BLUE Synthetic Fluorphlogopite CIR EXPERT PANEL MEETING JUNE

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Synthetic Fluorphlogopite

CIR EXPERT PANEL MEETING JUNE 11-12, 2012

June 11, 2012

MEMORANDUM

To: CIR Expert Panel and Liaisons

From: Lillian C. Becker, M.S. Scientific Analyst and Writer

Subject: Draft Final Report for synthetic fluorphlogopite as used in cosmetics

In December, 2011, the Panel issued a tentative safety assessment for synthetic fluorphlogopite with a safe in the present practices of use and concentration conclusion. For scheduling reasons, we did not include this report in the March, 2012 agenda. Now it is time to wrap this up.

Wave 2 from last December’s meeting has been incorporated into the report as well as summaries of the data from the magnesium aluminum silicate report. Comments from industry have been addressed.

New data on mutagenicity, ocular and dermal irritation, and water solubility have been submitted and incorporated into the report. This data are consistent with the data already considered by the Panel.

The Panel should review the draft final report and make sure that the discussion reflects the Panel’s thinking. The Panel is to then issue a final report.

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History of Synthetic Fluorphlogopite

August, 2011 – SLR announced.

December, 2011 – Panel examined Draft Report, Wave 2 and the magnesium aluminum silicate report. Synthetic fluorphlogopite is safe in the present practices of use and concentration described in this safety assessment.

June, 2012 – Panel examines draft final report and issues a final report.

CIR Panel Book Page 2 Synthetic Fluorphlogopite Data Profile for June 2012. Writer ‐ Lillian Becker Repeated dose ADME Acute toxicity Irritation Sensitization toxicity Penetration Penetration Dermal Log K toxicity Genotoxicity Carcinogenicity Phototoxicity Use Oral Dermal Inhale Oral Dermal Inhale Irritation Ocular Animal Irr. Dermal Human Irr Dermal Animal Sensitization Human Sensitization Repro/devel

Synthetic X X X X X X X X X X fluorphlogopite Magnesium aluminum X X X X X X X X X silicate & related clays

Distributed for CIR Comment Panel Only Book -- Page Do Not 3 Cite or Quote Distributed for Comment Only -- Do Not Cite or Quote

Search Strategy for Synthentic Fluorphlogopite Date Terms Results Aug 25, Substance Identifier "disteardimonium hectorite " > 5 possibly 2011 substances (1) > get references (490) > refine "Book useful SciFinder Clinical Trial Commentary Conference Dissertation Editorial Journal Letter Preprint Report Review" (31) > Opened saved answer set "Fluorphlogopite" (1) > get references (279) > refine "Book Clinical Trial Conference Dissertation Journal Letter Preprint Report Review" (223) Sept 14, Fluorphlogopite Patents (2) 2 possibly 2011 Raw search of patents for possible references on toxicity. useful SciFinder Substance Identifier "12003-38-2 " > substances (1) > get references (71) Sept 14, Fluorphlogopite, 12003-38-2 Background 2011 information, product data

CIR Panel Book Page 4 Transcript

Distributed for Comment Only -- Do Not Cite or Quote Transcrips of Synthetic Fluorphlogopites

Dr. Belsito’s Team

DR. BELSITO: Right, and why that's not pertinent to the cosmetic product. Okay. Who comes up with these names? I'm usually very good at pronouncing difficult things, but synthetic fluorphlogopites. Is that close? Okay. MS. BECKER: And you have some more data. DR. LIEBLER: It's not flurophlogopity? DR. BELSITO: Okay. So it's the first time that we're seeing this and, you know, it's similar to all the other clays and big molecular silicate sheets that we've been looking at, except now we have some fluorine. I don't know what's in this data package, but I thought we could go with safe and with the boilerplate for inhalation. So, unpublished data, local lymph node assay. Was it a sensitizer or was the SI 3? No, okay. MS. BECKER: No, it's not. DR. BELSITO: I wouldn't expect it to be. Four-hour acute inhalation toxicity in rats, and a bacterial mutagenesis that I would predict would be negative. MS. BECKER: Yes. DR. BERGFELD: And the results of inhalation? MS. BECKER: Not toxic.

--MALIC ACID DISCUSSION--

DR. BELSITO: Okay. So, a little bit more data on fluorphlogopite. Safe as used is where I went. How about you guys? DR. LIEBLER: Safe as used. DR. SNYDER: Agree. DR. BELSITO: Any specific comments? Any data points we need to address, other than our respiratory boilerplate? I mean, these are just huge, old molecules that are going to be used to stick stuff to the skin. Okay. DR. ANDERSEN: Don, before we -- oh, go ahead, Dan. DR. LIEBLER: Oh, sorry. When I first looked at this I was wondering about fluoride release from this compound. And there was a sentence about it. However fluoride gets its -- top of page, report page 3, Panel Book page 8. However, fluorine ions probably should be fluoride ions, are reported to leach out of synthetic fluorphlogopite particles in bricks. But when I read further, the description of the purification process to minimize fluoride ions, stoichiometric equivalent of fluorine is decreased to less than, the melt temperature is decreased -- in other words, they actually do a subsequent clean up of this, and they also heated it up to 1,300 degrees, which is way beyond anything you would imagine in a product formulation. And then the residual fluoride in a couple of the product spec sheets was very low. So, I just wanted to go on record as I considered that. I don't know if Ron brings that up tomorrow, but I considered that, and that's something we have any concern about. DR. BELSITO: So that would be the one point you'd want to stress in the discussion? Really, I mean, that's the only flag. DR. LIEBLER: Yeah, since it was mentioned here. Yeah, and this is actually -- this distinguishes this compound from one of the things that distinguishes the next ingredient we'll talk about. This synthetic stuff has this fluoride in it instead of the hydroxyls substituents. DR. BELSITO: Mm-hmm. DR. LIEBLER: So I don't think it's a hazard issue. DR. BELSITO: Okay. DR. ANDERSEN: Dan, a question for you in terms of the picture that we're painting about the structure of these compounds. I was struck that for whatever reason, Bart was thinking differently when he drew the

CIR Panel Book Page 5 Distributed for Comment Only -- Do Not Cite or Quote pictures for the synthetic fluorphlogopite versus the ammonium hectorites when, in fact, they're both sheets of magnesium silicate sandwiching whatever it is they sandwich. And should the structure for the hectorites which seem to be more descriptive, would that be useful here as well? DR. LIEBLER: Yeah, I agree. I think that's a good idea. In the hectorites, you have sort of the big picture showing the sheets, and then a zoom in of the structure. Here you just got the zoom in of the molecular structure. It would be better to have the larger macromolecular structure present, as well. That was a nice representation he had in the other report, so that can be included here.

