10 µm.
14 DR. EISENMANN: But even then --
15 DR. SHANK: Percent of what?
16 DR. EISENMANN: -- the slides that
17 focused on the level that's below 20, those were
18 fairly low concentrations also.
19 DR. BOYER: Yes. I think the likelihood
20 of overload, as she expressed it, is very, very
21 small. It's negligible, at least in terms of the
22 use of spray products, in a human.
256
1 DR. EISENMANN: Because, I mean, it's
2 very --
3 DR. BERGFELD: You're agreeing it's
4 overload, though? That the interpretation is
5 correct? It's overload in the study?
6 DR. BOYER: In an animal study it's
7 overload that they largely describe.
8 DR. MARKS: So, translating that --
9 Ivan, instead of "overload," you would say the
10 dose exposed to these animals was much greater
11 than would be in the present use and exposure in
12 cosmetics.
13 DR. BOYER: Absolutely. The dose of
14 respirable particles was much, much greater in
15 those studies.
16 And you get --
17 DR. MARKS: But I guess there, we don't
18 have a NOEL, do we? So you'd say, okay, a high
19 dose you get granulomas, but at what does don't
20 you get a granuloma. Isn't that --
21 DR. BOYER: At high dose and at -- well,
22 again, it's high dose of respirable particles. So
257
1 it's that --
2 DR. EISENMANN: Although there's not a
3 lot of details, there are two additional studies
4 that are not in here yet, that are at lower doses,
5 that show a NOEL. One's a monkey study. But it's
6 not a lot of details. But it's in there.
7 DR. MARKS: So that, to me, that would
8 be very reassuring.
9 DR. EISENMANN: So, I mean, I'd be fine
10 if you want to wait until you actually get a
11 chance to look more carefully at the information.
12 So if you haven't had time, that's appropriate,
13 too.
14 And I also -- if you wanted to read this
15 study, this is the study where -- the 35, where
16 the granulomas were. They compare it to quartz.
17 I think it's a kind of an interesting, useful
18 study to look at. And you might want to actually
19 read it.
20 They do several different types of
21 silica quartz, one of the surface-treated, and
22 then a couple of the silica that you've already --
258
1 DR. MARKS: So were these studies sent
2 out in Wave 2, or are these new studies?
3 DR. EISENMANN: Part of this document
4 was sent out in Wave 2.
5 MS. BECKER: I just handed the copy to
6 Dr. Slaga that I brought with me. But the
7 summaries were all sent to you in Wave 2.
8 DR. MARKS: This boilerplate is the last
9 agenda item on my list. So I don't know if we
10 want to try and finish with this ingredient, or
11 try and arrive at some conclusion with a
12 boilerplate?
13 Because can we -- Ron, do we need to
14 change, since we even are questioning what does
15 "inhaled" mean, it seems like the conclusion is
16 going to have to be changed anyway in this, since
17 we say that there's insufficient data to support
18 the safety of these ingredients and products that
19 might be inhaled.
20 So we have some uncertainty what we mean
21 by "inhaled." And then you're talking about we do
22 have a NOEL, if it does reach the alveoli, that it
259
1 doesn't cause toxic effects.
2 Am I interpreting your comments
3 correctly, Carol?
4 DR. EISENMANN: That's how I see it,
5 yes.
6 DR. BOYER: And there is a fairly
7 precise definition of what it means to be
8 "inhalable." Any particle under about 100 µm or
9 so is considered "inhalable," and that just means
10 it's going to get into the upper respiratory
11 tract.
12 When you're below 10 µm or so, that's
13 when you're talking about "respirable" particles
14 -- okay?
15 DR. MARKS: And that's what I think
16 we've generally used as a cutoff, in terms of its
17 inhalation safety.
18 DR. BOYER: Right.
19 DR. MARKS: Whereas actually this
20 morning's presentation, it's not only -- as Ron
21 said, the aerodynamics of these particles, but
22 it's also the device it's put in.
260
1 So how do you want to proceed? Shall we
2 handle this ingredient? And then, Ivan, you're
3 here. Can you stay with us? We have two other
4 ingredients before we get to the boilerplate. Or
5 shall we again go out of order and do the
6 boilerplate right after the ingredient? Lillian,
7 do you have a comment?
8 MS. BECKER: I'm thinking do it at the
9 same time.
10 DR. SHANK: Okay, the use -- it says
11 it's used "in powders." What kind of "powders?"
12 The presentation we had today was
13 basically hair sprays. Okay?
14 What I'm having difficulty with is
15 extrapolating from the presentation on hair sprays
16 to all aerosol powders and sprays, airborne
17 things. I got a feeling that there was quite a
18 bit of variation between products and dispensers.
19 And to use the hair spray data to extrapolate to
20 what it says in here, just "powders", is causing
21 me some concern.
22 DR. BOYER: And actually, toward the end
261
1 of her presentation, she did discuss powders, and
2 gave several reasons why she didn't think that
3 powders would generally be of concern with respect
4 to particle sizes.
5 They're basically formulated to be
6 applied to the skin. They typically agglomerate,
7 so they form fairly large particles in product.
8 They're applied directly to the skin, and so
9 forth.
10 DR. SHANK: Okay, then I think we need
11 those data in the report.
12 MS. BECKER: In the Wave 2, with the
13 comment from the Council, where they also included
14 their survey, there's face powders at 4 percent,
15 there's blushers up to 3 percent. There's --
16 DR. EISENMANN: (Inaudible)
17 MS. BECKER: Correct. Yes, blushers may
18 not all be powders. But -- I'm sorry, face
19 powders, up to 2 percent. Powders, as in dusting
20 and talcum, up to 4 percent. Face, neck cream
21 lotions and powders, up to 5 percent -- but that's
22 not broken out. Body powders, up to 3 percent --
262
1 but not broken out from lotions and creams.
2 Moisturizer creams, lotions, powders, up to 2
3 percent.
4 So that kind of range for powders,
5 possible inhalation.
6 DR. MARKS: So, let's get back to
7 silylates. How do you want to proceed? Do you
8 like that conclusion? Or do we need to change it?
9 And if we change it, obviously then it's going to
10 be a re-revised tentative safety assessment.
11 DR. SHANK: Well, there are two
12 conclusions. So, it's not final, anyway. We have
13 a choice of two conclusions here, do we not?
14 Isn't that this report?
15 DR. MARKS: No, it said concluded "safe
16 in leave-on and rinse-off." But there is
17 "insufficient data to support the safety of the
18 ingredients in products that might be inhaled."
19 And that's what we've been talking about, is the
20 potential of inhaling it, or aerosol powders, or
21 sprays.
22 DR. SHANK: Okay, and then there's an
263
1 alternate conclusion, too. So --
2 DR. MARKS: Well, was that proposed in
3 the tentative safety assessment? Because this is
4 what was sent out, as I understand it. Is that
5 not --
6 MS. BECKER: The --
7 DR. BERGFELD: Page 33.
8 MS. BECKER: -- the alternate conclusion
9 is what we proposed after we got more information.
10 The first one, not in italics, is what you all
11 decided at the last Panel meeting.
12 And if you stick with that, we're going
13 final. If you want to change it or adjust it as
14 the italics one, the one we're suggesting, then
15 it's coming back in December.
16 DR. MARKS: Yes, that's -- thank you,
17 Lillian, that's the point I was making.
18 DR. BERGFELD: Do you mean it's going
19 out again for days?
20 MS. BECKER: Correct.
21 DR. MARKS: Yes, because it would be a
22 revised conclusion. Therefore it would have to be
264
1 a revised tentative.
2 Do you like the alternative conclusion
3 better?
4 DR. SHANK: Not anymore. I did. But I
5 think that the non-italicized conclusion, the one
6 we came up with last time, is more appropriate.
7 DR. MARKS: And, Ivan, when we use the
8 word "inhaled," is that generally known? We could
9 obviously put what that means in the discussion,
10 or the summary, so that we could define what
11 "inhaled" is, if anybody had issues about that.
12 DR. BOYER: That's well defined in
13 inhalation toxicology.
14 DR. MARKS: Right. That's what I
15 figured.
16 DR. BOYER: "Inhaled" versus "respired."
17 DR. MARKS: So, do you like the
18 conclusion as it is? Cross out the alternate? I
19 agree. I mean, we talked about the alternate
20 conclusion emphasizes particle size, which is only
21 part of it, and would be really misleading, I
22 think, to the reader.
265
1 Okay. So, so far, we don't have to
2 re-revise. Ron Hill, you wanted to say something.
3 DR. HILL: Well, I think you addressed
4 -- because I was going to make a comment about
5 that potential alternative conclusion, which was
6 the particle size as supplied to formulators are
7 not respirable. In practicality, that's
8 impossible, I think.
9 DR. MARKS: Yes. Okay.
10 DR. HILL: It's what fraction is
11 respirable of the total that's there.
12 DR. MARKS: So can we move forward with
13 a final safety assessment with the silylates, with
14 the conclusion as stated on Panel Book page 33?
15 And the main thing there is, of course, the
16 inhalation -- that we have an "insufficient data."
17 Ron, Tom, Ron? Move forward with that
18 conclusion?
19 DR. LORETZ: Just one quick comment? So
20 what data, then, are you looking for?
21 DR. MARKS: I think it's probably that
22 NOEL effect. You know --
266
1 DR. SHANK: Oh, in our discussion we ask
2 for a 13- week inhalation toxicity study. Now you
3 say these are available. Actually,
4 carcinogenicity studies -- yes?
5 DR. EISENMANN: Umm --
6 DR. SHANK: Inhalation carcinogenicity
7 studies?
8 DR. EISENMANN: There's a one-year
9 monkey study.
10 DR. SHANK: Okay. But the other --
11 DR. EISENMANN: And I think there's a
12 rat study that might be long-term. I mean, she
13 provided it and highlighted it. It would be nice
14 if we would take a little --
15 DR. SHANK: Well, I looked at the PDF
16 that came in Wave 2.
17 DR. EISENMANN: Okay.
18 DR. SHANK: That's only half of the
19 problem. The other half of the problem is what is
20 the consumer exposed to?
21 DR. EISENMANN: Well --
22 DR. SHANK: And I don't think we have a
267
1 handle on that.
2 DR. EISENMANN: Well, but -- yeah, it's
3 going to be very low. I mean, this is an overload
4 effect. So overload, generally -- so they're
5 putting so much more that the lungs cannot remove
6 the particles.