Dr. Marks’ Team

DR. MARKS: So we're now going to look at the synthetic fluorphlogopite ingredient. And this is the first time the panelists have seen this report. And in addition to that we actually have received a number of additional data, what we affectionately refer to as Wave 2 electrons, and even more some paper data. So is there -- are there needs? Any further needs for these ingredients from a safety point of view? And then I think one of the other questions would be as we reviewed the magnesium aluminum silicate, which is -- didn't -- was found to be -- concluded to be safe as long as it's not respirable in the past. So we came to that conclusion -- MS. EISENMANN: Actually that's not in the conclusion. DR. MARKS: Oh, isn't it? MS. EISENMANN: No. The conclusion is safe as used in cosmetic products as long as in the discussion you state the Panel recognized that most of the formulations are not respirable and of the preparations that are respirable the concentrations of the ingredient is very low. Even so, the Panel considered that any spray containing these solids should be formulated to minimize certain inhalation is what you say in the discussion. The conclusion just says safe as used. It does not say formulated to be not respirable. The discussion says to minimize the inhalation. So. DR. MARKS: Thank you, Carol. That's exactly right. Now that I look on page 96 of the conclusion in our Panel Book it's exactly what you say. So we concluded safe. I was going from the memo on the front here. Okay. So let's get back to proceeding with do we need any more data? Tom, Ron, and Ron? DR. SHANK: Does this ingredient remain as a solid formulation? I got that impression. DR. SLAGA: That's the same question I got, too. MS. EISENMANN: As far as I know -- DR. SHANK: I think it's always a solvent. Okay. Then it's unlikely to penetrate the skin. And now you have inhalation data here? DR. SLAGA: And genotoxicity and some sensitivity, right? A lymph node. DR. MARKS: Yes. And the local lymph node assay at percent didn't show evidence of sensitivity. In Wave 2, we have 55 percent of this ingredient with a number of animal studies showing that it's -- it's neither an irritant, sensitizer, phototoxic, although I had Lillian ask to clarify it. It talks about a 55 percent paste mixed with water, so I assume it was probably very minimally diluted out. MS. BECKER: That would be my impression. DR. MARKS: Yeah. MS. BECKER: Just enough to make it -- DR. MARKS: Placed on. MS. BECKER: Right. DR. MARKS: Okay. That's what I said. DR. SLAGA: And genotoxicity was and many tested strains of (inaudible) as well as E. coli, but they were (inaudible) basically. MS. BECKER: Dr. Marks, would you share the papers I just gave you with Professor Hill? DR. MARKS: Oh, yes. Here. Go ahead. I'm sorry. I didn't realize you hadn't given us all one. MS. BECKER: Yeah. That came in Friday after I went home. Yeah, I only -- it's 75 pages. DR. MARKS: Yeah, no, that's fine. So actually going back, Lillian, based on what Carol said and I didn't pick it up, although I have a checkmark next to it, on page 7. That would be important in the introduction to change that second paragraph. To leave that part about formulated to be nonrespiratory.

CIR Panel Book Page 6 Distributed for Comment Only -- Do Not Cite or Quote DR. SHANK: We have inhalation data here. DR. MARKS: Well, that's -- DR. SHANK: And respirable particle sites. DR. MARKS: Yeah, no, I was referring back to the previous report. DR. SLAGA: That was not in the previous conclusion. DR. MARKS: I have use tables, skin up to 67 percent; eye 48 percent. There is the potential of inhalation. It's used in products where it could be. So any needs or can we proceed to a conclusion? DR. SLAGA: I think we can proceed with a conclusion. As long as we're comparing some of it back to the, what's it called? DR. SHANK: Magnesium? DR. SLAGA: Yeah, magnesium aluminum silicate. Now that we have several additional data related directly to this name that we need to change. DR. MARKS: Okay. So we would move forward with issuing a tentative. Is that right? Is that the next step, Lillian? Tentative report? MS. BECKER: Yes. DR. MARKS: With a conclusion that it's safe. Any caveats in that conclusion? Hearing none. MS. BECKER: How about discussion? DR. HILL: So how are we dealing with the face powder again? DR. SHANK: We have inhalation toxicology data in the new Wave 3. DR. HILL: Okay. DR. SHANK: And the particle size was point two or three or something like that, micrometers. DR. HILL: Actually, given the chemistry I was looking for things like mouthwashes but I didn't see anything along those lines. Very small incidental oral exposure for fluoride or lasic given there's a stability issue. MS. BECKER: It's not used where fluoride would be the formulated (inaudible)? DR. HILL: Well, and I think the amounts would never reach anything where toxicology would be a concern. I just -- I was looking for anything. I didn't see anything. DR. MARKS: Okay. So is there anything we need to -- I guess, Lillian, you'll just proceed with the usual discussion. Nothing to specifically highlight in this other than Ron Shank, do you think we need to talk about the inhalation a little bit since the previous report that we'll refer back to with the aluminum -- the magnesium aluminum silicate is in that previous report and has -- DR. SHANK: To say in the discussion that we have inhalation data for (inaudible). DR. MARKS: Okay. MS. BECKER: Inhalation boilerplate. DR. SLAGA: Also in the discussion, since we only had bacterial mutagenicity, but we had mammalian related to the magnesium aluminum silicate. You'd have both so I think we're fine there, too. DR. MARKS: So we have human carcinogenicity. Tom, is that human? DR. SLAGA: No. DR. MARKS: No? DR. SLAGA: When are we -- mammalian mutagenicity? DR. SHANK: Mammalian. DR. MARKS: Mammalian. Yes. I thought I heard human. Mammalian. DR. SLAGA: You only do that in prisons, right? DR. MARKS: Yeah, I was going to say. Mammalian. In this one the only thing we had you said was genotox. DR. SLAGA: Yeah. In the new data. DR. SHANK: Well, bacterial. We had mammalian in the magnesium (inaudible). DR. MARKS: Okay. So Lillian, you've caught that how we -- MS. BECKER: Mm-hmm. DR. MARKS: -- used the previous data as a read- across so to speak? Okay. So we have the genotox is taken care of and then we have the inhalations taken care of. We'll talk about that in the discussion. DR. SLAGA: And you need penetration because it's a solid salt.