7 DR. SHANK: That's not a proven
8 mechanism.
9 DR. EISENMANN: We'll have to provide
10 some more information on that, then.
11 DR. MARKS: I don't hear compelling
12 evidence for the team to not issue the final
13 safety assessment, with this conclusion.
14 Is that correct? Tom? Ron?
15 DR. SLAGA: Yes.
16 DR. SHANK: But we'll have to come up
17 with what is insufficient.
18 DR. MARKS: And you summarize that.
19 DR. SHANK: Well, we have the studies
20 that came in Wave 2. That's half of the problem
21 -- a very important part. We still have a problem
22 of what is "inhaled" or "respired."
268
1 DR. HILL: Would there be a way to word
2 it such that the maximum respirable -- and by
3 "respirable," I mean "respirable" -- the maximum
4 respirable load was somehow specified?
5 I'm not suggesting we do that tomorrow,
6 I'm just -- if we're talking about an overload,
7 that means it's what amounts to a threshold
8 effect.
9 DR. SHANK: If you have a
10 no-effect-level after a year, in the monkey,
11 inhalation, you could use that as your standard,
12 if you will, for respirable products. I'm still
13 concerned, is what is actually being delivered to
14 the consumer.
15 DR. HILL: Yes, and I think then maybe
16 we'd be in a situation where you build in a margin
17 of safety and make some conservative estimates
18 based on -- but again, you know, now we're down to
19 products again, as opposed to ingredients. That's
20 the problem.
21 And I don't see the way out -- easily.
22 DR. MARKS: Okay. Well, this should
269
1 make, probably, for an interesting discussion
2 tomorrow. I will go ahead and certainly propose
3 our team's conclusion, which is the one in the
4 book.
5 And then, in terms of the identification
6 in the discussion, what is insufficient, and that
7 is what is inhaled or respired by the consumer.
8 Okay --
9 DR. BERGFELD: Could I just ask a
10 question? Ron, define for me "inhaled" versus
11 "respiratory?"
12 DR. SHANK: "Inhaled" focuses on the
13 entire respiratory tract, so that includes what is
14 deposited in the nasal sinus, the nasal pharynx.
15 "Respirable" is deeper lung --
16 DR. BERGFELD: Okay.
17 DR. SHANK: -- below the trachea.
18 DR. BERGFELD: Thank you.
19 DR. MARKS: Okay. And Ivan took off.
20 MS. BECKER: Monice needed him in the
21 other room.
22 DR. MARKS: Okay. Well, we'll come back
270
1 to -- this has been an interesting dance.
2 So we will keep it at the end of the
3 agenda, the inhalation boilerplate.
4 Pentaerythrityl Tetraisostearate and Other
5 Pentaerythrityl Esters.
6 So let's move on to the PET
7 tetraisostearate and other PET esters. I think
8 that should be next in order. Is that correct?
9 And, Lillian -- okay, good. So we
10 issued a tentative safety assessment in June of
11 this year for these ingredients. And our job
12 today is to decide whether we want to move forward
13 with a final safety assessment -- with the
14 conclusion that these ingredients are safe.
15 And all the ingredients are listed on
16 page 32. Now, you saw in the memo from Lillian
17 that the Council has redefined PET cocoate as a
18 monoester. And so it wouldn't fit into the
19 tetraesters, and it's been removed from the
20 report.
21 Even though it's in the conclusion, I
22 look at that as a relatively minor change. If we
271
1 were adding things, I'd be concerned. But
2 removing one thing doesn't bother me particularly.
3 But, again, I'll ask my teammates how
4 they feel about that?
5 DR. SLAGA: Well, that's still changing
6 the conclusion.
7 DR. MARKS: Yes, it is changing the
8 conclusion. Absolutely. Correct? In the
9 tentative it was there, and now it isn't.
10 MS. BECKER: Correct.
11 DR. MARKS: I'm usually the stickler for
12 conclusions.
13 DR. SLAGA: Well, we have to be
14 consistent.
15 DR. MARKS: Correct. So, with this, we
16 would issue a revised tentative safety assessment
17 having removed the PET cocoate.
18 Now, one could say, well, we don't want
19 to remove it, but chemically, it doesn't seem
20 logical to include it. Is that --Bart, you want
21 to -- you were actually obviously instrumental in
22 saying, "This doesn't belong. We should take it
272
1 out." Too bad we didn't do that before we sent
2 out the tentative safety assessment.
3 DR. HELDRETH: Chemically, the mono
4 would be quite different. Chemically quite
5 different.
6 DR. MARKS: So we should issue a
7 revised, removing the PET cocoate, and still with
8 the conclusion, obviously, a "safe."
9 Ron, Tom, Ron?
10 DR. EISENMANN: One comment. I'm still
11 working on concentration of -- updated use
12 information on two ingredients in this report.
13 They asked for me to do it at the last one, but I
14 -- there hasn't been enough time.
15 DR. MARKS: So that helps you out.
16 DR. EISENMANN: Well, I already asked.
17 I'm already collecting it. So -- no, not really,
18 but. So you're going to go final, and I will give
19 the data to you.
20 DR. MARKS: So we'll issue a revised --
21 I'll move tomorrow that we issue a revised
22 tentative safety assessment. And the reason for
273
1 that is that the PET cocoate has been removed
2 since it's not a tetraester.
3 And we continue to await the use and
4 concentration updated table. Will we have that by
5 the next time we see it, do you think, Carol?
6 DR. EISENMANN: This is your last time
7 seeing it -- correct?
8 DR. HILL: No, we're saying we're going
9 to issue a revised conclusion.
10 DR. EISENMANN: Oh, you're going to
11 revise because you took it out. Okay.
12 DR. MARKS: Oh, yes.
13 DR. EISENMANN: Okay, I didn't think you
14 were going to revise it. Okay.
15 DR. MARKS: No. We --
16 DR. SHANK: What is being revised? The
17 conclusion does not contain monococoate.
18 MS. BECKER: Yes, at the --
19 DR. SHANK: Where?
20 MS. BECKER: It contains tetracocoate,
21 but not the monococoate.
22 The last time you saw this, it had
274
1 cocoate. But now it's been redefined as a
2 monoester, not a tetraester.
3 So we went ahead and took it out, since
4 it didn't fit the group anymore.
5 DR. SHANK: And that's what was
6 distributed, right? That was distributed, because
7 that's what I have here.
8 MS. BECKER: Ahh -- that redefinition
9 came after we posted this for comment. You've
10 gotten it after we changed it. But it was put out
11 for public comment before the change.
12 DR. SHANK: Okay. So you're saying, in
13 our Blue Book now, where it says "tetracocoate"
14 it's really "monococoate?"
15 MS. BECKER: Okay --
16 DR. SHANK: There's no monococoate in
17 the conclusion.
18 MS. BECKER: Right. Yeah, it's actually
19 a monoester. But there is a tetracocoate which
20 stayed in.
21 DR. SHANK: Yes.
22 MS. BECKER: We did have both in, the
275
1 last time you saw that.
2 DR. SHANK: Okay, but this time we saw
3 it, it's just the tetraester. So what's being
4 revised? I don't --
5 MS. BECKER: When it went out for public
6 comment after the June meeting it was still in
7 there. The redefinition didn't happen until after
8 it went out for public comment.
9 DR. SHANK: Okay, so what went out for
10 public comment contained the mono.
11 MS. BECKER: Correct.
12 DR. SHANK: What we got did not.
13 MS. BECKER: Correct.
14 DR. SHANK: Now I understand. Thank
15 you.
16 DR. BERGFELD: Could I ask a question
17 about the inhalation? It says it's used in
18 aerosols. And we have stated in our discussion
19 that toxicity is not available in aerosol.
20 But particle size are not respirable.
21 Are we going to attack that? Do we say "inhaled?"
22 MS. WEINTRAUB: Doesn't it also say
276
1 "typically?"
2 DR. BERGFELD: What's that?
3 MS. WEINTRAUB: Doesn't it also say
4 "typically," in the discussion? And that sort of
5 bothered me. It's an unusual word for us, I
6 think, in a discussion.
7 DR. SHANK: Well, the aerosol
8 boilerplate has to go in the conclusion. So that
9 means it's going to have to go out -- it's going
10 to go out again anyway.
11 DR. BERGFELD: What is "the aerosol
12 boilerplate?" I'm not sure I know what it is
13 today.
14 DR. MARKS: Well, we're going to find
15 out -- maybe.
16 DR. BERGFELD: But that sentence would
17 change.
18 DR. MARKS: Yes. I think, Lillian, when
19 this -- this probably shouldn't go immediately out
20 as revised until we are sure we know what the
21 boilerplate is. That's how I would handle it.
22 Because you raise a good question,
277
1 Rachel. And so that's important. That's how I
2 would handle it. We're going to send it out as a
3 revised, anyway, because we removed one of the
4 ingredients from the conclusion that was sent out
5 for comment.
6 And before it would be sent out again,
7 let's make sure of two things: we have the use and
8 concentration, Carol, that you said you were going
9 to give us. And then the second thing is the
10 inhaled/respiratory boilerplate. Yep.
11 Any other comments? Do you think that's
12 going to -- and then we'll change the wording
13 appropriately at that point. Because we know from
14 this morning's presentation, just particle size
15 may not be totally -- obviously, if it's huge, I
16 don't care what they put it in, you probably can't
17 get it down into the alveoli. But we'll deal with
18 that on the revised --
19 DR. SHANK: How about rather than
20 concentrating on particle size, a whole other
21 take, and just say if it's used in aerosolized
22 products, it should not cause irritation to the
278
1 nasal pharynx or lung?
2 DR. SLAGA: I actually would like --
3 DR. MARKS: Write that down, Ron.
4 Because we're going to get to the boilerplate
5 shortly. So please write that down.
6 DR. SHANK: Okay.
7 DR. MARKS: Did you write that down?
8 You better. Or remember it. Lillian, are you
9 going to be -- Ivan's still not here with the
10 boilerplate. Okay, so tomorrow I'm going to move
11 that we issue a revised safety assessment, and the
12 reason is because that one of the ingredients
13 which was sent out was deleted, or removed. But
14 we also want to await the use concentration and
15 the inhalation boilerplate.
16 Yes -- Ron Hill.
17 DR. HILL: One other thing, in both the
18 toxicokinetics, discussion of the toxicokinetics
19 data that is or is not available, and also the
20 discussion -- because I'd asked the question last
21 time was the possibility of esterase-mediated
22 hydrolysis. I actually doubt that occurs.