CIR Panel Book Page 7 Distributed for Comment Only -- Do Not Cite or Quote DR. MARKS: Penetration. Solid. DR. HILL: I really thought there was very little of any data that was need other than to make sure it didn't cause problems if you put it in a powder and inhaled it. DR. MARKS: And three is inhalation. DR. SLAGA: But it's nice to have extra. DR. HILL: It is, but it just -- DR. MARKS: And this'll be the discussion. Okay. Anything else? I'll move that a tentative report be issued on the synthetic fluorphlogopites and that it's safe as used. In the discussion we'll talk about the lack of penetration because it's solid. We have genotox covered with this ingredient bacterial but we also have the previous mammalian and then we have inhalation data to support its safety, too. Anything else? If not, let's move on to the ammonium hectorites.

DAY TWO

DR. MARKS: The synthetic fluorphlogopites. DR. BERGFELD: Phligo -- phlogopites. DR. MARKS: So, this is the first time that we had seen this report, and after reviewing the data in this report, Wave 2, 3, 4, and 5, waves, we decided that we could issue a tentative report on the synthetic fluorphlogopites, that they were safe as used. DR. BELSITO: Second. DR. BERGFELD: Any other discussion? DR. MARKS: Yes. We thought that in the discussion, things -- issues that should be discussed would be, one, that penetration is unlikely. These are solids, that we do have geno-tox data in the bacteria. Is that right, Tom? Did I capture your end? And that we would obviously put the inhalation boiler plate, and that we also had, even though it's the magnesium aluminum silicate from the previous report, we have mammalian geno-tox, which is safe. So, combination of the mammalian and the present bacterial geno-tox, we thought this would be safe from that point of view. DR. BERGFELD: Paul?

DR. SNYDER: It was the second wave. We did receive an inhalation study, which the LD50 was greater than the highs tested. DR. MARKS: So then, let's go back to the boiler plate. Was there -- do we even need to include it now? DR. SNYDER: I don't believe so. DR. MARKS: Thank you. DR. BERGFELD: Don? All right. It's been moved and seconded and voted upon. So, we'll move on to the next item, which is the Dr. Belsito, looking at -- DR. MARKS: We've got to vote. DR. BERGFELD: I thought we did. DR. BELSITO: No. DR. BERGFELD: No, we didn't? I'm sorry. All those in favor? Confusing. All right, good. All right.

CIR Panel Book Page 8 Report

Distributed for Comment Only -- Do Not Cite or Quote Draft Final Report on the Safety Assessment of

Synthetic Fluorphlogopite As Used in Cosmetics

June 11, 2012

The 2012 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is F. Alan Andersen, Ph.D. This report was prepared by Lillian C. Becker, Scientific Analyst/Writer.

CIR Panel Book Page 9 Distributed for Comment Only -- Do Not Cite or Quote TABLE OF CONTENTS TABLE OF CONTENTS ...... ii ABSTRACT ...... 1 INTRODUCTION ...... 1 CHEMISTRY ...... 1 Definition and Structure ...... 1 Physical and Chemical Properties ...... 1 Method of Manufacture ...... 2 USE ...... 2 Cosmetic ...... 2 Non-Cosmetic ...... 2 TOXICOKINETICS ...... 2 Absorption, Distribution, Metabolism, and Excretion ...... 2 Cytotoxicity ...... 2 Miscellaneous Studies ...... 3 TOXICOLOGICAL STUDIES ...... 3 Acute Toxicity ...... 3 Dermal ...... 3 Oral-Non-Human ...... 3 Inhalation ...... 3 Repeated Dose Toxicity ...... 3 Oral – Non-Human ...... 3 Inhalation – Human ...... 3 REPRODUCTIVE AND DEVELOPMENTAL TOXICITY ...... 4 GENOTOXICITY ...... 4 CARCINOGENICITY ...... 4 Inhalation ...... 4 Other Exposures ...... 4 IRRITATION AND SENSITIZATION ...... 5 Irritation ...... 5 Dermal Non-Human ...... 5 Dermal - Human ...... 5 Ocular Non-Human ...... 5 Sensitization ...... 6 Non-Human ...... 6 Human ...... 6 Photosensitization/Phototoxicity ...... 6 SUMMARY ...... 6 DISCUSSION ...... 7 CONCLUSION ...... 7 TABLES AND FIGURES ...... 8 REFERENCES ...... 10

CIR Panel Book Page 10 Distributed for Comment Only -- Do Not Cite or Quote ABSTRACT The Cosmetic Ingredient Review Expert Panel (the Panel) reviewed the safety of synthetic fluorphlogopite as used in cosmetics. Synthetic fluorphlogopite functions as a bulking agent and a viscosity increasing agent. The Panel reviewed available animal and human data related to this ingredient along with a previous safety assessment of other magnesium silicates. The Panel concluded that synthetic fluorphlogopite was safe as cosmetic ingredients in the practices of use and concentration as given in this safety assessment.

INTRODUCTION This is a safety assessment of the cosmetic ingredient synthetic fluorphlogopite (sometimes spelled fluorophlogopite). Synthetic fluorphlogopite is a synthetic mimic of a natural mineral that functions in cosmetics as a bulking agent and a viscosity increasing agent – aqueous. The silicate clay, magnesium aluminum silicate, as well as other clays were previously reviewed by thePanel as part of a group of aluminum silicate clays and found to be safe as used in cosmetic products.1 Summaries of the relevant data from that report are included in the appropriate sections below. The similar chemical structures and physicochemical properties as well as functions and concentrations in cosmetics of magnesium aluminum silicate and related clays enable referring to these ingredients and reading across the available toxicological data to support the safety assessment synthetic fluorphlogopite.