279
1 And so I think speculating that it might
2 occur, but we don't have a problem with the fatty
3 acids, and we don't have a problem with
4 pentaerythrityl, the questions in my mind were
5 actually related to possible things that might
6 happen with mono and diesters. But, in fact, we
7 don't have any evidence that those were even
8 formed.
9 So, to me, it clouds the discussion to
10 even make mention, because it's all speculation
11 when, in fact, with the tetraesters -- since we're
12 paring out anything but the tetraesters -- they
13 probably don't even get formed.
14 So I'm just tossing that out for
15 discussion. But I think it would be better to
16 just delete that speculation, having no data to
17 suggest that that goes on.
18 DR. MARKS: So, that's -- what Panel
19 Book page are you at?
20 DR. HILL: I mean, it would be nice to
21 have data that suggests that it doesn't happen,
22 but --
280
1 DR. MARKS: So, what --
2 DR. HILL: Well, it shows up in the
3 discussion, which is on page --
4 DR. MARKS: That's page 32.
5 DR. HILL: 32 -- and also the
6 toxicokinetics discussion, page 29.
7 DR. MARKS: Okay. So let's -- Lillian,
8 if you would see the editorial comments that Dr.
9 Hill has mentioned.
10 And Ron and Tom, you're fine with that.
11 Yeah. Okay. Anything else about the PET
12 tetraisostearates? And now we have all tetra
13 compounds? Okay. Now we're to an easy one. I
14 think we're next to the last agenda item. We have
15 the formaldehyde methylene glycol, Blue Book, to
16 discuss. And then we'll come back to the aerosol
17 inhalation boilerplate, once Ivan gets back.
18 Priority List.
19 MR. JOHNSON: We also have "Priorities."
20 DR. MARKS: Oh, yes. Thank you. We've
21 got- "Priorities" are before or after --
22 DR. HELDRETH: Before.
281
1 DR. MARKS: Okay. And that's in the
2 Buff Book. Thank you for reminding me. There
3 have been so many changes in the list today.
4 So that's in Buff Book, page 16. And my
5 comment Bart, was I like the pics, especially the
6 sheep.
7 DR. HELDRETH: Yeah, I liked that, as
8 well.
9 DR. MARKS: And I wanted to confirm that
10 the picture -- that clearly the photo of the plant
11 was in that family of plants. But I just wanted
12 to be sure you got the right one there -- that,
13 indeed, it was in the chamomile group of plants,
14 and not another one of the plants in that family.
15 Okay. So with those rather lighthearted
16 comments -- any comments about the priority list
17 on page 16?
18 DR. BERGFELD: I have a comment. My
19 comment is "Why not?" But the second part of it
20 is, when you're devising these again, would you
21 update us on how you select the priorities by
22 frequency of use? Certainly not biological
282
1 activity anymore, because we've taken up all the
2 baddies.
3 What else?
4 DR. HELDRETH: All right -- so
5 definitely, number of uses. There's also, we're
6 requested, you know, by FDA, by the Council, to do
7 certain ones. You'll see there at the bottom
8 6-hydroxyindole. We were requested to do a hair
9 dye. And there's a letter from the Council to
10 that effect.
11 But otherwise, we stick to primarily the
12 number of uses of ingredients that we haven't
13 reviewed before, and then try to group those
14 together.
15 DR. BERGFELD: And then you add in a
16 couple of re- reviews?
17 DR. HELDRETH: The re-reviews are
18 actually a separate --
19 DR. BERGFELD: Okay.
20 DR. HELDRETH: If you go to Panel Book,
21 18 -- and these are just informational on purpose.
22 You know, really, the Panel just has to decide on
283
1 the new ingredients to review. The re-review
2 priority list is really just for informational
3 purposes.
4 DR. BERGFELD: Okay.
5 DR. HELDRETH: And those are based on --
6 you know, "It's been 15 years since the last time
7 we looked at these," and, you know, possibly we
8 just need to look at it and say that it's worth
9 looking at again or not. And then there's other
10 cases where, to be consistent, we might want to
11 pull some previous reviews together and add in the
12 other -- for example pegylated oils.
13 DR. BERGFELD: Mm-hmm. Thank you.
14 DR. MARKS: Any comments -- thank you,
15 Wilma. Yes, I would spell out that "FOU," at the
16 top of the table. I was wondering whether this
17 was some sort of flying object, there, that the
18 "F" stood for. But "Frequency of use," once you
19 go into it, you see what it is. But somebody
20 who's not familiar might not know what an "FOU"
21 is.
22 DR. HELDRETH: Will do.
284
1 DR. MARKS: Comments? Any other? Ron,
2 Tom? Ron Hill?
3 DR. HELDRETH: The primary difference
4 between what you saw at the last Panel meeting and
5 this iteration is one, the addition of the
6 standard alpha-amino acids, which we talked about
7 before. And then, secondly, you'll see that
8 there's three groups that have a red asterisk,
9 that either pertain to amino acids or are built up
10 as a polypeptide of those amino acids, that we're
11 going to keep on the back burner, but plan to
12 actually do in 2012 -- but once amino acids is up
13 and running. And that particular report's
14 already, you know, in the can, and you're going to
15 see it very soon.
16 So that there will be an opportunity,
17 most likely halfway through next year, to get
18 started on these amino acid-derived ingredients,
19 or broken-down proteins.
20 DR. MARKS: Okay.
21 DR. EISENMANN: I have one comment about
22 the proteins. We're a little concerned about the
285
1 big group of proteins, especially -- I don't know,
2 because hydrolyzed wheat does have some allergy
3 issues, and its anaphylactic reactions.
4 And I'm a little concerned that we
5 really haven't dealt with that issue much. And it
6 would be nice to have -- to do one more in depth.
7 And maybe you could put all of them together, but
8 it would be nice to start out with one to help us
9 know what are the appropriate questions to ask
10 about a protein.
11 I looked, there are 40 suppliers of
12 hydrolyzed wheat protein and, you know, it's going
13 to be multiple -- which proteins? What sizes? How
14 are they hydrolyzing it?
15 I just think it might be a little
16 complex. And then you have all of the proteins to
17 do all together, make it very complex. So it
18 would be kind of -- maybe to do them all together,
19 but start out with one so we know a little bit
20 what are the right questions to ask, so then we
21 can ask the right questions for the other
22 proteins.
286
1 That's just a suggestion. You have to
2 do the amino acids first. So we're not there yet,
3 but --
4 DR. HILL: My personal opinion is
5 lumping any two proteins together, unless they're
6 highly analogous, is going to be problematic, from
7 where I sit. Because immediately, as soon as you
8 start hydrolyzing things, then you have multiple
9 peptides, and then you have to be concerned about
10 whatever might happen with those particular
11 trimers, and tetramers, and pentamers, and so
12 forth. And that lumping any two proteins
13 together, and dealing with them -- unless they're
14 known to be hydrolyzed down to individual amino
15 acids -- is going to prove problematic.
16 From where I sit, proteins ought to be
17 done one at a time. That's going to run in the
18 face of somebody else's idea, but that's from
19 where I sit.
20 DR. MARKS: Does that help you, Carol?
21 (Laughter.)
22 DR. EISENMANN: I think we would agree
287
1 with that, for the most part.
2 DR. MARKS: Okay. Any other comments
3 about the priority list?
4 If not, I guess we'll move on --
5 although the memorandums from Alan -- the Director
6 -- do we need Alan in here to discuss formaldehyde
7 and methylene glycol? Or do we just move forward?
8 And who's going to take notes? You are.
9 Okay. So let's go ahead, do that.
10 Re-Review Summaries. And actually, we
11 had one re-review summary, which should be pretty
12 darn quick. You like the re-review summary. Any
13 other comments? Ron, Ron? I only had that you
14 needed the epidemiology boilerplate, obviously, on
15 it. Okay. We're done with the re-review summary.
16 Good.
17 Formaldehyde and Methylene Glycol. So
18 let's get to formaldehyde and methylene glycol.
19 My first reaction when I looked at the
20 memorandum was -- at least I couldn't remember
21 when we had one or two ingredients where we said
22 they were "safe," "insufficient," and "unsafe" all
288
1 in the same report. So that was pretty
2 interesting. So let's go through that.
3 At the June meeting we issued a revised
4 tentative amended safety assessment for
5 formaldehyde and methylene glycol. And, as you'll
6 recall, we reopened formaldehyde to include
7 methylene glycol. That they're safe in cosmetics
8 applied to skin when formulated to ensure use at
9 minimum effective concentration, but should be --
10 in no case should be greater than 0.074 percent
11 formaldehyde equivalents. We'll get into that
12 terminology in a minute.
13 That "insufficient" for nail-hardening
14 products. I think we've received information, and
15 now we could change that to "safe," and just
16 eliminate the nail-hardening products. But I'll
17 ask the team's input.
18 And that it's unsafe for hair-smoothing
19 products. And, of course, that was probably the
20 precipitating incident to reopen this, because of
21 the Brazilian Blowout epidemic of adverse effects.
22 So, conclusions? And then we had a lot
289
1 of discussion and input from various sources, in
2 terms of the issue of formaldehyde equivalents.
3 So where do want to -- do we want to take the
4 second part, the "insufficient?" Is that now
5 "safe" for nail hardening?
6 Ron, Tom, Ron Hill?
7 DR. SLAGA: I think that part can be
8 deleted.
9 DR. MARKS: Okay.
10 DR. HILL: Okay, I'm not clear what
11 you're seeing.
12 DR. BERGFELD: I thought so, too.
13 "Nail-hardener" defined.
14 DR. MARKS: Yes, that was brought up,
15 remember? As I recollect, Don-yes, this is the
16 memorandum, right inside there. Don had concern
17 about nail-hardeners. He had seen a couple
18 individuals with contact dermatitis. And then
19 we've subsequently gotten information that that
20 was a higher concentration.
21 So I think we can say the nail hardeners
22 are safe. Okay. So we can eliminate the second
290
1 portion of the conclusion.
2 How about, do we want to go back to the
3 first, and deal with formaldehyde equivalents? Do
4 we like that terminology? Because there was a lot
5 of -- I think I would characterize it as differing
6 opinions as to what nail equivalents are. And I
7 see David laughing there. So anytime you want to
8 come up and comment, David, you're welcome to do
9 that. Since you actually wrote one of the
10 letters.
11 And that's, of course, trying to go with
12 what was in the original, where we arrived at that
13 concentration.
14 Ron? Ron Shank?
15 DR. SHANK: I have no problem with the
16 term "formaldehyde equivalents." I know it
17 bothers chemists. But biologically, formaldehyde
18 and methylene glycol, in equilibrium -- and to
19 call that "equivalents" is fine with me.
20 For the part one of the conclusion, I
21 would just add at the very end that the 0.04
22 percent in the final product. Because it doesn't
291
1 say -- it could be in the ingredient, and our
2 interest is in the final product.
3 And I have a major -- and I think
4 eliminating, too, the nail-hardening statement,
5 that can be eliminated entirely.
6 And then I would change the
7 hair-smoothing products conclusion.
8 DR. BERGFELD: To what?
9 DR. SHANK: Okay. Here goes. I think
10 we can rely on precedents by the Panel. We had a
11 similar problem when we handled glycolates and
12 lactates which produced very severe skin
13 reactions. And we put in a caveat that they were
14 safe when the products -- or the products are safe
15 when applied by trained professionals, using
16 ventilation procedures to prevent irritation to
17 the eyes, nose, throat and lungs.
18 I think that would apply here. And
19 we've done this before. We have to remember that
20 the carcinogenicity of methylene chloride
21 formaldehyde requires chronic irritation, not
22 occasional irritation. We have a lot of data to
292
1 support that.
2 We can also include other examples with
3 the diacylglycerol esters. We said "safe" --
4 provided that the content at the one- two-diesters
5 is not high enough to induce dermal hyperplasia --
6 a very specific caveat.
7 With the alphahydroxy acids we had a
8 caveat, "safe" as long as application is
9 accompanied by directions for daily use of sun
10 protection. Without that, we had concerns.
11 Another one, placental enzymes, we had a
12 very definite caveat. They were safe if they did
13 not deliver metabolic interconnectivity.
14 So I think, using the one from the
15 glycolates -- or the Panel can reword it if they
16 want -- products are safe for the hair-smoothing
17 products when applied by trained professionals,
18 utilizing, using ventilation procedures to prevent
19 irritation to the eyes, nose, throat and lungs.
20 That's it for that part.
21 DR. SLAGA: I like that. I mean, those
22 are our concerns. So --
293
1 DR. MARKS: Read the last part, " --
2 when applied by trained professionals -- " -- so
3 that's --
4 DR. SHANK: The hair-smoothing products,
5 they need a caveat.
6 DR. MARKS: Right.
7 DR. SHANK: So part one is not enough.
8 So part two would see that the hair-smoothing
9 products would be safe when the products -- the
10 products would be safe "when applied by trained
11 professionals using ventilation procedures to
12 prevent irritation to the eyes, nose, throat and
13 lungs."
14 DR. HILL: Could we add, "sufficient to
15 prevent -- " --? Say "sufficient to prevent,"
16 "shown to be sufficient to prevent" -- something
17 like that?
18 DR. SHANK: That's fine. Massage it.
19 But I think our concern is any formulation, any
20 product that would cause irritation, and not to
21 pick out one -- as we have here -- saying that
22 hair-smoothing products are unsafe. They can be
294
1 safe, under strict control, I think.
2 DR. BERGFELD: Would you put that in
3 your discussion a little broader?
4 DR. SHANK: Yeah -- absolutely. The
5 discussion would have to reflect all of this, and
6 go back to the precedents that I had mentioned,
7 the glycolates, lactates, the acylglycerol esters.
8 We've frequently used caveats to restrict how
9 these products can be used.
10 DR. BERGFELD: Would you consider adding
11 -- because we did hear this this morning -- it's
12 also the volume or amount that's applied.
13 DR. SHANK: Yes.
14 DR. BERGFELD: It should be minimized.
15 And the temperatures can be minimized.
16 DR. SHANK: Yes.
17 DR. BERGFELD: So, somehow we could work
18 with those other factors that cause greater
19 release?
20 DR. SHANK: Yes.
21 DR. MARKS: I think that would be part
22 of the "trained professionals."
295
1 DR. SHANK: I think so. That's what I
2 thought.
3 DR. MARKS: And then at the end, Ron,
4 you mentioned "all parts." Can you just say "the
5 respiratory tract," rather than saying, upper,
6 lower, middle -- whatever? Can you just say "to
7 prevent irritation to the respiratory tract."
8 DR. BERGFELD: Eyes.
9 DR. SHANK: Eyes and respiratory tract.
10 That's good. Better.
11 DR. MARKS: Tom? Is that --
12 DR. SLAGA: That pretty well adds the
13 biological aspect.
14 DR. MARKS: Right.
15 DR. SLAGA: That's very important.
16 DR. MARKS: Ron Hill?
17 DR. HILL: It's consistent with what
18 I've said from the get-go.
19 DR. MARKS: Right. So, this would be
20 sent out as another re-revised tentative amended.
21 DR. SLAGA: How many times has this --
22 DR. MARKS: And the conclusions would be
296
1 that -- basically, on page 73, the first
2 conclusion, we would modify that. We like the
3 "formaldehyde equivalents," despite the input
4 we've had from others.
5 DR. HILL: While we're on that, can we
6 just speak to that? Is that the way it's used
7 here refers back to foreign and methylene glycol.
8 DR. MARKS: Right.
9 DR. HILL: So I think it's not as
10 ambiguous as it would be in the letter that
11 professor Haas suggested, for example.
12 DR. MARKS: Right. Yes, I think, again,
13 that would be robustly discussed.
14 In the final product, we would delete
15 part two, with reference to the nail products.
16 And then we would add that, as far as
17 the hair- smoothing products, it's safe for use in
18 hair-smoothing products when applied by trained
19 professionals, using ventilation procedures to
20 prevent irritation to the eyes and respiratory
21 tract.
22 Is that consistent with what you said,
297
1 Ron? Yeah, I think --
2 DR. SHANK: Yes.
3 DR. MARKS: -- I think that handles --
4 obviously, these have been used in hair-smoothing
5 products before we had Brazilian Blowout.
6 DR. BERGFELD: Could I ask where you're
7 putting nail? Because --
8 DR. MARKS: We delete the nail, because
9 it's --
10 DR. BERGFELD: But --
11 DR. MARKS: -- tied to the skin. Do we
12 have to specifically say "nail?"
13 DR. BERGFELD: Well, "skin and nails" --
14 we could put it.
15 DR. MARKS: Mm-hmm.
16 DR. BERGFELD: I would say you should do
17 that. It's a major issue.
18 DR. EISENMANN: Well, the purported use
19 concentrations were as applied to the hair, so I
20 don't know --
21 DR. BERGFELD: So you're talking about
22 hair rather than skin?
298
1 DR. EISENMANN: Well, I wonder why there
2 was dermal in the first place.
3 DR. MARKS: I don't quite follow, Carol.
4 Do you like that? So I think, in part one of the
5 conclusion, on 73, do you want to just delete the
6 skin? "Safe for use in cosmetics when formulated
7 to ensure -- " --
8 DR. BERGFELD: That's good.
9 DR. EISENMANN: Yes.
10 DR. MARKS: -" -- minimal effective
11 concentration -- " --?
12 DR. BERGFELD: I like that.
13 DR. MARKS: "Safe for use in
14 hair-smoothing products -- " -- the use we refer
15 to. So we don't pick out skin or nail.
16 Does that sound appropriate? Ron, Tom?
17 So in that first portion we would say are "safe
18 for use in cosmetics, when formulated -- " -- and
19 remove "applied to the skin." That would take
20 care of the nails.
21 DR. EISENMANN: An additional comment --
22 we are still getting questions from people
299
1 wondering does this apply to
2 formaldehyde-releasing preservatives. Which is
3 one of the reasons why we suggested the
4 alternative, to put the formaldehyde equivalents
5 first. Then a recent -- if I can read this,
6 "Formaldehyde equivalents, formaldehyde, and
7 methylene glycol are safe for use in cosmetics
8 when formulated to ensure use at minimal effective
9 concentration. But in no case should added
10 formalin exceed 0.2 percent, which is 0.074
11 percent w/w calculated as formaldehyde, or 0.118
12 percent w/w calculated as methylene glycol."
13 That would be to make it even more
14 clear. That would be -- everything would be in
15 there. So you'd have the equivalents -- that you
16 mean it's formaldehyde and methylene glycol.
17 You'd have the concentration of formalin. And
18 then you'd have the concentration of formaldehyde
19 and methylene glycol that would be in there, that
20 you would calculate to be in there.
21 DR. MARKS: So I would ask Ron, Tom, and
22 Ron how comfortable you feel in setting limits, as
300
1 you have, Carol, for formaldehyde and methylene
2 glycol, when we know it's a dynamic relationship?
3 We kind of address --
4 DR. EISENMANN: You're calculating -- I
5 mean, it's a calculative value for them. Similar
6 to when you do different salts, and calculate it
7 as the acid.
8 DR. HILL: Maybe the referencing is
9 ambiguous, but I interpret the way it's currently
10 written in here, when it says, "Should
11 formaldehyde equivalents -- " -- I interpret
12 implicitly that to mean -- and maybe it's too
13 implicit -- formaldehyde and methylene glycol.
14 DR. EISENMANN: We're getting questions
15 --
16 DR. HILL: You're getting questions
17 which suggest that people --
18 DR. EISENMANN: -- so they're not
19 interpreting --
20 DR. HILL: -- aren't reading it that
21 way.
22 DR. EISENMANN: Right.
301
1 DR. MARKS: So I like the brevity of the
2 conclusion. Can that be handled in the
3 discussion?
4 DR. SLAGA: I think it can be handled in
5 the discussion.
6 And then also, in the discussion we're
7 going to have to be pretty certain what we mean by
8 "trained professionals," too.
9 DR. MARKS: Alan?
10 DR. ANDERSON: A couple of questions.
11 Page 5 of the report, Panel Book page 59, clearly
12 says, "Moreover, the ingredients in this review
13 are not to be confused with
14 formaldehyde-releasers, which are not analogous --
15 " -- yadayadayada.
16 I'm not quite sure what the problem is,
17 folks? It said that it ain't covered.
18 I could go through the old story of the
19 mule and the two-by-four, but I don't think I need
20 to. I don't understand the elimination of the
21 second bullet. I don't get it.
22 Formaldehyde/methylene glycol is used in
302
1 nail-hardeners.