CHEMISTRY Definition and Structure Synthetic fluorphlogopite (CAS No. 12003-38-2) is a synthetic mimic of a mica-type, fluorine substituted mineral composed of magnesium aluminum silicate sheets, weakly bound together with potassium (Figure 1).2 Phlogopite, the non-flourine substituted mineral, like other micas, has a layered structure of magnesium aluminum silicate sheets weakly bonded together by layers of potassium ions.3 These potassium ion layers produce the perfect cleavage. Single large plates or “books” of phlogopite can grow to considerable size. Fluorphlogopite differs in that two of the hydroxyl groups, per aluminum atom, are replaced with fluorine atoms. Fluorine is present in the phyllosilicate mineral group in general and in the micas particularly as a substitute for OH. The presence of fluorine enhances the thermal stability of the trioctahedral mica structure. In the previous safety assessment of silicate clays noted above, hectorite (magnesium/lithium silicate) clay was given as containing fluorine,1 which would have suggested a structural similarity to synthetic fluorphlogopite, but current information suggest that fluorine is not a significant component of hectorite.

Physical and Chemical Properties Physical and chemical properties of synthetic fluorphlogopite are presented in Table 1. In large pieces, fluorphlogopite is pale yellow and is transparent and non-fluorescent with vitreous to resinous luster; it shows yellowish-white color in thin section.4 Mohs’ hardness is 2–3. A product description sheet describes synthetic fluorphlogopite as a white to grey free-flowing powder with an average particle size of 10 – 15 μm and a pH range of 5 – 8.5 The particles have a low degree of surface reactivity (in contrast to natural phlogopites). Another product data sheet reports that synthetic fluorphlogopite has a pH value of 7.0 - 11.0 (in a 10% Aqueous slurry), a bulk density of 0.240 - 0.300 g/cm3, and a particle size distribution of 9.0 - 45 μm.6 Another source reports particles sizes ranging from 20 – 150 μm.7 Possible impurities are listed in Table 2. Acid soluble substances are potentially leachable from synthetic fluorphlogopite, including fluorine ions.8 Synthetic fluorphlogopite is not soluble in water.9 In a test of the solubility of the ions in distilled water, magnesium, aluminum, and potassium were present at < 5 x 10-6, < 5 x 10-5, and < 5 x 10-4 g/L, respectively, after stirring for up to 72 h at 30°C. The amount of potassium in the blank was similar to the amount in the test substance, suggesting that the detected potassium was in the water and not from the synthetic fluorphlogopite. Synthetic fluorphlogopite, as opposed to natural fluorphlogopite, is virtually iron free.4 However, synthetic fluorphlogopite may be intentionally manufactured with iron to more efficiently absorb UV-rays.8 Fluorphlogopite has some unique properties due to the replacement of most of the hydroxyl groups on aluminum (that are normally present in non-fluoro phlogopite) with fluoride. However, the aluminum-fluoride bond is only moderately thermodynamically stable. Over time and exposure, atmospheric oxygen and water can replace those fluorides ions, regenerating the more stable hydroxyl groups. Synthetic fluorphlogopite is stable for 5 years in a sealed container at < 25°C and for at least 1 year once opened.7 However, fluorine ions (F-) are reported to leach out of synthetic fluorphlogopite particles and bricks.10,11 The Japanese Standard of Quasi-Drugs require that synthetic fluorplogopite have a pH between 5.5 and 7.5, a maximum of 2% acid soluble substance, ≤ 20 ppm lead, ≤ 5 ppm arsenic, and ≤20 ppm dissolution amount of fluoride.12 Synthetic fluorphlogopite meeting these standards are reported to be > 99% pure. 1

CIR Panel Book Page 11 Distributed for Comment Only -- Do Not Cite or Quote Method of Manufacture A reported manufacturing method of synthetic fluorphlogopite designed for industrial-scale batches (up to several tons) involved melting oxide (metal; i.e., aluminum and manganese)-fluoride mixtures at a given "soak" temperature (wherein the contents are liquid; up to 1450°C), and then cooling at a continuous rate of a few degrees per hour between 1400 and 1300°C.13 This technique produced large fluorphlogopite monocrystals (several centimeters). Another method synthesized fluorphlogopite single crystals, several millimeters in size, suited to laboratory uses. 14 A mixture of SiO2, γ-Al2O2, MgO, and K2SiF6 was first melted at 1450°C for 3 h then cooled to 1385°C at a rate of 100°C/h and then quenched into cold water. The resulting charge was loaded back into the furnace, heated from ~1000°C to 1385°C at a rate of 500°C/h and finally cooled at a rate of 1°C/h down to 1300°C. This procedure led to the formation of large and detachable monocrystals of synthetic fluorphlogopite up to 1 cm in diameter. The extent of fluorine substitution for OH groups depends on several factors.4,15 The most important are (1) hydrofluoric acid activity in the fluid during the crystallization and post-crystallization phase; (2) temperature; and (3) cation population of the octahedral sheet. Crystal structure may be altered by adjusting the pressure during cooling.3 In order to minimize the number of fluoride ions available for leaching, the stoichiometric equivalent of fluorine is 10 decreased to less than one (i.e., less K2SiF6 is added) and the melt temperature is decreased (between 900 and 1000ºC). To remove any free fluoride, the resulting ingot is pulverized and the resulting powder is then heat treated at 600 to 1350ºC and then washed with an aqueous solution containing one or more acids or chelating agents.

USE Cosmetic Data on ingredients usage are provided to the Food and Drug Administration (FDA) Voluntary Cosmetic Registration Program (VCRP). The VCRP reports that synthetic fluorphlogopite is used in 560 leave-on products and 5 rinse-off products (Table 3).16,17 The Personal Care Products Council reports maximum use concentrations of 0.00002% to 67%. It is used up to 67% in leave on products (face powders) and 30% in rinse off products (bath soaps and detergents). It is used up to 20% in lipsticks and 15% in eye makeup products. Synthetic fluorphlogopite is used in perfumes with the maximum reported concentration of use of 0.05% and indoor tanning preparations at 2% as possible propellant and pump spray products, and could possibly be inhaled. In practice, 95% - 99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters >10 µm, with propellant sprays yielding a greater fraction of droplets/particles below 10 µm compared with pump sprays.18,19 Therefore, most droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal region and would not be respirable (i.e., they would not enter the lungs) to any appreciable amount.20,21 However, the potential for inhalation toxicity is not limited to respirable droplets/particles deposited in the lungs. Inhaled droplets/particles deposited in the nasopharyngeal and thoracic regions of the respiratory tract may cause toxic effects depending on their chemical and other properties.