2 Is that safe or not? I can't tell, if
3 you delete that. Why wouldn't you say, "Safe in
4 nail-hardeners, in the present practices of use?"
5 DR. SHANK: You're right. Because
6 the.07 percent in the final product would
7 eliminate the nail-hardeners from the conclusion.
8 DR. ANDERSON: And I don't think --
9 DR. SHANK: So it has to be back in.
10 You're right.
11 DR. ANDERSON: Yes, I think so.
12 DR. HILL: I was going to ask about
13 that, but I assumed somebody else would notice it.
14 DR. ANDERSON: Yep.
15 DR. MARKS: So, Alan, we'd go back -- I
16 wouldn't eliminate that, then, "cosmetics applied
17 to the skin, and nail-hardeners?" Would we
18 include it?
19 DR. ANDERSON: Well, no. I think the
20 first -- I actually agree with Carol's pushing to
21 delete that "applied to the skin" phrase, because
22 it creates more trouble than it may be worth.
303
1 So, "are safe for use in cosmetics" in
2 that first bullet is a just fine thing. And I'm
3 not sure that you can have too much information
4 content in that.
5 I'm not sure I like the idea of
6 mentioning formalin, because it's not listed as an
7 ingredient. But the discussion can explain all of
8 that.
9 So, again, more information is probably
10 better than less information in that first bullet
11 -- with the exception of let's get rid of "applied
12 to the skin."
13 Then the second part focuses on
14 nail-hardeners, and is very targeted.
15 Nail-hardener, safe in the present practices of
16 use. Again, assuming that you came to the
17 conclusion that you believe that 2 percent is the
18 kind of upper limit and that's what you're going
19 to see in nail- hardener products, and that
20 doesn't bother you.
21 And then, number three, your conclusion
22 was equally clear.
304
1 DR. HILL: I take your comments to mean
2 that you support the language that was proposed by
3 the Science and Support Committee.
4 DR. ANDERSON: For --
5 DR. HILL: For bullet one.
6 DR. ANDERSON: For bullet one. I think
7 you can argue whether formaldehyde equivalents
8 goes first in the sentence or at the end. But,
9 no, I don't think that the world will stop turning
10 if that language is used.
11 DR. HILL: Add the detail that she was
12 proposing. I agree with you.
13 DR. ANDERSON: Add formalin --
14 DR. HILL: -- it's just longer.
15 DR. ANDERSON: -- specifically target
16 the formaldehyde, specifically target methylene
17 glycol. It makes it much more difficult to
18 misunderstand.
19 DR. HILL: I certainly agree with that.
20 It's very clear, what she said, as long as we
21 understand the meaning of "calculated as." It's
22 much clearer.
305
1 DR. ANDERSON: Well, it will be
2 misinterpreted.
3 DR. HILL: Oh, sure. Yeah, yeah.
4 DR. MARKS: So, Ron Shank -- Carol,
5 would you re-read your proposal, where it has all
6 three? Because now can we still add at the end,
7 "in final product?"
8 So, go ahead. Because we added that.
9 DR. EISENMANN: So I'm reading the first
10 part of the conclusion?
11 DR. MARKS: Whether or not "formaldehyde
12 equivalents" is in the beginning or in the middle,
13 that's not the issue. It's --
14 DR. ANDERSON: Read it as you've got it.
15 DR. MARKS: Yes.
16 DR. EISENMANN: I'll read it.
17 "Formaldehyde equivalents, formaldehyde, and
18 methylene glycol are safe for use in cosmetics
19 when formulated to ensure use at the minimal
20 effective concentration. But in no case should
21 added formalin exceed 0.2 percent, which is 0.074
22 w/w calculated as formaldehyde, or 0.118 w/w
306
1 calculated as a methylene glycol."
2 DR. ANDERSON: And you can take your "in
3 final product," and put it right after "minimal
4 effective concentration."
5 DR. SLAGA: Yes.
6 DR. MARKS: What was the methylene
7 glycol percent you gave?
8 DR. EISENMANN: 0.118.
9 DR. MARKS: Okay. Ron, Ron? Do you
10 like that being that specific?
11 DR. SHANK: That's fine with me.
12 DR. MARKS: And those calculations -- I
13 assume, Carol, particularly the methylene glycol,
14 is correct.
15 DR. ANDERSON: Jim, one more.
16 DR. MARKS: Sure. Absolutely.
17 DR. ANDERSON: Formaldehyde and
18 methylene glycol, are they safe or unsafe in
19 products not applied by trained professionals?
20 Because it's happening.
21 DR. HILL: You can say, " -- and are not
22 safe if -- " --
307
1 DR. BERGFELD: We haven't said that
2 before, with the nail-hardeners and nail
3 preparations. We've only done the positive
4 portion of that statement.
5 DR. ANDERSON: Yes, I agree with that.
6 MS. WEINTRAUB: What does "a trained
7 professional" mean? Does it mean a trained
8 stylist? Does it mean a stylist who's had
9 specific training in the use of this product by
10 the manufacturer?
11 What does that mean?
12 DR. SHANK: We'll have to define that in
13 the discussion.
14 DR. GOLDEN: Could I just say something?
15 COURT REPORTER: Turn on the mic,
16 please.
17 DR. MARKS: Please identify yourself.
18 DR. GOLDEN: Hi, Bob Golden. I mean,
19 I'm not an authority on this, but it's my
20 understanding that stylists who use these products
21 do have training above and beyond what they need
22 to become a stylist. There's classes. And I know
308
1 that all the manufacturers are going around and
2 doing seminars, and educating them on -- in fact,
3 it's now being tweaked again as a result of that
4 study that could link different tasks with
5 airborne levels.
6 So I know they're already revising it
7 again, to do exactly what you're talking about.
8 DR. HILL: I think what people have been
9 troubled by -- at least anecdotally -- is that in
10 the face of that training, perhaps because there's
11 not an understanding of the scientific basis
12 behind it, or it can't be conveyed adequately, or
13 something, that those safeguards are being
14 ignored.
15 DR. GOLDEN: I agree that --
16 DR. HILL: And that maybe there's
17 nothing in force of law right now -- although I
18 think FDA is moving to do something to people who
19 do ignore. But if you just totally eliminate all
20 possibility of using these, you probably just
21 force it all underground, which is not a good
22 thing anyway. That's not science, that's just
309
1 pragmatism.
2 DR. GOLDEN: Exactly. And, obviously,
3 there's better ways of doing it. In fact, in that
4 study they had, in addition to the room
5 ventilation, they had a portable source
6 ventilation. And even though the stylist had
7 specifically been told how to use that, she still
8 used it wrong when they did the study.
9 And so she stood between the customer,
10 her, and the ventilation source, so it drew the
11 air sample directly across her sampling badge.
12 So, obviously, if she had been on the other side,
13 that would have been better.
14 So you're absolutely right about that.
15 DR. MARKS: So, Rachel, I would say the
16 same is "using ventilation procedures,"what does
17 that mean? So, again, I think in the discussion,
18 I think the idea is to alert the users of this
19 ingredient that when it's in hair- smoothing
20 products, that they should be trained on how to
21 use these hair-smoothing products. And that they
22 should be alerted to have ventilation procedures,
310
1 that it wouldn't be in a closed salon or
2 something.
3 But I know that's more vague than maybe
4 you would prefer.
5 MS. WEINTRAUB: Yes. And I do have
6 concerns about this language. I think it is
7 vague. And I think that things would radically
8 need to change.
9 And I would like an understanding of
10 whether you think, you know, based on the incident
11 reports that have been coming in, whether this is
12 being applied by trained professionals, and
13 whether the ventilation has been adequate.
14 Because what I've been finding is that
15 even people who have been trained are unaware --
16 unaware of how to apply this, minimizing exposure
17 to themselves and to consumers.
18 So I think -- I don't think it is a lack
19 of understanding by the stylist. I think the
20 information is not being communicated.
21 Second, I think ventilation has varied
22 widely, from an open window, to fans that may or
311
1 may not work. So the ambiguity -- and also, the
2 fact that it leaves room for interpretation, and
3 relies upon enforcement by some entity who may or
4 may not be enforcing, definitely raises concerns
5 for me.
6 DR. HELDRETH: I'd like to say I agree
7 with Rachel. I think there's a general
8 misunderstanding of even what ventilation is. If
9 you take a walk-in chemical fume hood, you lower
10 that sash just an inch, the face velocity changes
11 drastically. I seriously doubt even the best-
12 trained hair stylist would understand that.
13 DR. SHANK: That's why you put in
14 "ventilation to prevent irritation to the eyes and
15 respiratory tract." You don't need to say fans,
16 fume hoods, vacuum cleaners or whatever.
17 And if they're to be properly trained,
18 they should be trained with the understanding that
19 they have to prevent irritation. If they're not
20 trained that way, then they're not properly
21 trained. We'll have to say that in the
22 discussion.
312
1 DR. MARKS: Tom? Ron?
2 DR. SLAGA: I agree with Ron's last
3 statement.
4 DR. ANDERSON: I think -- I'm trying to
5 think of how it would get implemented. And I
6 harken back to Ron's citing the example of the
7 glycerol diesters.
8 We put the burden on somebody to test
9 these ingredients, either as the ingredients
10 before they're used, or in formulation -- and I
11 don't think we really cared -- to demonstrate that
12 they would not induce hyperplasia. The
13 expectation is that that was going to be a
14 scientific piece of data on which you could rely.
15 This puts implementation in the hands of
16 not very educated people about the things that
17 they're dealing with to make that judgment. And
18 I'm just having a little bit of trouble seeing how
19 it actually gets implemented.
20 Certainly, because you linked it to
21 sensory irritation, it's not like you're going to
22 have to do a test to figure it out. If your eyes
313
1 start watering and your nose is being severely
2 irritated, you know, "Dear Reader -- You've hit
3 that level, and whatever you're doing ain't
4 working. So stop."
5 So that being put in instructions, I
6 guess I can see it being linked to, "You'll know
7 it when you see it," so to speak. Because you
8 damn well will.
9 I just don't know what that person does
10 next. That user has already accepted the 400
11 bucks for the treatment. You're going to stop?
12 The salon owner -- whoever's hat you want, I'm not
13 sure there's a self-interest that can be effective
14 in that circumstance.
15 Now, having said that, I'm not sure
16 there was a real self-interest when we did the
17 methacrylates, either. So there's holes on my
18 side as well, in terms of thinking about it.