Non-Cosmetic Flourphlogopite has been approved as a colorant in all types of food contact substances at levels not to exceed 5.0% by weight of the finished polymer in contact with all types of food.17 Natural phlogopites are used for their heat and electrical insulating properties.4

TOXICOKINETICS Absorption, Distribution, Metabolism, and Excretion SYNTHETIC FLUORPHLOGOPITE There were no absorption, distribution, metabolism, or excretion studies of synthetic fluorphlogopite discovered. MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS There was no absorption of aluminum and elevated levels of silicon were observed in assayed plasma samples of dogs administered magnesium trisilicate and zeolite orally.22,23 The urinary excretion of silica was 5.2% in male subjects given 20 g of magnesium trisilicate.23 Heat treated montmorillonite (5, 15, and 45 mg) administered to rats by means of intratracheal instillation was restricted to alveoli within and adjacent to alveolar ducts.24

Cytotoxicity MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS A sample of aluminum silicate was toxic to pulmonary alveolar macrophages (PAM) measured by lactate dehydrogenase activity (LDH), β-galactosidase (β-GAL) activity, lactic acid production, cellular ATP activity, and the cellular DNA contents.25 LDH activity and β-GAL release were increased at 33.3 μg/ml and 166.7 μg/ml aluminum silicate. Aluminum silicate had relatively no effect on the hemolysis of rat red blood cells (RBC) up to 1000 μg/ml. Attapulgite (0.05 – 0.5 mg/ml) samples and calcium silicate (5 and 10 mg/ml) caused increased hemolysis of human

CIR Panel Book Page 12 Distributed for Comment Only -- Do Not Cite or Quote RBCs; a greater fibrous character of calcium silicate samples caused increased LDH and β-GAL release.26,27 Many clays (attapulgite, bentonite, hectorite, kaolin, montmorillonite, pyrophyllite, and zeolite) demonstrated cytotoxicity to several macrophage type cell lines and have hemolyticactivity towards several species' RBCs (as low as 0.2 μg/ml attapulgite to bovine RBCs).1,25,26,28-59 Particle size, fibrogenicity, concentration, and mineral composition had the greatest effect on toxicity. Larger particle size and longer and wider fibers cause more adverse effects. In most of the studies, a dose dependent effect on cytotoxicity or lysis was observed. Most mineral samples were not 100% pure and many samples already contained toxic dusts or minerals like quartz or cristobalite.

Miscellaneous Studies MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS In mice, intratracheal injections of bentonite and group C Streptococcus species caused an 85% mortality compared to a 5% control mortality; another intratracheal injection caused loose reticulin fibrils with no collagen.40 Kaolin injected with the Streptococcus species caused statistically significant but modest mortality in mice.40

TOXICOLOGICAL STUDIES Acute Toxicity Dermal MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS 60 The acute dermal LD50 was >3.5 g/kg for rabbits exposed to VEEGUM (magnesium aluminum silicate).

Oral-Non-Human SYNTHETIC FLUORPHLOGOPITE The oral LD50 for female ICR (Crj: CD-1) mice and SD (Crj: CD) rats was > 9000 mg//kg synthetic fluorphlogopite.61 There were no adverse clinical signs or physical findings at necropsy. MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS Rats consuming bentonite (10%) in the diets overcame T-2 toxicosis completely.62 The following are a list of acute oral LD50 determinations: calcium silicate, 3400 mg/kg in rats; magnesium aluminum silicate, 50000 mg/kg in mice; zirconium silicate, > 200 mg/kg in mice; hectorite, >5 g/kg in rats; kaolin, 149 g/kg in rats (death due to bowel obstruction).63-67

Inhalation SYNTHETIC FLUORPHLOGOPITE In a 4-h acute inhalation study, synthetic fluorphlogopite (4.1 mg/L; median aerodynamic diameter of 2.44 μm with a geometric standard deviation of 2.18 and 2.20 μm) was administered to HanRcc:WIST(SPF) albino rats (n = 5/sex) in a nose-only system.68 There were no clinical signs during exposure and during the 15-day observation period. There were no findings at necropsy. The LC50 was determined to be > 5.1 mg/L.

Repeated Dose Toxicity Oral – Non-Human MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS In short-term oral toxicity studies, no adverse effects were seen in mice or rabbits dosed up to 5 g/kg magnesium aluminum silicate.69 Various zeolites were added to the diets of pigs for 6 weeks.70 No adverse effects were noted by the supplementation. A feeding test with dogs and rats ingesting large amounts of VEEGUM (magnesium aluminum silicate; 10% of ration) for 90 days, showed that there were no adverse effects and VEEGUM was considered nontoxic.71 Guinea pigs had renal lesions after 4 months of drinking magnesium trisilicate (250 mg/L) in their tap water.72 Rats fed 10% magnesium aluminum silicate had slightly elevated silicon levels of the spleen and dogs and rats fed 10% VEEGUM had no adverse effects in 90-day feeding studies.71 No lesions were found in rats dosed up to 1000 mg/kg for 104 weeks.73

OCCUPATIONAL EXPOSURE MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS Occupational exposure to mineral dusts has been studied extensively. Fibrosis and pneumoconiosis has been documented in workers involved in the mining and processing of aluminum silicate, calcium silicate, zirconium silicate, Fuller's earth, kaolin, montmorillonite, pyrophyllite, and zeolite.

CIR Panel Book Page 13 Distributed for Comment Only -- Do Not Cite or Quote REPRODUCTIVE AND DEVELOPMENTAL TOXICITY SYNTHETIC FLUORPHLOGOPITE There were no reproductive or developmental toxicity studies of synthetic fluorphlogopite discovered. MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS Calcium silicate (250 to 1600 mg/kg on days 6 – 18 of gestation) had no discernible effect on nidation or on maternal or fetal survival in rabbits.74 Magnesium aluminum silicate (6000 mg/kg on days 7 – 12 of gestation) had neither a teratogenic nor adverse effects on the mouse fetus.75 Female rats receiving a 20% kaolin diet for up to 117 days prior to insemination through nidation exhibited maternal anemia but no significant reduction in birth weight of the pups was recorded.76 Type A Zeolite produced no adverse effects on the dam, embryo, or fetus in either rats (administered days 6 – 15) or rabbits (administered days 6 – 18) at any dose level (74 or 1600 mg/kg).77 Clinoptilolite administered in feed for 13 weeks had no effect on female rat reproductive performance.78

GENOTOXICITY SYNTHETIC FLUORPHLOGOPITE In a chromosomal aberration test of synthetic fluorphlogopite (0.02 – 0.16 mg/mL), there were no chromosomal structural abnormalities observed to Chinese hamster lung-derived fibroblast cells at 24 and 48 h.61 Synthetic fluophlogopite (0.500 – 5000 μg ) was not mutagenic to Salmonell typhimurium (strains TA98, TA100, TA102, TA1535, TA1537) and Escherichia coli (strain WP2 uvrA) with and without metabolic activation.79 In a micronucleous test using V79 Chinese hamster cells, synthetic fluorphlogopite (5 – 100 μL) was not mutagenic with or without metabolic activation.80 Controls had the expected results. In an in vitro mammalian cell gene mutation test, synthetic fluorphlogopite (15.8 – 500 μg/mL)) was not mutagenic with or without metabolic activation.81 Controls had the expected results. MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS No increase mutation frequencies were seen in the Salmonella TA-1530 or G-46 assay and no significant increase in recombinant activity in the Saccharomyces D3 assay treated with calcium silicate.65 A subacute dose of 150 mg/kg of calcium silicate produced 3% breaks in bone marrow cells arrested in c-metaphase. In a metaphase spread of bone marrow cells, calcium silicate produced no significant increase in the number of aberrations compared to controls. In a dominant lethal assay using rats, calcium silicate did not induce any dominant lethal mutations. In the S. typhimurium LT2 spot test (TA98, TA100, TA1535, TA1537, and TA1538) with or without metabolic activation, magnesium aluminum silicate and hectorite were found nonmutagenic.82,83 In primary hepatocyte cultures, the addition of attapulgite at 10 μg/cm2 had no significant unscheduled DNA 2 synthesis (UDS) response or modulated response to AAF (a positive control); attapulgite at 10 μg/cm caused significant increases in UDS in rat pleural mesothelial cells.30,84 Zeolite particles (10 μm) produced an increase in the percentage of aberrant metaphases, mostly chromatid breaks.85

CARCINOGENICITY SYNTHETIC FLUORPHLOGOPITE There were no carcinogenicity studies of synthetic fluorphlogopite discovered.

Inhalation MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS Small primary neoplastic lesions were found in two of 48 rats exposed to a calcium silicate dust at a concentration of 10 mg/m3 for 7 h/day, 5 days/week, for a total of 224 days over an elapsed period of 12 calendar months in an inhalation chamber.86 Lebrija and Leichester Attapulgite (10 mg/m3; 6 h/d for 5 d/wk; 3 – 12 months) samples caused one peritoneal mesothelioma, one adenocarcinoma, and three bronchoalveolar hyperplasia and two mesotheliomas, one peritoneal mesothelioma, one malignant alveolar tumor and eight bronchoalveolar hyperplasia (inhalation route) in rats (n = 20/sex).87 Both samples contained long fibers. Moderate to extensive respiratory disease was noted in rats chronically exposed to Synthetic Zeolite A (20 mg/m3; 5 h/d, 3/week) by inhalation methods.73

Other Exposures MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS Intratracheal injections of aluminum silicate in rats caused lesions in a dose-dependent manner and the intrapleural injections of four different aluminum silicate samples all resulted in lesions.88 One aluminosilicate injection caused three malignant mesotheliomas, one pleural and two peritoneal. No mesotheliomas developed in rats injected intraperitoneally with 25 mg of calcium silicate dust.86 4

CIR Panel Book Page 14 Distributed for Comment Only -- Do Not Cite or Quote Subcutaneous injection into the oral mucosa and into the back, periosteal injections into periosteal tissue, and intramuscular injections into the thigh of rats and guinea pigs with zirconium silicate resulted in mild inflammatory reactions.67 Attapulgite was injected intraperitoneally, intrapleurally, and intratracheally in various studies in rats.42,87,89-93 Most studies reported that lesions and mesotheliomas were dependent on fiber length. Samples with a longer length caused greater numbers of mesotheliomas. In a series of intrapleural injections of rats, Kaolin was used as a negative control.87 Minor inflammatory reactions, but no lesions, were found in rats given intratracheal injections of zeolite (clinoptilolite), and intraperitoneal injections of mordenite, Synthetic Zeolite 4A, and Synthetic Zeolite MS5A (one mesothelioma was seen in rats given MS4A).73,94-99 An intrapleural injection of Nonfibrous Japanese Zeolite caused two mesotheliomas in rats.99 Subplantar injections of bentonite caused granulomas in rats.100

IRRITATION AND SENSITIZATION Irritation Dermal Non-Human SYNTHETIC FLUORPHLOGOPITE Synthetic fluorphlogopite (55% in distilled water; 0.3 g) was not irritating to the scratched skin of male Japanese White rabbits (n = 6) after 24 h under occlusion.61 Synthetic fluorphlogopite (55% in distilled water; 0.3 g; 5 d/week) was not dermally irritating to Hartley albino guinea pigs (n = 10) in a cumulative irritation test after 4 weeks.61 There were no effects on body weights and necropsy did not reveal any changes in the organs. Synthetic fluorphlogopite (0.5 g with a few drops of aqua da iniectabilia; ~ 6 cm2 semi-occlusion patch) was not adermal irritant to female Crl:KBL(NZW) rabbits after 4 h.101 MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS Magnesium aluminum silicate (4%) was a weak primary skin irritant in rabbits and had no cumulative skin irritation in guinea pigs. No gross effects were reported in any of these studies.60

Dermal - Human SYNTHETIC FLUORPHLOGOPITE In a dermal patch test (n = 42), a past of synthetic fluorphlogopite (0.05 g in distilled water; 55%; 1.6 cm diameter patch) was not irritating after 48 h under oclusion.61 A powdery foundation containing synthetic fluorphlogopite (38.5%; diluted in distilled water to 21.2%) was tested in a 48 hour patch test. The test substance was not irritating.61 In an in vitro Human Skin Model Test, tissue treated with synthetic fluorphlogopite (1 mg) had a viability > 50%, therefore, was considered to lack irritant potential.102 Controls had the expected results. MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS Applications of 2 g of VEEGUM made to the skin of two humans daily for 1 week caused no effects.66