19 But for this one, I'm just -- if I
20 wanted to explain it to somebody, how is this
21 going to work, that's the piece I'm missing right
22 now.
314
1 DR. MARKS: So, Linda, do you have --
2 I'm not sure we're blending, but a lot of the
3 discussion gets into the end-use of this. And
4 that becomes perhaps out of the purview of the
5 CIR, and more of a regulatory issue.
6 Obviously, that's what happened with
7 Brazilian Blowout. It wasn't because of something
8 we did at the CIR.
9 DR. LORETZ: Well, actually, you're
10 correct. It crosses multi-jurisdictional regions
11 or areas -- that the FDA regulates the product
12 towards, and how it's used for the use itself, if
13 it's actually being sold to the user.
14 In the salon setting, OSHA and the
15 states have regulatory jurisdiction. OSHA, over
16 what is released into the air, the environment,
17 for safety for the salon workers, and the states
18 in the practice of the use of the products
19 themselves, which is outside of FDA's
20 jurisdiction.
21 So as a result, there are multiple
22 places where multiple different agencies need to
315
1 be involved to make sure that things happen the
2 way that they should happen. And we have been
3 working together with OSHA and the states to try
4 to see, as much possible, to make things as safe
5 as possible for consumers.
6 Where the FDA got involved with issuing
7 a warning letter -- because, on the face of it,
8 the product itself, Brazilian Blowout, was both
9 viewed to be adulterated and misbranded --
10 adulterated because it had a harmful ingredient,
11 misbranded because the labeling itself failed to
12 disclose, or actually went to the opposite
13 extreme, to say that it was "formaldehyde free."
14 So that it was both an adulterated and a
15 misbranded product.
16 OSHA has gotten involved because in
17 several places where they've gone to look at the
18 salons and to analyze the head space, that the
19 levels of formaldehyde present exceeded the levels
20 that they say are safe.
21 So that we've been working together, and
22 across -- really, it's a multi-agency effort, to
316
1 try to come up with some way to make sure that
2 when the product is used, it's used safely.
3 But that being said, your
4 recommendations as to what you like to see, if
5 you'd like any particular campaigns where the onus
6 becomes on the supplier, the manufacturer of the
7 products, what they need to do, would also be
8 useful in being able to help us do our job.
9 But where we need to take the things
10 back is from the regulatory standpoint as to when
11 we decide is something safe, not safe, and how it
12 should be used. I don't know if that makes it
13 clearer or not.
14 But unfortunately this is not an easy
15 black or white answer to a problem. Because
16 technically speaking, there are different
17 jurisdictions, there are different regulations
18 that cover different parts of this product, and
19 these products in general.
20 DR. MARKS: Do you think --
21 DR. ANDERSON: Go ahead, Jim.
22 DR. MARKS: No, go ahead, Alan.
317
1 DR. ANDERSON: Well, I think the
2 scenario that Ron outlined in his way of crafting
3 the conclusion addresses the question of is it
4 possible to use these products safely. And I
5 think the answer to that is almost certainly yes.
6 With enough controls so that exposures don't reach
7 levels, there's no reason for any of these adverse
8 effects to be seen.
9 My concern is focusing on the present
10 practices of use. And in the present practices of
11 use, I just don't see it. And use would have to
12 change. And I think that's part of what you were
13 driving at in crafting the conclusion, is to drive
14 change in the way these are being used.
15 And I'd love to see what additional
16 controls could be put into place to make that
17 happen.
18 I'm also not unmindful of the comment
19 that Ron Hill made -- in passing, but it's a real
20 phenomenon -- if this stuff goes underground,
21 controlling it is going to be impossible.
22 DR. BERGFELD: I'm not sure it's in our
318
1 purview to protect, physically, the population.
2 We are trying to protect them by reviewing these
3 chemicals, to find the safety in them, and give
4 warning and some direction.
5 But there's no way, other than to press
6 the industry that formulates these products and
7 has education of their suppliers and those who
8 apply all these products -- that is their
9 responsibility.
10 So if we are to say what we've decided
11 to say, that is then for them to carry that
12 forward and do it. And we can make that statement
13 in public, that unless these are non-irritating,
14 they're unsafe.
15 I just don't think that we can worry
16 about who's not going to do it. Because you can't
17 have zero risk.
18 DR. LORETZ: Yes, and I was going to
19 agree that that's exactly what you, as a Panel,
20 should be determining, is whether or not the
21 ingredient could be used safely, and under what
22 conditions it could be used safely -- as you've
319
1 done with other ingredients in the past. And then
2 the rest of it becomes the purview, so to say, of
3 making sure that industry warns the clients that
4 are using it, purchasing it, that FDA is doing its
5 job, OSHA is doing its job, and the states are
6 doing their jobs, and making sure that things are
7 being done appropriately.
8 DR. MARKS: So I think the corollary, to
9 me, would be when we recommend something be
10 formulated to not have an adverse biological
11 effect, we're assuming that the formulators --
12 even the, say, non -- formulator will do that,
13 even maybe the ones that aren't -- what would I
14 say -- not as sophisticated are still going to
15 formulate it so it doesn't have a biologic effect.
16 We did, as you mentioned, Alan, say,
17 with the users, with the acrylates, say they
18 should use it in a way that it wouldn't cause
19 sensitivity. In this case we're saying that this
20 product should be used in a way that it won't
21 cause the biologic end effect of irritation.
22 So I can see where tomorrow the
320
1 dichotomy may occur, whether you leave point three
2 still the same, that it's unsafe, whereas we're
3 trying to craft a way where it could be used
4 safely.
5 Rachel, you were going to say something.
6 MS. WEINTRAUB: I was going to say I
7 think, if you were to move forward with this type
8 of language, I think it needs to be very clear in
9 the discussion that the current practices of use
10 are inconsistent with this conclusion -- making
11 clear that professionals haven't been trained
12 adequately, and ventilation procedures have not
13 been used that adequately minimize and sensory --
14 DR. MARKS: Actually, I'm not sure we
15 know that.
16 MS. WEINTRAUB: Well, I think -- but we
17 do know that there's been many reactions from
18 consumers.
19 DR. MARKS: Well, that's with these
20 products which have very large concentrations to
21 begin with, of formaldehyde, much greater than
22 what we would have set in point one.
321
1 MS. WEINTRAUB: Because my concern is,
2 based on what we've been hearing from the
3 industry, is that this may not necessarily cause a
4 change. Because from what the industry submitted,
5 I guess that we received on Thursday night, they
6 seem to think -- and they've been arguing that the
7 conditions have been such that the levels of
8 formaldehyde have been low. There seems to be a
9 disconnect between the levels that they recorded
10 in their limited study, versus irritation impact.
11 So I'm concerned that a conclusion like
12 this, as interpreted, may not actually reduce
13 incidence of irritation.
14 DR. MARKS: So you would like to see it
15 remain "unsafe" for hair-smoothing products -- if
16 I hear what you said, Rachel. Or somehow you
17 would feel more comfortable, from the consumer's
18 point of view, that this was robustly discussed in
19 --
20 MS. WEINTRAUB: Yes, I think there's
21 different ways to thread the needle here. And I
22 realize it is very complicated in terms of the
322
1 role of CIR and the role of Federal regulatory
2 agencies, and different agencies at that, and then
3 also at the state level.
4 But I do think that CIR's statement
5 should be clear and not ambiguous. And I fear
6 that this warning -- or this wording may be too
7 ambiguous.
8 DR. MARKS: So I'm not sure we have what
9 I think are the two options. One is to leave the
10 third conclusion as is, with it being "unsafe."
11 The other would be to modify it as Ron
12 Shank has suggested, using the biologic endpoint
13 of irritation as the one in which we want to
14 avoid. And that the way that occurs is both by
15 trained professionals and ventilation procedures.
16 So, Ron -- I'll just go down. I think
17 it's probably -- unless somebody has a different
18 option, or a different comment.
19 Wilma, you do?
20 DR. BERGFELD: Well, I'm going speak
21 strongly. I think that three is incorrect. We
22 heard it today.
323
1 It's not the temperature always. It's
2 the amount placed on the scalp. So right off the
3 bat, it's an incorrect statement. So it has to be
4 modified.
5 And I think, Rachel, an opposite view
6 that you have, is if you're very specific about
7 what is allowable and considered to be safe by
8 percentage of what is included in a product, that
9 you have greatly restricted it.
10 And then the third thing is that our
11 experience here at the CIR is, if we have been so
12 restrictive, and compliance is down, that the
13 public takes this up. And if there is any injury
14 done, this document serves as a document of
15 support for litigation.
16 And so what we have seen over time, that
17 those things that we have either restricted --
18 very low restriction so that it's almost
19 impossible to use, or we have said that there's
20 been some adverse reaction, that if that has
21 occurred, that these documents have been great
22 sources for the lawyers. So we have seen the use
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1 go down.
2 So, you know, there is the indirect
3 methodology of controlling, as well.
4 DR. MARKS: Just to sort of flesh out
5 one other thing -- so, would point one, Alan, in
6 the conclusion, apply to point three? In other
7 words, with hair-smoothing products, formaldehyde
8 should be no greater than 0.2 percent -- or
9 formalin, I mean. That formaldehyde, .074
10 percent, and methylene glycol, 0.18 percent?
11 Because if it would, aren't these levels
12 likely to predict, even with heating, that there
13 would be unlikely irritation? And then we add
14 "trained professionals," and ventilation
15 procedures to further reduce the potential of
16 irritation.
17 DR. ANDERSON: The risks of Mr.
18 Einstein's theories' being thrown out with the
19 recent neutrino data -- it still is the case that
20 the fundamental premise can control.
21 So, if condition one is met --
22 formaldehyde and methylene glycol are at 2 percent
325
1 or less, formalin -- and with the two separate
2 numbers -- then I'm not sure I care what product
3 it's in. I also don't think it will work for
4 hair-smoothing products, so --
5 DR. GOLDEN: Well, that's what I was
6 going to say.
7 DR. ANDERSON: But the point is, if that
8 were to be applied, it would work just fine.
9 But I also think, one way or the other,
10 you need a point three targeted at those products,
11 because they are involving higher concentrations.
12 So whether it's crafted as, "Sorry,
13 Charlie, they're unsafe." Or "They can be safe
14 when you follow the following practices," I think
15 you need something separately for hair-smoothers.
16 DR. GOLDEN: Yes, I would concur. Once
17 again, I'm not an expert on how much you need, but
18 I don't think products would work at that
19 concentration. It's just not going to happen.
20 DR. MARKS: So that's important. That's
21 why we need a point three, just as we've addressed
22 the nail-hardeners separately, we need to address
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1 the hair-smoothing products.
2 DR. GOLDEN: And "efficacious
3 concentration."
4 DR. LORETZ: But just to comment -- in
5 the past, I mean, the example of glycolic acid was
6 brought up, and it was professionally trained, but
7 then there were numbers associated with it. And
8 that made it -- with this one, there's no numbers,
9 and "ventilation" is a bit open to interpretation,
10 as is training. So that kind of puts it in a bit
11 of a different category.
12 DR. HILL: Right. But the idea is we're
13 using a highly sensitive biologic endpoint and
14 saying, "This can't happen."
15 Now, in practicality, when the money's
16 been paid, the irritation starts being sensed, do
17 people stop, or do they just live with it go right
18 forward? That's the question, and I agree it's an
19 important practical question.
20 But effectively, by putting that
21 biomarker, if you will, that biologic endpoint in
22 place to say if this happens, you're not doing it
327
1 right, or the product is wrong, or there's too
2 much heating, or there's inadequate ventilation --
3 you're accounting for all the factors
4 simultaneously, and you're accounting for them
5 quite sufficiently.
6 DR. MARKS: So --
7 DR. HILL: What happens in practicality
8 with the public -- but I liked everything that
9 Wilma said, is question two.
10 DR. MARKS: Yes. So, Rachel, I'd asked
11 you -- to me, it looks like there are two options:
12 "unsafe," versus the way that was crafted that it
13 can be safe if there are true trained
14 professionals and ventilation procedures.
15 Is there another option? Or is there
16 another way to word that that you think the
17 consumer would be protected better? Than just
18 "unsafe?"
19 Because it seems to me those are our two
20 options. Either it's safe or it's unsafe. And if
21 we say it's safe, it has to be done under
22 particular use --
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1 MS. WEINTRAUB: I'm trying to -- I think
2 what's missing -- and I understand, and agree,
3 that the current language is problematic, and
4 there's many other factors other than high
5 temperatures.
6 But I think what's missing here is
7 distinguishing between what you're recommending
8 and current practices.
9 DR. MARKS: Okay. Ron Shank, you
10 proposed the revised third bullet. Do you still
11 --
12 DR. SHANK: I think our conclusion would
13 say that current -- some current practices need to
14 be changed.
15 DR. MARKS: Yes. But that's -- so, you
16 would move forward with the conclusion point three
17 as you proposed.
18 DR. SHANK: Correct.
19 DR. MARKS: Tom?
20 DR. SLAGA: I agree.
21 DR. MARKS: Ron?
22 DR. HILL: (Nodding)
329
1 DR. MARKS: Agree. Okay.
2 DR. BERGFELD: Can you repeat the --
3 DR. MARKS: That formaldehyde and
4 methylene glycol are safe for use in
5 hair-smoothing products when applied by trained
6 professionals, using ventilation procedures to
7 prevent irritation to the eyes and respiratory
8 tract.
9 Did I get that correct, Ron?
10 DR. SHANK: Yes, you did.
11 DR. MARKS: Okay.
12 DR. BERGFELD: But that's three. But
13 what's --
14 DR. MARKS: Well, that's three. Number
15 one, we already talked about, and I won't -- I
16 don't have all the wording. Carol has it. But
17 essentially it says that it's safe in cosmetics
18 when formulated to ensure that a minimal effective
19 concentration, but in no case formaldehyde
20 equivalents exceed.074 percent, formalin, 0.2
21 percent -- the formaldehyde, which you were
22 specific, formaldehyde, not formaldehyde
330
1 equivalents, 0.74 percent, and methylene glycol,
2 0.118 percent.
3 And then the second bullet is that the
4 nail-hardeners are safe, in the present use and
5 concentration.
6 DR. BERGFELD: Now, no one will have a
7 problem with the first one, because it's "use in
8 cosmetics." Does that include hair care? We left
9 the general statement.
10 DR. MARKS: Well, that's what I tried to
11 --
12 DR. SHANK: Yes, you did.
13 DR. ANDERSON: That's not terribly
14 function in hair products, but --
15 DR. GOLDSTEIN: It is functional in hair
16 products at.2 percent as a preservative.
17 DR. ANDERSON: Oh, okay. Point well
18 taken.
19 DR. GOLDSTEIN: We don't use it, but it
20 has been used, historically, up to -- usually that
21 is the maximum level we've ever used to preserve a
22 shampoo or conditioner.
331
1 DR. ANDERSON: Good point. But, yeah, I
2 think that the first conclusion is somehow
3 fundamental. And if you want to go higher than
4 that -- okay, let's talk. Nail hardeners. Okay
5 -- safe in the present practices of use.
6 Hair-smoothers? Well, we have different views of
7 what that should be, but it's a separate question,
8 and deserves a separate answer.
9 DR. BERGFELD: We've never had a
10 conclusion that had one, two, three. Somehow I'm
11 agreeing with everything that's been said, but
12 we've never had one that looked like this.
13 One, two, three. Is there some other
14 way of organizing this?
15 DR. MARKS: Yes, you could put "with the
16 exception of nail hardeners, which are safe in the
17 present use and concentration," and "with the
18 exception of hair-smoothing products -- " -- da,
19 da, da, da.
20 DR. ANDERSON: No reason it couldn't be
21 put into a sentence that includes all three.
22 At this meeting, we're talking about
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1 amending --
2 DR. MARKS: This would be a re-revision.
3 This is a re-revised tentative amendment.
4 DR. ANDERSON: The current conclusion
5 for glutaral is a three-piece conclusion -- safe
6 up to half a percent for leave-on, insufficient
7 data for rinse-offs, and should not be used in
8 aerosols.
9 So we have often had three-part
10 conclusions.
11 DR. BERGFELD: No, we haven't had --
12 DR. ANDERSON: But we've never had one,
13 two three.
14 DR. BERGFELD: One, period, two, period,
15 three, period.
16 DR. ANDERSON: Well, it seems somehow
17 important to focus this one.
18 DR. BERGFELD: I don't mind the periods,
19 but somehow to put this into a decent sentence --
20 DR. ANDERSON: But it can be put into a
21 sentence.
22 DR. MARKS: I think that's -- if we go
333
1 by our precedents set before, it will be all in
2 one sentence. Or two -- with the exceptions, not
3 as sort of numbered points or bolded points.
4 Any other comments? So tomorrow this is
5 going to be presented by the Belsito team. I'm
6 sure there are going to be some differences.
7 (Laughter.) I'll elucidate our differences.
8 DR. BERGFELD: Three hours.
9 DR. MARKS: And then we'll see what the
10 vote shows.
11 DR. EISENMANN: I have one comment. In
12 your discussion, I'd like to see you discuss a
13 little bit what you mean by "irritation." Because
14 I think sometimes people find it acceptable to be
15 irritated for a few minutes. But if that's
16 acceptable -- so to define a little bit what you
17 mean by -- you know, is it okay to have a little
18 bit of irritation?
19 DR. SHANK: Why do we have to define it
20 for this ingredient, when we've used it for
21 hundreds of other ingredients?
22 DR. EISENMANN: Because usually it's
334
1 dermal irritation. And I think it's a little bit
2 different than -- and because once you see this
3 irritation, there's --
4 DR. SHANK: What do we mean by "dermal
5 irritation?" I mean, come on.
6 DR. MARKS: Yeah. Okay.
7 DR. BERGFELD: He already said "eyes."
8 DR. MARKS: Yes, eyes and respiratory
9 tract. Okay, I think we will -- one could say
10 this discussion has been irritating. (Laughter.)
11 Let's move on. I think, unless there are any
12 other comments -- I don't want to truncate what's
13 been really, I think, a very good and robust
14 discussion of these ingredients, formaldehyde and
15 methylene glycol. Aerosol Inhalation Boilerplate.
16 Okay, I think the last is the aerosol inhalation
17 boilerplate. Am I correct, Ivan?
18 Team members, am I correct?
19 DR. ANDERSON: You guys didn't spend all
20 afternoon talking about that on each individual
21 report?
22 DR. MARKS: We -- yes, we talked about
335
1 it with the silylates. And then we decided to
2 defer.
3 So the boilerplate is in Buff Book --
4 no, do we have our boilerplate?
5 DR. BERGFELD: No, we don't. We didn't
6 have (inaudible).
7 DR. MARKS: Oh, yeah, we had -- when I
8 go in Buff Book.
9 DR. BOYER: It was an insert.
10 DR. ANDERSON: It was inserted into the
11 book. It may have fallen out.
12 MS. WEINTRAUB: It's in the memo dated
13 September 1st.
14 DR. MARKS: Okay. "Inhalation Toxicity
15 and Aerosols- Precedents," dated September 1st.
16 So it's in a separate -- and the memo comes from
17 the Director. So one potential was, "Safe when
18 formulated to be non-respirable." So how do we
19 kick this off? Ivan, do you want to --
20 DR. ANDERSON: Well, that sounded like a
21 great idea when we were putting all of this
22 together. But I'm not sure, after this morning's
336
1 presentation, that it's reasonable to say "when
2 formulated to be non-respirable."
3 The data that -- how they're presented
4 show a distribution with tails. And the tail goes
5 into the respirable region.
6 Now, is most of it higher than 10
7 microns? Yeah. But if that tail, let's say, for
8 aerosols, is 5 percent of the total, you know, 5
9 percent is not chopped liver. It's enough that
10 were the chemical to be of toxicologic concern for
11 the lungs, would we problematic.
12 So, in a sense, the answer to the
13 question may not be resolved. And I think the
14 package that Ivan put together had already hinted
15 at this. That now that you start to see that
16 particle size is below 10 microns are not
17 impossible, and maybe not even rare, but regularly
18 occurring. And the only question is at what
19 percentage.
20 Now, you're asking a different question.
21 Is what we know about the toxicity of this
22 chemical, coupled with a low exposure to the lungs
337
1 -- no question about that, this isn't all getting
2 in -- does that make it okay?
3 And in the case in which there are no
4 inhalation tox data, what is the Panel's comfort
5 level, and how do we express that?
6 And I think, you know, there's a lot of
7 material that we have put together, but my take on
8 the, if you will, the nervousness, and the reason
9 that Ivan has been pushing to get this back on the
10 table, is that our hand-waving that none of this
11 is going to get in the lungs just ain't so.