Ocular Non-Human SYNTHETIC FLUORPHLOGOPITE In an chorioallantoic membrane (HET-CAM) eye irritation potential test, synthetic fluorphlogopite (100%) demonstrated no irritation potential.103 In a Bovine Corneal Opacity and Permeability Assay (BCOP), synthetic fluorphlogopite (20% in 0.9% sodium chloride solution) did not increase opacity or permeability of the treated corneas.104 The author concluded that synthetic fluorphlogopinte did not show ocular irritant or corrosive potential. Controls had the expected results. In a primary eye irritation test using albino Crl:KBL(NZW) rabbits (n = 3), synthetic fluorphlogopite (0.1 g) was not an ocular irritant.105 All animals had discharge and redness of conjunctiva 1 h after administration. One rabbit had chemosis at 1 h after administration. MAGNESIUM ALUMINUM SILICATE AND RELATED CLAYS A 4% solution of magnesium aluminum silicate and a 4% solution of sodium magnesium silicate caused minimal eye irritation in a Draize eye irritation test.71,71 Bentonite (1 – 5 mg/ml) caused severe iritis after injection into the anterior chamber of the eyes of rabbits.106 When injected intralamellarly (0. – 0.25 mg/ml), widespread corneal infiltrates and retrocorneal membranes were recorded. In a primary eye irritation study in rabbits, hectorite (100 mg) was moderately irritating without washing and practically non-irritating to the eye with a washout.64 Rats tolerated a single 10 g dose of Zeolite A without any adverse reaction in the eye.73

CIR Panel Book Page 15 Distributed for Comment Only -- Do Not Cite or Quote Sensitization Non-Human SYNTHETIC FLUORPHLOGOPITE In a modified guinea pig maximization test (n = 10) with adjuvant exposure, synthetic fluorphlogopite (55% in distilled water; 0.1 g) was not sensitizing.61 In a local lymph node assay using mice (n = 5), synthetic fluorphogopite (5%, 10%, 25% w/v in acetone:olive oil 4:1) was not a dermal sensitizer.107

Human SYNTHETIC FLUORPHLOGOPITE A human repeated insult patch test (HRIPT; n = 107) was conducted of a pressed powder that contained synthetic fluorphlogopite (13.824%) under semi-occlusion.108 The authors concluded that this product did not elicit dermal irritation or sensitization.

Photosensitization/Phototoxicity SYNTHETIC FLUORPHLOGOPITE Repeated administrations (days 1 - 4) of synthetic fluorphlogopite (55% in distilled water; 0.1g) in a adjuvant-strip assay was not dermally photosensitizing to female Hartley albino guinea pigs (n = 10) when exposed to UVA light (320 - 400 nm) at 10.2 joules/cm2 and then challenged on day 21 (20 mg).61 Synthetic flurophlogopite (55% in distilled water) was not phototoxic to male Hartley albino guinea pigs (n = 5) when administered to shaved skin prior to a single exposure to UVA light (320 – 400 nm) at 14.0 joules/cm2 for 30 min.61 No skin reaction was observed at 24, 48 and 72 h after exposure.

SUMMARY Synthetic fluorphlogopite is a synthetic mimic of a natural mica-type mineral that functions in cosmetics as a bulking agent and a viscosity increasing agent – aqueous. Synthetic fluorphlogopite is composed of magnesium aluminum silicate sheets, weakly bound together with potassium. Magnesium aluminum silicate clays were previously reviewed by CIR with the conclusion that they are safe as used in cosmetic products. The VCRP reports that synthetic fluorphlogopite is used in 560 leave-on products and 5 rinse-off products, at concentrations up to 67% in leave-on products (face powders) and up to 30% in rinse-off products (bath soaps and detergents). There was no absorption of aluminum and elevated levels of silicon were observed in assayed plasma samples of dogs administered magnesium trisilicate and zeolite orally. Silica was excreted in the urine in human males orally administered magnesium trisilicate. The acute dermal LD50 for magnesium aluminum silicate was >3.5 g/kg for rabbits. The oral LD50 for mice and rats was > 9000 mg//kg synthetic fluorphlogopite. The acute oral LD50 for calcium silicate was 3400 mg/kg in rats; 50000 mg/kg magnesium aluminum silicate in mice; > 200 g/kg zirconium silicate in mice; >5 g/kg hectorite in rats; 149 g/kg kaolin in rats. The inhalation LC50 of synthetic fluorphlogopite for rats was > 5.1 mg/L. In short-term oral toxicity studies, no adverse effects were seen in mice or rabbits dosed up to 5 g/kg magnesium aluminum silicate. Long-term feeding and drinking water studies revealed no adverse effects for magnesium aluminum silicate at 10% for dogs and rats and for magnesium trisilicate at 250 mg/L for guinea pigs. Occupational exposure to aluminum silicate, calcium silicate, zirconium silicate, Fuller's earth, kaolin, montmorillonite, pyrophyllite, and zeolite has lead to fibrosis and pneumoconiosis. There were no reproductive effects for calcium silicate at 1600 mg/kg for rabbits, type Z Zeolite at 74 or 1600 mg/kg for rats or rabbits. Magnesium aluminum silicate at 6000 mg/kg caused neither teratogenic nor adverse effects on the mouse fetus. Clinoptilolite had no effect on female rat reproductive performance. Synthetic fluorphlogopite was not genotoxic in a chromosomal aberration test up to 0.16 mg/mL using Chinese hamster lung-derived fibroblast cells nor was mutagenic to Salmonella and E. coli up to 5000 μg. Magnesium aluminum silicate and related clays were not mutgenic to in multiple assays. Calcium silicate dust at 10 mg/m3, attapulgite at 10 mg/m3, and synthetic Zeolite A at 20 mg/m3 showed signs of carcinogenicty in multiple assays with chronic exposures. Synthetic fluorphlogopite was not dermally irritating to rabbits and guinea pigs at 55%. Magnesium aluminum silicate was a week primary skin irritant in rabbits at 4%. Synthetic fluorphlogopite was not dermally irritating to humans at 0.05 g in two 48-h assays; neither was VEEGUM at 2 g daily for 1 week. Magnesium aluminum silicate, hectorite, and Zeolite A were not ocular irritants to rabbits or rats. Synthetic fluophlogopite was sensitizing to guinea pigs or mice. Synthetic fluorphlogopite was not irritating or sensitizing in a product at 13.824%. Synthetic fluorphlogopite was not photosensitizing or phototoxic to guinea pigs at 55%. 6