12 And now that we're there, where do we
13 go? And I'm not sure I have infinite wisdom to
14 suggest.
15 But I think that our previous comfort
16 level of ensuring everybody on earth that cosmetic
17 aerosols aren't inhaled isn't any longer a good
18 approach.
19 And I don't know that putting the monkey
20 on the industry's back solves anything, either. I
21 think we still have a need to look at Chemical X
22 and think, "What are we concerned about?" And if
338
1 the absence of inhalation tox data bothers us,
2 then we probably better ask for it.
3 DR. SLAGA: Well, that deals with going
4 down to the lung. But I think we always forget
5 that nasal, pharyngeal and other parts of the
6 respiratory tract are important, too.
7 And, you know, if there's any
8 irritation, or any long-term problems, you develop
9 some bad effects from it.
10 A Well, formaldehyde.
11 DR. SHANK: I would like to suggest
12 considering a different approach, where we don't
13 have inhalation toxicity data for an ingredient,
14 use a phrase such as, "Use in products formulated
15 to be non-irritating to the respiratory tract."
16 If there is a specific toxic effect that
17 we're interested in, then we would ask for the
18 toxicity data, the inhalation toxicity data. But
19 if it's a more general problem, with no toxicity
20 data, what do we do?
21 I would suggest using the very sensitive
22 indicator in the respiratory tract, irritation,
339
1 and just say, "When formulated to be
2 non-irritating to the respiratory tract." That
3 gets rid of all of this particle size difficulty.
4 DR. ANDERSON: But it acknowledges, in a
5 sense, that the amount that is going to come in is
6 not huge. I mean, even if particle size is
7 subtracted, a spray directed at the foot is going
8 to have a smaller chance of being inhaled than a
9 spray directed at the hair. And deodorants
10 directed at underarms are somewhere in between.
11 So the acceptance that not all of what's
12 sprayed is going to go in, and where there are
13 inhalation tox data, we use them. Where there
14 aren't we go in this direction.
15 This is kind of the biological version
16 of my non- respirable language.
17 DR. HILL: Let me ask the hypothetical
18 question, then.
19 You're proposing that irritation would
20 be the sentry. Let's suppose we had a compound
21 that was solid in formulation, and there were at
22 least a modest number of particles -- let's say 2
340
1 percent of the distribution -- that could be truly
2 respirable. In other words, they're making it
3 down into alveoli. And then they dissolve there.
4 And then they're biotransformed by P-450s that are
5 enriched in lungs and nowhere else in the body, of
6 which there are some.
7 How are we going to capture, if we use
8 irritation as the sentry, that that could occur?
9 DR. SHANK: You ask for inhalation
10 toxicology data on that individual ingredient.
11 DR. HILL: Because we'd have information
12 from that ingredient that that would be a concern.
13 DR. SHANK: That's right.
14 DR. HILL: But how would we know it was
15 a concern, hypothetically, if it was something
16 that was occurring because of biotransformation of
17 enzymes that are there in the human lungs and
18 nowhere else? In other words, by it being
19 bioactivated by metabolism, that we aren't picking
20 up in other studies.
21 I think we would pick them up, probably,
22 in our standard mutagenesis profile. I'm just --
341
1 DR. BOYER: Well, a similar point,
2 respirable particles, as we said, are going to end
3 up in the alveoli. They're more likely, much more
4 likely, to be absorbed there. The residence time
5 in the alveoli is going to be much longer than it
6 would be if the particle was trapped in the
7 mucociliary escalator.
8 So if you're concerned about potential
9 systemic toxicity, that would be also a
10 consideration.
11 DR. HILL: I'm talking not about
12 systemic toxicity, I'm talking about toxicities
13 expressed in the cells of the lungs.
14 DR. BOYER: Right.
15 DR. HILL: And the alveoli.
16 DR. MARKS: I guess, Ron, then you would
17 be to the point where you would have to have every
18 ingredient have an inhalation testing. Because
19 there's no way, what we're trying -- obviously,
20 what we're crafting with this, is if there's no
21 alerts from the chemical structure, and no
22 metabolites that you're concerned about, then
342
1 presumably we're not going to be worrying if it's
2 non-irritable.
3 So I would probably handle it that way.
4 Ron Shank, I wonder whether I might put one more
5 caveat in here, after what we heard this morning
6 -- "Formulated and delivered in a way to be
7 non-irritating to the respiratory tract."
8 Because she emphasized, this morning,
9 that the delivery methodology was quite important
10 also, besides the formulation.
11 DR. SHANK: Excellent. Definitely add
12 that.
13 DR. MARKS: Any other comments?
14 DR. BERGFELD: I think we shouldn't
15 forget the particle size. But I love this.
16 DR. MARKS: Well, that would be --
17 obviously, in the boilerplate, we're going to have
18 robust discussion of all this background
19 information, I would think. And then we always
20 refer to -- we could do just the same as the hair-
21 dye epidemiology, as we use our boilerplate. And
22 then we have a link to what the full discussion
343
1 would be.
2 That's probably how I would suggest
3 handling it. I don't think we want to have a full
4 discussion on every ingredient that we just went
5 -- that we go through.
6 DR. ANDERSON: Well, I think part of my
7 wish-list -- although I don't know that it's
8 possible to provide it -- is that all uncertainty
9 about use of Chemical X in products be eliminated.
10 So if it's in the category of deodorant, that you
11 actually know whether it's a spray or not. Right
12 now, the VCRP doesn't give us those data.
13 And the Council survey often elicits
14 that information. And that's great. But I don't
15 think I can expect that we're going to know every
16 single time. Or if it's in a suntan preparation,
17 whether that's one of the new spray ones or not.
18 So I think there are always going to be
19 gaps. We can strive to gather as much information
20 as possible. We've seen hair color sprays a
21 couple of times in reports in this thing. And I'm
22 not sure we really know what to expect from hair
344
1 color sprays, compared to the two data sets that
2 Dr. Rothe showed us this morning. And I think I'd
3 like to.
4 But we don't right now have those data.
5 And as we move to the future, it would be nice to
6 have a better characterization of those particle
7 sizes, so that we would actually have a better
8 handle on thinking through what are we going to
9 rely on for that particular aerosol exposure.
10 DR. BERGFELD: Can that come in the
11 chemical composition description that we get in
12 table form? Particle size could be added to that?
13 DR. ANDERSON: Right now, I don't think
14 there is a source. And Linda and Carol can jump
15 in to help -- but I don't think there is a Dr.
16 Duke that you can go to to find out what the
17 particle sizes are for each and every spray
18 product that's on the market.
19 I think there's limited --
20 DR. BERGFELD: Well, that would include
21 talcs? A lot of products could emanate some kind
22 of particle.
345
1 There is a report in the medical
2 literature about women who have applied lotions to
3 their skin who, on autopsy, show lotion in their
4 lung.
5 So particle size could be a very
6 interesting notation on all ingredients.
7 DR. MARKS: Okay, any other -- I'm
8 sorry. Go ahead.
9 DR. ANDERSON: I think that -- well, I
10 have to leave that to Carol and Linda to think
11 about. I don't think we find any such data when
12 we're searching for information.
13 There are data available for categories
14 of things that we know are sprayed, like aerosols
15 that we saw the data presented today. Or pump
16 sprays. We have information there. But those are
17 generic, in a sense of this is a category. And
18 you start changing the nozzle, you change the
19 pressure of the aerosol, and as we heard this
20 morning, things can change.
21 So I think that would have to be in what
22 we would ask suppliers, or formulators, to
346
1 actually provide. I don't think you can expect it
2 to be anyplace.
3 DR. MARKS: And I guess, to me, what I
4 heard this morning, even particle size, it's just
5 a direction. So besides in the aerosol and the
6 pump has a significant impact of how much is
7 delivered, she stated in the powders it's the
8 solvent and the pressure in which the powder is
9 delivered that can also affect how much is
10 respirable.
11 So, I think the statement "formulated
12 and delivered" covers both the formulation, in
13 terms of, say, size, solvents, et cetera, and the
14 way it's delivered would cover the physical
15 aspects of the pump, the aerosol, or whatever the
16 pressured delivery device is.
17 DR. ANDERSON: Our discussion, when it
18 focuses on particle size, is talking droplet
19 technology. When we go to describe a particle of
20 a silylate, it ain't a sphere. And I'm not sure
21 that any of that information directly applies.
22 So we have separate problems ahead of us
347
1 as we try to talk about the places that particles
2 get that aren't droplets.
3 DR. BOYER: And on that note, I think we
4 need to be careful that when we're talking about
5 particle sizes that we're actually -- we mean
6 aerodynamic diameter.
7 DR. MARKS: Okay. Well, that -- Ivan's
8 is going to be a robust discussion of what this
9 boilerplate really means, and what the limitations
10 are, too.
11 Any other comments? Any ingredients or
12 agenda items that I overlooked? We danced around
13 a bit, based on availability of writers, et
14 cetera.
15 Okay, if not --
16 COURT REPORTER: Excuse me, sir. The
17 re-review was all off mike and laughing.
18 DR. MARKS: Oh, the re-review was fine.
19 No comments.
20 DR. BERGFELD: Well, you said addition
21 of the hair-dye --
22 DR. MARKS: Oh, I said, yeah, the
348
1 addition of the hair-dye epidemiology. Thank you,
2 Wilma.
3 Okay. Any other comments? We're
4 adjourned.
5 (Whereupon, at 4:40 p.m., the
6 PROCEEDINGS were adjourned.)
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349
1 CERTIFICATE OF NOTARY PUBLIC
2 DISTRICT OF COLUMBIA
3 I, Christine Allen, notary public in and
4 for the District of Columbia, do hereby certify
5 that the forgoing PROCEEDING was duly recorded and
6 thereafter reduced to print under my direction;
7 that the witnesses were sworn to tell the truth
8 under penalty of perjury; that said transcript is a
9 true record of the testimony given by witnesses;
10 that I am neither counsel for, related to, nor
11 employed by any of the parties to the action in
12 which this proceeding was called; and, furthermore,
13 that I am not a relative or employee of any
14 attorney or counsel employed by the parties hereto,
15 nor financially or otherwise interested in the
16 outcome of this action.
17
18
19 -----------------------------------
20 Notary Public, in and for the District of Columbia
21 My Commission Expires: January 14, 2013
22