CIR Panel Book Page 16 Distributed for Comment Only -- Do Not Cite or Quote DISCUSSION Although there are data gaps, the similar chemical structures, physicochemical properties, and functions of the magnesium aluminum silicate clay ingredients allow for the interpolation of the available toxicological data to support the safety of synthetic fluorphlogopite. Synthetic fluophlogopite contains fluoride ions. The Panel concluded that these ions are secure in the compounds and unlikely to leach out of formulation due to the high heat in the manufacturing process. Because the particles are large and insoluble in water, synthetic fluorphlogopite is unlikely to penetrate the skin. The Panel noted that there was bacterial and mammal mutagenicity data for synthetic fluorphlogopite. The mammalian data for magnesium aluminum silicate also supports assurance against mutagenicity. Because this ingredient can be used in products that may be aerosolized, including perfumes and indoor tanning preparations (possible propellant and pump spray products), the Panel discussed the issue of incidental inhalation exposure. The acute inhalation data on the synthetic fluorphlogopite showed no adverse effects to rats. However, the chronic human industrial exposure data on the magnesium aluminum silicate related clays resulted in fibrosis and pneumoconiosis. Although particles appear to have reached the lungs in these studies, the sizes of the particles used were either clearly within the respirable range (ie, ≤10 µm) or were not reported. The Panel determined that the sizes of a substantial majority of the particles of synthetic fluorphlogopite, as manufactured, would be larger than the respirable range and/or aggregate and agglomerate to form much larger particles in formulation. Thus, the adverse effects reported using high doses of respirable particles in the inhalation studies did indicate risks posed by use in cosmetics. The Panel considered other data available to characterize the potential for synthetic fluorphlogopite to cause systemic toxicity, irritation, sensitization, or phototoxicity. They noted the lack of systemic toxicity in acute oral exposure and no irritation or sensitization. The genotoxicity assays were negative for synthetic fluorphlogopite and the magnesium aluminum silicate clays in a chromosomal aberration assay and multiple bacterial assays. In addition, this ingredient consists of large macromolecules, insoluble in water, and chemically inert under physiological conditions or conditions of use, which supports the view that they are unlikely to be absorbed or cause local effects in the respiratory tract. Further, this ingredient is reportedly used at concentrations of 0.05% - 2% in cosmetic products that may be aerosolized and 0.6% – 67% in powders. The Panel noted that 95% – 99% of droplets/particles produced in cosmetic aerosols would not be respirable to any appreciable amount. Furthermore, this ingredient is used for viscosity increasing functions, indicating that they tend to swell and aggregate in water and other solvents and would, thus, be too large to be inhaled or respired. Coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, this information indicates that incidental inhalation would not be a significant route of exposure that might lead to local respiratory or systemic toxic effects.

CONCLUSION

The CIR Expert Panel concluded that synthetic fluorphlogopite is safe for use in cosmetics in the present practices of use and concentration described in this safety assessment.

CIR Panel Book Page 17 Distributed for Comment Only -- Do Not Cite or Quote TABLES AND FIGURES

Table 1. Chemical and physical properties of synthetic fluorphlogopite. Property Value Reference Platelet; crystalline; Physical Form 5,109,110 Fine grained powder Color White to grey 5 Density/Specific Gravity 2.8 109 Melting Point oC 1393-1403 14 Water Solubility Insoluble 7,9

Table 2. Possible impurities in synthetic fluophlogopite. Impurity Amount Reference Acid soluble substances 0.7% 111 Lead < 1.0 ppm 111 Arsenic < 0.5 ppm 111 Dissolution amount of (leachable) fluorine 11 ppm 111 Iron 0.008 w/w% 8 Titanium 0.002% 8 Barium 0.001% 8 Sodium 0.025% 8 Manganese 0.001% 8 Chromium 0.002% 8 Vanadium 0.001% 8 Zinc 0.001% 8 Strontium >0.001% 8 Copper >0.001% 8

Table 3. Current frequency of use according to duration and type of exposure provided in 2011.16,17 Synthetic fluorphlogopite # of Uses Concentration (%) Total/Conc. range 565 0.00002-67 Duration of Use Leave-on 560 0.0000-67 Rinse-off 5 0.009-30 Diluted for (bath) use NR NR Exposure Type Eye 169 0.001-48 Incidental ingestion 200 0.0008-20 Incidental inhalation- 15 0.05-2 sprays Incidental inhalation- 44 0.6-67 powders Dermal contact 336 0.00002-67 Deodorant (underarm) NR NR Hair – non coloring 2 0.009-0.05 Hair - coloring NR NR Nail 27 0.3-3 Mucous Membrane 203 0.0008-30 Baby products NR NR NR = Not Reported; Totals = Rinse-off + Leave-on Product Uses. Note: Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure type uses may not equal the sum total uses.

CIR Panel Book Page 18 Distributed for Comment Only -- Do Not Cite or Quote O Mg2

Si O O O O O 2 Mg Al Si F F K O O O Si

O 2 Mg

Figure 1. The structure and average formula of synthetic fluorphlogopite.112

CIR Panel Book Page 19 Distributed for Comment Only -- Do Not Cite or Quote REFERENCES 1. Elmore AR and Cosmetic Ingredient Review Expert Panel. Final Report on the Safety Assessment of Aluminum Silicate, Calcium Silicate, Magnesium Aluminum Silicate, Magnesium Silicate, Magnesium Trisilicate, Sodium Magnesium Silicate, Zirconium Silicate, Attapulgite, Bentonite, Fuller's Earth, Hectorite, Kaolin, Lithium Magnesium Silicate, Lithium Magnesium Sodium Silicate, Montmorillonite, Pyrophyllite, and Zeolite. International Journal of Toxicology. 2003;22:(suppl 1):37-102.

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CIR Panel Book Page 21 Distributed for Comment Only -- Do Not Cite or Quote 46. M'anyai S, Kabai J, Kis J, Suveges E, and Timar M. The effect of heat treatment on the surface of kaolin and its in vitro hemolytic activity. Environmental Research. 1970;3:(3):187-198.

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